Addressing Disparities in Health Care

Cardiovascular disease became the leading cause of death in the United States in the early 20th century, and it accounts for nearly half of all deaths in industrialized nations.¹ The mortality it inflicts was thought to be shared equally between both sexes and among all age groups and races.² The cardiology community implemented innovative epidemiologic research, through which risk factors for cardiovascular disease were established.¹ The development of coronary care units reduced in-hospital mortality from acute myocardial infarction from 30% to 15%.^2–5 Further advances in pharmacology, revascularization, and imaging have aided in the detection and treatment of cardiovascular disease.⁶ Though cardiovascular disease remains the number-one cause of death worldwide, rates are on the decline.⁷

For several decades, health disparities have been recognized as a source of pathology in cardiovascular medicine, resulting in inequity of care administration among select populations. In this review, we examine whether the same forward thinking that has resulted in a decline in cardiovascular disease has had an impact on the pervasive disparities in cardiovascular medicine.

DISPARITIES DEFINED

Compared with whites, members of minority groups have a higher burden of chronic diseases, receive lower quality care, and have less access to medical care. Recognizing the potential public health ramifications, in 1999 the US Congress tasked the Institute of Medicine to study and assess the extent of healthcare disparities. This led to the landmark publication, Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care.⁸

The Institute of Medicine defines disparities in healthcare as racial or ethnic differences in the quality of healthcare that are not due to access-related factors, clinical needs, preferences, and appropriateness of intervention.⁸ Disparities can also exist according to socioeconomic status and sex.⁹

In an early study documenting the concept of disparities in cardiovascular disease, Stone and Vanzant¹⁰ concluded that heart disease was more common in African Americans than in whites, and that hypertension was the principal cause of cardiovascular disease mortality in African Americans.

Data from US Centers for Disease Control and Prevention, reference 11

Although avoidable deaths from heart disease, stroke, and hypertensive disease declined between 2001 and 2010, African Americans still have a higher mortality rate than other racial and ethnic groups (Figure 1).¹¹

DISPARITIES AND CARDIOVASCULAR HEALTH

The concept of cardiovascular health was established by the American Heart Association (AHA) in efforts to achieve an additional 20% reduction in cardiovascular disease-related mortality by 2020.⁷ Cardiovascular health is defined as the absence of clinically manifest cardiovascular disease and is measured by 7 components:

• Not smoking or abstaining from smoking for at least 1 year
• A normal body weight, defined as a body mass index less than 25 kg/m²
• Optimal physical activity, defined as 75 minutes of vigorous physical activity or 150 minutes of moderate-intensity physical activity per week
• Regular consumption of a healthy diet
• Total cholesterol below 200 mg/dL
• Blood pressure less than 120/80 mm Hg
• Fasting blood sugar below 100 mg/dL.

Nearly 70% of the US population can claim 2, 3, or 4 of these components, but differences exist according to race,¹² and 60% of adult white Americans are limited to achieving no more than 3 of these healthy metrics, compared with 70% of adult African Americans and Hispanic Americans.

Smoking

Smoking is a major risk factor for cardiovascular disease.^12–14

Data from National Health Interview Surgery, Jamal et al, reference 16

During adolescence, white males are more likely to smoke than African American and Hispanic males,¹² but this trend reverses in adulthood, when African American men have a higher prevalence of smoking than white men (21.4% vs 19%).⁷ Rates of lifetime use are highest among American Indian or Alaskan natives and whites (75.9%), followed by African Americans (58.4%), native Hawaiians (56.8%), and Hispanics (56.7%).¹⁵ Trends for current smoking are similar (Figure 2).¹⁶ Moreover, households with lower socioeconomic status have a higher prevalence of smoking.⁷

Physical activity

People with a sedentary lifestyle are more likely to die of cardiovascular disease. As many as 250,000 deaths annually in the United States are attributed to lack of regular physical activity.¹⁷

Recognizing the potential public health ramifications, the AHA and the 2018 Federal Guidelines on Physical Activity recommend that children engage in 60 minutes of daily physical activity and that adults participate in 150 minutes of moderate-intensity or 75 minutes of vigorous physical activity weekly.^18,19

Data from Behavioral Risk Factor Surveillance System, Omura et al, reference 20

In the United States, 15.2% of adolescents reported being physically inactive, according to data published in 2016.⁷ Similar to most cardiovascular risk factors, minority populations and those of lower socioeconomic status had the worst profiles. The prevalence of physical inactivity was highest in African Americans and Hispanics (Figure 3).²⁰

Studies have shown an association between screen-based sedentary behavior (computers, television, and video games) and cardiovascular disease.^21–23 In the United States, 41% of adolescents used computers for activities other than homework for more than 3 hours per day on a school day.⁷ The pattern of use was highest in African American boys and African American girls, followed by Hispanic girls and Hispanic boys.¹⁸ Trends were similar with regard to watching television for more than 3 hours per day.

Sedentary behavior persists into adulthood, with rates of inactivity of 38.3% in African Americans, 40.1% in Hispanics, and 26.3% in white adults.⁷

Nutrition plays a major role in cardiovascular disease, specifically in the pathogenesis of atherosclerotic disease and hypertension.²⁴ Most Americans do not meet dietary recommendations, with minority communities performing worse in specific metrics.⁷

Dietary patterns are reflected in the rate of obesity in this nation. Studies have shown a direct correlation between obesity and cardiovascular disease such as coronary artery disease, heart failure, and atrial fibrillation.^25–28 According to data from the National Health and Nutrition Examination Survey (NHANES), 31% of children between the ages of 2 and 19 years are classified as obese or overweight. The highest rates of obesity are seen in Hispanic and African American boys and girls. The obesity epidemic is disproportionately rampant in children living in households with low income, low education, and high unemployment rates.^7,29–31

Despite the risks associated with obesity, only 64.8% of obese adults report being informed by a doctor or health professional that they were overweight. The proportion of obese adults informed that they were overweight was significantly lower for African Americans and Hispanics compared with whites. Similar differences are seen based on socioeconomic status, as middle-income patients were less likely to be informed than those in the higher income strata (62.4% vs 70.6%).^7,31

Blood pressure

Hypertension is a well-established risk factor for cardiovascular disease and stroke, and a blood pressure of 120/80 mm Hg or lower is identified as a component of ideal cardiovascular health.

In the United States the prevalence of hypertension in adults older than 20 is 32%.⁷ The prevalence of hypertension in African Americans is among the highest in the world.^32,33 African Americans develop high blood pressure at earlier ages, and their average resting blood pressures are higher than in whites.^34,35 For a 45-year-old without hypertension, the 40-year risk of developing hypertension is 92.7% for African Americans and 86% for whites.³⁵ Hypertension is a major risk factor for stroke, and African Americans have a 1.8 times greater rate of fatal stroke than whites.⁷

In 2013 there were 71,942 deaths attributable to high blood pressure, and the 2011 death rate associated with hypertension was 18.9 per 100,000. By race, the death rate was 17.6 per 100,000 for white males and an alarming 47.1 per 100,000 for African American males; rates were 15.2 per 100,000 for white females and 35.1 per 100,000 for African American females.⁷

It is unclear what accounts for the racial difference in prevalence in hypertension. Studies have shown that African Americans are more likely than whites to have been told on more than 2 occasions that they have hypertension. And 85.7% of African Americans are aware that they have high blood pressure, compared with 82.7% of whites.¹⁴

African Americans and Hispanics have poorer hypertension control compared with whites.^36,37 These observed differences cannot be attributed to access alone, as African Americans were more likely to be on higher-intensity blood pressure therapy, whereas Hispanics were more likely to be undertreated.^36,38 In a meta-analysis of 13 trials, Peck et al³⁹ showed that African Americans showed a lesser reduction in systolic and diastolic blood pressure when treated with angiotensin-converting enzyme (ACE) inhibitors.

The 2017 American College of Cardiology (ACC) and AHA guidelines for the prevention, detection, evaluation, and management of high blood pressure in adults⁴⁰ identifies 4 drug classes as reducing cardiovascular disease morbidity and mortality: thiazide diuretics, ACE inhibitors, angiotensin II receptor blockers (ARBs), and calcium channel blockers. Of these 4 classes, thiazide diuretics and calcium channel blockers have been shown to lower blood pressure more effectively in African Americans than renin-angiotensin-aldosterone inhibition with ACE inhibitors or ARBs.

Glycemic control

Type 2 diabetes mellitus secondary to insulin resistance disproportionately affects minority groups, as the prevalence of diabetes mellitus in African Americans is almost twice as high as that in whites, and 35% higher in Hispanics compared with whites.^7,41 Based on NHANES data between 1984 and 2004, the prevalence of diabetes mellitus is expected to increase by 99% in whites, 107% in African Americans, and 127% in Hispanics by 2050. Alarmingly, African Americans over age 75 are expected to experience a 606% increase by 2050.⁴²

With regard to mortality, 21.7 deaths per 100,000 population were attributable to diabetes mellitus according to reports by the AHA in 2016. The death rate in white males was 24.3 per 100,000 compared with 44.9 per 100,000 for African Americans males. The associated mortality rate for white women was 16.2 per 100,000, and 35.8 per 100,000 for African American females.⁷

The management of coronary artery disease has evolved from prolonged bed rest to surgical, pharmacologic, and percutaneous revascularization.^2,5 Coronary revascularization procedures are now relatively common: 950,000 percutaneous coronary interventions and 397,000 coronary artery bypass procedures were performed in 2010.⁷

Nevertheless, despite similar clinical presentations, African Americans with acute myocardial infarction were less likely to be referred for coronary artery bypass grafting than whites.^43–46 They were also less likely to be given thrombolytics⁴⁷ and less likely to undergo coronary angiography with percutaneous coronary intervention.⁴⁸ Similar differences have been reported when comparing Hispanics with whites.⁴⁹

Some suggest that healthcare access is a key mediator of health disparities.⁵⁰ In 2009, Hispanics and African Americans accounted for more than 50% of those without health insurance.⁵¹ Improved access to healthcare might mitigate the disparity in revascularizations.

Massachusetts was one of the first states to mandate that all residents obtain health insurance. As a result, the uninsured rates declined in African Americans and Hispanics in Massachusetts, but a disparity in revascularization persisted. African Americans and Hispanics were 27% and 16% less likely to undergo revascularization procedures (coronary artery bypass grafting or percutaneous coronary intervention) than whites,⁵¹ suggesting that disparities in revascularization are not solely secondary to healthcare access.

These findings are consistent with a 2004 Veterans Administration study,⁵² in which healthcare access was equal among races. The study showed that African Americans received fewer cardiac procedures after an acute myocardial infarction compared with whites.

Have we made progress? The largest disparity between African Americans and whites in coronary artery disease mortality existed in 1990. The disparity persisted to 2012, and although decreased, it is projected to persist to 2030.⁵³

DISPARITIES IN HEART FAILURE

An estimated 5.7 million Americans have heart failure, and 915,000 new cases are diagnosed annually.⁷ Unlike coronary artery disease, heart failure is expected to increase in prevalence by 46%, to 8 million Americans with heart failure by 2030.^7,54

Our knowledge of disparities in the area of heart failure is derived primarily from epidemiologic studies. The Multi-Ethnic Study of Atherosclerosis⁵⁵ showed that African Americans (4.6 per 1,000), followed by Hispanics (3.5 per 1,000) had a higher risk of developing heart failure compared with whites (2.4 per 1,000).The higher risk is in part due to disparities in socioeconomic status and prevalence of hypertension, as African Americans accounted for 75% of cases of nonischemic-related heart failure.⁵⁵ African Americans also have a higher 5-year mortality rate than whites.⁵⁵

Even though the 5-year mortality rate in heart failure is still 50%, the past 30 years have seen innovations in pharmacologic and device therapy and thus improved outcomes in heart failure patients. Still, significant gaps in the use of guideline-recommended therapies, quality of care, and clinical outcomes persist in contemporary practice for racial minorities with heart failure.

Disparities in inpatient care for heart failure

Patients admitted for heart failure and cared for by a cardiologist are more likely to be discharged on guideline-directed medical therapy, have fewer heart failure readmissions, and lower mortality.^56,57 Breathett et al,⁵⁸ in a study of 104,835 patients hospitalized in an intensive care unit for heart failure, found that primary intensive care by a cardiologist was associated with higher survival in both races. However, in the same study, white patients had a higher odds of receiving care from a cardiologist than African American patients.

Disparities and cardiac resynchronization therapy devices

In one-third of patients with heart failure, conduction delays result in dyssynchronous left ventricular contraction.⁵⁹ Dyssynchrony leads to reduced cardiac performance, left ventricular remodeling, and increased mortality.⁵⁶

Cardiac resynchronization therapy (CRT) was approved for clinical use in 2001, and studies have shown that it improves quality of life, exercise tolerance, cardiac performance, and morbidity and mortality rates.^59–66 The 2013 ACC/AHA guidelines for the management of heart failure give a class IA recommendation (the highest) for its use in patients with a left ventricular ejection fraction of 35% or less, sinus rhythm, left bundle branch block and a QRS duration of 150 ms or greater, and New York Heart Association class II, III, or ambulatory IV symptoms while on guideline-directed medical therapy.⁶⁷

Despite these recommendations, racial differences are observed. A study using the Nationwide Inpatient Sample database⁵⁹ showed that between 2002 and 2010, a total of 374,202 CRT devices were implanted, averaging 41,578 annually. After adjusting for heart failure admissions, the study showed that CRT use was favored in men and in whites.

Another study, using the National Cardiovascular Data Registry,⁶⁸ looked at patients who received implantable cardiac defibrillators (ICDs) and were eligible to receive CRT. It found that African Americans and Hispanics were less likely than whites to receive CRT, even though they were more likely to meet established criteria.

Disparities and left ventricular assist devices

The Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart failure (REMATCH) trial and Heart Mate II trial demonstrated that left ventricular assist devices (LVADs) were durable options for long-term support for patients with end-stage heart failure.^69,70 Studies that examined the role of race and clinical outcomes after LVAD implantation have reported mixed findings.^71,72 Few studies have looked at the role racial differences play in accessing LVAD therapy.

Joyce et al⁷³ reviewed data from the Nationwide Inpatient Sample from 2002 to 2003 on patients admitted to the hospital with a primary diagnosis of heart failure or cardiogenic shock. A total of 297,866 patients were included in the study, of whom only 291 underwent LVAD implantation. A multivariate analysis found that factors such as age over 65, female sex, admission to a nonacademic center, geographic region, and African American race adversely influenced access to LVAD therapy.

Breathett et al⁷⁴ evaluated racial differences in LVAD implantations from 2012 to 2015, a period that corresponds to increased health insurance expansion, and found LVAD implantations increased among African American patients with advanced heart failure, but no other racial or ethnic group.

For patients with end-stage heart failure, orthotopic heart transplant is the most definitive and durable option for long-term survival. According to data from the United Network for Organ Sharing, 62,508 heart transplants were performed from January 1, 1988 to December 31, 2015. Compared with transplants of other solid organs, heart transplant occurs in significantly infrequent rates.

Barriers to transplant include lack of health insurance, considered a surrogate for low socioeconomic status. Hispanics and African Americans are less likely to have private health insurance than non-Hispanic whites, and this difference is magnified among the working poor.

Despite these perceived barriers, Kilic et al⁷⁵ found that African Americans comprised 16.4% of heart transplant recipients, although they make up only approximately 13% of the US population. They also had significantly shorter wait-list times than whites. On the negative side, African Americans had a higher unadjusted mortality rate than whites (15% vs 12% P = .002). African Americans also tended to receive their transplants at centers with lower transplant volumes and higher transplant mortality rates.

Several other studies also showed that African Americans compared to whites have significantly worse outcomes after transplant.^76–79 What accounts for this difference? Kilic et al⁷⁵ showed that African Americans had the lowest proportion of blood type matching and lowest human leukocyte antigen matching, were younger (because African Americans develop more advanced heart failure at younger ages), had higher serum creatinine levels, and were more often bridged to transplant with an LVAD.

DISPARITIES IN CARDIOVASCULAR RESEARCH

Although the United States has the most sophisticated and robust medical system in the world, select groups have significant differences in delivery and healthcare outcomes. There are many explanations for these differences, but a contributing factor may be the paucity of research dedicated to understand racial and ethnic differences.⁸⁰

Differences observed in epidemiologic studies may be secondary to pathophysiology, genetic differences, environment, and lifestyle choices. Historically, clinical trials were conducted in homogeneous populations with respect to age (middle-aged), sex (male), and race (white), and the results were generalized to heterogeneous populations.⁸⁰

Disparities in research have implications in clinical practice. Overall, the primary cause of heart failure is ischemia; however, in African Americans, the primary cause is hypertensive heart disease.⁸¹ Studies in hypertension have shown that African Americans have less of a response to neurohormonal blockade with ACE inhibitors and beta-blockers than non-African Americans.⁸² Nevertheless, neurohormonal blockade has become the cornerstone of heart failure treatment.

Retrospective analysis of the Vasodilator-Heart Failure trials⁸³ showed that treatment with isosorbide dinitrate plus hydralazine, compared with placebo, conferred a survival benefit for African Americans but not whites.⁸⁰ No survival advantage was noted when isosorbide dinitrate/hydralazine was compared to enalapril in African Americans, although enalapril was superior to isosorbide dinitrate in whites.⁴⁵ These observations were recognized 10 to 15 years after trial completion, and were only possible because the trials included sufficient numbers of African American patients to complete analysis.

In 1993, the US Congress passed the National Institutes of Health (NIH) Revitalization Act, which established guidelines requiring NIH grant applicants to include minorities in human subject research, as they were historically underrepresented in clinical research trials.^84,85

In 2001, the Beta-Blocker Evaluation of Survival Trial⁸⁶ reported its results investigating whether bucindolol, a nonselective beta-blocker, would reduce mortality in patients with advanced heart failure (New York Heart Association class III or IV). This was one of the first trials to prospectively investigate racial and ethnic differences in response to treatment. Though it showed no overall benefit in the use of bucindolol in the treatment of advanced heart failure, subgroup analysis showed that whites did enjoy a benefit in terms of lower mortality, whereas African Americans did not.

Results of the Vasodilator-Heart Failure trials led to further population-directed research, most notably the African American Heart Failure Trial,⁸⁷ a double-blind, placebo-controlled, randomized trial in patients who identified as African American. Patients who were randomized to receive a fixed dose of hydralazine and isosorbide dinitrate had a 43% lower mortality rate, a 33% lower hospitalization rate for heart failure, and better quality of life than patients in the placebo group, leading to early termination of the trial. The outcomes suggested that the combination of isosorbide dinitrate and hydralazine treats heart failure in a manner independent of pure neurohormonal blockade.

CHALLENGES IN STUDY PARTICIPATION

Recruitment of minority participants in biomedical research is a challenging task for clinical investigators.^88,89 Some of the factors thought to pose potential barriers for racial and ethnic minority participation in health research include poor access to primary medical care, failure of researchers to recruit minority populations actively, and language and cultural barriers.⁹⁰

Further, it is widely claimed that African Americans are less willing than nonminority individuals to participate in clinical research trials due to general distrust of the medical community as a result of the Tuskegee Syphilis Experiment.⁹¹ That infamous study, conducted by the US Public Health Service between 1932 and 1972, sought to record the natural progression of untreated syphilis in poor African American men in Alabama. The participants were not informed of the true purpose of the study, and they were under the impression that they were simply receiving free healthcare from the US government. Further, they were denied appropriate treatment even after it became readily available, in order for researchers to observe the progression of the disease.

While the 1993 mandate did in fact increase pressure on researchers to develop strategies to overcome participation barriers, the issue of underrepresentation of racial minorities in clinical research, including cardiovascular research, has not been resolved and continues to be a problem today.

The overall goal of clinical research is to determine the best strategies to prevent and treat disease. But if the study population is not representative of the affected population at large, the results cannot be generalized to underrepresented subgroups. The implications of underrepresentation in research are far-reaching, and can further contribute to disparate care of minority patients such as African Americans, who have a higher prevalence of cardiovascular risk factors and greater burden of heart failure.

Between 1986 and 2018, according to a PUBMED search, 10,462 articles highlighted the presence of a health-related disparity. Solutions to address and ultimately eradicate disparities will need to eliminate healthcare bias, increase patient access, and increase diversity and inclusion in the physician work force.

Eliminating bias

Implicit bias refers to attitudes, thoughts, and feelings that exist outside of the conscious awareness.⁹² These biases can be triggered by race, gender, or socioeconomic status. They have manifested in society as stereotypes that men are more competent than women, women are more verbal than men, and African Americans are more athletic than whites.⁹³

The concept of implicit bias is important, in that the populations that experience the greatest health disparities also suffer from negative cultural stereotypes.⁹⁴ Healthcare professionals are not inoculated against implicit bias.⁹⁵ Studies have shown that most healthcare providers have implicit biases that reflect positive attitudes toward whites and negative attitudes toward people of color.^{92,94,96–98}

The Implicit Association Test, introduced in 1998, is widely used to measure implicit bias. It measures response time of subjects to match particular social groups to particular attributes.⁹⁹ Green et al,⁹⁹ using this test, showed that although physicians reported no explicit preference for white vs African American patients or differences in perceived cooperativeness, the test revealed implicit preference favoring white Americans and implicit stereotypes of African Americans as less cooperative for medical procedures and in general. This also manifested in clinical decision-making, as white Americans were more likely, and African Americans less likely, to be treated with thrombolysis.⁹⁹

Sabin et al¹⁰⁰ showed that implicit bias was present among pediatricians, although less than in society as a whole and in other healthcare professionals.

But how does one change feelings that exist outside of the conscious awareness? Green et al⁹⁹ showed that making physicians aware of their susceptibility to bias changed their behavior. A subset of physicians who were made aware that bias was a focus of the study were more likely to refer African Americans for thrombolysis even if they had a high degree of implicit pro-white bias.^94,100 Perhaps mandating that all healthcare providers take a self-administered and confidentially reported Implicit Association Test will lead to awareness of implicit bias and minimize healthcare behaviors that contribute to the current state of disparities.

Improving access

Common indicators of access to healthcare include health insurance status, having a usual source of healthcare, and having a regular physician.¹⁰¹ Health insurance does offer protection from the costs associated with illness and health maintenance.¹⁰¹ It is also a major contributing factor in racial and ethnic disparities.

Chen et al¹⁰² examined the effects of the Affordable Care Act and found that it was associated with reduction in the probability of being uninsured, delaying necessary care, and forgoing necessary care, and increased probability of having a physician. However, earlier studies showed that access to health insurance by itself does not equate to equitable care.^103,104

Diversifying the work force

African Americans comprise 4% of physicians and Hispanic Americans 5%, despite accounting for 13% and 16% of the US population.¹⁰⁵ This underrepresentation has led to African American and Hispanic American patients being more likely than white patients to be treated by a physician from a dissimilar racial or ethnic background.¹⁰⁶ Studies have shown that minority patients in a race- or ethnic-concordant relationship are more likely to use needed health services, less likely to postpone seeking care, and report greater satisfaction.^106,107 Minority physicians often locate and practice in neighborhoods with high minority populations, and they disproportionately care for disadvantaged patients of lower socioeconomic status and poorer health.^106,108

WE ARE STILL IN THE TUNNEL, BUT THERE IS LIGHT AT THE END

The cardiovascular community has faced tremendous challenges in the past and responded with innovative research that has led to imaging that aids in the diagnosis of subclinical cardiovascular disease and invasive and pharmacologic strategies that have improved cardiovascular outcomes. One may say that there is light at the end of the tunnel; however, the existence of disparate care reminds us that we are still in the tunnel.

Disparities in cardiovascular disease management present a unique challenge for the community. There is no drug, device, or invasive procedure to eliminate this pathology. However, by acknowledging the problem and implementing changes at the system, provider, and patient level, the cardiovascular community can achieve yet another momentous achievement: the end of cardiovascular health disparities. Cardiovascular disease makes no distinction in race, sex, age, or socioeconomic status, and neither should the medical community.

Cardiovascular disease became the leading cause of death in the United States in the early 20th century, and it accounts for nearly half of all deaths in industrialized nations.¹ The mortality it inflicts was thought to be shared equally between both sexes and among all age groups and races.² The cardiology community implemented innovative epidemiologic research, through which risk factors for cardiovascular disease were established.¹ The development of coronary care units reduced in-hospital mortality from acute myocardial infarction from 30% to 15%.^2–5 Further advances in pharmacology, revascularization, and imaging have aided in the detection and treatment of cardiovascular disease.⁶ Though cardiovascular disease remains the number-one cause of death worldwide, rates are on the decline.⁷

For several decades, health disparities have been recognized as a source of pathology in cardiovascular medicine, resulting in inequity of care administration among select populations. In this review, we examine whether the same forward thinking that has resulted in a decline in cardiovascular disease has had an impact on the pervasive disparities in cardiovascular medicine.

DISPARITIES DEFINED

Compared with whites, members of minority groups have a higher burden of chronic diseases, receive lower quality care, and have less access to medical care. Recognizing the potential public health ramifications, in 1999 the US Congress tasked the Institute of Medicine to study and assess the extent of healthcare disparities. This led to the landmark publication, Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care.⁸

The Institute of Medicine defines disparities in healthcare as racial or ethnic differences in the quality of healthcare that are not due to access-related factors, clinical needs, preferences, and appropriateness of intervention.⁸ Disparities can also exist according to socioeconomic status and sex.⁹

In an early study documenting the concept of disparities in cardiovascular disease, Stone and Vanzant¹⁰ concluded that heart disease was more common in African Americans than in whites, and that hypertension was the principal cause of cardiovascular disease mortality in African Americans.

