User login
What treatments relieve painful heel cracks?
Emollient cream may alleviate pain and dryness and improve the appearance of heel cracks (strength of recommendation [SOR]: B, one small randomized trial).
Foot soaks followed by mechanical debridement and topical petrolatum may decrease the depth of cracks and thickness of calluses in patients with leprosy (SOR: C, 1 small cohort study).
Keratolytic agents, such as salicylic acid, may reduce hyperkeratosis, cracks, and pain (SOR: C, one case-control study).
Cyanoacrylate tissue adhesives, such as Superglue or Krazy Glue, may reduce pain and speed closure of heel cracks (SOR: C, one case series). Maintenance therapy with emollients and appropriate footwear also may help heel cracks (SOR: C, expert opinion).
Evidence summary
In a randomized, double-blind study, 58 patients with heel cracks applied one of 2 emollients twice daily.1 After 4 weeks of treatment, both groups reported improved scores for pain, appearance, and dryness (using a clinical xerosis score) and also skin scaling and desquamation (using a D-Squame score). Both groups reported improvement, but investigators didn’t say in the research abstract whether it was statistically or clinically significant.
In plain or soapy water, foot soaks seem to help
To compare foot soaks in plain and soapy water, a prospective cohort study enrolled 15 leprosy patients who had callosities and heel cracks.2 Investigators graded the severity of the callosities and cracks clinically and photographically on a 0 to 4 scale (0=no cracks or calluses; 4=deep cracks and thick calluses). Each day, patients soaked one foot in plain water and the other in soapy water for 20 minutes, debrided both feet with a clay tool, and covered the soles with petrolatum.
By Day 7, both groups improved by more than one clinical grade. Soap soaks appeared to raise scores more than plain water, but the investigators reported no statistical comparisons. The study was limited by its size, lack of controls, and inability to generalize results to patients without leprosy.
Salicylic acid cream also brings improvement
One case-control study of 2 women found that 6% salicylic acid controlled-release cream improved hyperkeratosis, heel cracks, and pain after one or 2 weeks. The women treated one foot and used the other as a control.3 The investigator was blinded as to which foot was treated and used photographs to evaluate improvement over time. This study was limited by its size and short duration.
Tissue adhesive keeps it together
A case series involving 10 people with 14 heel cracks suggests that Super Glue may reduce pain and speed closure.4 Patients applied 2 to 3 drops of glue along the length of each crack and held the edges together for 60 seconds. After 5 to 7 days, 12 of the 14 cracks remained closed and pain free. Investigators then instructed patients to begin mechanical debridement.
Recommendations
Expert recommendations for treating heel cracks include the use of keratolytics, emulsifying ointments, silver nitrate, and 10% glycerol in sorbolene cream, along with treatment of any underlying conditions.5-7 The New Zealand Dermatological Society recommends proper fitting shoes and daily moisturizers to prevent skin cracks. To treat cracks, the Society recommends keratolytics, debridement, strapping or heel cups to redistribute the weight on the heel, and tissue glue.8
1. Smillie S, Landorf K, Keenan A. The effect of a 25% urea cream and sorbolene in the treatment of heel fissures: a double blind randomised controlled trial. Australas J Podiatr Med. 2004;38:56.-
2. Premkumar R, Pannikar VK, Fritschi EP. Foot soaks for callosities and fissures. Indian J Lepr. 1990;62:478-482.
3. Bikowski J. Hyperkeratosis of the heels: treatment with salicylic acid in a novel delivery system. Skinmed. 2004;3:350-351.
4. Hashimoto H. Superglue for the treatment of heel fissures. J Am Podiatr Med Assoc. 1999;89:434-435.
5. Omura EF, Rye B. Dermatologic disorders of the foot. Clin Sports Med. 1994;13:825-841.
6. Royle H. Cracked hands and feet. Aust Fam Physician. 1988;17:960-962.
7. About this time of year my skin gets very dry and my heels develop cracks. Are there ways to prevent this from happening? Mayo Clin Health Lett. 2002;20:8.-
8. Ngan V. Cracked heels. New Zealand Dermatological Society, 2006. Updated June 15, 2009. Available at: http://dermnetnz.org/scaly/cracked-heels.html. Accessed June 17, 2012.
Emollient cream may alleviate pain and dryness and improve the appearance of heel cracks (strength of recommendation [SOR]: B, one small randomized trial).
Foot soaks followed by mechanical debridement and topical petrolatum may decrease the depth of cracks and thickness of calluses in patients with leprosy (SOR: C, 1 small cohort study).
Keratolytic agents, such as salicylic acid, may reduce hyperkeratosis, cracks, and pain (SOR: C, one case-control study).
Cyanoacrylate tissue adhesives, such as Superglue or Krazy Glue, may reduce pain and speed closure of heel cracks (SOR: C, one case series). Maintenance therapy with emollients and appropriate footwear also may help heel cracks (SOR: C, expert opinion).
Evidence summary
In a randomized, double-blind study, 58 patients with heel cracks applied one of 2 emollients twice daily.1 After 4 weeks of treatment, both groups reported improved scores for pain, appearance, and dryness (using a clinical xerosis score) and also skin scaling and desquamation (using a D-Squame score). Both groups reported improvement, but investigators didn’t say in the research abstract whether it was statistically or clinically significant.
In plain or soapy water, foot soaks seem to help
To compare foot soaks in plain and soapy water, a prospective cohort study enrolled 15 leprosy patients who had callosities and heel cracks.2 Investigators graded the severity of the callosities and cracks clinically and photographically on a 0 to 4 scale (0=no cracks or calluses; 4=deep cracks and thick calluses). Each day, patients soaked one foot in plain water and the other in soapy water for 20 minutes, debrided both feet with a clay tool, and covered the soles with petrolatum.
By Day 7, both groups improved by more than one clinical grade. Soap soaks appeared to raise scores more than plain water, but the investigators reported no statistical comparisons. The study was limited by its size, lack of controls, and inability to generalize results to patients without leprosy.
Salicylic acid cream also brings improvement
One case-control study of 2 women found that 6% salicylic acid controlled-release cream improved hyperkeratosis, heel cracks, and pain after one or 2 weeks. The women treated one foot and used the other as a control.3 The investigator was blinded as to which foot was treated and used photographs to evaluate improvement over time. This study was limited by its size and short duration.
Tissue adhesive keeps it together
A case series involving 10 people with 14 heel cracks suggests that Super Glue may reduce pain and speed closure.4 Patients applied 2 to 3 drops of glue along the length of each crack and held the edges together for 60 seconds. After 5 to 7 days, 12 of the 14 cracks remained closed and pain free. Investigators then instructed patients to begin mechanical debridement.
Recommendations
Expert recommendations for treating heel cracks include the use of keratolytics, emulsifying ointments, silver nitrate, and 10% glycerol in sorbolene cream, along with treatment of any underlying conditions.5-7 The New Zealand Dermatological Society recommends proper fitting shoes and daily moisturizers to prevent skin cracks. To treat cracks, the Society recommends keratolytics, debridement, strapping or heel cups to redistribute the weight on the heel, and tissue glue.8
Emollient cream may alleviate pain and dryness and improve the appearance of heel cracks (strength of recommendation [SOR]: B, one small randomized trial).
Foot soaks followed by mechanical debridement and topical petrolatum may decrease the depth of cracks and thickness of calluses in patients with leprosy (SOR: C, 1 small cohort study).
Keratolytic agents, such as salicylic acid, may reduce hyperkeratosis, cracks, and pain (SOR: C, one case-control study).
Cyanoacrylate tissue adhesives, such as Superglue or Krazy Glue, may reduce pain and speed closure of heel cracks (SOR: C, one case series). Maintenance therapy with emollients and appropriate footwear also may help heel cracks (SOR: C, expert opinion).
Evidence summary
In a randomized, double-blind study, 58 patients with heel cracks applied one of 2 emollients twice daily.1 After 4 weeks of treatment, both groups reported improved scores for pain, appearance, and dryness (using a clinical xerosis score) and also skin scaling and desquamation (using a D-Squame score). Both groups reported improvement, but investigators didn’t say in the research abstract whether it was statistically or clinically significant.
In plain or soapy water, foot soaks seem to help
To compare foot soaks in plain and soapy water, a prospective cohort study enrolled 15 leprosy patients who had callosities and heel cracks.2 Investigators graded the severity of the callosities and cracks clinically and photographically on a 0 to 4 scale (0=no cracks or calluses; 4=deep cracks and thick calluses). Each day, patients soaked one foot in plain water and the other in soapy water for 20 minutes, debrided both feet with a clay tool, and covered the soles with petrolatum.
By Day 7, both groups improved by more than one clinical grade. Soap soaks appeared to raise scores more than plain water, but the investigators reported no statistical comparisons. The study was limited by its size, lack of controls, and inability to generalize results to patients without leprosy.
Salicylic acid cream also brings improvement
One case-control study of 2 women found that 6% salicylic acid controlled-release cream improved hyperkeratosis, heel cracks, and pain after one or 2 weeks. The women treated one foot and used the other as a control.3 The investigator was blinded as to which foot was treated and used photographs to evaluate improvement over time. This study was limited by its size and short duration.
Tissue adhesive keeps it together
A case series involving 10 people with 14 heel cracks suggests that Super Glue may reduce pain and speed closure.4 Patients applied 2 to 3 drops of glue along the length of each crack and held the edges together for 60 seconds. After 5 to 7 days, 12 of the 14 cracks remained closed and pain free. Investigators then instructed patients to begin mechanical debridement.
Recommendations
Expert recommendations for treating heel cracks include the use of keratolytics, emulsifying ointments, silver nitrate, and 10% glycerol in sorbolene cream, along with treatment of any underlying conditions.5-7 The New Zealand Dermatological Society recommends proper fitting shoes and daily moisturizers to prevent skin cracks. To treat cracks, the Society recommends keratolytics, debridement, strapping or heel cups to redistribute the weight on the heel, and tissue glue.8
1. Smillie S, Landorf K, Keenan A. The effect of a 25% urea cream and sorbolene in the treatment of heel fissures: a double blind randomised controlled trial. Australas J Podiatr Med. 2004;38:56.-
2. Premkumar R, Pannikar VK, Fritschi EP. Foot soaks for callosities and fissures. Indian J Lepr. 1990;62:478-482.
3. Bikowski J. Hyperkeratosis of the heels: treatment with salicylic acid in a novel delivery system. Skinmed. 2004;3:350-351.
4. Hashimoto H. Superglue for the treatment of heel fissures. J Am Podiatr Med Assoc. 1999;89:434-435.
5. Omura EF, Rye B. Dermatologic disorders of the foot. Clin Sports Med. 1994;13:825-841.
6. Royle H. Cracked hands and feet. Aust Fam Physician. 1988;17:960-962.
7. About this time of year my skin gets very dry and my heels develop cracks. Are there ways to prevent this from happening? Mayo Clin Health Lett. 2002;20:8.-
8. Ngan V. Cracked heels. New Zealand Dermatological Society, 2006. Updated June 15, 2009. Available at: http://dermnetnz.org/scaly/cracked-heels.html. Accessed June 17, 2012.
1. Smillie S, Landorf K, Keenan A. The effect of a 25% urea cream and sorbolene in the treatment of heel fissures: a double blind randomised controlled trial. Australas J Podiatr Med. 2004;38:56.-
2. Premkumar R, Pannikar VK, Fritschi EP. Foot soaks for callosities and fissures. Indian J Lepr. 1990;62:478-482.
3. Bikowski J. Hyperkeratosis of the heels: treatment with salicylic acid in a novel delivery system. Skinmed. 2004;3:350-351.
4. Hashimoto H. Superglue for the treatment of heel fissures. J Am Podiatr Med Assoc. 1999;89:434-435.
5. Omura EF, Rye B. Dermatologic disorders of the foot. Clin Sports Med. 1994;13:825-841.
6. Royle H. Cracked hands and feet. Aust Fam Physician. 1988;17:960-962.
7. About this time of year my skin gets very dry and my heels develop cracks. Are there ways to prevent this from happening? Mayo Clin Health Lett. 2002;20:8.-
8. Ngan V. Cracked heels. New Zealand Dermatological Society, 2006. Updated June 15, 2009. Available at: http://dermnetnz.org/scaly/cracked-heels.html. Accessed June 17, 2012.
Evidence-based answers from the Family Physicians Inquiries Network
Does digoxin decrease morbidity for those in sinus rhythm with heart failure?