Data from US Centers for Disease Control and Prevention, reference 11

Although avoidable deaths from heart disease, stroke, and hypertensive disease declined between 2001 and 2010, African Americans still have a higher mortality rate than other racial and ethnic groups (Figure 1).¹¹

DISPARITIES AND CARDIOVASCULAR HEALTH

The concept of cardiovascular health was established by the American Heart Association (AHA) in efforts to achieve an additional 20% reduction in cardiovascular disease-related mortality by 2020.⁷ Cardiovascular health is defined as the absence of clinically manifest cardiovascular disease and is measured by 7 components:

• Not smoking or abstaining from smoking for at least 1 year
• A normal body weight, defined as a body mass index less than 25 kg/m²
• Optimal physical activity, defined as 75 minutes of vigorous physical activity or 150 minutes of moderate-intensity physical activity per week
• Regular consumption of a healthy diet
• Total cholesterol below 200 mg/dL
• Blood pressure less than 120/80 mm Hg
• Fasting blood sugar below 100 mg/dL.

Nearly 70% of the US population can claim 2, 3, or 4 of these components, but differences exist according to race,¹² and 60% of adult white Americans are limited to achieving no more than 3 of these healthy metrics, compared with 70% of adult African Americans and Hispanic Americans.

Smoking

Smoking is a major risk factor for cardiovascular disease.^12–14

Data from National Health Interview Surgery, Jamal et al, reference 16

During adolescence, white males are more likely to smoke than African American and Hispanic males,¹² but this trend reverses in adulthood, when African American men have a higher prevalence of smoking than white men (21.4% vs 19%).⁷ Rates of lifetime use are highest among American Indian or Alaskan natives and whites (75.9%), followed by African Americans (58.4%), native Hawaiians (56.8%), and Hispanics (56.7%).¹⁵ Trends for current smoking are similar (Figure 2).¹⁶ Moreover, households with lower socioeconomic status have a higher prevalence of smoking.⁷

Physical activity

People with a sedentary lifestyle are more likely to die of cardiovascular disease. As many as 250,000 deaths annually in the United States are attributed to lack of regular physical activity.¹⁷

Recognizing the potential public health ramifications, the AHA and the 2018 Federal Guidelines on Physical Activity recommend that children engage in 60 minutes of daily physical activity and that adults participate in 150 minutes of moderate-intensity or 75 minutes of vigorous physical activity weekly.^18,19

Data from Behavioral Risk Factor Surveillance System, Omura et al, reference 20

In the United States, 15.2% of adolescents reported being physically inactive, according to data published in 2016.⁷ Similar to most cardiovascular risk factors, minority populations and those of lower socioeconomic status had the worst profiles. The prevalence of physical inactivity was highest in African Americans and Hispanics (Figure 3).²⁰

Studies have shown an association between screen-based sedentary behavior (computers, television, and video games) and cardiovascular disease.^21–23 In the United States, 41% of adolescents used computers for activities other than homework for more than 3 hours per day on a school day.⁷ The pattern of use was highest in African American boys and African American girls, followed by Hispanic girls and Hispanic boys.¹⁸ Trends were similar with regard to watching television for more than 3 hours per day.

Sedentary behavior persists into adulthood, with rates of inactivity of 38.3% in African Americans, 40.1% in Hispanics, and 26.3% in white adults.⁷

Nutrition plays a major role in cardiovascular disease, specifically in the pathogenesis of atherosclerotic disease and hypertension.²⁴ Most Americans do not meet dietary recommendations, with minority communities performing worse in specific metrics.⁷

Dietary patterns are reflected in the rate of obesity in this nation. Studies have shown a direct correlation between obesity and cardiovascular disease such as coronary artery disease, heart failure, and atrial fibrillation.^25–28 According to data from the National Health and Nutrition Examination Survey (NHANES), 31% of children between the ages of 2 and 19 years are classified as obese or overweight. The highest rates of obesity are seen in Hispanic and African American boys and girls. The obesity epidemic is disproportionately rampant in children living in households with low income, low education, and high unemployment rates.^7,29–31

Despite the risks associated with obesity, only 64.8% of obese adults report being informed by a doctor or health professional that they were overweight. The proportion of obese adults informed that they were overweight was significantly lower for African Americans and Hispanics compared with whites. Similar differences are seen based on socioeconomic status, as middle-income patients were less likely to be informed than those in the higher income strata (62.4% vs 70.6%).^7,31

Blood pressure

Hypertension is a well-established risk factor for cardiovascular disease and stroke, and a blood pressure of 120/80 mm Hg or lower is identified as a component of ideal cardiovascular health.

In the United States the prevalence of hypertension in adults older than 20 is 32%.⁷ The prevalence of hypertension in African Americans is among the highest in the world.^32,33 African Americans develop high blood pressure at earlier ages, and their average resting blood pressures are higher than in whites.^34,35 For a 45-year-old without hypertension, the 40-year risk of developing hypertension is 92.7% for African Americans and 86% for whites.³⁵ Hypertension is a major risk factor for stroke, and African Americans have a 1.8 times greater rate of fatal stroke than whites.⁷

In 2013 there were 71,942 deaths attributable to high blood pressure, and the 2011 death rate associated with hypertension was 18.9 per 100,000. By race, the death rate was 17.6 per 100,000 for white males and an alarming 47.1 per 100,000 for African American males; rates were 15.2 per 100,000 for white females and 35.1 per 100,000 for African American females.⁷

It is unclear what accounts for the racial difference in prevalence in hypertension. Studies have shown that African Americans are more likely than whites to have been told on more than 2 occasions that they have hypertension. And 85.7% of African Americans are aware that they have high blood pressure, compared with 82.7% of whites.¹⁴

African Americans and Hispanics have poorer hypertension control compared with whites.^36,37 These observed differences cannot be attributed to access alone, as African Americans were more likely to be on higher-intensity blood pressure therapy, whereas Hispanics were more likely to be undertreated.^36,38 In a meta-analysis of 13 trials, Peck et al³⁹ showed that African Americans showed a lesser reduction in systolic and diastolic blood pressure when treated with angiotensin-converting enzyme (ACE) inhibitors.

The 2017 American College of Cardiology (ACC) and AHA guidelines for the prevention, detection, evaluation, and management of high blood pressure in adults⁴⁰ identifies 4 drug classes as reducing cardiovascular disease morbidity and mortality: thiazide diuretics, ACE inhibitors, angiotensin II receptor blockers (ARBs), and calcium channel blockers. Of these 4 classes, thiazide diuretics and calcium channel blockers have been shown to lower blood pressure more effectively in African Americans than renin-angiotensin-aldosterone inhibition with ACE inhibitors or ARBs.

Glycemic control

Type 2 diabetes mellitus secondary to insulin resistance disproportionately affects minority groups, as the prevalence of diabetes mellitus in African Americans is almost twice as high as that in whites, and 35% higher in Hispanics compared with whites.^7,41 Based on NHANES data between 1984 and 2004, the prevalence of diabetes mellitus is expected to increase by 99% in whites, 107% in African Americans, and 127% in Hispanics by 2050. Alarmingly, African Americans over age 75 are expected to experience a 606% increase by 2050.⁴²

With regard to mortality, 21.7 deaths per 100,000 population were attributable to diabetes mellitus according to reports by the AHA in 2016. The death rate in white males was 24.3 per 100,000 compared with 44.9 per 100,000 for African Americans males. The associated mortality rate for white women was 16.2 per 100,000, and 35.8 per 100,000 for African American females.⁷

The management of coronary artery disease has evolved from prolonged bed rest to surgical, pharmacologic, and percutaneous revascularization.^2,5 Coronary revascularization procedures are now relatively common: 950,000 percutaneous coronary interventions and 397,000 coronary artery bypass procedures were performed in 2010.⁷

Nevertheless, despite similar clinical presentations, African Americans with acute myocardial infarction were less likely to be referred for coronary artery bypass grafting than whites.^43–46 They were also less likely to be given thrombolytics⁴⁷ and less likely to undergo coronary angiography with percutaneous coronary intervention.⁴⁸ Similar differences have been reported when comparing Hispanics with whites.⁴⁹

Some suggest that healthcare access is a key mediator of health disparities.⁵⁰ In 2009, Hispanics and African Americans accounted for more than 50% of those without health insurance.⁵¹ Improved access to healthcare might mitigate the disparity in revascularizations.

Massachusetts was one of the first states to mandate that all residents obtain health insurance. As a result, the uninsured rates declined in African Americans and Hispanics in Massachusetts, but a disparity in revascularization persisted. African Americans and Hispanics were 27% and 16% less likely to undergo revascularization procedures (coronary artery bypass grafting or percutaneous coronary intervention) than whites,⁵¹ suggesting that disparities in revascularization are not solely secondary to healthcare access.

These findings are consistent with a 2004 Veterans Administration study,⁵² in which healthcare access was equal among races. The study showed that African Americans received fewer cardiac procedures after an acute myocardial infarction compared with whites.

Have we made progress? The largest disparity between African Americans and whites in coronary artery disease mortality existed in 1990. The disparity persisted to 2012, and although decreased, it is projected to persist to 2030.⁵³

DISPARITIES IN HEART FAILURE

An estimated 5.7 million Americans have heart failure, and 915,000 new cases are diagnosed annually.⁷ Unlike coronary artery disease, heart failure is expected to increase in prevalence by 46%, to 8 million Americans with heart failure by 2030.^7,54

Our knowledge of disparities in the area of heart failure is derived primarily from epidemiologic studies. The Multi-Ethnic Study of Atherosclerosis⁵⁵ showed that African Americans (4.6 per 1,000), followed by Hispanics (3.5 per 1,000) had a higher risk of developing heart failure compared with whites (2.4 per 1,000).The higher risk is in part due to disparities in socioeconomic status and prevalence of hypertension, as African Americans accounted for 75% of cases of nonischemic-related heart failure.⁵⁵ African Americans also have a higher 5-year mortality rate than whites.⁵⁵

Even though the 5-year mortality rate in heart failure is still 50%, the past 30 years have seen innovations in pharmacologic and device therapy and thus improved outcomes in heart failure patients. Still, significant gaps in the use of guideline-recommended therapies, quality of care, and clinical outcomes persist in contemporary practice for racial minorities with heart failure.

Disparities in inpatient care for heart failure

Patients admitted for heart failure and cared for by a cardiologist are more likely to be discharged on guideline-directed medical therapy, have fewer heart failure readmissions, and lower mortality.^56,57 Breathett et al,⁵⁸ in a study of 104,835 patients hospitalized in an intensive care unit for heart failure, found that primary intensive care by a cardiologist was associated with higher survival in both races. However, in the same study, white patients had a higher odds of receiving care from a cardiologist than African American patients.

Disparities and cardiac resynchronization therapy devices

In one-third of patients with heart failure, conduction delays result in dyssynchronous left ventricular contraction.⁵⁹ Dyssynchrony leads to reduced cardiac performance, left ventricular remodeling, and increased mortality.⁵⁶

Cardiac resynchronization therapy (CRT) was approved for clinical use in 2001, and studies have shown that it improves quality of life, exercise tolerance, cardiac performance, and morbidity and mortality rates.^59–66 The 2013 ACC/AHA guidelines for the management of heart failure give a class IA recommendation (the highest) for its use in patients with a left ventricular ejection fraction of 35% or less, sinus rhythm, left bundle branch block and a QRS duration of 150 ms or greater, and New York Heart Association class II, III, or ambulatory IV symptoms while on guideline-directed medical therapy.⁶⁷

Despite these recommendations, racial differences are observed. A study using the Nationwide Inpatient Sample database⁵⁹ showed that between 2002 and 2010, a total of 374,202 CRT devices were implanted, averaging 41,578 annually. After adjusting for heart failure admissions, the study showed that CRT use was favored in men and in whites.

Another study, using the National Cardiovascular Data Registry,⁶⁸ looked at patients who received implantable cardiac defibrillators (ICDs) and were eligible to receive CRT. It found that African Americans and Hispanics were less likely than whites to receive CRT, even though they were more likely to meet established criteria.

Disparities and left ventricular assist devices

The Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart failure (REMATCH) trial and Heart Mate II trial demonstrated that left ventricular assist devices (LVADs) were durable options for long-term support for patients with end-stage heart failure.^69,70 Studies that examined the role of race and clinical outcomes after LVAD implantation have reported mixed findings.^71,72 Few studies have looked at the role racial differences play in accessing LVAD therapy.

Joyce et al⁷³ reviewed data from the Nationwide Inpatient Sample from 2002 to 2003 on patients admitted to the hospital with a primary diagnosis of heart failure or cardiogenic shock. A total of 297,866 patients were included in the study, of whom only 291 underwent LVAD implantation. A multivariate analysis found that factors such as age over 65, female sex, admission to a nonacademic center, geographic region, and African American race adversely influenced access to LVAD therapy.

Breathett et al⁷⁴ evaluated racial differences in LVAD implantations from 2012 to 2015, a period that corresponds to increased health insurance expansion, and found LVAD implantations increased among African American patients with advanced heart failure, but no other racial or ethnic group.

For patients with end-stage heart failure, orthotopic heart transplant is the most definitive and durable option for long-term survival. According to data from the United Network for Organ Sharing, 62,508 heart transplants were performed from January 1, 1988 to December 31, 2015. Compared with transplants of other solid organs, heart transplant occurs in significantly infrequent rates.

Barriers to transplant include lack of health insurance, considered a surrogate for low socioeconomic status. Hispanics and African Americans are less likely to have private health insurance than non-Hispanic whites, and this difference is magnified among the working poor.

Despite these perceived barriers, Kilic et al⁷⁵ found that African Americans comprised 16.4% of heart transplant recipients, although they make up only approximately 13% of the US population. They also had significantly shorter wait-list times than whites. On the negative side, African Americans had a higher unadjusted mortality rate than whites (15% vs 12% P = .002). African Americans also tended to receive their transplants at centers with lower transplant volumes and higher transplant mortality rates.

Several other studies also showed that African Americans compared to whites have significantly worse outcomes after transplant.^76–79 What accounts for this difference? Kilic et al⁷⁵ showed that African Americans had the lowest proportion of blood type matching and lowest human leukocyte antigen matching, were younger (because African Americans develop more advanced heart failure at younger ages), had higher serum creatinine levels, and were more often bridged to transplant with an LVAD.

DISPARITIES IN CARDIOVASCULAR RESEARCH

Although the United States has the most sophisticated and robust medical system in the world, select groups have significant differences in delivery and healthcare outcomes. There are many explanations for these differences, but a contributing factor may be the paucity of research dedicated to understand racial and ethnic differences.⁸⁰

Differences observed in epidemiologic studies may be secondary to pathophysiology, genetic differences, environment, and lifestyle choices. Historically, clinical trials were conducted in homogeneous populations with respect to age (middle-aged), sex (male), and race (white), and the results were generalized to heterogeneous populations.⁸⁰

Disparities in research have implications in clinical practice. Overall, the primary cause of heart failure is ischemia; however, in African Americans, the primary cause is hypertensive heart disease.⁸¹ Studies in hypertension have shown that African Americans have less of a response to neurohormonal blockade with ACE inhibitors and beta-blockers than non-African Americans.⁸² Nevertheless, neurohormonal blockade has become the cornerstone of heart failure treatment.

Retrospective analysis of the Vasodilator-Heart Failure trials⁸³ showed that treatment with isosorbide dinitrate plus hydralazine, compared with placebo, conferred a survival benefit for African Americans but not whites.⁸⁰ No survival advantage was noted when isosorbide dinitrate/hydralazine was compared to enalapril in African Americans, although enalapril was superior to isosorbide dinitrate in whites.⁴⁵ These observations were recognized 10 to 15 years after trial completion, and were only possible because the trials included sufficient numbers of African American patients to complete analysis.

In 1993, the US Congress passed the National Institutes of Health (NIH) Revitalization Act, which established guidelines requiring NIH grant applicants to include minorities in human subject research, as they were historically underrepresented in clinical research trials.^84,85

In 2001, the Beta-Blocker Evaluation of Survival Trial⁸⁶ reported its results investigating whether bucindolol, a nonselective beta-blocker, would reduce mortality in patients with advanced heart failure (New York Heart Association class III or IV). This was one of the first trials to prospectively investigate racial and ethnic differences in response to treatment. Though it showed no overall benefit in the use of bucindolol in the treatment of advanced heart failure, subgroup analysis showed that whites did enjoy a benefit in terms of lower mortality, whereas African Americans did not.

Results of the Vasodilator-Heart Failure trials led to further population-directed research, most notably the African American Heart Failure Trial,⁸⁷ a double-blind, placebo-controlled, randomized trial in patients who identified as African American. Patients who were randomized to receive a fixed dose of hydralazine and isosorbide dinitrate had a 43% lower mortality rate, a 33% lower hospitalization rate for heart failure, and better quality of life than patients in the placebo group, leading to early termination of the trial. The outcomes suggested that the combination of isosorbide dinitrate and hydralazine treats heart failure in a manner independent of pure neurohormonal blockade.

CHALLENGES IN STUDY PARTICIPATION

Recruitment of minority participants in biomedical research is a challenging task for clinical investigators.^88,89 Some of the factors thought to pose potential barriers for racial and ethnic minority participation in health research include poor access to primary medical care, failure of researchers to recruit minority populations actively, and language and cultural barriers.⁹⁰

Further, it is widely claimed that African Americans are less willing than nonminority individuals to participate in clinical research trials due to general distrust of the medical community as a result of the Tuskegee Syphilis Experiment.⁹¹ That infamous study, conducted by the US Public Health Service between 1932 and 1972, sought to record the natural progression of untreated syphilis in poor African American men in Alabama. The participants were not informed of the true purpose of the study, and they were under the impression that they were simply receiving free healthcare from the US government. Further, they were denied appropriate treatment even after it became readily available, in order for researchers to observe the progression of the disease.

While the 1993 mandate did in fact increase pressure on researchers to develop strategies to overcome participation barriers, the issue of underrepresentation of racial minorities in clinical research, including cardiovascular research, has not been resolved and continues to be a problem today.

The overall goal of clinical research is to determine the best strategies to prevent and treat disease. But if the study population is not representative of the affected population at large, the results cannot be generalized to underrepresented subgroups. The implications of underrepresentation in research are far-reaching, and can further contribute to disparate care of minority patients such as African Americans, who have a higher prevalence of cardiovascular risk factors and greater burden of heart failure.

Between 1986 and 2018, according to a PUBMED search, 10,462 articles highlighted the presence of a health-related disparity. Solutions to address and ultimately eradicate disparities will need to eliminate healthcare bias, increase patient access, and increase diversity and inclusion in the physician work force.

Eliminating bias

Implicit bias refers to attitudes, thoughts, and feelings that exist outside of the conscious awareness.⁹² These biases can be triggered by race, gender, or socioeconomic status. They have manifested in society as stereotypes that men are more competent than women, women are more verbal than men, and African Americans are more athletic than whites.⁹³

The concept of implicit bias is important, in that the populations that experience the greatest health disparities also suffer from negative cultural stereotypes.⁹⁴ Healthcare professionals are not inoculated against implicit bias.⁹⁵ Studies have shown that most healthcare providers have implicit biases that reflect positive attitudes toward whites and negative attitudes toward people of color.^{92,94,96–98}

The Implicit Association Test, introduced in 1998, is widely used to measure implicit bias. It measures response time of subjects to match particular social groups to particular attributes.⁹⁹ Green et al,⁹⁹ using this test, showed that although physicians reported no explicit preference for white vs African American patients or differences in perceived cooperativeness, the test revealed implicit preference favoring white Americans and implicit stereotypes of African Americans as less cooperative for medical procedures and in general. This also manifested in clinical decision-making, as white Americans were more likely, and African Americans less likely, to be treated with thrombolysis.⁹⁹

Sabin et al¹⁰⁰ showed that implicit bias was present among pediatricians, although less than in society as a whole and in other healthcare professionals.

But how does one change feelings that exist outside of the conscious awareness? Green et al⁹⁹ showed that making physicians aware of their susceptibility to bias changed their behavior. A subset of physicians who were made aware that bias was a focus of the study were more likely to refer African Americans for thrombolysis even if they had a high degree of implicit pro-white bias.^94,100 Perhaps mandating that all healthcare providers take a self-administered and confidentially reported Implicit Association Test will lead to awareness of implicit bias and minimize healthcare behaviors that contribute to the current state of disparities.

Improving access

Common indicators of access to healthcare include health insurance status, having a usual source of healthcare, and having a regular physician.¹⁰¹ Health insurance does offer protection from the costs associated with illness and health maintenance.¹⁰¹ It is also a major contributing factor in racial and ethnic disparities.

Chen et al¹⁰² examined the effects of the Affordable Care Act and found that it was associated with reduction in the probability of being uninsured, delaying necessary care, and forgoing necessary care, and increased probability of having a physician. However, earlier studies showed that access to health insurance by itself does not equate to equitable care.^103,104

Diversifying the work force

African Americans comprise 4% of physicians and Hispanic Americans 5%, despite accounting for 13% and 16% of the US population.¹⁰⁵ This underrepresentation has led to African American and Hispanic American patients being more likely than white patients to be treated by a physician from a dissimilar racial or ethnic background.¹⁰⁶ Studies have shown that minority patients in a race- or ethnic-concordant relationship are more likely to use needed health services, less likely to postpone seeking care, and report greater satisfaction.^106,107 Minority physicians often locate and practice in neighborhoods with high minority populations, and they disproportionately care for disadvantaged patients of lower socioeconomic status and poorer health.^106,108

WE ARE STILL IN THE TUNNEL, BUT THERE IS LIGHT AT THE END

The cardiovascular community has faced tremendous challenges in the past and responded with innovative research that has led to imaging that aids in the diagnosis of subclinical cardiovascular disease and invasive and pharmacologic strategies that have improved cardiovascular outcomes. One may say that there is light at the end of the tunnel; however, the existence of disparate care reminds us that we are still in the tunnel.

Disparities in cardiovascular disease management present a unique challenge for the community. There is no drug, device, or invasive procedure to eliminate this pathology. However, by acknowledging the problem and implementing changes at the system, provider, and patient level, the cardiovascular community can achieve yet another momentous achievement: the end of cardiovascular health disparities. Cardiovascular disease makes no distinction in race, sex, age, or socioeconomic status, and neither should the medical community.

Cardiovascular disease became the leading cause of death in the United States in the early 20th century, and it accounts for nearly half of all deaths in industrialized nations.¹ The mortality it inflicts was thought to be shared equally between both sexes and among all age groups and races.² The cardiology community implemented innovative epidemiologic research, through which risk factors for cardiovascular disease were established.¹ The development of coronary care units reduced in-hospital mortality from acute myocardial infarction from 30% to 15%.^2–5 Further advances in pharmacology, revascularization, and imaging have aided in the detection and treatment of cardiovascular disease.⁶ Though cardiovascular disease remains the number-one cause of death worldwide, rates are on the decline.⁷

For several decades, health disparities have been recognized as a source of pathology in cardiovascular medicine, resulting in inequity of care administration among select populations. In this review, we examine whether the same forward thinking that has resulted in a decline in cardiovascular disease has had an impact on the pervasive disparities in cardiovascular medicine.

DISPARITIES DEFINED

Compared with whites, members of minority groups have a higher burden of chronic diseases, receive lower quality care, and have less access to medical care. Recognizing the potential public health ramifications, in 1999 the US Congress tasked the Institute of Medicine to study and assess the extent of healthcare disparities. This led to the landmark publication, Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care.⁸

The Institute of Medicine defines disparities in healthcare as racial or ethnic differences in the quality of healthcare that are not due to access-related factors, clinical needs, preferences, and appropriateness of intervention.⁸ Disparities can also exist according to socioeconomic status and sex.⁹

In an early study documenting the concept of disparities in cardiovascular disease, Stone and Vanzant¹⁰ concluded that heart disease was more common in African Americans than in whites, and that hypertension was the principal cause of cardiovascular disease mortality in African Americans.

Data from US Centers for Disease Control and Prevention, reference 11

Although avoidable deaths from heart disease, stroke, and hypertensive disease declined between 2001 and 2010, African Americans still have a higher mortality rate than other racial and ethnic groups (Figure 1).¹¹

DISPARITIES AND CARDIOVASCULAR HEALTH

The concept of cardiovascular health was established by the American Heart Association (AHA) in efforts to achieve an additional 20% reduction in cardiovascular disease-related mortality by 2020.⁷ Cardiovascular health is defined as the absence of clinically manifest cardiovascular disease and is measured by 7 components:

• Not smoking or abstaining from smoking for at least 1 year
• A normal body weight, defined as a body mass index less than 25 kg/m²
• Optimal physical activity, defined as 75 minutes of vigorous physical activity or 150 minutes of moderate-intensity physical activity per week
• Regular consumption of a healthy diet
• Total cholesterol below 200 mg/dL
• Blood pressure less than 120/80 mm Hg
• Fasting blood sugar below 100 mg/dL.

Nearly 70% of the US population can claim 2, 3, or 4 of these components, but differences exist according to race,¹² and 60% of adult white Americans are limited to achieving no more than 3 of these healthy metrics, compared with 70% of adult African Americans and Hispanic Americans.