In patients with congestive heart failure due to systolic dysfunction who are in normal sinus rhythm, digoxin therapy reduces rates of hospitalization, as well as clinical deterioration, defined as worsening New York Heart Association (NYHA) classification or an increase in clinical signs and symptoms (strength of recommendation [SOR]: A, systematic review of randomized controlled trials [RCT]).1 These benefits appear to be more pronounced for men.2
Patients treated with digoxin are at increased risk of developing supraventricular dysrhythmias and second- or third-degree atrioventricular block (SOR: A, large RCT).3 It is unclear if patients with diastolic dysfunction experience similar benefits or harms (SOR: A, systematic review of RCTs).1 Digoxin has not been shown to have any effect on mortality for men with congestive heart failure in sinus rhythm (SOR: A, systematic review of RCTs).1 Digoxin use for women may be associated with an increased risk of mortality2 (SOR: B, extrapolation from RCT).
Evidence summary
A recent Cochrane systematic review summarizes the clinical effects of digoxin when used for patients with heart failure in normal sinus rhythm. Thirteen studies including 7896 participants, most of whom had systolic dysfunction, met the criteria for inclusion. Ninety-four percent of all study participants came from a single large randomized placebo-controlled trial.3 Because the studies did not all measure the same outcomes, subgroup analyses were performed.
Four studies with 1096 participants contributed to the findings on clinical status, 12 studies with 7262 participants contributed to the findings of hospitalization and 8 studies including 7755 patients contributed to the data on mortality. Patients receiving digoxin experienced reduced rates of hospitalization due to worsening heart failure (odds ratio [OR]=0.68; 95% confidence interval [CI], 0.61–0.75; number needed to treat [NNT]=13–17) and less clinical deterioration (OR=0.31; 95% CI, 0.21–0.43; NNT=3–61). The wide range in NNT for the reduction in clinical deterioration reflects varying baseline rates of worsening clinical status found among the 12 studies for patients receiving placebo. The narrow CI associated with the odds ratio for reduced rates of clinical deterioration reflects the fact that the majority of patients whose clinical status was evaluated as an outcome came from a single large study, the DIG trial.3 This trial followed 6800 patients with NYHA classifications I to III. Ninety-four percent of patients in this trial were additionally on angiotensin-converting enzyme (ACE) inhibitors and 82% were taking diuretics. Patients were followed for a mean of 37 months.
A subgroup analysis of 988 patients with diastolic dysfunction (ejection fraction >45%) in this study3 suggested no clear benefits or harms when digoxin was used in combination with other therapies vs placebo; however, it did show a positive trend towards the combined outcome of reduced hospitalizations and less clinical deterioration (relative risk [RR]=0.82; 95% CI, 0.63–1.07). Increased rates of supraventricular dysrhythmias (RR=2.08; 95% CI, 1.44–2.99; number needed to harm [NNH]=77) and second- and third-degree heart block were demonstrated for patients receiving digoxin (RR=2.93; 95% CI, 1.61–5.34; NNH=125). There was no difference in mortality between patients receiving digoxin or those receiving placebo (OR=0.98; 95% CI, 0.89–1.09).1
A post-hoc subgroup analysis focusing only on sex-based differences in the DIG trial suggested women benefit less than men from reduced hospitalizations: –4.2% (95% CI, –8.9 to 0.5) vs –8.9% (95% CI, –11.4 to –6.5) (P=.053).2 When a multivariable analysis was performed, digoxin use for women was associated with a higher risk of mortality (adjusted hazard ratio vs placebo=1.23; 95% CI, 1.02–1.47).2
Two randomized controlled withdrawal studies, in which patients who were being treated with digoxin had it discontinued, were also included in the systematic review. These patients’ clinical outcomes were then compared with persons who had continued to receive digoxin for the duration of the trial. Six parallel design studies, in which patients taking digoxin underwent a washout period before being randomized to either digoxin or placebo, were also included in the evaluation of digoxin’s effect on clinical status. Because these patients had already demonstrated the ability to tolerate digoxin, these studies may have been biased in favor of digoxin.4,5
Recommendations from others
The American College of Cardiology/ American Heart Association6 and Heart Failure Society of America7 guidelines both recommend that digoxin be used in NYHA class II–III patients in sinus rhythm who remain symptomatic on standard therapy (described as ACE inhibitors, diuretics, and beta-blockers). Guidelines from the Scottish Intercollegiate Society,8 the European Society of Cardiology,9 and the American Medical Directors Association10 all offer similar recommendations.
Digoxin unlikely to benefit most patients with mild heart failure
It is clear that ACE inhibitors, diuretics, and beta-blockers should all be the first drugs chosen for therapy for patients with CHF. They have not only been shown to improve mortality and reduce symptoms but they do not carry any of the significant risks associated with digoxin toxicity.
Digoxin is unlikely to benefit patients with Class I heart failure, as their risk of clinical deterioration and hospitalizations are low. However, for patients who cannot tolerate any of the first-line drugs or who remain symptomatic while taking them, digoxin carefully dosed and monitored is a useful adjunct in practice.
While it is true that these patients need periodic laboratory monitoring, by the time they require digoxin therapy, their visits for care are already frequent and they would likely require few, if any, additional visits.
1. Hood WB, Jr, Dans AL, Guyatt GH, Jaeschke R, McMurray JJV. Digitalis for treatment of congestive heart failure in patients in sinus rhythm. Cochrane Database Syst Rev 2004;(2):CD002901.-
2. Rathore SS, Wang Y, Krumholz HM. Sex based differences in the effect of digoxin for the treatment of heart failure. N Engl J Med 2002;347:1403-1411.
3. The effect of digoxin on mortality and morbidity in patients with heart failure. The Digitalis Investigation Group. N Engl J Med 1997;336:525-333.
4. Uretsky BF, Young JB, Shahidi FE, Yellen LG, Harrison MC, Jolly MK. Randomized study assessing the effect of digoxin withdrawal in patients with mild to moderate chronic congestive heart failure: results of the PROVED trial. PROVED Investigative Group. J Am Coll Cardiol 1993;22:955-962.
5. Packer M, Gheoghiade M, Young JB, et al. Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors. RADIANCE Study. N Engl J Med 1993;329:1-7.
6. Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult. Bethesda, Md: American College of Cardiology Foundation; 2001.
7. Heart Failure Society of America guidelines for management of patients with heart failure caused by left ventricular systolic dysfunction-pharmacological management. J Card Fail 1999;5:357-382.
8. Diagnosis and treatment of heart failure due to left ventricular systolic dysfunction. Edinburgh: Scottish Intercollegiate Guidelines Network; 1999. Available at: www.sign.ac.uk/guidelines/fulltext/35/index.html.
9. Remme WJ, Swedberg K. Task Force for the Diagnosis and Treatment of Chronic Heart Failure. European Guidelines for the diagnosis and treatment of chronic heart failure. Eur Heart J 2001;22:1527-1560.
10. American Medical Directors Association. Heart failure. Columbia, Md: American Medical Directors Association (AMDA); 2002.
In patients with congestive heart failure due to systolic dysfunction who are in normal sinus rhythm, digoxin therapy reduces rates of hospitalization, as well as clinical deterioration, defined as worsening New York Heart Association (NYHA) classification or an increase in clinical signs and symptoms (strength of recommendation [SOR]: A, systematic review of randomized controlled trials [RCT]).1 These benefits appear to be more pronounced for men.2
Patients treated with digoxin are at increased risk of developing supraventricular dysrhythmias and second- or third-degree atrioventricular block (SOR: A, large RCT).3 It is unclear if patients with diastolic dysfunction experience similar benefits or harms (SOR: A, systematic review of RCTs).1 Digoxin has not been shown to have any effect on mortality for men with congestive heart failure in sinus rhythm (SOR: A, systematic review of RCTs).1 Digoxin use for women may be associated with an increased risk of mortality2 (SOR: B, extrapolation from RCT).
Evidence summary
A recent Cochrane systematic review summarizes the clinical effects of digoxin when used for patients with heart failure in normal sinus rhythm. Thirteen studies including 7896 participants, most of whom had systolic dysfunction, met the criteria for inclusion. Ninety-four percent of all study participants came from a single large randomized placebo-controlled trial.3 Because the studies did not all measure the same outcomes, subgroup analyses were performed.
Four studies with 1096 participants contributed to the findings on clinical status, 12 studies with 7262 participants contributed to the findings of hospitalization and 8 studies including 7755 patients contributed to the data on mortality. Patients receiving digoxin experienced reduced rates of hospitalization due to worsening heart failure (odds ratio [OR]=0.68; 95% confidence interval [CI], 0.61–0.75; number needed to treat [NNT]=13–17) and less clinical deterioration (OR=0.31; 95% CI, 0.21–0.43; NNT=3–61). The wide range in NNT for the reduction in clinical deterioration reflects varying baseline rates of worsening clinical status found among the 12 studies for patients receiving placebo. The narrow CI associated with the odds ratio for reduced rates of clinical deterioration reflects the fact that the majority of patients whose clinical status was evaluated as an outcome came from a single large study, the DIG trial.3 This trial followed 6800 patients with NYHA classifications I to III. Ninety-four percent of patients in this trial were additionally on angiotensin-converting enzyme (ACE) inhibitors and 82% were taking diuretics. Patients were followed for a mean of 37 months.
A subgroup analysis of 988 patients with diastolic dysfunction (ejection fraction >45%) in this study3 suggested no clear benefits or harms when digoxin was used in combination with other therapies vs placebo; however, it did show a positive trend towards the combined outcome of reduced hospitalizations and less clinical deterioration (relative risk [RR]=0.82; 95% CI, 0.63–1.07). Increased rates of supraventricular dysrhythmias (RR=2.08; 95% CI, 1.44–2.99; number needed to harm [NNH]=77) and second- and third-degree heart block were demonstrated for patients receiving digoxin (RR=2.93; 95% CI, 1.61–5.34; NNH=125). There was no difference in mortality between patients receiving digoxin or those receiving placebo (OR=0.98; 95% CI, 0.89–1.09).1
A post-hoc subgroup analysis focusing only on sex-based differences in the DIG trial suggested women benefit less than men from reduced hospitalizations: –4.2% (95% CI, –8.9 to 0.5) vs –8.9% (95% CI, –11.4 to –6.5) (P=.053).2 When a multivariable analysis was performed, digoxin use for women was associated with a higher risk of mortality (adjusted hazard ratio vs placebo=1.23; 95% CI, 1.02–1.47).2
Two randomized controlled withdrawal studies, in which patients who were being treated with digoxin had it discontinued, were also included in the systematic review. These patients’ clinical outcomes were then compared with persons who had continued to receive digoxin for the duration of the trial. Six parallel design studies, in which patients taking digoxin underwent a washout period before being randomized to either digoxin or placebo, were also included in the evaluation of digoxin’s effect on clinical status. Because these patients had already demonstrated the ability to tolerate digoxin, these studies may have been biased in favor of digoxin.4,5
Recommendations from others
The American College of Cardiology/ American Heart Association6 and Heart Failure Society of America7 guidelines both recommend that digoxin be used in NYHA class II–III patients in sinus rhythm who remain symptomatic on standard therapy (described as ACE inhibitors, diuretics, and beta-blockers). Guidelines from the Scottish Intercollegiate Society,8 the European Society of Cardiology,9 and the American Medical Directors Association10 all offer similar recommendations.
Digoxin unlikely to benefit most patients with mild heart failure
It is clear that ACE inhibitors, diuretics, and beta-blockers should all be the first drugs chosen for therapy for patients with CHF. They have not only been shown to improve mortality and reduce symptoms but they do not carry any of the significant risks associated with digoxin toxicity.
Digoxin is unlikely to benefit patients with Class I heart failure, as their risk of clinical deterioration and hospitalizations are low. However, for patients who cannot tolerate any of the first-line drugs or who remain symptomatic while taking them, digoxin carefully dosed and monitored is a useful adjunct in practice.
While it is true that these patients need periodic laboratory monitoring, by the time they require digoxin therapy, their visits for care are already frequent and they would likely require few, if any, additional visits.
In patients with congestive heart failure due to systolic dysfunction who are in normal sinus rhythm, digoxin therapy reduces rates of hospitalization, as well as clinical deterioration, defined as worsening New York Heart Association (NYHA) classification or an increase in clinical signs and symptoms (strength of recommendation [SOR]: A, systematic review of randomized controlled trials [RCT]).1 These benefits appear to be more pronounced for men.2
Patients treated with digoxin are at increased risk of developing supraventricular dysrhythmias and second- or third-degree atrioventricular block (SOR: A, large RCT).3 It is unclear if patients with diastolic dysfunction experience similar benefits or harms (SOR: A, systematic review of RCTs).1 Digoxin has not been shown to have any effect on mortality for men with congestive heart failure in sinus rhythm (SOR: A, systematic review of RCTs).1 Digoxin use for women may be associated with an increased risk of mortality2 (SOR: B, extrapolation from RCT).