Smoking

Smoking is a major risk factor for cardiovascular disease.^12–14

Data from National Health Interview Surgery, Jamal et al, reference 16

During adolescence, white males are more likely to smoke than African American and Hispanic males,¹² but this trend reverses in adulthood, when African American men have a higher prevalence of smoking than white men (21.4% vs 19%).⁷ Rates of lifetime use are highest among American Indian or Alaskan natives and whites (75.9%), followed by African Americans (58.4%), native Hawaiians (56.8%), and Hispanics (56.7%).¹⁵ Trends for current smoking are similar (Figure 2).¹⁶ Moreover, households with lower socioeconomic status have a higher prevalence of smoking.⁷

Physical activity

People with a sedentary lifestyle are more likely to die of cardiovascular disease. As many as 250,000 deaths annually in the United States are attributed to lack of regular physical activity.¹⁷

Recognizing the potential public health ramifications, the AHA and the 2018 Federal Guidelines on Physical Activity recommend that children engage in 60 minutes of daily physical activity and that adults participate in 150 minutes of moderate-intensity or 75 minutes of vigorous physical activity weekly.^18,19

Data from Behavioral Risk Factor Surveillance System, Omura et al, reference 20

In the United States, 15.2% of adolescents reported being physically inactive, according to data published in 2016.⁷ Similar to most cardiovascular risk factors, minority populations and those of lower socioeconomic status had the worst profiles. The prevalence of physical inactivity was highest in African Americans and Hispanics (Figure 3).²⁰

Studies have shown an association between screen-based sedentary behavior (computers, television, and video games) and cardiovascular disease.^21–23 In the United States, 41% of adolescents used computers for activities other than homework for more than 3 hours per day on a school day.⁷ The pattern of use was highest in African American boys and African American girls, followed by Hispanic girls and Hispanic boys.¹⁸ Trends were similar with regard to watching television for more than 3 hours per day.

Sedentary behavior persists into adulthood, with rates of inactivity of 38.3% in African Americans, 40.1% in Hispanics, and 26.3% in white adults.⁷

Nutrition plays a major role in cardiovascular disease, specifically in the pathogenesis of atherosclerotic disease and hypertension.²⁴ Most Americans do not meet dietary recommendations, with minority communities performing worse in specific metrics.⁷

Dietary patterns are reflected in the rate of obesity in this nation. Studies have shown a direct correlation between obesity and cardiovascular disease such as coronary artery disease, heart failure, and atrial fibrillation.^25–28 According to data from the National Health and Nutrition Examination Survey (NHANES), 31% of children between the ages of 2 and 19 years are classified as obese or overweight. The highest rates of obesity are seen in Hispanic and African American boys and girls. The obesity epidemic is disproportionately rampant in children living in households with low income, low education, and high unemployment rates.^7,29–31

Despite the risks associated with obesity, only 64.8% of obese adults report being informed by a doctor or health professional that they were overweight. The proportion of obese adults informed that they were overweight was significantly lower for African Americans and Hispanics compared with whites. Similar differences are seen based on socioeconomic status, as middle-income patients were less likely to be informed than those in the higher income strata (62.4% vs 70.6%).^7,31

Blood pressure

Hypertension is a well-established risk factor for cardiovascular disease and stroke, and a blood pressure of 120/80 mm Hg or lower is identified as a component of ideal cardiovascular health.

In the United States the prevalence of hypertension in adults older than 20 is 32%.⁷ The prevalence of hypertension in African Americans is among the highest in the world.^32,33 African Americans develop high blood pressure at earlier ages, and their average resting blood pressures are higher than in whites.^34,35 For a 45-year-old without hypertension, the 40-year risk of developing hypertension is 92.7% for African Americans and 86% for whites.³⁵ Hypertension is a major risk factor for stroke, and African Americans have a 1.8 times greater rate of fatal stroke than whites.⁷

In 2013 there were 71,942 deaths attributable to high blood pressure, and the 2011 death rate associated with hypertension was 18.9 per 100,000. By race, the death rate was 17.6 per 100,000 for white males and an alarming 47.1 per 100,000 for African American males; rates were 15.2 per 100,000 for white females and 35.1 per 100,000 for African American females.⁷

It is unclear what accounts for the racial difference in prevalence in hypertension. Studies have shown that African Americans are more likely than whites to have been told on more than 2 occasions that they have hypertension. And 85.7% of African Americans are aware that they have high blood pressure, compared with 82.7% of whites.¹⁴

African Americans and Hispanics have poorer hypertension control compared with whites.^36,37 These observed differences cannot be attributed to access alone, as African Americans were more likely to be on higher-intensity blood pressure therapy, whereas Hispanics were more likely to be undertreated.^36,38 In a meta-analysis of 13 trials, Peck et al³⁹ showed that African Americans showed a lesser reduction in systolic and diastolic blood pressure when treated with angiotensin-converting enzyme (ACE) inhibitors.

The 2017 American College of Cardiology (ACC) and AHA guidelines for the prevention, detection, evaluation, and management of high blood pressure in adults⁴⁰ identifies 4 drug classes as reducing cardiovascular disease morbidity and mortality: thiazide diuretics, ACE inhibitors, angiotensin II receptor blockers (ARBs), and calcium channel blockers. Of these 4 classes, thiazide diuretics and calcium channel blockers have been shown to lower blood pressure more effectively in African Americans than renin-angiotensin-aldosterone inhibition with ACE inhibitors or ARBs.

Glycemic control

Type 2 diabetes mellitus secondary to insulin resistance disproportionately affects minority groups, as the prevalence of diabetes mellitus in African Americans is almost twice as high as that in whites, and 35% higher in Hispanics compared with whites.^7,41 Based on NHANES data between 1984 and 2004, the prevalence of diabetes mellitus is expected to increase by 99% in whites, 107% in African Americans, and 127% in Hispanics by 2050. Alarmingly, African Americans over age 75 are expected to experience a 606% increase by 2050.⁴²

With regard to mortality, 21.7 deaths per 100,000 population were attributable to diabetes mellitus according to reports by the AHA in 2016. The death rate in white males was 24.3 per 100,000 compared with 44.9 per 100,000 for African Americans males. The associated mortality rate for white women was 16.2 per 100,000, and 35.8 per 100,000 for African American females.⁷

The management of coronary artery disease has evolved from prolonged bed rest to surgical, pharmacologic, and percutaneous revascularization.^2,5 Coronary revascularization procedures are now relatively common: 950,000 percutaneous coronary interventions and 397,000 coronary artery bypass procedures were performed in 2010.⁷

Nevertheless, despite similar clinical presentations, African Americans with acute myocardial infarction were less likely to be referred for coronary artery bypass grafting than whites.^43–46 They were also less likely to be given thrombolytics⁴⁷ and less likely to undergo coronary angiography with percutaneous coronary intervention.⁴⁸ Similar differences have been reported when comparing Hispanics with whites.⁴⁹

Some suggest that healthcare access is a key mediator of health disparities.⁵⁰ In 2009, Hispanics and African Americans accounted for more than 50% of those without health insurance.⁵¹ Improved access to healthcare might mitigate the disparity in revascularizations.

Massachusetts was one of the first states to mandate that all residents obtain health insurance. As a result, the uninsured rates declined in African Americans and Hispanics in Massachusetts, but a disparity in revascularization persisted. African Americans and Hispanics were 27% and 16% less likely to undergo revascularization procedures (coronary artery bypass grafting or percutaneous coronary intervention) than whites,⁵¹ suggesting that disparities in revascularization are not solely secondary to healthcare access.

These findings are consistent with a 2004 Veterans Administration study,⁵² in which healthcare access was equal among races. The study showed that African Americans received fewer cardiac procedures after an acute myocardial infarction compared with whites.

Have we made progress? The largest disparity between African Americans and whites in coronary artery disease mortality existed in 1990. The disparity persisted to 2012, and although decreased, it is projected to persist to 2030.⁵³

DISPARITIES IN HEART FAILURE

An estimated 5.7 million Americans have heart failure, and 915,000 new cases are diagnosed annually.⁷ Unlike coronary artery disease, heart failure is expected to increase in prevalence by 46%, to 8 million Americans with heart failure by 2030.^7,54

Our knowledge of disparities in the area of heart failure is derived primarily from epidemiologic studies. The Multi-Ethnic Study of Atherosclerosis⁵⁵ showed that African Americans (4.6 per 1,000), followed by Hispanics (3.5 per 1,000) had a higher risk of developing heart failure compared with whites (2.4 per 1,000).The higher risk is in part due to disparities in socioeconomic status and prevalence of hypertension, as African Americans accounted for 75% of cases of nonischemic-related heart failure.⁵⁵ African Americans also have a higher 5-year mortality rate than whites.⁵⁵

Even though the 5-year mortality rate in heart failure is still 50%, the past 30 years have seen innovations in pharmacologic and device therapy and thus improved outcomes in heart failure patients. Still, significant gaps in the use of guideline-recommended therapies, quality of care, and clinical outcomes persist in contemporary practice for racial minorities with heart failure.

Disparities in inpatient care for heart failure

Patients admitted for heart failure and cared for by a cardiologist are more likely to be discharged on guideline-directed medical therapy, have fewer heart failure readmissions, and lower mortality.^56,57 Breathett et al,⁵⁸ in a study of 104,835 patients hospitalized in an intensive care unit for heart failure, found that primary intensive care by a cardiologist was associated with higher survival in both races. However, in the same study, white patients had a higher odds of receiving care from a cardiologist than African American patients.

Disparities and cardiac resynchronization therapy devices

In one-third of patients with heart failure, conduction delays result in dyssynchronous left ventricular contraction.⁵⁹ Dyssynchrony leads to reduced cardiac performance, left ventricular remodeling, and increased mortality.⁵⁶

Cardiac resynchronization therapy (CRT) was approved for clinical use in 2001, and studies have shown that it improves quality of life, exercise tolerance, cardiac performance, and morbidity and mortality rates.^59–66 The 2013 ACC/AHA guidelines for the management of heart failure give a class IA recommendation (the highest) for its use in patients with a left ventricular ejection fraction of 35% or less, sinus rhythm, left bundle branch block and a QRS duration of 150 ms or greater, and New York Heart Association class II, III, or ambulatory IV symptoms while on guideline-directed medical therapy.⁶⁷

Despite these recommendations, racial differences are observed. A study using the Nationwide Inpatient Sample database⁵⁹ showed that between 2002 and 2010, a total of 374,202 CRT devices were implanted, averaging 41,578 annually. After adjusting for heart failure admissions, the study showed that CRT use was favored in men and in whites.

Another study, using the National Cardiovascular Data Registry,⁶⁸ looked at patients who received implantable cardiac defibrillators (ICDs) and were eligible to receive CRT. It found that African Americans and Hispanics were less likely than whites to receive CRT, even though they were more likely to meet established criteria.

Disparities and left ventricular assist devices

The Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart failure (REMATCH) trial and Heart Mate II trial demonstrated that left ventricular assist devices (LVADs) were durable options for long-term support for patients with end-stage heart failure.^69,70 Studies that examined the role of race and clinical outcomes after LVAD implantation have reported mixed findings.^71,72 Few studies have looked at the role racial differences play in accessing LVAD therapy.

Joyce et al⁷³ reviewed data from the Nationwide Inpatient Sample from 2002 to 2003 on patients admitted to the hospital with a primary diagnosis of heart failure or cardiogenic shock. A total of 297,866 patients were included in the study, of whom only 291 underwent LVAD implantation. A multivariate analysis found that factors such as age over 65, female sex, admission to a nonacademic center, geographic region, and African American race adversely influenced access to LVAD therapy.

Breathett et al⁷⁴ evaluated racial differences in LVAD implantations from 2012 to 2015, a period that corresponds to increased health insurance expansion, and found LVAD implantations increased among African American patients with advanced heart failure, but no other racial or ethnic group.

For patients with end-stage heart failure, orthotopic heart transplant is the most definitive and durable option for long-term survival. According to data from the United Network for Organ Sharing, 62,508 heart transplants were performed from January 1, 1988 to December 31, 2015. Compared with transplants of other solid organs, heart transplant occurs in significantly infrequent rates.

Barriers to transplant include lack of health insurance, considered a surrogate for low socioeconomic status. Hispanics and African Americans are less likely to have private health insurance than non-Hispanic whites, and this difference is magnified among the working poor.

Despite these perceived barriers, Kilic et al⁷⁵ found that African Americans comprised 16.4% of heart transplant recipients, although they make up only approximately 13% of the US population. They also had significantly shorter wait-list times than whites. On the negative side, African Americans had a higher unadjusted mortality rate than whites (15% vs 12% P = .002). African Americans also tended to receive their transplants at centers with lower transplant volumes and higher transplant mortality rates.

Several other studies also showed that African Americans compared to whites have significantly worse outcomes after transplant.^76–79 What accounts for this difference? Kilic et al⁷⁵ showed that African Americans had the lowest proportion of blood type matching and lowest human leukocyte antigen matching, were younger (because African Americans develop more advanced heart failure at younger ages), had higher serum creatinine levels, and were more often bridged to transplant with an LVAD.

DISPARITIES IN CARDIOVASCULAR RESEARCH

Although the United States has the most sophisticated and robust medical system in the world, select groups have significant differences in delivery and healthcare outcomes. There are many explanations for these differences, but a contributing factor may be the paucity of research dedicated to understand racial and ethnic differences.⁸⁰

Differences observed in epidemiologic studies may be secondary to pathophysiology, genetic differences, environment, and lifestyle choices. Historically, clinical trials were conducted in homogeneous populations with respect to age (middle-aged), sex (male), and race (white), and the results were generalized to heterogeneous populations.⁸⁰

Disparities in research have implications in clinical practice. Overall, the primary cause of heart failure is ischemia; however, in African Americans, the primary cause is hypertensive heart disease.⁸¹ Studies in hypertension have shown that African Americans have less of a response to neurohormonal blockade with ACE inhibitors and beta-blockers than non-African Americans.⁸² Nevertheless, neurohormonal blockade has become the cornerstone of heart failure treatment.

Retrospective analysis of the Vasodilator-Heart Failure trials⁸³ showed that treatment with isosorbide dinitrate plus hydralazine, compared with placebo, conferred a survival benefit for African Americans but not whites.⁸⁰ No survival advantage was noted when isosorbide dinitrate/hydralazine was compared to enalapril in African Americans, although enalapril was superior to isosorbide dinitrate in whites.⁴⁵ These observations were recognized 10 to 15 years after trial completion, and were only possible because the trials included sufficient numbers of African American patients to complete analysis.

In 1993, the US Congress passed the National Institutes of Health (NIH) Revitalization Act, which established guidelines requiring NIH grant applicants to include minorities in human subject research, as they were historically underrepresented in clinical research trials.^84,85

In 2001, the Beta-Blocker Evaluation of Survival Trial⁸⁶ reported its results investigating whether bucindolol, a nonselective beta-blocker, would reduce mortality in patients with advanced heart failure (New York Heart Association class III or IV). This was one of the first trials to prospectively investigate racial and ethnic differences in response to treatment. Though it showed no overall benefit in the use of bucindolol in the treatment of advanced heart failure, subgroup analysis showed that whites did enjoy a benefit in terms of lower mortality, whereas African Americans did not.

Results of the Vasodilator-Heart Failure trials led to further population-directed research, most notably the African American Heart Failure Trial,⁸⁷ a double-blind, placebo-controlled, randomized trial in patients who identified as African American. Patients who were randomized to receive a fixed dose of hydralazine and isosorbide dinitrate had a 43% lower mortality rate, a 33% lower hospitalization rate for heart failure, and better quality of life than patients in the placebo group, leading to early termination of the trial. The outcomes suggested that the combination of isosorbide dinitrate and hydralazine treats heart failure in a manner independent of pure neurohormonal blockade.

CHALLENGES IN STUDY PARTICIPATION

Recruitment of minority participants in biomedical research is a challenging task for clinical investigators.^88,89 Some of the factors thought to pose potential barriers for racial and ethnic minority participation in health research include poor access to primary medical care, failure of researchers to recruit minority populations actively, and language and cultural barriers.⁹⁰

Further, it is widely claimed that African Americans are less willing than nonminority individuals to participate in clinical research trials due to general distrust of the medical community as a result of the Tuskegee Syphilis Experiment.⁹¹ That infamous study, conducted by the US Public Health Service between 1932 and 1972, sought to record the natural progression of untreated syphilis in poor African American men in Alabama. The participants were not informed of the true purpose of the study, and they were under the impression that they were simply receiving free healthcare from the US government. Further, they were denied appropriate treatment even after it became readily available, in order for researchers to observe the progression of the disease.

While the 1993 mandate did in fact increase pressure on researchers to develop strategies to overcome participation barriers, the issue of underrepresentation of racial minorities in clinical research, including cardiovascular research, has not been resolved and continues to be a problem today.

The overall goal of clinical research is to determine the best strategies to prevent and treat disease. But if the study population is not representative of the affected population at large, the results cannot be generalized to underrepresented subgroups. The implications of underrepresentation in research are far-reaching, and can further contribute to disparate care of minority patients such as African Americans, who have a higher prevalence of cardiovascular risk factors and greater burden of heart failure.

Between 1986 and 2018, according to a PUBMED search, 10,462 articles highlighted the presence of a health-related disparity. Solutions to address and ultimately eradicate disparities will need to eliminate healthcare bias, increase patient access, and increase diversity and inclusion in the physician work force.

Eliminating bias

Implicit bias refers to attitudes, thoughts, and feelings that exist outside of the conscious awareness.⁹² These biases can be triggered by race, gender, or socioeconomic status. They have manifested in society as stereotypes that men are more competent than women, women are more verbal than men, and African Americans are more athletic than whites.⁹³

The concept of implicit bias is important, in that the populations that experience the greatest health disparities also suffer from negative cultural stereotypes.⁹⁴ Healthcare professionals are not inoculated against implicit bias.⁹⁵ Studies have shown that most healthcare providers have implicit biases that reflect positive attitudes toward whites and negative attitudes toward people of color.^{92,94,96–98}

The Implicit Association Test, introduced in 1998, is widely used to measure implicit bias. It measures response time of subjects to match particular social groups to particular attributes.⁹⁹ Green et al,⁹⁹ using this test, showed that although physicians reported no explicit preference for white vs African American patients or differences in perceived cooperativeness, the test revealed implicit preference favoring white Americans and implicit stereotypes of African Americans as less cooperative for medical procedures and in general. This also manifested in clinical decision-making, as white Americans were more likely, and African Americans less likely, to be treated with thrombolysis.⁹⁹

Sabin et al¹⁰⁰ showed that implicit bias was present among pediatricians, although less than in society as a whole and in other healthcare professionals.

But how does one change feelings that exist outside of the conscious awareness? Green et al⁹⁹ showed that making physicians aware of their susceptibility to bias changed their behavior. A subset of physicians who were made aware that bias was a focus of the study were more likely to refer African Americans for thrombolysis even if they had a high degree of implicit pro-white bias.^94,100 Perhaps mandating that all healthcare providers take a self-administered and confidentially reported Implicit Association Test will lead to awareness of implicit bias and minimize healthcare behaviors that contribute to the current state of disparities.

Improving access

Common indicators of access to healthcare include health insurance status, having a usual source of healthcare, and having a regular physician.¹⁰¹ Health insurance does offer protection from the costs associated with illness and health maintenance.¹⁰¹ It is also a major contributing factor in racial and ethnic disparities.

Chen et al¹⁰² examined the effects of the Affordable Care Act and found that it was associated with reduction in the probability of being uninsured, delaying necessary care, and forgoing necessary care, and increased probability of having a physician. However, earlier studies showed that access to health insurance by itself does not equate to equitable care.^103,104

Diversifying the work force

African Americans comprise 4% of physicians and Hispanic Americans 5%, despite accounting for 13% and 16% of the US population.¹⁰⁵ This underrepresentation has led to African American and Hispanic American patients being more likely than white patients to be treated by a physician from a dissimilar racial or ethnic background.¹⁰⁶ Studies have shown that minority patients in a race- or ethnic-concordant relationship are more likely to use needed health services, less likely to postpone seeking care, and report greater satisfaction.^106,107 Minority physicians often locate and practice in neighborhoods with high minority populations, and they disproportionately care for disadvantaged patients of lower socioeconomic status and poorer health.^106,108

WE ARE STILL IN THE TUNNEL, BUT THERE IS LIGHT AT THE END

The cardiovascular community has faced tremendous challenges in the past and responded with innovative research that has led to imaging that aids in the diagnosis of subclinical cardiovascular disease and invasive and pharmacologic strategies that have improved cardiovascular outcomes. One may say that there is light at the end of the tunnel; however, the existence of disparate care reminds us that we are still in the tunnel.

Disparities in cardiovascular disease management present a unique challenge for the community. There is no drug, device, or invasive procedure to eliminate this pathology. However, by acknowledging the problem and implementing changes at the system, provider, and patient level, the cardiovascular community can achieve yet another momentous achievement: the end of cardiovascular health disparities. Cardiovascular disease makes no distinction in race, sex, age, or socioeconomic status, and neither should the medical community.

Editor’s note: This Medical Grand Rounds was presented as the 14th Annual Lawrence “Chris” Crain Memorial Lecture, a series that has been dedicated to discussing kidney disease, hypertension, and health care disparities in the African American community. In 1997, Dr. Crain became the first African American chief medical resident at Cleveland Clinic, and was a nephrology fellow in 1998–1999. Dr. Nally was his teacher and mentor.

African Americans have a greater burden of chronic kidney disease than whites. They are more than 3 times as likely as whites to develop end-stage renal disease, even after adjusting for age, disease stage, smoking, medications, and comorbidities. Why this is so has been the focus of much speculation and research.

This article reviews recent advances in the understanding of the progression of chronic kidney disease, with particular scrutiny of the disease in African Americans. Breakthroughs in genetics that help explain the greater disease burden in African Americans are also discussed, as well as implications for organ transplant screening.

ADVANCING UNDERSTANDING OF CHRONIC KIDNEY DISEASE

In the 1990s, dialysis rolls grew by 8% to 10% annually. Unfortunately, many patients first met with a nephrologist on the eve of their first dialysis treatment; there was not yet an adequate way to recognize the disease earlier and slow its progression. And disease definitions were not yet standardized, which led to inadequate metrics and hampered the ability to move disease management forward.

Standardizing definitions

The situation improved in 2002, when the National Kidney Foundation published clinical practice guidelines for chronic kidney disease that included disease definitions and staging.¹ Chronic kidney disease was defined as a structural or functional abnormality of the kidney lasting at least 3 months, as manifested by either of the following:

• Kidney damage, with or without decreased glomerular filtration rate (GFR), as defined by pathologic abnormalities or markers of kidney damage in the blood, urine, or on imaging tests

• 

  GFR less than 60 mL/min/1.73 m², with or without kidney damage.

A subsequent major advance was the recognition that not only GFR but also albuminuria was important for staging of chronic kidney disease (Figure 1).²

Developing large databases

Surveillance and monitoring of chronic kidney disease have generated large databases that enable researchers to detect trends in disease progression.

US Renal Data System. The US Renal Data System has collected and reported on data for more than 20 years from the National Health and Nutrition Examination Survey and the Centers for Medicare and Medicaid Services about chronic and end-stage kidney disease in the United States.

Cleveland Clinic database. Cleveland Clinic has developed a validated chronic kidney disease registry based on its electronic health record.³ The data include demographics (age, sex, ethnic group), comorbidities, medications, and complete laboratory data.⁴

Alberta Kidney Disease Network. This Canadian research consortium links large laboratory and demographic databases to facilitate defining patient populations, such as those with kidney disease and other comorbidities.

Kaiser Permanente Renal Registry. Kaiser Permanente of Northern California insures more than one-third of adults in the San Francisco Bay Area. The renal registry includes all adults whose kidney function is known. Data on age, sex, and racial or ethnic group are available from the health-plan databases.

DEATHS FROM KIDNEY DISEASE

The mortality rate in patients with end-stage renal disease who are on dialysis has steadily fallen over the past 20 years, from an annual rate of about 25% in 1996 to 17% in 2014, suggesting that care improved during that time. Patients with transplants have a much lower mortality rate: less than 5% annually.⁵ But these data also highlight the persistent risk faced by patients with chronic kidney disease; even those with transplants have death rates comparable to those of patients with cancer, diabetes, or heart failure.

Death rates correlate with GFR

After the publication of definitions and staging by the National Kidney Foundation in 2002, Go et al⁶ studied more than 1 million patients with chronic kidney disease from the Kaiser Permanente Renal Registry and found that the rates of cardiovascular events and death from any cause increased with decreasing estimated GFR. These findings were confirmed in a later meta-analysis, which also found that an elevated urinary albumin-to-creatinine ratio (> 1.1 mg/mmol) is an independent predictor of all-cause mortality and cardiovascular mortality.⁷

Keith et al⁸ followed nearly 28,000 patients with chronic kidney disease (with an estimated GFR of less than 90 mL/min/1.73 m²) over 5 years. Patients with stage 3 disease (moderate disease, GFR = 30–59 mL/min/1.73 m²) were 20 times more likely to die than to progress to end-stage renal disease (24.3% vs 1.2%). Even those with stage 4 disease (severe disease, GFR = 15–29 mL/min/1.73 m²) were more than twice as likely to die as to progress to dialysis (45.7% vs 19.9%).

Similar observations were made by Thompson et al¹⁰ based on the Alberta Kidney Disease Network database. They tracked cardiovascular causes of death and found that regardless of estimated GFR, cardiovascular deaths were most often attributed to ischemic heart disease (about 55%). Other trends were also apparent: as the GFR fell, the incidence of stroke decreased, and heart failure and valvular heart disease increased.

AFRICAN AMERICANS WITH KIDNEY DISEASE: A DISTINCT GROUP

African Americans constitute about 12% of the US population but account for:

• 31% of end-stage renal disease
• 34% of the kidney transplant waiting list
• 28% of kidney transplants in 2015 (12% of living donor transplants, 35% of deceased donor transplants).

In addition, African Americans with chronic kidney disease tend to be:

• Younger and have more advanced kidney disease than whites¹¹
• Much more likely than whites to have diabetes, and somewhat more likely to have hypertension

• 

  Adapted from Navaneethan SD, Schold JD, Arrigain S, Jolly SE, Nally JV Jr. Cause-specific deaths in non-dialysis-dependent CKD. J Am Soc Nephrol 2015; 26:2512–2520.

  More likely than whites to die of cardiovascular disease (37.4% vs 34.2%) (Figure 2).⁹

Overall, the prevalence of chronic kidney disease is slightly higher in African Americans than in whites. Interestingly, African Americans are slightly less likely than whites to have low estimated GFR values (6.2% vs 7.6% incidence of < 60 mL/min/1.73 m²) but are about 50% more likely to have proteinuria (12.3% vs 8.4% incidence of urine albumin-to-creatinine ratio ≥ 30 mg/g).

More likely to be on dialysis, but less likely to die

Although African Americans have only a slightly higher prevalence of chronic kidney disease (about 15% increased prevalence) than whites,¹² they are 3 times more likely to be on dialysis.

Nevertheless, for unknown reasons, African American adults on dialysis have about a 26% lower all-cause mortality rate than whites.⁵ One proposed explanation for this survival advantage has been that the mortality rate in African Americans with chronic kidney disease before entering dialysis is higher than in whites, leading to a “healthier population” on dialysis.¹³ However, this theory is based on a small study from more than a decade ago and has not been borne out by subsequent investigation.

African Americans with chronic kidney disease: Death rates not increased

African Americans over age 65 with chronic kidney disease have all-cause mortality rates similar to those of whites: about 11% annually. Breaking it down by disease severity, death rates in stage 3 disease are about 10% and jump to more than 15% in higher stages in both African Americans and whites.⁵

However, African Americans with chronic kidney disease have more heart disease and much more end-stage renal disease than whites.

Disease advances faster despite care

The incidence of end-stage renal disease is consistently more than 3 times higher in African Americans than in whites in the United States.^5,14

Multiple investigations have tried to determine why African Americans are disproportionately affected by progression of chronic kidney disease to end-stage renal disease. We recently examined this question in our Cleveland Clinic registry data. Even after adjusting for 17 variables (including demographics, comorbidities, insurance, medications, smoking, and chronic kidney disease stage), African Americans with chronic kidney disease were found to have an increased risk of progressing to end-stage renal disease compared with whites (subhazard ratio 1.38, 95% confidence interval 1.19–1.60).

We examined care measures from the Cleveland Clinic database. In terms of the number of laboratory tests ordered, clinic visits, and nephrology referrals, African Americans had at least as much care as whites, if not more. Similarly, African Americans’ access to renoprotective medicines (angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, statins, beta-blockers) was the same as or more than for whites.

Although the frequently attributed reasons surrounding compliance and socioeconomic issues are worthy of examination, they do not appear to completely explain the differences in incidence and outcomes. This dichotomy of a marginally increased prevalence of chronic kidney disease in African Americans with mortality rates similar to those of whites, yet with a 3 times higher incidence of end-stage renal disease in African Americans, suggests a faster progression of the disease in African Americans, which may be genetically based.

In 2010, two variant alleles of the APOL1 gene on chromosome 22 were found to be associated with nondiabetic kidney disease.¹⁵ Three nephropathies are associated with being homozygous for these alleles:

• Focal segmental glomerulosclerosis, the leading cause of nephrotic syndrome in African Americans
• Hypertension-associated kidney disease with scarring of glomeruli in vessels, the primary cause of end-stage renal disease in African Americans
• Human immunodeficiency virus (HIV)- associated nephropathy, usually a focal segmental glomerulosclerosis type of lesion.

The first two conditions are about 3 to 5 times more prevalent in African Americans than in whites, and HIV-associated nephropathy is about 20 to 30 times more common. 

African sleeping sickness and chronic kidney disease

Retrospective analysis of biologic samples from trials of kidney disease in African Americans has revealed interesting results.

From Parsa A, Kao WH, Xie D, et al; AASK Study Investigators; CRIC Study Investigators. APOL1 risk variants, race, and progression of chronic kidney disease. N Engl J Med 2013; 369:2183–2196. Reprinted with permission from Massachusetts Medical Society.

The Chronic Renal Insufficiency Cohort (CRIC) observation study¹⁸ enrolled patients with an estimated GFR of 20 to 70 mL/min/1.73 m², with a preference for African Americans and patients with diabetes. Nearly 3,000 participants had adequate samples for DNA testing. They found that African Americans with the double variant allele had worse outcomes, whether or not they had diabetes, compared with whites and African Americans without the homozygous gene variant.

Mechanism not well understood

The mechanism of renal injury is not well understood. Apolipoprotein L1, the protein coded for by APOL1, is a component of high-density lipoprotein. It is found in a different distribution pattern in people with normal kidneys vs those with nondiabetic kidney disease, especially in the arteries, arterioles, and podocytes.^19,20 It can be detected in blood plasma, but levels do not correlate with kidney disease.²¹ Not all patients with the high-risk variant develop chronic kidney disease; a “second hit” such as infection with HIV may be required.

Investigators have recently developed knockout mouse models of APOL1-associated kidney diseases that are helping to elucidate mechanisms.^22,23

EFFECT OF GENOTYPE ON KIDNEY TRANSPLANTS IN AFRICAN AMERICANS

African Americans receive about 30% of kidney transplants in the United States and represent about 15% to 20% of all donors.

Lee et al²⁴ reviewed 119 African American recipients of kidney transplants, about half of whom were homozygous for an APOL1 variant. After 5 years, no differences were found in allograft survival between recipients with 0, 1, or 2 risk alleles.

However, looking at the issue from the other side, Reeves-Daniel et al²⁵ studied the fate of more than 100 kidneys that were transplanted from African American donors, 16% of whom had the high-risk, homozygous genotype. In this case, graft failure was much likelier to occur with the high-risk donor kidneys (hazard ratio 3.84, P = .008). Similar outcomes were shown in a study of 2 centers²⁶ involving 675 transplants from deceased donors, 15% of which involved the high-risk genotype. The hazard ratio for graft failure was found to be 2.26 (P = .001) with high-risk donor kidneys.

These studies, which examined data from about 5 years after transplant, found that kidney failure does not tend to occur immediately in all cases, but gradually over time. Most high-risk kidneys were not lost within the 5 years of the studies.

The fact that the high-risk kidneys do not all fail immediately also suggests that a second hit is required for failure. Culprits postulated include a bacterial or viral infection (eg, BK virus, cytomegalovirus), ischemia or reperfusion injury, drug toxicity, and immune-mediated allograft injury (ie, rejection). 

Genetic testing for APOL1 risk variants is on the horizon for kidney transplant. But at this point, providing guidance for patients can be tricky. Two case studies^27,28 and epidemiologic data suggest that donors homozygous for an APOL1 variant and those with a family history of end-stage kidney disease are at increased risk of chronic kidney disease. Even so, most recipients even of these high-risk organs have good outcomes. If an African American patient needs a kidney and his or her sibling offers one, it is difficult to advise against it when the evidence is weak for immediate risk and when other options may not be readily available. Further investigation is clearly needed into whether APOL1 variants and other biomarkers can predict an organ’s success as a transplant.

The National Institutes of Health are currently funding prospective longitudinal studies with the APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO) to determine the impact of APOL1 genetic factors on transplant recipients as well as on living donors. Possible second hits will also be studied, as will other markers of renal dysfunction or disease in donors. Researchers are actively investigating these important questions.

KEEPING SCIENCE RELEVANT

In a recent commentary related to the murine knockout model of APOL1-associated kidney disease, O’Toole et al offered insightful observations regarding the potential clinical impact of these new genetic discoveries.²³

As we study the genetics of kidney disease in African American patients, we should keep in mind 3 critical questions of clinical importance:

Will findings identify better treatments for chronic kidney disease? The AASK trial found that knowing the genetics did not affect outcomes of routine therapy. However, basic science investigations are currently underway targeting APOL1 variants which might reduce the increased kidney disease risk among people of African descent.

Should patients be genotyped for APOL1 risk variants? For patients with chronic kidney disease, it does not seem useful at this time. But for renal transplant donors, the answer is probably yes.

How does this discovery help us to understand our patients better? The implications are enormous for combatting the assumptions that rapid chronic kidney disease progression reflects poor patient compliance or other socioeconomic factors. We now understand that genetics, at least in part, drives renal disease outcomes in African American patients.

Editor’s note: This Medical Grand Rounds was presented as the 14th Annual Lawrence “Chris” Crain Memorial Lecture, a series that has been dedicated to discussing kidney disease, hypertension, and health care disparities in the African American community. In 1997, Dr. Crain became the first African American chief medical resident at Cleveland Clinic, and was a nephrology fellow in 1998–1999. Dr. Nally was his teacher and mentor.

African Americans have a greater burden of chronic kidney disease than whites. They are more than 3 times as likely as whites to develop end-stage renal disease, even after adjusting for age, disease stage, smoking, medications, and comorbidities. Why this is so has been the focus of much speculation and research.

This article reviews recent advances in the understanding of the progression of chronic kidney disease, with particular scrutiny of the disease in African Americans. Breakthroughs in genetics that help explain the greater disease burden in African Americans are also discussed, as well as implications for organ transplant screening.

ADVANCING UNDERSTANDING OF CHRONIC KIDNEY DISEASE

In the 1990s, dialysis rolls grew by 8% to 10% annually. Unfortunately, many patients first met with a nephrologist on the eve of their first dialysis treatment; there was not yet an adequate way to recognize the disease earlier and slow its progression. And disease definitions were not yet standardized, which led to inadequate metrics and hampered the ability to move disease management forward.

Standardizing definitions

The situation improved in 2002, when the National Kidney Foundation published clinical practice guidelines for chronic kidney disease that included disease definitions and staging.¹ Chronic kidney disease was defined as a structural or functional abnormality of the kidney lasting at least 3 months, as manifested by either of the following:

• Kidney damage, with or without decreased glomerular filtration rate (GFR), as defined by pathologic abnormalities or markers of kidney damage in the blood, urine, or on imaging tests

• 

  GFR less than 60 mL/min/1.73 m², with or without kidney damage.

A subsequent major advance was the recognition that not only GFR but also albuminuria was important for staging of chronic kidney disease (Figure 1).²

Developing large databases

Surveillance and monitoring of chronic kidney disease have generated large databases that enable researchers to detect trends in disease progression.

US Renal Data System. The US Renal Data System has collected and reported on data for more than 20 years from the National Health and Nutrition Examination Survey and the Centers for Medicare and Medicaid Services about chronic and end-stage kidney disease in the United States.

Cleveland Clinic database. Cleveland Clinic has developed a validated chronic kidney disease registry based on its electronic health record.³ The data include demographics (age, sex, ethnic group), comorbidities, medications, and complete laboratory data.⁴

Alberta Kidney Disease Network. This Canadian research consortium links large laboratory and demographic databases to facilitate defining patient populations, such as those with kidney disease and other comorbidities.

Kaiser Permanente Renal Registry. Kaiser Permanente of Northern California insures more than one-third of adults in the San Francisco Bay Area. The renal registry includes all adults whose kidney function is known. Data on age, sex, and racial or ethnic group are available from the health-plan databases.

DEATHS FROM KIDNEY DISEASE

The mortality rate in patients with end-stage renal disease who are on dialysis has steadily fallen over the past 20 years, from an annual rate of about 25% in 1996 to 17% in 2014, suggesting that care improved during that time. Patients with transplants have a much lower mortality rate: less than 5% annually.⁵ But these data also highlight the persistent risk faced by patients with chronic kidney disease; even those with transplants have death rates comparable to those of patients with cancer, diabetes, or heart failure.

Death rates correlate with GFR

After the publication of definitions and staging by the National Kidney Foundation in 2002, Go et al⁶ studied more than 1 million patients with chronic kidney disease from the Kaiser Permanente Renal Registry and found that the rates of cardiovascular events and death from any cause increased with decreasing estimated GFR. These findings were confirmed in a later meta-analysis, which also found that an elevated urinary albumin-to-creatinine ratio (> 1.1 mg/mmol) is an independent predictor of all-cause mortality and cardiovascular mortality.⁷

Keith et al⁸ followed nearly 28,000 patients with chronic kidney disease (with an estimated GFR of less than 90 mL/min/1.73 m²) over 5 years. Patients with stage 3 disease (moderate disease, GFR = 30–59 mL/min/1.73 m²) were 20 times more likely to die than to progress to end-stage renal disease (24.3% vs 1.2%). Even those with stage 4 disease (severe disease, GFR = 15–29 mL/min/1.73 m²) were more than twice as likely to die as to progress to dialysis (45.7% vs 19.9%).

Similar observations were made by Thompson et al¹⁰ based on the Alberta Kidney Disease Network database. They tracked cardiovascular causes of death and found that regardless of estimated GFR, cardiovascular deaths were most often attributed to ischemic heart disease (about 55%). Other trends were also apparent: as the GFR fell, the incidence of stroke decreased, and heart failure and valvular heart disease increased.

AFRICAN AMERICANS WITH KIDNEY DISEASE: A DISTINCT GROUP

African Americans constitute about 12% of the US population but account for:

• 31% of end-stage renal disease
• 34% of the kidney transplant waiting list
• 28% of kidney transplants in 2015 (12% of living donor transplants, 35% of deceased donor transplants).

In addition, African Americans with chronic kidney disease tend to be:

• Younger and have more advanced kidney disease than whites¹¹
• Much more likely than whites to have diabetes, and somewhat more likely to have hypertension

• 

  Adapted from Navaneethan SD, Schold JD, Arrigain S, Jolly SE, Nally JV Jr. Cause-specific deaths in non-dialysis-dependent CKD. J Am Soc Nephrol 2015; 26:2512–2520.

  More likely than whites to die of cardiovascular disease (37.4% vs 34.2%) (Figure 2).⁹

Overall, the prevalence of chronic kidney disease is slightly higher in African Americans than in whites. Interestingly, African Americans are slightly less likely than whites to have low estimated GFR values (6.2% vs 7.6% incidence of < 60 mL/min/1.73 m²) but are about 50% more likely to have proteinuria (12.3% vs 8.4% incidence of urine albumin-to-creatinine ratio ≥ 30 mg/g).

More likely to be on dialysis, but less likely to die

Although African Americans have only a slightly higher prevalence of chronic kidney disease (about 15% increased prevalence) than whites,¹² they are 3 times more likely to be on dialysis.

Nevertheless, for unknown reasons, African American adults on dialysis have about a 26% lower all-cause mortality rate than whites.⁵ One proposed explanation for this survival advantage has been that the mortality rate in African Americans with chronic kidney disease before entering dialysis is higher than in whites, leading to a “healthier population” on dialysis.¹³ However, this theory is based on a small study from more than a decade ago and has not been borne out by subsequent investigation.

African Americans with chronic kidney disease: Death rates not increased

African Americans over age 65 with chronic kidney disease have all-cause mortality rates similar to those of whites: about 11% annually. Breaking it down by disease severity, death rates in stage 3 disease are about 10% and jump to more than 15% in higher stages in both African Americans and whites.⁵

However, African Americans with chronic kidney disease have more heart disease and much more end-stage renal disease than whites.

Disease advances faster despite care

The incidence of end-stage renal disease is consistently more than 3 times higher in African Americans than in whites in the United States.^5,14

Multiple investigations have tried to determine why African Americans are disproportionately affected by progression of chronic kidney disease to end-stage renal disease. We recently examined this question in our Cleveland Clinic registry data. Even after adjusting for 17 variables (including demographics, comorbidities, insurance, medications, smoking, and chronic kidney disease stage), African Americans with chronic kidney disease were found to have an increased risk of progressing to end-stage renal disease compared with whites (subhazard ratio 1.38, 95% confidence interval 1.19–1.60).

We examined care measures from the Cleveland Clinic database. In terms of the number of laboratory tests ordered, clinic visits, and nephrology referrals, African Americans had at least as much care as whites, if not more. Similarly, African Americans’ access to renoprotective medicines (angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, statins, beta-blockers) was the same as or more than for whites.

Although the frequently attributed reasons surrounding compliance and socioeconomic issues are worthy of examination, they do not appear to completely explain the differences in incidence and outcomes. This dichotomy of a marginally increased prevalence of chronic kidney disease in African Americans with mortality rates similar to those of whites, yet with a 3 times higher incidence of end-stage renal disease in African Americans, suggests a faster progression of the disease in African Americans, which may be genetically based.

In 2010, two variant alleles of the APOL1 gene on chromosome 22 were found to be associated with nondiabetic kidney disease.¹⁵ Three nephropathies are associated with being homozygous for these alleles:

• Focal segmental glomerulosclerosis, the leading cause of nephrotic syndrome in African Americans
• Hypertension-associated kidney disease with scarring of glomeruli in vessels, the primary cause of end-stage renal disease in African Americans
• Human immunodeficiency virus (HIV)- associated nephropathy, usually a focal segmental glomerulosclerosis type of lesion.

The first two conditions are about 3 to 5 times more prevalent in African Americans than in whites, and HIV-associated nephropathy is about 20 to 30 times more common. 

African sleeping sickness and chronic kidney disease

Retrospective analysis of biologic samples from trials of kidney disease in African Americans has revealed interesting results.

From Parsa A, Kao WH, Xie D, et al; AASK Study Investigators; CRIC Study Investigators. APOL1 risk variants, race, and progression of chronic kidney disease. N Engl J Med 2013; 369:2183–2196. Reprinted with permission from Massachusetts Medical Society.

The Chronic Renal Insufficiency Cohort (CRIC) observation study¹⁸ enrolled patients with an estimated GFR of 20 to 70 mL/min/1.73 m², with a preference for African Americans and patients with diabetes. Nearly 3,000 participants had adequate samples for DNA testing. They found that African Americans with the double variant allele had worse outcomes, whether or not they had diabetes, compared with whites and African Americans without the homozygous gene variant.

Mechanism not well understood

The mechanism of renal injury is not well understood. Apolipoprotein L1, the protein coded for by APOL1, is a component of high-density lipoprotein. It is found in a different distribution pattern in people with normal kidneys vs those with nondiabetic kidney disease, especially in the arteries, arterioles, and podocytes.^19,20 It can be detected in blood plasma, but levels do not correlate with kidney disease.²¹ Not all patients with the high-risk variant develop chronic kidney disease; a “second hit” such as infection with HIV may be required.

Investigators have recently developed knockout mouse models of APOL1-associated kidney diseases that are helping to elucidate mechanisms.^22,23

EFFECT OF GENOTYPE ON KIDNEY TRANSPLANTS IN AFRICAN AMERICANS

African Americans receive about 30% of kidney transplants in the United States and represent about 15% to 20% of all donors.

Lee et al²⁴ reviewed 119 African American recipients of kidney transplants, about half of whom were homozygous for an APOL1 variant. After 5 years, no differences were found in allograft survival between recipients with 0, 1, or 2 risk alleles.

However, looking at the issue from the other side, Reeves-Daniel et al²⁵ studied the fate of more than 100 kidneys that were transplanted from African American donors, 16% of whom had the high-risk, homozygous genotype. In this case, graft failure was much likelier to occur with the high-risk donor kidneys (hazard ratio 3.84, P = .008). Similar outcomes were shown in a study of 2 centers²⁶ involving 675 transplants from deceased donors, 15% of which involved the high-risk genotype. The hazard ratio for graft failure was found to be 2.26 (P = .001) with high-risk donor kidneys.

These studies, which examined data from about 5 years after transplant, found that kidney failure does not tend to occur immediately in all cases, but gradually over time. Most high-risk kidneys were not lost within the 5 years of the studies.

The fact that the high-risk kidneys do not all fail immediately also suggests that a second hit is required for failure. Culprits postulated include a bacterial or viral infection (eg, BK virus, cytomegalovirus), ischemia or reperfusion injury, drug toxicity, and immune-mediated allograft injury (ie, rejection). 

Genetic testing for APOL1 risk variants is on the horizon for kidney transplant. But at this point, providing guidance for patients can be tricky. Two case studies^27,28 and epidemiologic data suggest that donors homozygous for an APOL1 variant and those with a family history of end-stage kidney disease are at increased risk of chronic kidney disease. Even so, most recipients even of these high-risk organs have good outcomes. If an African American patient needs a kidney and his or her sibling offers one, it is difficult to advise against it when the evidence is weak for immediate risk and when other options may not be readily available. Further investigation is clearly needed into whether APOL1 variants and other biomarkers can predict an organ’s success as a transplant.

The National Institutes of Health are currently funding prospective longitudinal studies with the APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO) to determine the impact of APOL1 genetic factors on transplant recipients as well as on living donors. Possible second hits will also be studied, as will other markers of renal dysfunction or disease in donors. Researchers are actively investigating these important questions.

KEEPING SCIENCE RELEVANT

In a recent commentary related to the murine knockout model of APOL1-associated kidney disease, O’Toole et al offered insightful observations regarding the potential clinical impact of these new genetic discoveries.²³

As we study the genetics of kidney disease in African American patients, we should keep in mind 3 critical questions of clinical importance:

Will findings identify better treatments for chronic kidney disease? The AASK trial found that knowing the genetics did not affect outcomes of routine therapy. However, basic science investigations are currently underway targeting APOL1 variants which might reduce the increased kidney disease risk among people of African descent.

Should patients be genotyped for APOL1 risk variants? For patients with chronic kidney disease, it does not seem useful at this time. But for renal transplant donors, the answer is probably yes.

How does this discovery help us to understand our patients better? The implications are enormous for combatting the assumptions that rapid chronic kidney disease progression reflects poor patient compliance or other socioeconomic factors. We now understand that genetics, at least in part, drives renal disease outcomes in African American patients.

Editor’s note: This Medical Grand Rounds was presented as the 14th Annual Lawrence “Chris” Crain Memorial Lecture, a series that has been dedicated to discussing kidney disease, hypertension, and health care disparities in the African American community. In 1997, Dr. Crain became the first African American chief medical resident at Cleveland Clinic, and was a nephrology fellow in 1998–1999. Dr. Nally was his teacher and mentor.

African Americans have a greater burden of chronic kidney disease than whites. They are more than 3 times as likely as whites to develop end-stage renal disease, even after adjusting for age, disease stage, smoking, medications, and comorbidities. Why this is so has been the focus of much speculation and research.

This article reviews recent advances in the understanding of the progression of chronic kidney disease, with particular scrutiny of the disease in African Americans. Breakthroughs in genetics that help explain the greater disease burden in African Americans are also discussed, as well as implications for organ transplant screening.

ADVANCING UNDERSTANDING OF CHRONIC KIDNEY DISEASE

In the 1990s, dialysis rolls grew by 8% to 10% annually. Unfortunately, many patients first met with a nephrologist on the eve of their first dialysis treatment; there was not yet an adequate way to recognize the disease earlier and slow its progression. And disease definitions were not yet standardized, which led to inadequate metrics and hampered the ability to move disease management forward.

Standardizing definitions

The situation improved in 2002, when the National Kidney Foundation published clinical practice guidelines for chronic kidney disease that included disease definitions and staging.¹ Chronic kidney disease was defined as a structural or functional abnormality of the kidney lasting at least 3 months, as manifested by either of the following:

• Kidney damage, with or without decreased glomerular filtration rate (GFR), as defined by pathologic abnormalities or markers of kidney damage in the blood, urine, or on imaging tests

• 

  GFR less than 60 mL/min/1.73 m², with or without kidney damage.

A subsequent major advance was the recognition that not only GFR but also albuminuria was important for staging of chronic kidney disease (Figure 1).²

Developing large databases

Surveillance and monitoring of chronic kidney disease have generated large databases that enable researchers to detect trends in disease progression.

US Renal Data System. The US Renal Data System has collected and reported on data for more than 20 years from the National Health and Nutrition Examination Survey and the Centers for Medicare and Medicaid Services about chronic and end-stage kidney disease in the United States.

Cleveland Clinic database. Cleveland Clinic has developed a validated chronic kidney disease registry based on its electronic health record.³ The data include demographics (age, sex, ethnic group), comorbidities, medications, and complete laboratory data.⁴

Alberta Kidney Disease Network. This Canadian research consortium links large laboratory and demographic databases to facilitate defining patient populations, such as those with kidney disease and other comorbidities.

Kaiser Permanente Renal Registry. Kaiser Permanente of Northern California insures more than one-third of adults in the San Francisco Bay Area. The renal registry includes all adults whose kidney function is known. Data on age, sex, and racial or ethnic group are available from the health-plan databases.

DEATHS FROM KIDNEY DISEASE

The mortality rate in patients with end-stage renal disease who are on dialysis has steadily fallen over the past 20 years, from an annual rate of about 25% in 1996 to 17% in 2014, suggesting that care improved during that time. Patients with transplants have a much lower mortality rate: less than 5% annually.⁵ But these data also highlight the persistent risk faced by patients with chronic kidney disease; even those with transplants have death rates comparable to those of patients with cancer, diabetes, or heart failure.