Evidence summary
A recent Cochrane systematic review summarizes the clinical effects of digoxin when used for patients with heart failure in normal sinus rhythm. Thirteen studies including 7896 participants, most of whom had systolic dysfunction, met the criteria for inclusion. Ninety-four percent of all study participants came from a single large randomized placebo-controlled trial.3 Because the studies did not all measure the same outcomes, subgroup analyses were performed.
Four studies with 1096 participants contributed to the findings on clinical status, 12 studies with 7262 participants contributed to the findings of hospitalization and 8 studies including 7755 patients contributed to the data on mortality. Patients receiving digoxin experienced reduced rates of hospitalization due to worsening heart failure (odds ratio [OR]=0.68; 95% confidence interval [CI], 0.61–0.75; number needed to treat [NNT]=13–17) and less clinical deterioration (OR=0.31; 95% CI, 0.21–0.43; NNT=3–61). The wide range in NNT for the reduction in clinical deterioration reflects varying baseline rates of worsening clinical status found among the 12 studies for patients receiving placebo. The narrow CI associated with the odds ratio for reduced rates of clinical deterioration reflects the fact that the majority of patients whose clinical status was evaluated as an outcome came from a single large study, the DIG trial.3 This trial followed 6800 patients with NYHA classifications I to III. Ninety-four percent of patients in this trial were additionally on angiotensin-converting enzyme (ACE) inhibitors and 82% were taking diuretics. Patients were followed for a mean of 37 months.
A subgroup analysis of 988 patients with diastolic dysfunction (ejection fraction >45%) in this study3 suggested no clear benefits or harms when digoxin was used in combination with other therapies vs placebo; however, it did show a positive trend towards the combined outcome of reduced hospitalizations and less clinical deterioration (relative risk [RR]=0.82; 95% CI, 0.63–1.07). Increased rates of supraventricular dysrhythmias (RR=2.08; 95% CI, 1.44–2.99; number needed to harm [NNH]=77) and second- and third-degree heart block were demonstrated for patients receiving digoxin (RR=2.93; 95% CI, 1.61–5.34; NNH=125). There was no difference in mortality between patients receiving digoxin or those receiving placebo (OR=0.98; 95% CI, 0.89–1.09).1
A post-hoc subgroup analysis focusing only on sex-based differences in the DIG trial suggested women benefit less than men from reduced hospitalizations: –4.2% (95% CI, –8.9 to 0.5) vs –8.9% (95% CI, –11.4 to –6.5) (P=.053).2 When a multivariable analysis was performed, digoxin use for women was associated with a higher risk of mortality (adjusted hazard ratio vs placebo=1.23; 95% CI, 1.02–1.47).2
Two randomized controlled withdrawal studies, in which patients who were being treated with digoxin had it discontinued, were also included in the systematic review. These patients’ clinical outcomes were then compared with persons who had continued to receive digoxin for the duration of the trial. Six parallel design studies, in which patients taking digoxin underwent a washout period before being randomized to either digoxin or placebo, were also included in the evaluation of digoxin’s effect on clinical status. Because these patients had already demonstrated the ability to tolerate digoxin, these studies may have been biased in favor of digoxin.4,5
Recommendations from others
The American College of Cardiology/ American Heart Association6 and Heart Failure Society of America7 guidelines both recommend that digoxin be used in NYHA class II–III patients in sinus rhythm who remain symptomatic on standard therapy (described as ACE inhibitors, diuretics, and beta-blockers). Guidelines from the Scottish Intercollegiate Society,8 the European Society of Cardiology,9 and the American Medical Directors Association10 all offer similar recommendations.
Digoxin unlikely to benefit most patients with mild heart failure
It is clear that ACE inhibitors, diuretics, and beta-blockers should all be the first drugs chosen for therapy for patients with CHF. They have not only been shown to improve mortality and reduce symptoms but they do not carry any of the significant risks associated with digoxin toxicity.
Digoxin is unlikely to benefit patients with Class I heart failure, as their risk of clinical deterioration and hospitalizations are low. However, for patients who cannot tolerate any of the first-line drugs or who remain symptomatic while taking them, digoxin carefully dosed and monitored is a useful adjunct in practice.
While it is true that these patients need periodic laboratory monitoring, by the time they require digoxin therapy, their visits for care are already frequent and they would likely require few, if any, additional visits.
1. Hood WB, Jr, Dans AL, Guyatt GH, Jaeschke R, McMurray JJV. Digitalis for treatment of congestive heart failure in patients in sinus rhythm. Cochrane Database Syst Rev 2004;(2):CD002901.-
2. Rathore SS, Wang Y, Krumholz HM. Sex based differences in the effect of digoxin for the treatment of heart failure. N Engl J Med 2002;347:1403-1411.
3. The effect of digoxin on mortality and morbidity in patients with heart failure. The Digitalis Investigation Group. N Engl J Med 1997;336:525-333.
4. Uretsky BF, Young JB, Shahidi FE, Yellen LG, Harrison MC, Jolly MK. Randomized study assessing the effect of digoxin withdrawal in patients with mild to moderate chronic congestive heart failure: results of the PROVED trial. PROVED Investigative Group. J Am Coll Cardiol 1993;22:955-962.
5. Packer M, Gheoghiade M, Young JB, et al. Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors. RADIANCE Study. N Engl J Med 1993;329:1-7.
6. Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult. Bethesda, Md: American College of Cardiology Foundation; 2001.
7. Heart Failure Society of America guidelines for management of patients with heart failure caused by left ventricular systolic dysfunction-pharmacological management. J Card Fail 1999;5:357-382.
8. Diagnosis and treatment of heart failure due to left ventricular systolic dysfunction. Edinburgh: Scottish Intercollegiate Guidelines Network; 1999. Available at: www.sign.ac.uk/guidelines/fulltext/35/index.html.
9. Remme WJ, Swedberg K. Task Force for the Diagnosis and Treatment of Chronic Heart Failure. European Guidelines for the diagnosis and treatment of chronic heart failure. Eur Heart J 2001;22:1527-1560.