Death rates correlate with GFR

After the publication of definitions and staging by the National Kidney Foundation in 2002, Go et al⁶ studied more than 1 million patients with chronic kidney disease from the Kaiser Permanente Renal Registry and found that the rates of cardiovascular events and death from any cause increased with decreasing estimated GFR. These findings were confirmed in a later meta-analysis, which also found that an elevated urinary albumin-to-creatinine ratio (> 1.1 mg/mmol) is an independent predictor of all-cause mortality and cardiovascular mortality.⁷

Keith et al⁸ followed nearly 28,000 patients with chronic kidney disease (with an estimated GFR of less than 90 mL/min/1.73 m²) over 5 years. Patients with stage 3 disease (moderate disease, GFR = 30–59 mL/min/1.73 m²) were 20 times more likely to die than to progress to end-stage renal disease (24.3% vs 1.2%). Even those with stage 4 disease (severe disease, GFR = 15–29 mL/min/1.73 m²) were more than twice as likely to die as to progress to dialysis (45.7% vs 19.9%).

Similar observations were made by Thompson et al¹⁰ based on the Alberta Kidney Disease Network database. They tracked cardiovascular causes of death and found that regardless of estimated GFR, cardiovascular deaths were most often attributed to ischemic heart disease (about 55%). Other trends were also apparent: as the GFR fell, the incidence of stroke decreased, and heart failure and valvular heart disease increased.

AFRICAN AMERICANS WITH KIDNEY DISEASE: A DISTINCT GROUP

African Americans constitute about 12% of the US population but account for:

• 31% of end-stage renal disease
• 34% of the kidney transplant waiting list
• 28% of kidney transplants in 2015 (12% of living donor transplants, 35% of deceased donor transplants).

In addition, African Americans with chronic kidney disease tend to be:

• Younger and have more advanced kidney disease than whites¹¹
• Much more likely than whites to have diabetes, and somewhat more likely to have hypertension

• 

  Adapted from Navaneethan SD, Schold JD, Arrigain S, Jolly SE, Nally JV Jr. Cause-specific deaths in non-dialysis-dependent CKD. J Am Soc Nephrol 2015; 26:2512–2520.

  More likely than whites to die of cardiovascular disease (37.4% vs 34.2%) (Figure 2).⁹

Overall, the prevalence of chronic kidney disease is slightly higher in African Americans than in whites. Interestingly, African Americans are slightly less likely than whites to have low estimated GFR values (6.2% vs 7.6% incidence of < 60 mL/min/1.73 m²) but are about 50% more likely to have proteinuria (12.3% vs 8.4% incidence of urine albumin-to-creatinine ratio ≥ 30 mg/g).

More likely to be on dialysis, but less likely to die

Although African Americans have only a slightly higher prevalence of chronic kidney disease (about 15% increased prevalence) than whites,¹² they are 3 times more likely to be on dialysis.

Nevertheless, for unknown reasons, African American adults on dialysis have about a 26% lower all-cause mortality rate than whites.⁵ One proposed explanation for this survival advantage has been that the mortality rate in African Americans with chronic kidney disease before entering dialysis is higher than in whites, leading to a “healthier population” on dialysis.¹³ However, this theory is based on a small study from more than a decade ago and has not been borne out by subsequent investigation.

African Americans with chronic kidney disease: Death rates not increased

African Americans over age 65 with chronic kidney disease have all-cause mortality rates similar to those of whites: about 11% annually. Breaking it down by disease severity, death rates in stage 3 disease are about 10% and jump to more than 15% in higher stages in both African Americans and whites.⁵

However, African Americans with chronic kidney disease have more heart disease and much more end-stage renal disease than whites.

Disease advances faster despite care

The incidence of end-stage renal disease is consistently more than 3 times higher in African Americans than in whites in the United States.^5,14

Multiple investigations have tried to determine why African Americans are disproportionately affected by progression of chronic kidney disease to end-stage renal disease. We recently examined this question in our Cleveland Clinic registry data. Even after adjusting for 17 variables (including demographics, comorbidities, insurance, medications, smoking, and chronic kidney disease stage), African Americans with chronic kidney disease were found to have an increased risk of progressing to end-stage renal disease compared with whites (subhazard ratio 1.38, 95% confidence interval 1.19–1.60).

We examined care measures from the Cleveland Clinic database. In terms of the number of laboratory tests ordered, clinic visits, and nephrology referrals, African Americans had at least as much care as whites, if not more. Similarly, African Americans’ access to renoprotective medicines (angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, statins, beta-blockers) was the same as or more than for whites.

Although the frequently attributed reasons surrounding compliance and socioeconomic issues are worthy of examination, they do not appear to completely explain the differences in incidence and outcomes. This dichotomy of a marginally increased prevalence of chronic kidney disease in African Americans with mortality rates similar to those of whites, yet with a 3 times higher incidence of end-stage renal disease in African Americans, suggests a faster progression of the disease in African Americans, which may be genetically based.

In 2010, two variant alleles of the APOL1 gene on chromosome 22 were found to be associated with nondiabetic kidney disease.¹⁵ Three nephropathies are associated with being homozygous for these alleles:

• Focal segmental glomerulosclerosis, the leading cause of nephrotic syndrome in African Americans
• Hypertension-associated kidney disease with scarring of glomeruli in vessels, the primary cause of end-stage renal disease in African Americans
• Human immunodeficiency virus (HIV)- associated nephropathy, usually a focal segmental glomerulosclerosis type of lesion.

The first two conditions are about 3 to 5 times more prevalent in African Americans than in whites, and HIV-associated nephropathy is about 20 to 30 times more common. 

African sleeping sickness and chronic kidney disease

Retrospective analysis of biologic samples from trials of kidney disease in African Americans has revealed interesting results.

From Parsa A, Kao WH, Xie D, et al; AASK Study Investigators; CRIC Study Investigators. APOL1 risk variants, race, and progression of chronic kidney disease. N Engl J Med 2013; 369:2183–2196. Reprinted with permission from Massachusetts Medical Society.

The Chronic Renal Insufficiency Cohort (CRIC) observation study¹⁸ enrolled patients with an estimated GFR of 20 to 70 mL/min/1.73 m², with a preference for African Americans and patients with diabetes. Nearly 3,000 participants had adequate samples for DNA testing. They found that African Americans with the double variant allele had worse outcomes, whether or not they had diabetes, compared with whites and African Americans without the homozygous gene variant.

Mechanism not well understood

The mechanism of renal injury is not well understood. Apolipoprotein L1, the protein coded for by APOL1, is a component of high-density lipoprotein. It is found in a different distribution pattern in people with normal kidneys vs those with nondiabetic kidney disease, especially in the arteries, arterioles, and podocytes.^19,20 It can be detected in blood plasma, but levels do not correlate with kidney disease.²¹ Not all patients with the high-risk variant develop chronic kidney disease; a “second hit” such as infection with HIV may be required.

Investigators have recently developed knockout mouse models of APOL1-associated kidney diseases that are helping to elucidate mechanisms.^22,23

EFFECT OF GENOTYPE ON KIDNEY TRANSPLANTS IN AFRICAN AMERICANS

African Americans receive about 30% of kidney transplants in the United States and represent about 15% to 20% of all donors.

Lee et al²⁴ reviewed 119 African American recipients of kidney transplants, about half of whom were homozygous for an APOL1 variant. After 5 years, no differences were found in allograft survival between recipients with 0, 1, or 2 risk alleles.

However, looking at the issue from the other side, Reeves-Daniel et al²⁵ studied the fate of more than 100 kidneys that were transplanted from African American donors, 16% of whom had the high-risk, homozygous genotype. In this case, graft failure was much likelier to occur with the high-risk donor kidneys (hazard ratio 3.84, P = .008). Similar outcomes were shown in a study of 2 centers²⁶ involving 675 transplants from deceased donors, 15% of which involved the high-risk genotype. The hazard ratio for graft failure was found to be 2.26 (P = .001) with high-risk donor kidneys.

These studies, which examined data from about 5 years after transplant, found that kidney failure does not tend to occur immediately in all cases, but gradually over time. Most high-risk kidneys were not lost within the 5 years of the studies.

The fact that the high-risk kidneys do not all fail immediately also suggests that a second hit is required for failure. Culprits postulated include a bacterial or viral infection (eg, BK virus, cytomegalovirus), ischemia or reperfusion injury, drug toxicity, and immune-mediated allograft injury (ie, rejection). 

Genetic testing for APOL1 risk variants is on the horizon for kidney transplant. But at this point, providing guidance for patients can be tricky. Two case studies^27,28 and epidemiologic data suggest that donors homozygous for an APOL1 variant and those with a family history of end-stage kidney disease are at increased risk of chronic kidney disease. Even so, most recipients even of these high-risk organs have good outcomes. If an African American patient needs a kidney and his or her sibling offers one, it is difficult to advise against it when the evidence is weak for immediate risk and when other options may not be readily available. Further investigation is clearly needed into whether APOL1 variants and other biomarkers can predict an organ’s success as a transplant.

The National Institutes of Health are currently funding prospective longitudinal studies with the APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO) to determine the impact of APOL1 genetic factors on transplant recipients as well as on living donors. Possible second hits will also be studied, as will other markers of renal dysfunction or disease in donors. Researchers are actively investigating these important questions.

KEEPING SCIENCE RELEVANT

In a recent commentary related to the murine knockout model of APOL1-associated kidney disease, O’Toole et al offered insightful observations regarding the potential clinical impact of these new genetic discoveries.²³

As we study the genetics of kidney disease in African American patients, we should keep in mind 3 critical questions of clinical importance:

Will findings identify better treatments for chronic kidney disease? The AASK trial found that knowing the genetics did not affect outcomes of routine therapy. However, basic science investigations are currently underway targeting APOL1 variants which might reduce the increased kidney disease risk among people of African descent.

Should patients be genotyped for APOL1 risk variants? For patients with chronic kidney disease, it does not seem useful at this time. But for renal transplant donors, the answer is probably yes.

How does this discovery help us to understand our patients better? The implications are enormous for combatting the assumptions that rapid chronic kidney disease progression reflects poor patient compliance or other socioeconomic factors. We now understand that genetics, at least in part, drives renal disease outcomes in African American patients.

African American, Hispanic, American Indian, and Alaskan Native women continue to be disproportionately affected by cervical cancer compared with white women. From 2006 to 2010, the incidence of cervical cancer in African American women was 10.3 per 100,000; in white women it was 7.2.¹ The mortality rate from cervical cancer in African American women is twice that in white women.¹ Although cervical cancer rates have decreased nationwide, significant racial health disparities persist.

See related editorial

As the first-line healthcare providers for many women, the primary care physician and the general obstetrician-gynecologist are optimally positioned to reduce these disparities.

Cervical cancer is the third most common gynecologic cancer, after uterine and ovarian cancer. Nearly 13,000 new cases are diagnosed each year in the United States, and more than 4,000 women die of it.² Fortunately, cervical cancer can be significantly prevented with adequate screening and vaccination against human papillomavirus (HPV).

WHY ARE BLACK WOMEN MORE LIKELY TO DIE OF CERVICAL CANCER?

Later stage at diagnosis. African American women are more likely to present with advanced cervical cancer than non-Hispanic white women.^3–6

Less-aggressive treatment. African American women are more likely to receive no treatment after a cancer diagnosis.⁶ Differences in treatment may be attributed to comorbid conditions, stage at cancer diagnosis, and patient refusal.^5,7

Less access to care. A study from the Surveillance, Epidemiology, and End Results program of the National Cancer Institute looked at 7,267 women (4,431 non-Hispanic white women, 1,830 Hispanic white women, and 1,006 non-Hispanic African American women) who were diagnosed with primary invasive cervical cancer from 1992 to 1996 and followed through 2000. African American women had a 19% higher mortality rate compared with non-Hispanic white women during follow-up despite adjusting for age, stage, histology, and time of first treatment.⁸

However, a later study from the same program found no such difference after 1995, when the data were adjusted for marital status, disease stage, age, treatment, grade, and histology.⁶  

Equal access to healthcare may eliminate most of the disparity.⁷ A study in women with cervical cancer who sought treatment within the United States military healthcare system found no difference in treatment or 5- and 10-year survival rates between African American and white women.⁵ Equal access to comprehensive healthcare eliminated any disparity once cervical cancer was diagnosed.

CERVICAL CANCER SCREENING

The value of cervical cancer screening and prevention is well established. In 1941, Papanicolau reported that cervical cancer could be detected from vaginal smears.⁹ Since the development and widespread implementation of the “Pap” smear, cervical cancer rates have decreased dramatically in the United States.

Another major advance was the discovery that persistent infection with HPV is necessary for the development of cervical cancer, precancerous lesions, and genital warts.¹⁰

With advancing research, guidelines for cervical cancer screening have changed considerably over the years. Today, combined cervical cytologic and HPV testing is the mainstay. (Isolated HPV testing is generally not available outside clinical trials.)

Who should be screened?

Previous recommendations called for women to undergo Pap testing when they first became sexually active and then every year. However, cervical lesions are likely to regress in young women.¹¹ One study found that 28% of cervical intimal neoplasia (CIN) grade 2 and 3 lesions spontaneously regressed by 15 weeks, although lesions associated with HPV 16 infection were less likely to regress than with other HPV types.¹² A study of college women found that HPV infection persisted in only 9% of women after 24 months.¹³

To minimize unnecessary treatment of young women with dysplasia, the American Society for Colposcopy and Cervical Pathology in 2012 recommended cytologic screening for all women 21 years or older, regardless of age at first sexual encounter.¹⁴ Screening intervals were changed from every year to every 3 years until age 30, at which time cotesting with cytology and HPV testing is performed every 5 years. Routine cotesting is not recommended for women younger than 30, who have a high likelihood of HPV infection and spontaneous regression.

In 2014, the US Food and Drug Administration approved primary HPV screening (ie, testing for HPV first, and then performing cytology in samples that test positive) for women age 25 and older.¹⁵

Patients who need further evaluation and testing should be referred for colposcopy. The current guidelines for patients who have abnormal results on cervical cancer screening¹⁶ can be reviewed at www.asccp.org/asccp-guidelines.

As screening guidelines continue to evolve, primary care physicians will need to stay current and also help educate their patients. For example, many of our patients have undergone annual Pap screening for most of their lives and may not yet know about the new testing intervals.

Are there disparities in screening and follow-up?

Disparities in screening and follow-up may exist, but the evidence is not clear-cut.

In a 2013 National Health Interview Survey report, the rates of cervical cancer screening with Pap tests did not differ between African American and white women.¹⁷ However, the information on Pap testing was based on a single question asking participants if they had had a Pap test in the last 3 years. In our experience, patients may confuse Pap tests with speculum examinations.

Once women are screened, adequate and timely follow-up of abnormal results is key.

In a study from the National Breast and Cervical Cancer Early Detection Program,¹⁸ women who had cytology findings of atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesions were to undergo repeat Pap testing every 4 to 6 months for 2 years. African American women were the least likely to have a follow-up Pap smear compared with other racial groups.  

On the other hand, there was no difference related to race in follow-up rates of abnormal Pap tests in women ages 47 to 64 in the South Carolina Breast and Cervical Cancer Early Detection Program.¹⁹

In a study in an urban population (predominantly African African), the overall follow-up rate was only 26% at 12 months from an initial abnormal Pap smear. This study did not find any differences in follow-up according to race or ethnicity; however, it had insufficient power to detect a difference because only 15% of the study participants were white.²⁰

HPV is implicated in progression to both squamous cell carcinoma and adenocarcinoma of the cervix. Worldwide, HPV genotypes 16 and 18 are associated with 73% of cases of invasive cervical cancer; most of the remainder are associated with, in order of decreasing prevalence, genotypes 58, 33, 45, 31, 52, 35, 59, 39, 51, and 56.²¹

High-grade cervical lesions in African American women may less often be positive for HPV 16 and 18 than in white women.^22,23 On the other hand, the proportion of non-Hispanic black women infected with HPV 35 and 58 was significantly higher than in non-Hispanic white women.²² Regardless, HPV screening is recommended for women of all races and ethnicities.

The 2-valent and 4-valent HPV vaccines do not cover HPV 35 or 58. The newer 9-valent vaccine covers HPV 58 (but not 35) and so may in theory decrease any potential disparity related to infection with a specific oncogenic subtype.

THE ROLE OF PREVENTION

HPV vaccination

The Females United to Unilaterally Reduce Endo/Ectocervical Disease study demonstrated that the 4-valent vaccine was highly effective against cervical intraepithelial neoplasia due to HPV 16 and 18.²⁴ In another study, the 2-valent vaccine reduced the incidence of CIN 3 or higher by 87% in women who received all 3 doses and who had no evidence of HPV infection at baseline.²⁵

HPV vaccination is expensive. Each shot costs about $130, plus the cost of administering it. Although the Vaccines for Children program covers the HPV vaccine for uninsured and underinsured children and adolescents under age 19, Medicaid coverage varies from state to state for adults over age 21.

The Advisory Committee on Immunization Practices (ACIP)²⁶ recommends routine vaccination for:

• Males 11 or 12 years old
• Females ages 9 to 26.

In October 2016, the ACIP approved a 2-dose series given 6 to 12 months apart for patients starting vaccination at ages 9 through 14 years who are not immunocompromised. Others should receive a 3-dose series, with the second dose given 1 to 2 months after the first dose and the third dose given 6 months after the first dose.²⁷ Previously, 3 doses were recommended for everyone.

Disparities in HPV vaccination rates

HPV vaccination rates among adolescents in the United States increased from 33.6% in 2013 to 41.7% in 2014.²⁸ However, HPV vaccination rates continue to lag behind those of other routine vaccines, such as Tdap and meningococcal conjugate.

Reagan-Steiner et al²⁸ reported that more black than white girls age 13 through 17 received at least 1 dose of a 3-dose HPV vaccination series, but more white girls received all 3 doses (70.6% vs 61.6%). In contrast, a meta-analysis by Fisher et al²⁹ found African American and uninsured women generally less likely to initiate the HPV vaccination series. Kessels et al³⁰ reported similar findings.

Barriers to HPV vaccination

Barriers to HPV vaccination can be provider-dependent, parental, or institutional.

Malo et al³¹ surveyed Florida Medicaid providers and found that those who participated in the Vaccines for Children program were less likely to cite lack of reimbursement as a barrier to vaccination.

Meites et al³² surveyed sexually transmitted disease clinics and found that common reasons for not offering HPV vaccine were cost, staff time, and difficulty coordinating follow-up visits to complete the series.  

Providers report lack of urgency or lack of perception of cervical cancer as a true public health threat, safety concerns regarding the vaccine, and the inability to coadminister vaccines as barriers.³³

Studies have shown that relatively few parents (up to 18%) of parents are concerned about the effect of the vaccine on sexual activity.³⁴ Rather, they are most likely to cite lack of information regarding the vaccine, lack of physician recommendation, and not knowing where to receive the vaccine as barriers.^35,36

Guerry et al³⁷ determined that the single most important factor in vaccine initiation was physician recommendation, a finding reiterated in other studies.^35,38 A study in North Carolina identified failure of physician recommendation as one of the missed opportunities for vaccination of young women.³⁹

Therefore, the primary care physician, as the initial contact with the child or young adult, holds a responsibility to narrow this gap. In simply discussing and recommending the vaccine, physicians could increase vaccination rates.

REPRODUCTIVE HEALTH

Although 80% of women will be infected with HPV in their lifetime, only a small proportion will develop cervical cancer, suggesting there are other cofactors in the progression to cervical cancer.⁴⁰

Given the infectious etiology of cervical cancer, other contributing reproductive health factors have been described. As expected, the number of sexual partners correlates with HPV infection.^41,42 Younger age at first intercourse has been linked to development of cervical neoplasia, consistent with persistent infection leading to neoplasia.^41,42

Primary care physicians should provide timely and comprehensive sexual education, including information on safe sexual practices and pregnancy prevention.

Human immunodeficiency virus

In 2010, the estimated rate of new human immunodeficiency virus (HIV) infections in African American women was nearly 20 times greater than in white women.⁴³ Previous studies have shown a clear relationship between HIV and HPV-associated cancers, including cervical neoplasia and invasive cervical cancer.^44,45

Women with HIV should receive screening for cervical cancer at the time of diagnosis, 6 months after the initial diagnosis, and annually thereafter.⁴⁶

Conflicting evidence exists regarding the effect of highly active antiretroviral therapy on the incidence of HPV-related disease, so aggressive screening and management of cervical neoplasia is recommended for women with HIV, regardless of CD4+ levels or viral load.^47–49

Coinfection with other sexually transmitted infections, specifically Chlamydia, herpes, and HIV, has been associated with cervical neoplasia and invasive cervical cancer. A positive linear association exists between the number of sexually transmitted infections and cervical neoplasia.⁵⁰

C trachomatis is the most common sexually transmitted infection in the United States, with a 6-times higher rate in African American women.⁵¹ Women who are seropositive for C trachomatis are at twofold higher risk of developing squamous cell cervical cancer.^52,53 Women who are seropositive for Chlamydia infection, herpes virus 2, or HPV are at markedly increased risk of invasive cervical cancer.⁵⁰

Tobacco use

The negative impact of smoking on numerous other cancers resulted in investigation of its role in cervical cancer.

Early case-control studies found an association between cervical cancer and smoking,⁵⁴ but because these studies did not account for HPV infection status, they could not establish causality. Subsequently, several studies did control for HPV infection; the risk of squamous cervical cancer was twice as high in women who had ever smoked.⁵⁵ Furthermore, the more cigarettes smoked per day, the higher the risk of  cervical neoplasia.^41,56

According to the US Centers for Disease Control and Prevention in 2014, the highest prevalence of smoking was among American Indian and Alaskan Native women, 32.5% of whom said they smoked every day, compared with 17.2% of white women and 13.7% of African American women.⁵⁷

HOW CAN PRIMARY CARE PHYSICIANS CLOSE THE GAP?

By promoting HPV vaccination to children and young adults, primary care physicians can help prevent cervical cancer. Moreover, primary care physicians will see most adolescents for a nonpreventive health visit, an optimal opportunity to discuss sexual activity practices and HPV vaccination.⁵⁸ Including the HPV vaccine as routine with other vaccinations can close the gap.³⁸

Screening and treatment of sexually transmitted infection during these visits can affect the risk that future HPV infection will progress to neoplasia or cancer. Persistent lifestyle modification counseling, especially smoking cessation through motivational interviewing, can lessen the risk of cervical cancer neoplasia progression.

Additionally, in light of recent changes in cervical cancer screening guidelines, the primary care physician’s role as educator is of utmost importance. In one study, although 99% of women had received a Pap test, 87% could not identify the purpose of the Pap test.⁵⁹ The primary care physician’s role is perhaps the most influential in preventing disease and, as such, has the greatest impact on a patient’s disease process.

African American, Hispanic, American Indian, and Alaskan Native women continue to be disproportionately affected by cervical cancer compared with white women. From 2006 to 2010, the incidence of cervical cancer in African American women was 10.3 per 100,000; in white women it was 7.2.¹ The mortality rate from cervical cancer in African American women is twice that in white women.¹ Although cervical cancer rates have decreased nationwide, significant racial health disparities persist.

See related editorial

As the first-line healthcare providers for many women, the primary care physician and the general obstetrician-gynecologist are optimally positioned to reduce these disparities.

Cervical cancer is the third most common gynecologic cancer, after uterine and ovarian cancer. Nearly 13,000 new cases are diagnosed each year in the United States, and more than 4,000 women die of it.² Fortunately, cervical cancer can be significantly prevented with adequate screening and vaccination against human papillomavirus (HPV).

WHY ARE BLACK WOMEN MORE LIKELY TO DIE OF CERVICAL CANCER?

Later stage at diagnosis. African American women are more likely to present with advanced cervical cancer than non-Hispanic white women.^3–6

Less-aggressive treatment. African American women are more likely to receive no treatment after a cancer diagnosis.⁶ Differences in treatment may be attributed to comorbid conditions, stage at cancer diagnosis, and patient refusal.^5,7

Less access to care. A study from the Surveillance, Epidemiology, and End Results program of the National Cancer Institute looked at 7,267 women (4,431 non-Hispanic white women, 1,830 Hispanic white women, and 1,006 non-Hispanic African American women) who were diagnosed with primary invasive cervical cancer from 1992 to 1996 and followed through 2000. African American women had a 19% higher mortality rate compared with non-Hispanic white women during follow-up despite adjusting for age, stage, histology, and time of first treatment.⁸

However, a later study from the same program found no such difference after 1995, when the data were adjusted for marital status, disease stage, age, treatment, grade, and histology.⁶  

Equal access to healthcare may eliminate most of the disparity.⁷ A study in women with cervical cancer who sought treatment within the United States military healthcare system found no difference in treatment or 5- and 10-year survival rates between African American and white women.⁵ Equal access to comprehensive healthcare eliminated any disparity once cervical cancer was diagnosed.

CERVICAL CANCER SCREENING

The value of cervical cancer screening and prevention is well established. In 1941, Papanicolau reported that cervical cancer could be detected from vaginal smears.⁹ Since the development and widespread implementation of the “Pap” smear, cervical cancer rates have decreased dramatically in the United States.

Another major advance was the discovery that persistent infection with HPV is necessary for the development of cervical cancer, precancerous lesions, and genital warts.¹⁰

With advancing research, guidelines for cervical cancer screening have changed considerably over the years. Today, combined cervical cytologic and HPV testing is the mainstay. (Isolated HPV testing is generally not available outside clinical trials.)

Who should be screened?

Previous recommendations called for women to undergo Pap testing when they first became sexually active and then every year. However, cervical lesions are likely to regress in young women.¹¹ One study found that 28% of cervical intimal neoplasia (CIN) grade 2 and 3 lesions spontaneously regressed by 15 weeks, although lesions associated with HPV 16 infection were less likely to regress than with other HPV types.¹² A study of college women found that HPV infection persisted in only 9% of women after 24 months.¹³

To minimize unnecessary treatment of young women with dysplasia, the American Society for Colposcopy and Cervical Pathology in 2012 recommended cytologic screening for all women 21 years or older, regardless of age at first sexual encounter.¹⁴ Screening intervals were changed from every year to every 3 years until age 30, at which time cotesting with cytology and HPV testing is performed every 5 years. Routine cotesting is not recommended for women younger than 30, who have a high likelihood of HPV infection and spontaneous regression.

In 2014, the US Food and Drug Administration approved primary HPV screening (ie, testing for HPV first, and then performing cytology in samples that test positive) for women age 25 and older.¹⁵

Patients who need further evaluation and testing should be referred for colposcopy. The current guidelines for patients who have abnormal results on cervical cancer screening¹⁶ can be reviewed at www.asccp.org/asccp-guidelines.

As screening guidelines continue to evolve, primary care physicians will need to stay current and also help educate their patients. For example, many of our patients have undergone annual Pap screening for most of their lives and may not yet know about the new testing intervals.

Are there disparities in screening and follow-up?

Disparities in screening and follow-up may exist, but the evidence is not clear-cut.

In a 2013 National Health Interview Survey report, the rates of cervical cancer screening with Pap tests did not differ between African American and white women.¹⁷ However, the information on Pap testing was based on a single question asking participants if they had had a Pap test in the last 3 years. In our experience, patients may confuse Pap tests with speculum examinations.

Once women are screened, adequate and timely follow-up of abnormal results is key.

In a study from the National Breast and Cervical Cancer Early Detection Program,¹⁸ women who had cytology findings of atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesions were to undergo repeat Pap testing every 4 to 6 months for 2 years. African American women were the least likely to have a follow-up Pap smear compared with other racial groups.  

On the other hand, there was no difference related to race in follow-up rates of abnormal Pap tests in women ages 47 to 64 in the South Carolina Breast and Cervical Cancer Early Detection Program.¹⁹

In a study in an urban population (predominantly African African), the overall follow-up rate was only 26% at 12 months from an initial abnormal Pap smear. This study did not find any differences in follow-up according to race or ethnicity; however, it had insufficient power to detect a difference because only 15% of the study participants were white.²⁰

HPV is implicated in progression to both squamous cell carcinoma and adenocarcinoma of the cervix. Worldwide, HPV genotypes 16 and 18 are associated with 73% of cases of invasive cervical cancer; most of the remainder are associated with, in order of decreasing prevalence, genotypes 58, 33, 45, 31, 52, 35, 59, 39, 51, and 56.²¹

High-grade cervical lesions in African American women may less often be positive for HPV 16 and 18 than in white women.^22,23 On the other hand, the proportion of non-Hispanic black women infected with HPV 35 and 58 was significantly higher than in non-Hispanic white women.²² Regardless, HPV screening is recommended for women of all races and ethnicities.

The 2-valent and 4-valent HPV vaccines do not cover HPV 35 or 58. The newer 9-valent vaccine covers HPV 58 (but not 35) and so may in theory decrease any potential disparity related to infection with a specific oncogenic subtype.

THE ROLE OF PREVENTION

HPV vaccination

The Females United to Unilaterally Reduce Endo/Ectocervical Disease study demonstrated that the 4-valent vaccine was highly effective against cervical intraepithelial neoplasia due to HPV 16 and 18.²⁴ In another study, the 2-valent vaccine reduced the incidence of CIN 3 or higher by 87% in women who received all 3 doses and who had no evidence of HPV infection at baseline.²⁵

HPV vaccination is expensive. Each shot costs about $130, plus the cost of administering it. Although the Vaccines for Children program covers the HPV vaccine for uninsured and underinsured children and adolescents under age 19, Medicaid coverage varies from state to state for adults over age 21.

The Advisory Committee on Immunization Practices (ACIP)²⁶ recommends routine vaccination for:

• Males 11 or 12 years old
• Females ages 9 to 26.

In October 2016, the ACIP approved a 2-dose series given 6 to 12 months apart for patients starting vaccination at ages 9 through 14 years who are not immunocompromised. Others should receive a 3-dose series, with the second dose given 1 to 2 months after the first dose and the third dose given 6 months after the first dose.²⁷ Previously, 3 doses were recommended for everyone.

Disparities in HPV vaccination rates

HPV vaccination rates among adolescents in the United States increased from 33.6% in 2013 to 41.7% in 2014.²⁸ However, HPV vaccination rates continue to lag behind those of other routine vaccines, such as Tdap and meningococcal conjugate.

Reagan-Steiner et al²⁸ reported that more black than white girls age 13 through 17 received at least 1 dose of a 3-dose HPV vaccination series, but more white girls received all 3 doses (70.6% vs 61.6%). In contrast, a meta-analysis by Fisher et al²⁹ found African American and uninsured women generally less likely to initiate the HPV vaccination series. Kessels et al³⁰ reported similar findings.

Barriers to HPV vaccination

Barriers to HPV vaccination can be provider-dependent, parental, or institutional.

Malo et al³¹ surveyed Florida Medicaid providers and found that those who participated in the Vaccines for Children program were less likely to cite lack of reimbursement as a barrier to vaccination.

Meites et al³² surveyed sexually transmitted disease clinics and found that common reasons for not offering HPV vaccine were cost, staff time, and difficulty coordinating follow-up visits to complete the series.  

Providers report lack of urgency or lack of perception of cervical cancer as a true public health threat, safety concerns regarding the vaccine, and the inability to coadminister vaccines as barriers.³³

Studies have shown that relatively few parents (up to 18%) of parents are concerned about the effect of the vaccine on sexual activity.³⁴ Rather, they are most likely to cite lack of information regarding the vaccine, lack of physician recommendation, and not knowing where to receive the vaccine as barriers.^35,36

Guerry et al³⁷ determined that the single most important factor in vaccine initiation was physician recommendation, a finding reiterated in other studies.^35,38 A study in North Carolina identified failure of physician recommendation as one of the missed opportunities for vaccination of young women.³⁹

Therefore, the primary care physician, as the initial contact with the child or young adult, holds a responsibility to narrow this gap. In simply discussing and recommending the vaccine, physicians could increase vaccination rates.

REPRODUCTIVE HEALTH

Although 80% of women will be infected with HPV in their lifetime, only a small proportion will develop cervical cancer, suggesting there are other cofactors in the progression to cervical cancer.⁴⁰

Given the infectious etiology of cervical cancer, other contributing reproductive health factors have been described. As expected, the number of sexual partners correlates with HPV infection.^41,42 Younger age at first intercourse has been linked to development of cervical neoplasia, consistent with persistent infection leading to neoplasia.^41,42

Primary care physicians should provide timely and comprehensive sexual education, including information on safe sexual practices and pregnancy prevention.

Human immunodeficiency virus

In 2010, the estimated rate of new human immunodeficiency virus (HIV) infections in African American women was nearly 20 times greater than in white women.⁴³ Previous studies have shown a clear relationship between HIV and HPV-associated cancers, including cervical neoplasia and invasive cervical cancer.^44,45

Women with HIV should receive screening for cervical cancer at the time of diagnosis, 6 months after the initial diagnosis, and annually thereafter.⁴⁶

Conflicting evidence exists regarding the effect of highly active antiretroviral therapy on the incidence of HPV-related disease, so aggressive screening and management of cervical neoplasia is recommended for women with HIV, regardless of CD4+ levels or viral load.^47–49

Coinfection with other sexually transmitted infections, specifically Chlamydia, herpes, and HIV, has been associated with cervical neoplasia and invasive cervical cancer. A positive linear association exists between the number of sexually transmitted infections and cervical neoplasia.⁵⁰

C trachomatis is the most common sexually transmitted infection in the United States, with a 6-times higher rate in African American women.⁵¹ Women who are seropositive for C trachomatis are at twofold higher risk of developing squamous cell cervical cancer.^52,53 Women who are seropositive for Chlamydia infection, herpes virus 2, or HPV are at markedly increased risk of invasive cervical cancer.⁵⁰

Tobacco use

The negative impact of smoking on numerous other cancers resulted in investigation of its role in cervical cancer.

Early case-control studies found an association between cervical cancer and smoking,⁵⁴ but because these studies did not account for HPV infection status, they could not establish causality. Subsequently, several studies did control for HPV infection; the risk of squamous cervical cancer was twice as high in women who had ever smoked.⁵⁵ Furthermore, the more cigarettes smoked per day, the higher the risk of  cervical neoplasia.^41,56

According to the US Centers for Disease Control and Prevention in 2014, the highest prevalence of smoking was among American Indian and Alaskan Native women, 32.5% of whom said they smoked every day, compared with 17.2% of white women and 13.7% of African American women.⁵⁷

HOW CAN PRIMARY CARE PHYSICIANS CLOSE THE GAP?

By promoting HPV vaccination to children and young adults, primary care physicians can help prevent cervical cancer. Moreover, primary care physicians will see most adolescents for a nonpreventive health visit, an optimal opportunity to discuss sexual activity practices and HPV vaccination.⁵⁸ Including the HPV vaccine as routine with other vaccinations can close the gap.³⁸

Screening and treatment of sexually transmitted infection during these visits can affect the risk that future HPV infection will progress to neoplasia or cancer. Persistent lifestyle modification counseling, especially smoking cessation through motivational interviewing, can lessen the risk of cervical cancer neoplasia progression.

Additionally, in light of recent changes in cervical cancer screening guidelines, the primary care physician’s role as educator is of utmost importance. In one study, although 99% of women had received a Pap test, 87% could not identify the purpose of the Pap test.⁵⁹ The primary care physician’s role is perhaps the most influential in preventing disease and, as such, has the greatest impact on a patient’s disease process.

African American, Hispanic, American Indian, and Alaskan Native women continue to be disproportionately affected by cervical cancer compared with white women. From 2006 to 2010, the incidence of cervical cancer in African American women was 10.3 per 100,000; in white women it was 7.2.¹ The mortality rate from cervical cancer in African American women is twice that in white women.¹ Although cervical cancer rates have decreased nationwide, significant racial health disparities persist.

See related editorial

As the first-line healthcare providers for many women, the primary care physician and the general obstetrician-gynecologist are optimally positioned to reduce these disparities.

Cervical cancer is the third most common gynecologic cancer, after uterine and ovarian cancer. Nearly 13,000 new cases are diagnosed each year in the United States, and more than 4,000 women die of it.² Fortunately, cervical cancer can be significantly prevented with adequate screening and vaccination against human papillomavirus (HPV).

WHY ARE BLACK WOMEN MORE LIKELY TO DIE OF CERVICAL CANCER?

Later stage at diagnosis. African American women are more likely to present with advanced cervical cancer than non-Hispanic white women.^3–6

Less-aggressive treatment. African American women are more likely to receive no treatment after a cancer diagnosis.⁶ Differences in treatment may be attributed to comorbid conditions, stage at cancer diagnosis, and patient refusal.^5,7

Less access to care. A study from the Surveillance, Epidemiology, and End Results program of the National Cancer Institute looked at 7,267 women (4,431 non-Hispanic white women, 1,830 Hispanic white women, and 1,006 non-Hispanic African American women) who were diagnosed with primary invasive cervical cancer from 1992 to 1996 and followed through 2000. African American women had a 19% higher mortality rate compared with non-Hispanic white women during follow-up despite adjusting for age, stage, histology, and time of first treatment.⁸

However, a later study from the same program found no such difference after 1995, when the data were adjusted for marital status, disease stage, age, treatment, grade, and histology.⁶  

Equal access to healthcare may eliminate most of the disparity.⁷ A study in women with cervical cancer who sought treatment within the United States military healthcare system found no difference in treatment or 5- and 10-year survival rates between African American and white women.⁵ Equal access to comprehensive healthcare eliminated any disparity once cervical cancer was diagnosed.

CERVICAL CANCER SCREENING

The value of cervical cancer screening and prevention is well established. In 1941, Papanicolau reported that cervical cancer could be detected from vaginal smears.⁹ Since the development and widespread implementation of the “Pap” smear, cervical cancer rates have decreased dramatically in the United States.

Another major advance was the discovery that persistent infection with HPV is necessary for the development of cervical cancer, precancerous lesions, and genital warts.¹⁰

With advancing research, guidelines for cervical cancer screening have changed considerably over the years. Today, combined cervical cytologic and HPV testing is the mainstay. (Isolated HPV testing is generally not available outside clinical trials.)

Who should be screened?

Previous recommendations called for women to undergo Pap testing when they first became sexually active and then every year. However, cervical lesions are likely to regress in young women.¹¹ One study found that 28% of cervical intimal neoplasia (CIN) grade 2 and 3 lesions spontaneously regressed by 15 weeks, although lesions associated with HPV 16 infection were less likely to regress than with other HPV types.¹² A study of college women found that HPV infection persisted in only 9% of women after 24 months.¹³

To minimize unnecessary treatment of young women with dysplasia, the American Society for Colposcopy and Cervical Pathology in 2012 recommended cytologic screening for all women 21 years or older, regardless of age at first sexual encounter.¹⁴ Screening intervals were changed from every year to every 3 years until age 30, at which time cotesting with cytology and HPV testing is performed every 5 years. Routine cotesting is not recommended for women younger than 30, who have a high likelihood of HPV infection and spontaneous regression.

In 2014, the US Food and Drug Administration approved primary HPV screening (ie, testing for HPV first, and then performing cytology in samples that test positive) for women age 25 and older.¹⁵

Patients who need further evaluation and testing should be referred for colposcopy. The current guidelines for patients who have abnormal results on cervical cancer screening¹⁶ can be reviewed at www.asccp.org/asccp-guidelines.

As screening guidelines continue to evolve, primary care physicians will need to stay current and also help educate their patients. For example, many of our patients have undergone annual Pap screening for most of their lives and may not yet know about the new testing intervals.

Are there disparities in screening and follow-up?

Disparities in screening and follow-up may exist, but the evidence is not clear-cut.

In a 2013 National Health Interview Survey report, the rates of cervical cancer screening with Pap tests did not differ between African American and white women.¹⁷ However, the information on Pap testing was based on a single question asking participants if they had had a Pap test in the last 3 years. In our experience, patients may confuse Pap tests with speculum examinations.

Once women are screened, adequate and timely follow-up of abnormal results is key.

In a study from the National Breast and Cervical Cancer Early Detection Program,¹⁸ women who had cytology findings of atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesions were to undergo repeat Pap testing every 4 to 6 months for 2 years. African American women were the least likely to have a follow-up Pap smear compared with other racial groups.  

On the other hand, there was no difference related to race in follow-up rates of abnormal Pap tests in women ages 47 to 64 in the South Carolina Breast and Cervical Cancer Early Detection Program.¹⁹

In a study in an urban population (predominantly African African), the overall follow-up rate was only 26% at 12 months from an initial abnormal Pap smear. This study did not find any differences in follow-up according to race or ethnicity; however, it had insufficient power to detect a difference because only 15% of the study participants were white.²⁰

HPV is implicated in progression to both squamous cell carcinoma and adenocarcinoma of the cervix. Worldwide, HPV genotypes 16 and 18 are associated with 73% of cases of invasive cervical cancer; most of the remainder are associated with, in order of decreasing prevalence, genotypes 58, 33, 45, 31, 52, 35, 59, 39, 51, and 56.²¹

High-grade cervical lesions in African American women may less often be positive for HPV 16 and 18 than in white women.^22,23 On the other hand, the proportion of non-Hispanic black women infected with HPV 35 and 58 was significantly higher than in non-Hispanic white women.²² Regardless, HPV screening is recommended for women of all races and ethnicities.

The 2-valent and 4-valent HPV vaccines do not cover HPV 35 or 58. The newer 9-valent vaccine covers HPV 58 (but not 35) and so may in theory decrease any potential disparity related to infection with a specific oncogenic subtype.

THE ROLE OF PREVENTION

HPV vaccination

The Females United to Unilaterally Reduce Endo/Ectocervical Disease study demonstrated that the 4-valent vaccine was highly effective against cervical intraepithelial neoplasia due to HPV 16 and 18.²⁴ In another study, the 2-valent vaccine reduced the incidence of CIN 3 or higher by 87% in women who received all 3 doses and who had no evidence of HPV infection at baseline.²⁵

HPV vaccination is expensive. Each shot costs about $130, plus the cost of administering it. Although the Vaccines for Children program covers the HPV vaccine for uninsured and underinsured children and adolescents under age 19, Medicaid coverage varies from state to state for adults over age 21.

The Advisory Committee on Immunization Practices (ACIP)²⁶ recommends routine vaccination for:

• Males 11 or 12 years old
• Females ages 9 to 26.

In October 2016, the ACIP approved a 2-dose series given 6 to 12 months apart for patients starting vaccination at ages 9 through 14 years who are not immunocompromised. Others should receive a 3-dose series, with the second dose given 1 to 2 months after the first dose and the third dose given 6 months after the first dose.²⁷ Previously, 3 doses were recommended for everyone.

Disparities in HPV vaccination rates

HPV vaccination rates among adolescents in the United States increased from 33.6% in 2013 to 41.7% in 2014.²⁸ However, HPV vaccination rates continue to lag behind those of other routine vaccines, such as Tdap and meningococcal conjugate.

Reagan-Steiner et al²⁸ reported that more black than white girls age 13 through 17 received at least 1 dose of a 3-dose HPV vaccination series, but more white girls received all 3 doses (70.6% vs 61.6%). In contrast, a meta-analysis by Fisher et al²⁹ found African American and uninsured women generally less likely to initiate the HPV vaccination series. Kessels et al³⁰ reported similar findings.

Barriers to HPV vaccination

Barriers to HPV vaccination can be provider-dependent, parental, or institutional.

Malo et al³¹ surveyed Florida Medicaid providers and found that those who participated in the Vaccines for Children program were less likely to cite lack of reimbursement as a barrier to vaccination.

Meites et al³² surveyed sexually transmitted disease clinics and found that common reasons for not offering HPV vaccine were cost, staff time, and difficulty coordinating follow-up visits to complete the series.  

Providers report lack of urgency or lack of perception of cervical cancer as a true public health threat, safety concerns regarding the vaccine, and the inability to coadminister vaccines as barriers.³³

Studies have shown that relatively few parents (up to 18%) of parents are concerned about the effect of the vaccine on sexual activity.³⁴ Rather, they are most likely to cite lack of information regarding the vaccine, lack of physician recommendation, and not knowing where to receive the vaccine as barriers.^35,36

Guerry et al³⁷ determined that the single most important factor in vaccine initiation was physician recommendation, a finding reiterated in other studies.^35,38 A study in North Carolina identified failure of physician recommendation as one of the missed opportunities for vaccination of young women.³⁹

Therefore, the primary care physician, as the initial contact with the child or young adult, holds a responsibility to narrow this gap. In simply discussing and recommending the vaccine, physicians could increase vaccination rates.

REPRODUCTIVE HEALTH

Although 80% of women will be infected with HPV in their lifetime, only a small proportion will develop cervical cancer, suggesting there are other cofactors in the progression to cervical cancer.⁴⁰

Given the infectious etiology of cervical cancer, other contributing reproductive health factors have been described. As expected, the number of sexual partners correlates with HPV infection.^41,42 Younger age at first intercourse has been linked to development of cervical neoplasia, consistent with persistent infection leading to neoplasia.^41,42

Primary care physicians should provide timely and comprehensive sexual education, including information on safe sexual practices and pregnancy prevention.

Human immunodeficiency virus

In 2010, the estimated rate of new human immunodeficiency virus (HIV) infections in African American women was nearly 20 times greater than in white women.⁴³ Previous studies have shown a clear relationship between HIV and HPV-associated cancers, including cervical neoplasia and invasive cervical cancer.^44,45

Women with HIV should receive screening for cervical cancer at the time of diagnosis, 6 months after the initial diagnosis, and annually thereafter.⁴⁶

Conflicting evidence exists regarding the effect of highly active antiretroviral therapy on the incidence of HPV-related disease, so aggressive screening and management of cervical neoplasia is recommended for women with HIV, regardless of CD4+ levels or viral load.^47–49

Coinfection with other sexually transmitted infections, specifically Chlamydia, herpes, and HIV, has been associated with cervical neoplasia and invasive cervical cancer. A positive linear association exists between the number of sexually transmitted infections and cervical neoplasia.⁵⁰

C trachomatis is the most common sexually transmitted infection in the United States, with a 6-times higher rate in African American women.⁵¹ Women who are seropositive for C trachomatis are at twofold higher risk of developing squamous cell cervical cancer.^52,53 Women who are seropositive for Chlamydia infection, herpes virus 2, or HPV are at markedly increased risk of invasive cervical cancer.⁵⁰

Tobacco use

The negative impact of smoking on numerous other cancers resulted in investigation of its role in cervical cancer.

Early case-control studies found an association between cervical cancer and smoking,⁵⁴ but because these studies did not account for HPV infection status, they could not establish causality. Subsequently, several studies did control for HPV infection; the risk of squamous cervical cancer was twice as high in women who had ever smoked.⁵⁵ Furthermore, the more cigarettes smoked per day, the higher the risk of  cervical neoplasia.^41,56

According to the US Centers for Disease Control and Prevention in 2014, the highest prevalence of smoking was among American Indian and Alaskan Native women, 32.5% of whom said they smoked every day, compared with 17.2% of white women and 13.7% of African American women.⁵⁷

HOW CAN PRIMARY CARE PHYSICIANS CLOSE THE GAP?

By promoting HPV vaccination to children and young adults, primary care physicians can help prevent cervical cancer. Moreover, primary care physicians will see most adolescents for a nonpreventive health visit, an optimal opportunity to discuss sexual activity practices and HPV vaccination.⁵⁸ Including the HPV vaccine as routine with other vaccinations can close the gap.³⁸

Screening and treatment of sexually transmitted infection during these visits can affect the risk that future HPV infection will progress to neoplasia or cancer. Persistent lifestyle modification counseling, especially smoking cessation through motivational interviewing, can lessen the risk of cervical cancer neoplasia progression.

Additionally, in light of recent changes in cervical cancer screening guidelines, the primary care physician’s role as educator is of utmost importance. In one study, although 99% of women had received a Pap test, 87% could not identify the purpose of the Pap test.⁵⁹ The primary care physician’s role is perhaps the most influential in preventing disease and, as such, has the greatest impact on a patient’s disease process.

Despite the historic association of gout with royalty and “rich eating,” gout disproportionately affects those of lower socioeconomic status.¹ Risk factors for gout, including obesity, chronic kidney disease, diabetes, and hypertension, are more common in African Americans, resulting in a higher prevalence of the disease. In addition, African Americans are less likely to receive the aggressive treatment for gout advocated by professional societies, such as anti-inflammatory medications during flares and prophylactic urate-lowering therapy.

This article reviews the epidemiology of gout and its pathophysiology, risk factors, and optimal management, focusing on African Americans and strategies to reduce healthcare disparities in this patient population.

GOUT IS COMMON AND SERIOUS

Gout is the most common inflammatory arthritis in the United States today, affecting 4% of the adult US population.² It is a chronic disease associated with high levels of uric acid, usually manifesting as intermittent attacks of painful monoarthritis, although multiple joints may be involved.

Despite a popular misconception that gout is merely an episodic nuisance, it is a serious disease that can significantly affect physical function and quality of life.³ A 2013 systematic review found that quality of life was significantly reduced in patients with gout, particularly those with polyarticular gout, tophi, comorbidities, and radiographic damage.⁴

Economic costs include decreased worker productivity and increased absences from work.^5,6 From 2001 to 2005, an estimated 2 million visits were made to primary care providers due to gout.⁷ Because gout frequently coexists with diabetes, hypertension, coronary artery disease, and kidney disease, it is often overlooked during routine clinic visits.³

HIGH URIC ACID HAS MANY EFFECTS

Uric acid, a product of purine metabolism, is the key mediator of gouty arthritis. Accumulation of uric acid in joints and other tissues leads to an exuberant inflammatory response manifesting as a gouty attack. When uncontrolled, uric acid may crystallize in joints and other structures, leading to tophi formation, which can cause chronic deforming and erosive arthritis, known as chronic tophaceous gout.⁸

Although gout is considered to be a musculoskeletal disorder, recent evidence indicates that hyperuricemia plays an important role in the development of renal disease and contributes to cardiovascular morbidity and death.⁹ Several studies have found that reducing uric acid levels lowers cardiovascular mortality rates and retards the progression of chronic kidney disease.¹⁰

MEN AND CERTAIN RACIAL GROUPS MOST AFFECTED

Large-scale epidemiologic surveys have established that prevalence varies widely among population groups. Premenopausal women are less likely to be affected than men, presumably due to the effect of female hormones on renal tubular excretion of uric acid.¹¹

Certain Asian populations (Filipinos, Taiwanese, Micronesians, the Maoris of New Zealand, Hmong Chinese immigrants in Minnesota) and African Americans have a high prevalence, while people from several sub-Saharan African countries have a very low prevalence. These differences are likely due to a variety of reasons, including genetic predisposition; diet (Table 1); risk factors such as obesity, diabetes, and hypertension; less access to healthcare resources; and inappropriate treatment.^12,13

AFRICAN AMERICANS ARE A DIVERSE GROUP

“African Americans” are a highly heterogeneous group making up about 13% of the US population. Most scholars now consider racial identity largely a product of socioeconomic and political circumstances rather than a scientific concept.¹⁴ The US Census Bureau defines African Americans (or “blacks”) as those having origins in the black racial groups of Africa,¹⁵  but even this is problematic, since it combines people as diverse as descendants of 17th, 18th, and 19th century enslaved Africans with recent first-generation African immigrants, as well as with Caribbean- and Latino-Americans of African heritage.