10. American Medical Directors Association. Heart failure. Columbia, Md: American Medical Directors Association (AMDA); 2002.
1. Hood WB, Jr, Dans AL, Guyatt GH, Jaeschke R, McMurray JJV. Digitalis for treatment of congestive heart failure in patients in sinus rhythm. Cochrane Database Syst Rev 2004;(2):CD002901.-
2. Rathore SS, Wang Y, Krumholz HM. Sex based differences in the effect of digoxin for the treatment of heart failure. N Engl J Med 2002;347:1403-1411.
3. The effect of digoxin on mortality and morbidity in patients with heart failure. The Digitalis Investigation Group. N Engl J Med 1997;336:525-333.
4. Uretsky BF, Young JB, Shahidi FE, Yellen LG, Harrison MC, Jolly MK. Randomized study assessing the effect of digoxin withdrawal in patients with mild to moderate chronic congestive heart failure: results of the PROVED trial. PROVED Investigative Group. J Am Coll Cardiol 1993;22:955-962.
5. Packer M, Gheoghiade M, Young JB, et al. Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors. RADIANCE Study. N Engl J Med 1993;329:1-7.
6. Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult. Bethesda, Md: American College of Cardiology Foundation; 2001.
7. Heart Failure Society of America guidelines for management of patients with heart failure caused by left ventricular systolic dysfunction-pharmacological management. J Card Fail 1999;5:357-382.
8. Diagnosis and treatment of heart failure due to left ventricular systolic dysfunction. Edinburgh: Scottish Intercollegiate Guidelines Network; 1999. Available at: www.sign.ac.uk/guidelines/fulltext/35/index.html.
9. Remme WJ, Swedberg K. Task Force for the Diagnosis and Treatment of Chronic Heart Failure. European Guidelines for the diagnosis and treatment of chronic heart failure. Eur Heart J 2001;22:1527-1560.
10. American Medical Directors Association. Heart failure. Columbia, Md: American Medical Directors Association (AMDA); 2002.
Evidence-based answers from the Family Physicians Inquiries Network
Does tight control of blood glucose in pregnant women with diabetes improve neonatal outcomes?
In pregnant women with preexisting type 1 diabetes mellitus, maintaining near-normal blood glucose levels decreases the rate of major congenital anomalies (defined as those causing death or a serious handicap necessitating surgical correction or medical treatment). Prolonged preconception control of blood sugar to near normal levels reduces the rate of major congenital anomalies close to those seen in women without diabetes (strength of recommendation [SOR]: A, based on prospective cohort studies and randomized controlled trial [RCT]).
Intensive management reduces the risk of congenital anomalies more than conventional therapy, and lowers the risk of neonatal hypoglycemia (SOR: B, based on RCT). Very tight control does not reduce clinically significant neonatal morbidity but does increase the risk of maternal hypoglycemia (SOR: B, based on a systematic review). Evidence is insufficient about whether or not these statements hold true for women with type 2 diabetes.
In women with impaired glucose tolerance, dietary control reduces neonatal hypoglycemia. To date, studies have not found statistically significant reductions in admission rates to the special care nursery or birth weights above the 90th percentile (SOR: B, systematic review). Evidence is insufficient to suggest improved outcomes with therapy in women with gestational diabetes. Standard recommendations typically recommend tight control in this population as well.
Evidence summary
Two studies show that in type 1 diabetes mellitus, elevated blood glucose levels in early pregnancy (HbA1c=6%–8%) are associated with a threefold increase in fetal malformations.1,2 Maintaining preconception and early pregnancy blood glucose levels in the normal range can reduce this risk. A meta-analysis comparing 16 studies of women with pregestational diabetes—13 of which included only women with type 1 diabetes—found that women receiving preconception care had lower early first trimester HbA1c levels than those who did not (7.9% vs 9.6%) and delivered fewer infants with major congenital anomalies (relative risk [RR]=0.36; 95% confidence interval [CI], 0.22–0.59).2 One limitation of this study was that preconception care was not consistently defined among the included studies.
A 10-year RCT evaluated the outcomes of 270 pregnancies in women who had received either intensive (SQ infusion or multiple daily injections) or conventional insulin regimens prior to pregnancy. Women were advised to use intensive therapy when they were trying to conceive, and all were changed to intensive therapy if pregnancy was confirmed. Women in the intensive therapy group had normal HbA1c levels for an average of 40 months before conception. Women receiving intensive therapy had lower mean HbA1c levels at conception (7.4 ± 1.3 SD vs 8.1 ± 1.7 SD) and fewer major congenital anomalies (0.7% vs 5.9%; number needed to treat=19) than did women in the conventional group. When infants with genetic malformations were excluded from the analysis, rates of congenital malformations were similar in women switched to intensive therapy either before or after conception (3.8% vs 3.6%). No differences were seen between neonatal mortality, spontaneous abortion rates, birth weights, Apgar scores, and hypocalcemia or hypoglycemia rates.3
When tight and very tight control of glucose in pregnant women with pregestational diabetes were compared in a Cochrane systematic review, rates of maternal hypoglycemia in the very tightly controlled group were higher (odds ratio [OR]=25.96; 95% CI, 4.91–137.26).5 An RCT of 118 women with pregestational diabetes compared 4-times-daily vs twice-daily doses of insulin. Infants born to women receiving 4-times-daily insulin had significantly lower rates of neonatal hypoglycemia (RR=0.17; 95% CI, 0.04–0.74). While the trend was toward improved neonatal metabolic effects in the trials, the clinical significance of these findings is not clear.
Whether or not treatment of gestational diabetes improves outcomes is uncertain. A Cochrane systematic review evaluating a small number of trials, with variable quality and inconsistent outcome measures, compared dietary management to routine care in gestational diabetics. While fewer infants with birth weights >4000 g were delivered in the diet therapy group (OR=0.78; 95% CI, 0.45–1.35), the results were not statistically significant. No other important clinical differences were found.6
Another Cochrane systematic review evaluated the effects of dietary treatment of women with impaired glucose tolerance and gestational diabetes. Three trials with a total of 223 women with impaired glucose tolerance found a significant reduction in the rate of neonatal hypoglycemia (RR=0.25; 95% CI, 0.07–0.86). There was no significant change in the rates of cesarean section (RR=0.86; 95% CI, 0.51–1.45), admission to the special care nursery (RR=0.49; 95% CI, 0.19–1.24), or birth weights greater than the 90th percentile (RR=0.55; 95% CI, 0.19–1.61). Inadequate power may well account for the failure to reach significance in these outcomes.7
Recommendations from others
The American College of Obstetrics and Gynecology (ACOG) recommends that women with pregestational diabetes maintain fasting plasma glucose levels between 60–90 mg/dL and 2-hour postprandial levels <120 mg/dL.8 For women with gestational diabetes who are not controlled within these targets on dietary therapy alone, ACOG recommends the additional of insulin therapy.9
The American Diabetes Association recommends that women with pregestational diabetes maintain capillary plasma glucose levels of 80–110 mg/dL before and <155 mg/dL 2 hours after meals before pregnancy and while trying to conceive.10 The ADA does not list target glucose levels for women with pregestational diabetes once they become pregnant. The ADA recommends the use of diet and insulin therapy to maintain preprandial plasma glucose levels of <105 mg/dL and 2-hour postprandial levels below <130 mg/dL in gestational diabetes.11
Glucose control makes a difference for pregnancy outcomes in type I diabetes
Linda French, MD
Michigan State University, East Lansing
It is well accepted that glucose control makes a difference for pregnancy outcomes in women with type 1 diabetes. Since similar studies have not been done in women with preexisting type 2 diabetes, we have to assume that the risk is also high for them. Preconception counseling about glucose control is so important for women with diabetes. Fortunately, because they generally have routine visits for their chronic care, we have an opportunity to initiate discussion of glucose control in relationship to pregnancy planning. Routine diabetes care visits also give us the opportunity to discuss other important preconception topics.
- Allopurinol • Lopurin, Zyloprim
- Amitriptyline • Elavil, Endep
- Benzbromarone • Urinorm
- Botulinim toxin A • Botox
- Clindamycin • Cleocin
- Fluoxetine • Prozac
- Fluticasone • Flovent
- Gabapentin • Neurontin
- Metronidazole (intravaginal) • MetroGel
- Probenecid • Benemid, Probalan
- Sumatriptan • Imitrex
- Tizanidine • Zanaflex
- Triamcinolone • Azmacort
- Valproate • Depacon
1. Vaarasmaki MS, Hartikainen A, Anttila M, Pramila S, Koivisto M. Factors predicting peri- and neonatal outcome in diabetic pregnancy. Early Hum Dev 2000;59:61-70.
2. Ray JG, O’Brien TE, Chan WS. Preconception care and the risk of congenital anomalies in the offspring of women with diabetes mellitus: a meta-analysis. QJM 2001;94:435-444.
3. Pregnancy outcomes in the Diabetes Control and Complications Trial. Am J Obstet Gynecol 1996;174:1343-1353.
4. Nachum Z, Ben-Shlomo I, Weiner E, Shalev E. Twice daily versus four times daily insulin dose regimens for diabetes in pregnancy. BMJ 1999;319:1223-1227.
5. Walkinshaw SA. Very tight versus tight control for diabetes in pregnancy (Cochrane Review). In: The Cochrane Library, Issue 4, 2003. Chichester, UK: John Wiley & Sons, Ltd. Last updated 2-15-1999. Accessed on January 4, 2004.
6. Walkinshaw SA. Dietary regulation for ‘gestational diabetes’ (Cochrane Review). In: The Cochrane Library, Issue 4, 2003. Chichester, UK: John Wiley & Sons, Ltd. Last updated 2-25-1999. Accessed on January 4, 2004.
7. West J, Walkinshaw SA. Treatments for gestational diabetes and impaired glucose tolerance in pregnancy (Cochrane Review). In: The Cochrane Library, Issue 4, 2003. Chichester, UK: John Wiley & Sons, Ltd. Last updated 9-12-2002. Accessed on January 4, 2004.
8. ACOG technical bulletin Diabetes and pregnancy. Number 200—December 1994 (replaces No. 92, May 1986). Committee on Technical Bulletins of the American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet 1995;48:331-339.
9. Gestational Diabetes. ACOG Pract Bull No. 30. American College of Obstetricians and Gynecologists. Obstet Gynecol 2001;98:525-538.
10. Preconception care of women with diabetes. Diabetes Care 2004;27 Suppl 1:S76-S78.Available at: care.diabetesjournals.org/cgi/content/full/27/suppl_1/s76. Accessed on January 4, 2004.
11. Gestational diabetes mellitus. Diabetes Care 2003;26 Suppl 1:S103-S105.Available at: care.diabetesjournals.org/cgi/content/full/26/suppl_1/s103. Accessed on January 4, 2004.
In pregnant women with preexisting type 1 diabetes mellitus, maintaining near-normal blood glucose levels decreases the rate of major congenital anomalies (defined as those causing death or a serious handicap necessitating surgical correction or medical treatment). Prolonged preconception control of blood sugar to near normal levels reduces the rate of major congenital anomalies close to those seen in women without diabetes (strength of recommendation [SOR]: A, based on prospective cohort studies and randomized controlled trial [RCT]).
Intensive management reduces the risk of congenital anomalies more than conventional therapy, and lowers the risk of neonatal hypoglycemia (SOR: B, based on RCT). Very tight control does not reduce clinically significant neonatal morbidity but does increase the risk of maternal hypoglycemia (SOR: B, based on a systematic review). Evidence is insufficient about whether or not these statements hold true for women with type 2 diabetes.
In women with impaired glucose tolerance, dietary control reduces neonatal hypoglycemia. To date, studies have not found statistically significant reductions in admission rates to the special care nursery or birth weights above the 90th percentile (SOR: B, systematic review). Evidence is insufficient to suggest improved outcomes with therapy in women with gestational diabetes. Standard recommendations typically recommend tight control in this population as well.
Evidence summary
Two studies show that in type 1 diabetes mellitus, elevated blood glucose levels in early pregnancy (HbA1c=6%–8%) are associated with a threefold increase in fetal malformations.1,2 Maintaining preconception and early pregnancy blood glucose levels in the normal range can reduce this risk. A meta-analysis comparing 16 studies of women with pregestational diabetes—13 of which included only women with type 1 diabetes—found that women receiving preconception care had lower early first trimester HbA1c levels than those who did not (7.9% vs 9.6%) and delivered fewer infants with major congenital anomalies (relative risk [RR]=0.36; 95% confidence interval [CI], 0.22–0.59).2 One limitation of this study was that preconception care was not consistently defined among the included studies.