In addition, many African Americans trace their ancestry to other racial and ethnic groups, especially European and Native American. A study of nine European DNA markers among 10 African American populations in the United States and one population of Jamaicans of African descent found a range of frequencies from 7% among Jamaicans to 23% among African Americans living in New Orleans.¹⁶

Although such diversity argues against generalizing healthcare needs for the entire African American community, some evidence indicates that genetic markers for gene-disease associations may be consistent across traditional racial boundaries.¹⁷

GENETIC FACTORS CANNOT EXPLAIN GOUT DISPARITIES

Several small studies have found evidence of genetic factors mediating the risk for hyperuricemia and gout. Twin studies indicate that hyperuricemia is highly heritable,¹⁸ although they do not show a concordance in the heritability of gout, suggesting that environmental factors also have an important role in developing clinical manifestations of the disease.¹²

Genome-wide association studies have identified 28 separate loci influencing uric acid levels, including genes for uric acid transporters (eg, SLC2A9 and ABCG2), and metabolic pathway regulators (eg, PDZK1, SCL22A12, and PRPSAP1), but the distribution among African Americans is largely unknown.¹⁹ One important exception is SLC2A9, a renal tubular transporter of uric acid: variants of SLC2A9 were found exclusively in African Americans, but the clinical significance of this association is unclear.²⁰

Several epidemiologic studies have looked at gout in African Americans.

In the Coronary Artery Risk Development in Young Adults study,²¹ young African Americans had lower levels of uric acid than whites after adjusting for body mass index (BMI), glomerular filtration rate (GFR), diet, and medications. But after up to 20 years of follow-up, the risk of hyperuricemia was 2.3 times higher in African American women than in white women (95% confidence interval [CI] 1.34–3.99). Such differences were not found between African American and white men.

The National Health and Nutritional Examination Survey (NHANES) found that African American adolescents had lower uric acid levels than white adolescents after taking into account sugar intake, GFR, BMI, and onset of puberty.²²

The Multiple Risk Factor Intervention Trial²³ also found that among those with high cardiovascular risk, the incidence of hyperuricemia and gout was lower in African Americans than in whites.

COMORBID DISEASES MAY EXPLAIN DISPARITIES

Despite some evidence that African Americans have genetic factors that are protective against gout, they have a much greater frequency of acquired risk factors for gout, including obesity, physical inactivity, hypertension, diabetes mellitus, renal failure, high intake of seafood, elevated blood lead levels, and use of antihypertensive medications (Table 2).

Hochberg et al²⁴ examined the incidence of gout in 352 African American and 571 white physicians and found higher rates in African Americans (9% vs 5%). The authors suggested different rates of hypertension as an explanation, although the use of antihypertensive medications such as diuretics that promote hyperuricemia confounds the strength of this conclusion.

AFRICAN AMERICANS NEED STANDARD TREATMENT . . .

Unlike for heart failure, in which subgroup analyses of large prospective studies have found different efficacies of medications in African Americans than in whites, no such data exist for gout. Although there is a higher risk of allopurinol hypersensitivity in ethnic groups that express the HLA-B*5801 polymorphism (eg, Han Chinese, Korean, Thai, Japanese, Portuguese), African Americans are not known to be at greater risk.²⁵ There are also no special precautions for using febuxostat or probenecid in African Americans.

Absent any compelling reason, gout management should be the same regardless of ethnicity.²⁶ Patients should be counseled on primary prevention measures such as dietary and behavioral modification and, if necessary, started on aggressive urate-lowering therapy.²⁷

. . . BUT ARE LESS LIKELY TO HAVE GOUT APPROPRIATELY TREATED

African Americans with gout are less likely to receive urate-lowering therapy.²⁸ According to the 2002 National Ambulatory Medical Care Survey in the United States, African Americans with gout are far less likely to receive allopurinol than whites (42% vs 80%; odds ratio [OR] 0.18; 95% CI 0.04–0.78).²³ Even when therapy is prescribed, rates of nonadherence are greater in African Americans than in whites (OR 1.86, 95% CI 1.52–2.27), though the authors do not speculate why this is so.²⁹ No studies have compared rates of prescribing febuxostat to African Americans vs whites.

African Americans are also less likely to receive ongoing routine care for their gout. A 2007 study³⁰ of 663 veterans found that physicians were 1.41 times less likely to adhere to three selected quality indicators when dealing with nonwhite than white patients (95% CI 0.52–3.84). The three quality indicators studied were:

• Lowering of daily allopurinol dose to below 300 mg/day in the presence of renal insufficiency (no longer considered a quality measure)
• Monitoring of serum urate level at least once during the first 6 months of continued use of a xanthine oxidase inhibitor, such as allopurinol
• Monitoring of complete blood cell count and creatinine kinase at least every 6 months in patients with renal impairment receiving long-term prophylactic oral colchicine (> 0.5 mg/day for at least 6 months).

The finding was independent of age, comorbidity index, healthcare access, and utilization characteristics (eg, number of inpatient and outpatient visits, type of physician, most frequently seen physician).

LIFESTYLE MODIFICATION

Dietary modification is a useful initial step toward reducing uric acid levels (Table 1).²⁷ The following measures are recommended:

Reduce alcohol intake. Alcoholic beverages, particularly beer, are strongly linked to hyperuricemia, according to a 2013 meta-analysis.³¹ Although alcohol consumption is lower in African Americans than in whites, mortality rates from cirrhosis and other alcohol-related diseases are 10% higher, suggesting metabolic differences that render African Americans more susceptible to the negative health effects of alcohol.³²

Avoid sugary drinks. Sweetened beverages, especially those rich in fructose, are also implicated in hyperuricemia and gout. NHANES found an increase in serum uric acid of 0.33 mg/dL (95% CI, 0.11–0.73) in those consuming one to three sugar-sweetened drinks per day compared with nonconsumers, adjusting for total energy intake, age, sex, medications, hypertension, and GFR.³³ A prospective study also found a relative risk of 1.85 for those who drink two or more sugar-sweetened beverages per day compared with those who drink fewer than one per month (95% CI 1.08–3.16).³⁴

Unfortunately, African Americans consume a disproportionate amount of sugar from all sources: 17% of African Americans are considered heavy consumers vs 9% of whites.³⁵

Limit foods rich in purines. Red meat, seafood, and some vegetables, including asparagus, spinach, peas, cauliflower, and mushrooms, are associated with increased serum uric acid levels. NHANES found that greater meat and seafood consumption was associated with increased uric acid levels. Choi et al³⁶ found that the risk of gout increased by 21% with each additional daily serving of meat; the relative risk of developing gout was 1.41 (95% CI 1.07–1.86) in the fifth quintile of meat intake compared with the first quintile, and 1.51 (95% CI 1.17–1.95) in the fifth quintile of seafood consumption.

Despite these associations with high-purine food consumption and gout, many purine-rich foods may not contribute to hyperuricemia, and therefore a low-purine diet may not be protective. Interestingly, purine-rich vegetable protein intake is not associated with increased gout risk.³⁷

Increase dairy consumption. Dairy in the diet is associated with a lower incidence of gout, with a decrease of 0.21 mg/dL (95% CI –0.37 to –0.04) in serum uric acid levels between the highest and lowest quintiles of dairy consumption.³⁸ A randomized controlled trial found a 10% reduction in serum uric acid levels with milk consumption.³⁹

Enjoy coffee. Coffee intake has been inversely correlated with gout. Daily intake of 4 to 5 cups of coffee is associated with a relative risk of 0.60 (95% CI 0.41–0.87) vs no coffee.⁴⁰

Vitamin C and cherry juice^41,42 have also been linked to lower gout risk, but the data are less robust.

Control weight. Primary care providers should advise patients to increase physical activity and maintain a healthy weight.

In a prospective study, Choi et al⁴³ found that, in men, the risk of gout increased with the BMI. Compared with men with BMIs in the range of 21 to 22.9 kg/m², the relative risks were:

• 1.95 (95% CI 1.44–2.65) at BMI 25 to 29.9 kg/m²
• 2.33 (95% CI 1.62–3.36) at BMI 30 to 34.9 kg/m²
• 2.97 (95% CI 1.73–5.10) at BMI > 35 kg/m².

In addition, those who gained more than 13.6 kg since age 21 had a relative risk of 1.99 (95% CI 1.49–2.66) of developing gout compared with those whose weight remained within 1.8 kg.  

For those who cannot achieve weight loss through conservative measures, bariatric surgery has shown promise. In a prospective study of 60 obese patients (BMI > 35 kg/m²) with gout and type 2 diabetes mellitus, uric acid steadily declined during the first year after bariatric surgery.⁴⁴

TREATMENT OF ACUTE ATTACKS

Gout can be effectively managed in most patients. Behavioral and pharmacologic interventions are cheap and effective and have been shown to halt further damage to joints as well as retard the progression of renal disease and reduce cardiovascular morbidity.

During acute attacks, anti-inflammatory medications, principally glucocorticoids, nonsteroidal anti-inflammatory drugs, and colchicine, should be given promptly to reduce the intensity and duration of flares.

Although traditional teaching has been that urate-lowering therapy should not be initiated during an acute gout attack because it could prolong the duration of the attack, guidelines now permit it, based on studies showing that therapy does not prolong attacks.^45,46

AGGRESSIVE URATE-LOWERING THERAPY FOR PROPHYLAXIS

Long-term treatment of gout is aimed at reducing uric acid levels by mitigating modifiable risk factors and through urate-lowering therapy.⁴⁶ For many patients, conservative management with dietary and other behavioral changes is not sufficient to prevent further attacks of gout, necessitating urate-lowering therapy. Comorbid diseases such as obesity, hypertension, chronic kidney disease, and diabetes should also be addressed because they promote hyperuricemia and gouty attacks.⁴⁷

A number of organizations have issued gout management guidelines over the past decade, including the American College of Rheumatology (ACR) in 2012, the European League Against Rheumatism (2006, updated in 2014), and the British Society of Rheumatology (2007). All recommend urate-lowering therapy to prevent gout flares.

The American and European guidelines recommend a target uric acid level below 6 mg/dL, and the British guidelines recommend a target below 5 mg/dL.⁴⁸ For patients with palpable and visible tophi, the ACR guidelines state that lowering to below 5 mg/dL may be needed.⁴⁶

First-line agents for urate-lowering therapy are xanthine oxidase inhibitors, which include allopurinol (costing $0.48 per generic 100-mg tablet or $0.92 per 300-mg tablet), and febuxostat ($5.38 per 40-mg or 80-mg tablet). For patients with contraindications or intolerances to allopurinol or febuxostat, probenecid ($1.15 per 500-mg tablet), which functions as a uricosuric agent (ie, increases urinary excretion of uric acid), may be used.

Losartan ($1.68 per 25-mg tablet) and fenofibrate ($1.91 per 48-mg tablet) are also often used to reduce uric acid levels, but they have only modest effects and are not approved for this indication in the United States.⁴⁹

MANAGE CHRONIC CASES WITH CONTINUED THERAPY

ACR guidelines strongly emphasize continuing prophylaxis in case of ongoing gout activity (ie, detection of tophi on examination, recent gout attacks, or chronic gouty arthritis) (Table 3). The following durations have been proposed for prophylaxis:

• 6 months after an attack
• 6 months after achieving target uric acid level in patients with evidence of tophi
• 3 months after achieving target uric acid level in patients with resolved tophi. 

Two randomized controlled trials support the use of the anti-inflammatory agent colchicine ($4.30 per tablet) for prophylaxis when initiating urate-lowering therapy.^50,51

Monitor uric acid levels, renal function, adverse effects

The initial dosage of urate-lowering agents depends on the presence of kidney disease (Table 3).

Allopurinol is typically started at 50 mg to 100 mg oral daily, and titrated upward in increments of 100 mg depending on uric acid levels. According to the ACR guidelines, uric acid levels should be measured every 2 to 5 weeks.⁴⁶ The Febuxostat vs Allopurinol Streamline Trial found that 97% of patients reached target uric acid levels within two titrations.⁵²

Especially during the first months of therapy, physicians should be vigilant for adverse effects of allopurinol, including hypersensitivity reaction (rash, fever, Stevens-Johnson syndrome), hepatotoxicity, and myelotoxicity (bone marrow suppression), and for effects of febuxostat, such as rash, diarrhea, elevations in aminotransferase levels, and upper respiratory tract infections.⁵³ Although the maximum acceptable dose of allopurinol is 800 mg even in chronic kidney disease, regularly monitoring for hypersensitivity reactions and other adverse effects is needed if doses are above 300 mg per day.⁴⁶

Routine follow-up is essential

Adherence to therapy should be assessed at every visit. Patients should be counseled that gout is a chronic disease and that they should continue on urate-lowering therapy even if they are not having acute attacks. Adverse effects of medications should be monitored and addressed, although for allopurinol and febuxostat these are rare beyond the first few months of initiation and titration. If worsening of gout or uric acid levels occurs, therapy should be augmented and contributors to hyperuricemia reviewed. In refractory cases, rheumatology consultation may be needed; medications such as pegloticase ($16,800/mL) may be deemed necessary for severe tophaceous gout or for patients who need more rapid reduction of urates.⁴⁹

STRATEGIES TO ADDRESS DISPARITIES

Creative approaches are needed to engage African American communities to reduce the burden of gout. No trials have been published evaluating methods for reducing health disparities with gout, but strategies for other chronic conditions may be applicable.

Incorporate guidelines better. Although setting and disseminating guidelines should ensure that care is standardized, studies have found that primary care physicians and rheumatologists frequently do not implement them.^3,54 Reasons cited for poor adherence to gout guidelines include their relatively recent release, poor patient adherence, lack of measurement tools, and inadequate education of primary care physicians. Incorporating the guidelines as “best practice advisories” into electronic medical record systems has been proposed to improve their implementation.⁴⁶

Use a team approach. Some quality improvement projects have used pharmacists and nurses to help implement gout guidelines. In two studies, empowering nurses and pharmacists to better educate patients and implement standardized protocols for titrating urate-lowering medications led to sustained improvements in maintaining serum uric acid levels less than 6 mg/dL.^55–57

Multidisciplinary involvement by nutritionists, physicians, and community health workers have been found to help improve glycemic control in African Americans.⁵⁸ Similar efforts can be undertaken to improve control of uric acid levels through dietary modification and improved compliance.

Address patient concerns. Substantial gaps exist in knowledge about gout between providers and the general population, although large studies specifically focusing on African Americans are lacking.⁵⁹ Qualitative studies suggest that patient experience of gout may vary depending on race, with African Americans more likely than whites to rank the following concerns regarding gout as high: dietary restrictions, emotional burden, severe pain, the need for canes or crutches during flares, and gout bringing their day to a halt.⁶⁰ Another study among African Americans with gout found concerns about the effectiveness of urate-lowering therapy, side effects of medications, polypharmacy, pill size, cost, refill issues, and forgetting to take medications regularly.⁶¹

Despite the historic association of gout with royalty and “rich eating,” gout disproportionately affects those of lower socioeconomic status.¹ Risk factors for gout, including obesity, chronic kidney disease, diabetes, and hypertension, are more common in African Americans, resulting in a higher prevalence of the disease. In addition, African Americans are less likely to receive the aggressive treatment for gout advocated by professional societies, such as anti-inflammatory medications during flares and prophylactic urate-lowering therapy.

This article reviews the epidemiology of gout and its pathophysiology, risk factors, and optimal management, focusing on African Americans and strategies to reduce healthcare disparities in this patient population.

GOUT IS COMMON AND SERIOUS

Gout is the most common inflammatory arthritis in the United States today, affecting 4% of the adult US population.² It is a chronic disease associated with high levels of uric acid, usually manifesting as intermittent attacks of painful monoarthritis, although multiple joints may be involved.

Despite a popular misconception that gout is merely an episodic nuisance, it is a serious disease that can significantly affect physical function and quality of life.³ A 2013 systematic review found that quality of life was significantly reduced in patients with gout, particularly those with polyarticular gout, tophi, comorbidities, and radiographic damage.⁴

Economic costs include decreased worker productivity and increased absences from work.^5,6 From 2001 to 2005, an estimated 2 million visits were made to primary care providers due to gout.⁷ Because gout frequently coexists with diabetes, hypertension, coronary artery disease, and kidney disease, it is often overlooked during routine clinic visits.³

HIGH URIC ACID HAS MANY EFFECTS

Uric acid, a product of purine metabolism, is the key mediator of gouty arthritis. Accumulation of uric acid in joints and other tissues leads to an exuberant inflammatory response manifesting as a gouty attack. When uncontrolled, uric acid may crystallize in joints and other structures, leading to tophi formation, which can cause chronic deforming and erosive arthritis, known as chronic tophaceous gout.⁸

Although gout is considered to be a musculoskeletal disorder, recent evidence indicates that hyperuricemia plays an important role in the development of renal disease and contributes to cardiovascular morbidity and death.⁹ Several studies have found that reducing uric acid levels lowers cardiovascular mortality rates and retards the progression of chronic kidney disease.¹⁰

MEN AND CERTAIN RACIAL GROUPS MOST AFFECTED

Large-scale epidemiologic surveys have established that prevalence varies widely among population groups. Premenopausal women are less likely to be affected than men, presumably due to the effect of female hormones on renal tubular excretion of uric acid.¹¹

Certain Asian populations (Filipinos, Taiwanese, Micronesians, the Maoris of New Zealand, Hmong Chinese immigrants in Minnesota) and African Americans have a high prevalence, while people from several sub-Saharan African countries have a very low prevalence. These differences are likely due to a variety of reasons, including genetic predisposition; diet (Table 1); risk factors such as obesity, diabetes, and hypertension; less access to healthcare resources; and inappropriate treatment.^12,13

AFRICAN AMERICANS ARE A DIVERSE GROUP

“African Americans” are a highly heterogeneous group making up about 13% of the US population. Most scholars now consider racial identity largely a product of socioeconomic and political circumstances rather than a scientific concept.¹⁴ The US Census Bureau defines African Americans (or “blacks”) as those having origins in the black racial groups of Africa,¹⁵  but even this is problematic, since it combines people as diverse as descendants of 17th, 18th, and 19th century enslaved Africans with recent first-generation African immigrants, as well as with Caribbean- and Latino-Americans of African heritage.

In addition, many African Americans trace their ancestry to other racial and ethnic groups, especially European and Native American. A study of nine European DNA markers among 10 African American populations in the United States and one population of Jamaicans of African descent found a range of frequencies from 7% among Jamaicans to 23% among African Americans living in New Orleans.¹⁶

Although such diversity argues against generalizing healthcare needs for the entire African American community, some evidence indicates that genetic markers for gene-disease associations may be consistent across traditional racial boundaries.¹⁷

GENETIC FACTORS CANNOT EXPLAIN GOUT DISPARITIES

Several small studies have found evidence of genetic factors mediating the risk for hyperuricemia and gout. Twin studies indicate that hyperuricemia is highly heritable,¹⁸ although they do not show a concordance in the heritability of gout, suggesting that environmental factors also have an important role in developing clinical manifestations of the disease.¹²

Genome-wide association studies have identified 28 separate loci influencing uric acid levels, including genes for uric acid transporters (eg, SLC2A9 and ABCG2), and metabolic pathway regulators (eg, PDZK1, SCL22A12, and PRPSAP1), but the distribution among African Americans is largely unknown.¹⁹ One important exception is SLC2A9, a renal tubular transporter of uric acid: variants of SLC2A9 were found exclusively in African Americans, but the clinical significance of this association is unclear.²⁰

Several epidemiologic studies have looked at gout in African Americans.

In the Coronary Artery Risk Development in Young Adults study,²¹ young African Americans had lower levels of uric acid than whites after adjusting for body mass index (BMI), glomerular filtration rate (GFR), diet, and medications. But after up to 20 years of follow-up, the risk of hyperuricemia was 2.3 times higher in African American women than in white women (95% confidence interval [CI] 1.34–3.99). Such differences were not found between African American and white men.

The National Health and Nutritional Examination Survey (NHANES) found that African American adolescents had lower uric acid levels than white adolescents after taking into account sugar intake, GFR, BMI, and onset of puberty.²²

The Multiple Risk Factor Intervention Trial²³ also found that among those with high cardiovascular risk, the incidence of hyperuricemia and gout was lower in African Americans than in whites.

COMORBID DISEASES MAY EXPLAIN DISPARITIES

Despite some evidence that African Americans have genetic factors that are protective against gout, they have a much greater frequency of acquired risk factors for gout, including obesity, physical inactivity, hypertension, diabetes mellitus, renal failure, high intake of seafood, elevated blood lead levels, and use of antihypertensive medications (Table 2).

Hochberg et al²⁴ examined the incidence of gout in 352 African American and 571 white physicians and found higher rates in African Americans (9% vs 5%). The authors suggested different rates of hypertension as an explanation, although the use of antihypertensive medications such as diuretics that promote hyperuricemia confounds the strength of this conclusion.

AFRICAN AMERICANS NEED STANDARD TREATMENT . . .

Unlike for heart failure, in which subgroup analyses of large prospective studies have found different efficacies of medications in African Americans than in whites, no such data exist for gout. Although there is a higher risk of allopurinol hypersensitivity in ethnic groups that express the HLA-B*5801 polymorphism (eg, Han Chinese, Korean, Thai, Japanese, Portuguese), African Americans are not known to be at greater risk.²⁵ There are also no special precautions for using febuxostat or probenecid in African Americans.

Absent any compelling reason, gout management should be the same regardless of ethnicity.²⁶ Patients should be counseled on primary prevention measures such as dietary and behavioral modification and, if necessary, started on aggressive urate-lowering therapy.²⁷

. . . BUT ARE LESS LIKELY TO HAVE GOUT APPROPRIATELY TREATED

African Americans with gout are less likely to receive urate-lowering therapy.²⁸ According to the 2002 National Ambulatory Medical Care Survey in the United States, African Americans with gout are far less likely to receive allopurinol than whites (42% vs 80%; odds ratio [OR] 0.18; 95% CI 0.04–0.78).²³ Even when therapy is prescribed, rates of nonadherence are greater in African Americans than in whites (OR 1.86, 95% CI 1.52–2.27), though the authors do not speculate why this is so.²⁹ No studies have compared rates of prescribing febuxostat to African Americans vs whites.

African Americans are also less likely to receive ongoing routine care for their gout. A 2007 study³⁰ of 663 veterans found that physicians were 1.41 times less likely to adhere to three selected quality indicators when dealing with nonwhite than white patients (95% CI 0.52–3.84). The three quality indicators studied were:

• Lowering of daily allopurinol dose to below 300 mg/day in the presence of renal insufficiency (no longer considered a quality measure)
• Monitoring of serum urate level at least once during the first 6 months of continued use of a xanthine oxidase inhibitor, such as allopurinol
• Monitoring of complete blood cell count and creatinine kinase at least every 6 months in patients with renal impairment receiving long-term prophylactic oral colchicine (> 0.5 mg/day for at least 6 months).

The finding was independent of age, comorbidity index, healthcare access, and utilization characteristics (eg, number of inpatient and outpatient visits, type of physician, most frequently seen physician).

LIFESTYLE MODIFICATION

Dietary modification is a useful initial step toward reducing uric acid levels (Table 1).²⁷ The following measures are recommended:

Reduce alcohol intake. Alcoholic beverages, particularly beer, are strongly linked to hyperuricemia, according to a 2013 meta-analysis.³¹ Although alcohol consumption is lower in African Americans than in whites, mortality rates from cirrhosis and other alcohol-related diseases are 10% higher, suggesting metabolic differences that render African Americans more susceptible to the negative health effects of alcohol.³²

Avoid sugary drinks. Sweetened beverages, especially those rich in fructose, are also implicated in hyperuricemia and gout. NHANES found an increase in serum uric acid of 0.33 mg/dL (95% CI, 0.11–0.73) in those consuming one to three sugar-sweetened drinks per day compared with nonconsumers, adjusting for total energy intake, age, sex, medications, hypertension, and GFR.³³ A prospective study also found a relative risk of 1.85 for those who drink two or more sugar-sweetened beverages per day compared with those who drink fewer than one per month (95% CI 1.08–3.16).³⁴

Unfortunately, African Americans consume a disproportionate amount of sugar from all sources: 17% of African Americans are considered heavy consumers vs 9% of whites.³⁵

Limit foods rich in purines. Red meat, seafood, and some vegetables, including asparagus, spinach, peas, cauliflower, and mushrooms, are associated with increased serum uric acid levels. NHANES found that greater meat and seafood consumption was associated with increased uric acid levels. Choi et al³⁶ found that the risk of gout increased by 21% with each additional daily serving of meat; the relative risk of developing gout was 1.41 (95% CI 1.07–1.86) in the fifth quintile of meat intake compared with the first quintile, and 1.51 (95% CI 1.17–1.95) in the fifth quintile of seafood consumption.

Despite these associations with high-purine food consumption and gout, many purine-rich foods may not contribute to hyperuricemia, and therefore a low-purine diet may not be protective. Interestingly, purine-rich vegetable protein intake is not associated with increased gout risk.³⁷

Increase dairy consumption. Dairy in the diet is associated with a lower incidence of gout, with a decrease of 0.21 mg/dL (95% CI –0.37 to –0.04) in serum uric acid levels between the highest and lowest quintiles of dairy consumption.³⁸ A randomized controlled trial found a 10% reduction in serum uric acid levels with milk consumption.³⁹

Enjoy coffee. Coffee intake has been inversely correlated with gout. Daily intake of 4 to 5 cups of coffee is associated with a relative risk of 0.60 (95% CI 0.41–0.87) vs no coffee.⁴⁰

Vitamin C and cherry juice^41,42 have also been linked to lower gout risk, but the data are less robust.

Control weight. Primary care providers should advise patients to increase physical activity and maintain a healthy weight.

In a prospective study, Choi et al⁴³ found that, in men, the risk of gout increased with the BMI. Compared with men with BMIs in the range of 21 to 22.9 kg/m², the relative risks were:

• 1.95 (95% CI 1.44–2.65) at BMI 25 to 29.9 kg/m²
• 2.33 (95% CI 1.62–3.36) at BMI 30 to 34.9 kg/m²
• 2.97 (95% CI 1.73–5.10) at BMI > 35 kg/m².

In addition, those who gained more than 13.6 kg since age 21 had a relative risk of 1.99 (95% CI 1.49–2.66) of developing gout compared with those whose weight remained within 1.8 kg.  

For those who cannot achieve weight loss through conservative measures, bariatric surgery has shown promise. In a prospective study of 60 obese patients (BMI > 35 kg/m²) with gout and type 2 diabetes mellitus, uric acid steadily declined during the first year after bariatric surgery.⁴⁴

TREATMENT OF ACUTE ATTACKS

Gout can be effectively managed in most patients. Behavioral and pharmacologic interventions are cheap and effective and have been shown to halt further damage to joints as well as retard the progression of renal disease and reduce cardiovascular morbidity.

During acute attacks, anti-inflammatory medications, principally glucocorticoids, nonsteroidal anti-inflammatory drugs, and colchicine, should be given promptly to reduce the intensity and duration of flares.

Although traditional teaching has been that urate-lowering therapy should not be initiated during an acute gout attack because it could prolong the duration of the attack, guidelines now permit it, based on studies showing that therapy does not prolong attacks.^45,46

AGGRESSIVE URATE-LOWERING THERAPY FOR PROPHYLAXIS

Long-term treatment of gout is aimed at reducing uric acid levels by mitigating modifiable risk factors and through urate-lowering therapy.⁴⁶ For many patients, conservative management with dietary and other behavioral changes is not sufficient to prevent further attacks of gout, necessitating urate-lowering therapy. Comorbid diseases such as obesity, hypertension, chronic kidney disease, and diabetes should also be addressed because they promote hyperuricemia and gouty attacks.⁴⁷

A number of organizations have issued gout management guidelines over the past decade, including the American College of Rheumatology (ACR) in 2012, the European League Against Rheumatism (2006, updated in 2014), and the British Society of Rheumatology (2007). All recommend urate-lowering therapy to prevent gout flares.

The American and European guidelines recommend a target uric acid level below 6 mg/dL, and the British guidelines recommend a target below 5 mg/dL.⁴⁸ For patients with palpable and visible tophi, the ACR guidelines state that lowering to below 5 mg/dL may be needed.⁴⁶

First-line agents for urate-lowering therapy are xanthine oxidase inhibitors, which include allopurinol (costing $0.48 per generic 100-mg tablet or $0.92 per 300-mg tablet), and febuxostat ($5.38 per 40-mg or 80-mg tablet). For patients with contraindications or intolerances to allopurinol or febuxostat, probenecid ($1.15 per 500-mg tablet), which functions as a uricosuric agent (ie, increases urinary excretion of uric acid), may be used.

Losartan ($1.68 per 25-mg tablet) and fenofibrate ($1.91 per 48-mg tablet) are also often used to reduce uric acid levels, but they have only modest effects and are not approved for this indication in the United States.⁴⁹

MANAGE CHRONIC CASES WITH CONTINUED THERAPY

ACR guidelines strongly emphasize continuing prophylaxis in case of ongoing gout activity (ie, detection of tophi on examination, recent gout attacks, or chronic gouty arthritis) (Table 3). The following durations have been proposed for prophylaxis:

• 6 months after an attack
• 6 months after achieving target uric acid level in patients with evidence of tophi
• 3 months after achieving target uric acid level in patients with resolved tophi. 

Two randomized controlled trials support the use of the anti-inflammatory agent colchicine ($4.30 per tablet) for prophylaxis when initiating urate-lowering therapy.^50,51

Monitor uric acid levels, renal function, adverse effects

The initial dosage of urate-lowering agents depends on the presence of kidney disease (Table 3).

Allopurinol is typically started at 50 mg to 100 mg oral daily, and titrated upward in increments of 100 mg depending on uric acid levels. According to the ACR guidelines, uric acid levels should be measured every 2 to 5 weeks.⁴⁶ The Febuxostat vs Allopurinol Streamline Trial found that 97% of patients reached target uric acid levels within two titrations.⁵²

Especially during the first months of therapy, physicians should be vigilant for adverse effects of allopurinol, including hypersensitivity reaction (rash, fever, Stevens-Johnson syndrome), hepatotoxicity, and myelotoxicity (bone marrow suppression), and for effects of febuxostat, such as rash, diarrhea, elevations in aminotransferase levels, and upper respiratory tract infections.⁵³ Although the maximum acceptable dose of allopurinol is 800 mg even in chronic kidney disease, regularly monitoring for hypersensitivity reactions and other adverse effects is needed if doses are above 300 mg per day.⁴⁶

Routine follow-up is essential

Adherence to therapy should be assessed at every visit. Patients should be counseled that gout is a chronic disease and that they should continue on urate-lowering therapy even if they are not having acute attacks. Adverse effects of medications should be monitored and addressed, although for allopurinol and febuxostat these are rare beyond the first few months of initiation and titration. If worsening of gout or uric acid levels occurs, therapy should be augmented and contributors to hyperuricemia reviewed. In refractory cases, rheumatology consultation may be needed; medications such as pegloticase ($16,800/mL) may be deemed necessary for severe tophaceous gout or for patients who need more rapid reduction of urates.⁴⁹

STRATEGIES TO ADDRESS DISPARITIES

Creative approaches are needed to engage African American communities to reduce the burden of gout. No trials have been published evaluating methods for reducing health disparities with gout, but strategies for other chronic conditions may be applicable.

Incorporate guidelines better. Although setting and disseminating guidelines should ensure that care is standardized, studies have found that primary care physicians and rheumatologists frequently do not implement them.^3,54 Reasons cited for poor adherence to gout guidelines include their relatively recent release, poor patient adherence, lack of measurement tools, and inadequate education of primary care physicians. Incorporating the guidelines as “best practice advisories” into electronic medical record systems has been proposed to improve their implementation.⁴⁶

Use a team approach. Some quality improvement projects have used pharmacists and nurses to help implement gout guidelines. In two studies, empowering nurses and pharmacists to better educate patients and implement standardized protocols for titrating urate-lowering medications led to sustained improvements in maintaining serum uric acid levels less than 6 mg/dL.^55–57

Multidisciplinary involvement by nutritionists, physicians, and community health workers have been found to help improve glycemic control in African Americans.⁵⁸ Similar efforts can be undertaken to improve control of uric acid levels through dietary modification and improved compliance.

Address patient concerns. Substantial gaps exist in knowledge about gout between providers and the general population, although large studies specifically focusing on African Americans are lacking.⁵⁹ Qualitative studies suggest that patient experience of gout may vary depending on race, with African Americans more likely than whites to rank the following concerns regarding gout as high: dietary restrictions, emotional burden, severe pain, the need for canes or crutches during flares, and gout bringing their day to a halt.⁶⁰ Another study among African Americans with gout found concerns about the effectiveness of urate-lowering therapy, side effects of medications, polypharmacy, pill size, cost, refill issues, and forgetting to take medications regularly.⁶¹

Despite the historic association of gout with royalty and “rich eating,” gout disproportionately affects those of lower socioeconomic status.¹ Risk factors for gout, including obesity, chronic kidney disease, diabetes, and hypertension, are more common in African Americans, resulting in a higher prevalence of the disease. In addition, African Americans are less likely to receive the aggressive treatment for gout advocated by professional societies, such as anti-inflammatory medications during flares and prophylactic urate-lowering therapy.

This article reviews the epidemiology of gout and its pathophysiology, risk factors, and optimal management, focusing on African Americans and strategies to reduce healthcare disparities in this patient population.

GOUT IS COMMON AND SERIOUS

Gout is the most common inflammatory arthritis in the United States today, affecting 4% of the adult US population.² It is a chronic disease associated with high levels of uric acid, usually manifesting as intermittent attacks of painful monoarthritis, although multiple joints may be involved.

Despite a popular misconception that gout is merely an episodic nuisance, it is a serious disease that can significantly affect physical function and quality of life.³ A 2013 systematic review found that quality of life was significantly reduced in patients with gout, particularly those with polyarticular gout, tophi, comorbidities, and radiographic damage.⁴

Economic costs include decreased worker productivity and increased absences from work.^5,6 From 2001 to 2005, an estimated 2 million visits were made to primary care providers due to gout.⁷ Because gout frequently coexists with diabetes, hypertension, coronary artery disease, and kidney disease, it is often overlooked during routine clinic visits.³

HIGH URIC ACID HAS MANY EFFECTS

Uric acid, a product of purine metabolism, is the key mediator of gouty arthritis. Accumulation of uric acid in joints and other tissues leads to an exuberant inflammatory response manifesting as a gouty attack. When uncontrolled, uric acid may crystallize in joints and other structures, leading to tophi formation, which can cause chronic deforming and erosive arthritis, known as chronic tophaceous gout.⁸

Although gout is considered to be a musculoskeletal disorder, recent evidence indicates that hyperuricemia plays an important role in the development of renal disease and contributes to cardiovascular morbidity and death.⁹ Several studies have found that reducing uric acid levels lowers cardiovascular mortality rates and retards the progression of chronic kidney disease.¹⁰

MEN AND CERTAIN RACIAL GROUPS MOST AFFECTED

Large-scale epidemiologic surveys have established that prevalence varies widely among population groups. Premenopausal women are less likely to be affected than men, presumably due to the effect of female hormones on renal tubular excretion of uric acid.¹¹

Certain Asian populations (Filipinos, Taiwanese, Micronesians, the Maoris of New Zealand, Hmong Chinese immigrants in Minnesota) and African Americans have a high prevalence, while people from several sub-Saharan African countries have a very low prevalence. These differences are likely due to a variety of reasons, including genetic predisposition; diet (Table 1); risk factors such as obesity, diabetes, and hypertension; less access to healthcare resources; and inappropriate treatment.^12,13

AFRICAN AMERICANS ARE A DIVERSE GROUP

“African Americans” are a highly heterogeneous group making up about 13% of the US population. Most scholars now consider racial identity largely a product of socioeconomic and political circumstances rather than a scientific concept.¹⁴ The US Census Bureau defines African Americans (or “blacks”) as those having origins in the black racial groups of Africa,¹⁵  but even this is problematic, since it combines people as diverse as descendants of 17th, 18th, and 19th century enslaved Africans with recent first-generation African immigrants, as well as with Caribbean- and Latino-Americans of African heritage.

In addition, many African Americans trace their ancestry to other racial and ethnic groups, especially European and Native American. A study of nine European DNA markers among 10 African American populations in the United States and one population of Jamaicans of African descent found a range of frequencies from 7% among Jamaicans to 23% among African Americans living in New Orleans.¹⁶

Although such diversity argues against generalizing healthcare needs for the entire African American community, some evidence indicates that genetic markers for gene-disease associations may be consistent across traditional racial boundaries.¹⁷

GENETIC FACTORS CANNOT EXPLAIN GOUT DISPARITIES

Several small studies have found evidence of genetic factors mediating the risk for hyperuricemia and gout. Twin studies indicate that hyperuricemia is highly heritable,¹⁸ although they do not show a concordance in the heritability of gout, suggesting that environmental factors also have an important role in developing clinical manifestations of the disease.¹²

Genome-wide association studies have identified 28 separate loci influencing uric acid levels, including genes for uric acid transporters (eg, SLC2A9 and ABCG2), and metabolic pathway regulators (eg, PDZK1, SCL22A12, and PRPSAP1), but the distribution among African Americans is largely unknown.¹⁹ One important exception is SLC2A9, a renal tubular transporter of uric acid: variants of SLC2A9 were found exclusively in African Americans, but the clinical significance of this association is unclear.²⁰

Several epidemiologic studies have looked at gout in African Americans.

In the Coronary Artery Risk Development in Young Adults study,²¹ young African Americans had lower levels of uric acid than whites after adjusting for body mass index (BMI), glomerular filtration rate (GFR), diet, and medications. But after up to 20 years of follow-up, the risk of hyperuricemia was 2.3 times higher in African American women than in white women (95% confidence interval [CI] 1.34–3.99). Such differences were not found between African American and white men.

The National Health and Nutritional Examination Survey (NHANES) found that African American adolescents had lower uric acid levels than white adolescents after taking into account sugar intake, GFR, BMI, and onset of puberty.²²

The Multiple Risk Factor Intervention Trial²³ also found that among those with high cardiovascular risk, the incidence of hyperuricemia and gout was lower in African Americans than in whites.

COMORBID DISEASES MAY EXPLAIN DISPARITIES

Despite some evidence that African Americans have genetic factors that are protective against gout, they have a much greater frequency of acquired risk factors for gout, including obesity, physical inactivity, hypertension, diabetes mellitus, renal failure, high intake of seafood, elevated blood lead levels, and use of antihypertensive medications (Table 2).

Hochberg et al²⁴ examined the incidence of gout in 352 African American and 571 white physicians and found higher rates in African Americans (9% vs 5%). The authors suggested different rates of hypertension as an explanation, although the use of antihypertensive medications such as diuretics that promote hyperuricemia confounds the strength of this conclusion.

AFRICAN AMERICANS NEED STANDARD TREATMENT . . .

Unlike for heart failure, in which subgroup analyses of large prospective studies have found different efficacies of medications in African Americans than in whites, no such data exist for gout. Although there is a higher risk of allopurinol hypersensitivity in ethnic groups that express the HLA-B*5801 polymorphism (eg, Han Chinese, Korean, Thai, Japanese, Portuguese), African Americans are not known to be at greater risk.²⁵ There are also no special precautions for using febuxostat or probenecid in African Americans.

Absent any compelling reason, gout management should be the same regardless of ethnicity.²⁶ Patients should be counseled on primary prevention measures such as dietary and behavioral modification and, if necessary, started on aggressive urate-lowering therapy.²⁷

. . . BUT ARE LESS LIKELY TO HAVE GOUT APPROPRIATELY TREATED

African Americans with gout are less likely to receive urate-lowering therapy.²⁸ According to the 2002 National Ambulatory Medical Care Survey in the United States, African Americans with gout are far less likely to receive allopurinol than whites (42% vs 80%; odds ratio [OR] 0.18; 95% CI 0.04–0.78).²³ Even when therapy is prescribed, rates of nonadherence are greater in African Americans than in whites (OR 1.86, 95% CI 1.52–2.27), though the authors do not speculate why this is so.²⁹ No studies have compared rates of prescribing febuxostat to African Americans vs whites.

African Americans are also less likely to receive ongoing routine care for their gout. A 2007 study³⁰ of 663 veterans found that physicians were 1.41 times less likely to adhere to three selected quality indicators when dealing with nonwhite than white patients (95% CI 0.52–3.84). The three quality indicators studied were:

• Lowering of daily allopurinol dose to below 300 mg/day in the presence of renal insufficiency (no longer considered a quality measure)
• Monitoring of serum urate level at least once during the first 6 months of continued use of a xanthine oxidase inhibitor, such as allopurinol
• Monitoring of complete blood cell count and creatinine kinase at least every 6 months in patients with renal impairment receiving long-term prophylactic oral colchicine (> 0.5 mg/day for at least 6 months).

The finding was independent of age, comorbidity index, healthcare access, and utilization characteristics (eg, number of inpatient and outpatient visits, type of physician, most frequently seen physician).

LIFESTYLE MODIFICATION

Dietary modification is a useful initial step toward reducing uric acid levels (Table 1).²⁷ The following measures are recommended:

Reduce alcohol intake. Alcoholic beverages, particularly beer, are strongly linked to hyperuricemia, according to a 2013 meta-analysis.³¹ Although alcohol consumption is lower in African Americans than in whites, mortality rates from cirrhosis and other alcohol-related diseases are 10% higher, suggesting metabolic differences that render African Americans more susceptible to the negative health effects of alcohol.³²

Avoid sugary drinks. Sweetened beverages, especially those rich in fructose, are also implicated in hyperuricemia and gout. NHANES found an increase in serum uric acid of 0.33 mg/dL (95% CI, 0.11–0.73) in those consuming one to three sugar-sweetened drinks per day compared with nonconsumers, adjusting for total energy intake, age, sex, medications, hypertension, and GFR.³³ A prospective study also found a relative risk of 1.85 for those who drink two or more sugar-sweetened beverages per day compared with those who drink fewer than one per month (95% CI 1.08–3.16).³⁴

Unfortunately, African Americans consume a disproportionate amount of sugar from all sources: 17% of African Americans are considered heavy consumers vs 9% of whites.³⁵

Limit foods rich in purines. Red meat, seafood, and some vegetables, including asparagus, spinach, peas, cauliflower, and mushrooms, are associated with increased serum uric acid levels. NHANES found that greater meat and seafood consumption was associated with increased uric acid levels. Choi et al³⁶ found that the risk of gout increased by 21% with each additional daily serving of meat; the relative risk of developing gout was 1.41 (95% CI 1.07–1.86) in the fifth quintile of meat intake compared with the first quintile, and 1.51 (95% CI 1.17–1.95) in the fifth quintile of seafood consumption.

Despite these associations with high-purine food consumption and gout, many purine-rich foods may not contribute to hyperuricemia, and therefore a low-purine diet may not be protective. Interestingly, purine-rich vegetable protein intake is not associated with increased gout risk.³⁷

Increase dairy consumption. Dairy in the diet is associated with a lower incidence of gout, with a decrease of 0.21 mg/dL (95% CI –0.37 to –0.04) in serum uric acid levels between the highest and lowest quintiles of dairy consumption.³⁸ A randomized controlled trial found a 10% reduction in serum uric acid levels with milk consumption.³⁹

Enjoy coffee. Coffee intake has been inversely correlated with gout. Daily intake of 4 to 5 cups of coffee is associated with a relative risk of 0.60 (95% CI 0.41–0.87) vs no coffee.⁴⁰

Vitamin C and cherry juice^41,42 have also been linked to lower gout risk, but the data are less robust.

Control weight. Primary care providers should advise patients to increase physical activity and maintain a healthy weight.

In a prospective study, Choi et al⁴³ found that, in men, the risk of gout increased with the BMI. Compared with men with BMIs in the range of 21 to 22.9 kg/m², the relative risks were:

• 1.95 (95% CI 1.44–2.65) at BMI 25 to 29.9 kg/m²
• 2.33 (95% CI 1.62–3.36) at BMI 30 to 34.9 kg/m²
• 2.97 (95% CI 1.73–5.10) at BMI > 35 kg/m².

In addition, those who gained more than 13.6 kg since age 21 had a relative risk of 1.99 (95% CI 1.49–2.66) of developing gout compared with those whose weight remained within 1.8 kg.  

For those who cannot achieve weight loss through conservative measures, bariatric surgery has shown promise. In a prospective study of 60 obese patients (BMI > 35 kg/m²) with gout and type 2 diabetes mellitus, uric acid steadily declined during the first year after bariatric surgery.⁴⁴

TREATMENT OF ACUTE ATTACKS

Gout can be effectively managed in most patients. Behavioral and pharmacologic interventions are cheap and effective and have been shown to halt further damage to joints as well as retard the progression of renal disease and reduce cardiovascular morbidity.

During acute attacks, anti-inflammatory medications, principally glucocorticoids, nonsteroidal anti-inflammatory drugs, and colchicine, should be given promptly to reduce the intensity and duration of flares.

Although traditional teaching has been that urate-lowering therapy should not be initiated during an acute gout attack because it could prolong the duration of the attack, guidelines now permit it, based on studies showing that therapy does not prolong attacks.^45,46

AGGRESSIVE URATE-LOWERING THERAPY FOR PROPHYLAXIS

Long-term treatment of gout is aimed at reducing uric acid levels by mitigating modifiable risk factors and through urate-lowering therapy.⁴⁶ For many patients, conservative management with dietary and other behavioral changes is not sufficient to prevent further attacks of gout, necessitating urate-lowering therapy. Comorbid diseases such as obesity, hypertension, chronic kidney disease, and diabetes should also be addressed because they promote hyperuricemia and gouty attacks.⁴⁷

A number of organizations have issued gout management guidelines over the past decade, including the American College of Rheumatology (ACR) in 2012, the European League Against Rheumatism (2006, updated in 2014), and the British Society of Rheumatology (2007). All recommend urate-lowering therapy to prevent gout flares.

The American and European guidelines recommend a target uric acid level below 6 mg/dL, and the British guidelines recommend a target below 5 mg/dL.⁴⁸ For patients with palpable and visible tophi, the ACR guidelines state that lowering to below 5 mg/dL may be needed.⁴⁶

First-line agents for urate-lowering therapy are xanthine oxidase inhibitors, which include allopurinol (costing $0.48 per generic 100-mg tablet or $0.92 per 300-mg tablet), and febuxostat ($5.38 per 40-mg or 80-mg tablet). For patients with contraindications or intolerances to allopurinol or febuxostat, probenecid ($1.15 per 500-mg tablet), which functions as a uricosuric agent (ie, increases urinary excretion of uric acid), may be used.

Losartan ($1.68 per 25-mg tablet) and fenofibrate ($1.91 per 48-mg tablet) are also often used to reduce uric acid levels, but they have only modest effects and are not approved for this indication in the United States.⁴⁹

MANAGE CHRONIC CASES WITH CONTINUED THERAPY

ACR guidelines strongly emphasize continuing prophylaxis in case of ongoing gout activity (ie, detection of tophi on examination, recent gout attacks, or chronic gouty arthritis) (Table 3). The following durations have been proposed for prophylaxis:

• 6 months after an attack
• 6 months after achieving target uric acid level in patients with evidence of tophi
• 3 months after achieving target uric acid level in patients with resolved tophi. 

Two randomized controlled trials support the use of the anti-inflammatory agent colchicine ($4.30 per tablet) for prophylaxis when initiating urate-lowering therapy.^50,51

Monitor uric acid levels, renal function, adverse effects

The initial dosage of urate-lowering agents depends on the presence of kidney disease (Table 3).

Allopurinol is typically started at 50 mg to 100 mg oral daily, and titrated upward in increments of 100 mg depending on uric acid levels. According to the ACR guidelines, uric acid levels should be measured every 2 to 5 weeks.⁴⁶ The Febuxostat vs Allopurinol Streamline Trial found that 97% of patients reached target uric acid levels within two titrations.⁵²

Especially during the first months of therapy, physicians should be vigilant for adverse effects of allopurinol, including hypersensitivity reaction (rash, fever, Stevens-Johnson syndrome), hepatotoxicity, and myelotoxicity (bone marrow suppression), and for effects of febuxostat, such as rash, diarrhea, elevations in aminotransferase levels, and upper respiratory tract infections.⁵³ Although the maximum acceptable dose of allopurinol is 800 mg even in chronic kidney disease, regularly monitoring for hypersensitivity reactions and other adverse effects is needed if doses are above 300 mg per day.⁴⁶

Routine follow-up is essential

Adherence to therapy should be assessed at every visit. Patients should be counseled that gout is a chronic disease and that they should continue on urate-lowering therapy even if they are not having acute attacks. Adverse effects of medications should be monitored and addressed, although for allopurinol and febuxostat these are rare beyond the first few months of initiation and titration. If worsening of gout or uric acid levels occurs, therapy should be augmented and contributors to hyperuricemia reviewed. In refractory cases, rheumatology consultation may be needed; medications such as pegloticase ($16,800/mL) may be deemed necessary for severe tophaceous gout or for patients who need more rapid reduction of urates.⁴⁹

STRATEGIES TO ADDRESS DISPARITIES

Creative approaches are needed to engage African American communities to reduce the burden of gout. No trials have been published evaluating methods for reducing health disparities with gout, but strategies for other chronic conditions may be applicable.

Incorporate guidelines better. Although setting and disseminating guidelines should ensure that care is standardized, studies have found that primary care physicians and rheumatologists frequently do not implement them.^3,54 Reasons cited for poor adherence to gout guidelines include their relatively recent release, poor patient adherence, lack of measurement tools, and inadequate education of primary care physicians. Incorporating the guidelines as “best practice advisories” into electronic medical record systems has been proposed to improve their implementation.⁴⁶

Use a team approach. Some quality improvement projects have used pharmacists and nurses to help implement gout guidelines. In two studies, empowering nurses and pharmacists to better educate patients and implement standardized protocols for titrating urate-lowering medications led to sustained improvements in maintaining serum uric acid levels less than 6 mg/dL.^55–57

Multidisciplinary involvement by nutritionists, physicians, and community health workers have been found to help improve glycemic control in African Americans.⁵⁸ Similar efforts can be undertaken to improve control of uric acid levels through dietary modification and improved compliance.

Address patient concerns. Substantial gaps exist in knowledge about gout between providers and the general population, although large studies specifically focusing on African Americans are lacking.⁵⁹ Qualitative studies suggest that patient experience of gout may vary depending on race, with African Americans more likely than whites to rank the following concerns regarding gout as high: dietary restrictions, emotional burden, severe pain, the need for canes or crutches during flares, and gout bringing their day to a halt.⁶⁰ Another study among African Americans with gout found concerns about the effectiveness of urate-lowering therapy, side effects of medications, polypharmacy, pill size, cost, refill issues, and forgetting to take medications regularly.⁶¹