A 10-year RCT evaluated the outcomes of 270 pregnancies in women who had received either intensive (SQ infusion or multiple daily injections) or conventional insulin regimens prior to pregnancy. Women were advised to use intensive therapy when they were trying to conceive, and all were changed to intensive therapy if pregnancy was confirmed. Women in the intensive therapy group had normal HbA1c levels for an average of 40 months before conception. Women receiving intensive therapy had lower mean HbA1c levels at conception (7.4 ± 1.3 SD vs 8.1 ± 1.7 SD) and fewer major congenital anomalies (0.7% vs 5.9%; number needed to treat=19) than did women in the conventional group. When infants with genetic malformations were excluded from the analysis, rates of congenital malformations were similar in women switched to intensive therapy either before or after conception (3.8% vs 3.6%). No differences were seen between neonatal mortality, spontaneous abortion rates, birth weights, Apgar scores, and hypocalcemia or hypoglycemia rates.3
When tight and very tight control of glucose in pregnant women with pregestational diabetes were compared in a Cochrane systematic review, rates of maternal hypoglycemia in the very tightly controlled group were higher (odds ratio [OR]=25.96; 95% CI, 4.91–137.26).5 An RCT of 118 women with pregestational diabetes compared 4-times-daily vs twice-daily doses of insulin. Infants born to women receiving 4-times-daily insulin had significantly lower rates of neonatal hypoglycemia (RR=0.17; 95% CI, 0.04–0.74). While the trend was toward improved neonatal metabolic effects in the trials, the clinical significance of these findings is not clear.
Whether or not treatment of gestational diabetes improves outcomes is uncertain. A Cochrane systematic review evaluating a small number of trials, with variable quality and inconsistent outcome measures, compared dietary management to routine care in gestational diabetics. While fewer infants with birth weights >4000 g were delivered in the diet therapy group (OR=0.78; 95% CI, 0.45–1.35), the results were not statistically significant. No other important clinical differences were found.6
Another Cochrane systematic review evaluated the effects of dietary treatment of women with impaired glucose tolerance and gestational diabetes. Three trials with a total of 223 women with impaired glucose tolerance found a significant reduction in the rate of neonatal hypoglycemia (RR=0.25; 95% CI, 0.07–0.86). There was no significant change in the rates of cesarean section (RR=0.86; 95% CI, 0.51–1.45), admission to the special care nursery (RR=0.49; 95% CI, 0.19–1.24), or birth weights greater than the 90th percentile (RR=0.55; 95% CI, 0.19–1.61). Inadequate power may well account for the failure to reach significance in these outcomes.7
Recommendations from others
The American College of Obstetrics and Gynecology (ACOG) recommends that women with pregestational diabetes maintain fasting plasma glucose levels between 60–90 mg/dL and 2-hour postprandial levels <120 mg/dL.8 For women with gestational diabetes who are not controlled within these targets on dietary therapy alone, ACOG recommends the additional of insulin therapy.9
The American Diabetes Association recommends that women with pregestational diabetes maintain capillary plasma glucose levels of 80–110 mg/dL before and <155 mg/dL 2 hours after meals before pregnancy and while trying to conceive.10 The ADA does not list target glucose levels for women with pregestational diabetes once they become pregnant. The ADA recommends the use of diet and insulin therapy to maintain preprandial plasma glucose levels of <105 mg/dL and 2-hour postprandial levels below <130 mg/dL in gestational diabetes.11
Glucose control makes a difference for pregnancy outcomes in type I diabetes
Linda French, MD
Michigan State University, East Lansing
It is well accepted that glucose control makes a difference for pregnancy outcomes in women with type 1 diabetes. Since similar studies have not been done in women with preexisting type 2 diabetes, we have to assume that the risk is also high for them. Preconception counseling about glucose control is so important for women with diabetes. Fortunately, because they generally have routine visits for their chronic care, we have an opportunity to initiate discussion of glucose control in relationship to pregnancy planning. Routine diabetes care visits also give us the opportunity to discuss other important preconception topics.
- Allopurinol • Lopurin, Zyloprim
- Amitriptyline • Elavil, Endep
- Benzbromarone • Urinorm
- Botulinim toxin A • Botox
- Clindamycin • Cleocin
- Fluoxetine • Prozac
- Fluticasone • Flovent
- Gabapentin • Neurontin
- Metronidazole (intravaginal) • MetroGel
- Probenecid • Benemid, Probalan
- Sumatriptan • Imitrex
- Tizanidine • Zanaflex
- Triamcinolone • Azmacort
- Valproate • Depacon
In pregnant women with preexisting type 1 diabetes mellitus, maintaining near-normal blood glucose levels decreases the rate of major congenital anomalies (defined as those causing death or a serious handicap necessitating surgical correction or medical treatment). Prolonged preconception control of blood sugar to near normal levels reduces the rate of major congenital anomalies close to those seen in women without diabetes (strength of recommendation [SOR]: A, based on prospective cohort studies and randomized controlled trial [RCT]).
Intensive management reduces the risk of congenital anomalies more than conventional therapy, and lowers the risk of neonatal hypoglycemia (SOR: B, based on RCT). Very tight control does not reduce clinically significant neonatal morbidity but does increase the risk of maternal hypoglycemia (SOR: B, based on a systematic review). Evidence is insufficient about whether or not these statements hold true for women with type 2 diabetes.
In women with impaired glucose tolerance, dietary control reduces neonatal hypoglycemia. To date, studies have not found statistically significant reductions in admission rates to the special care nursery or birth weights above the 90th percentile (SOR: B, systematic review). Evidence is insufficient to suggest improved outcomes with therapy in women with gestational diabetes. Standard recommendations typically recommend tight control in this population as well.
Evidence summary
Two studies show that in type 1 diabetes mellitus, elevated blood glucose levels in early pregnancy (HbA1c=6%–8%) are associated with a threefold increase in fetal malformations.1,2 Maintaining preconception and early pregnancy blood glucose levels in the normal range can reduce this risk. A meta-analysis comparing 16 studies of women with pregestational diabetes—13 of which included only women with type 1 diabetes—found that women receiving preconception care had lower early first trimester HbA1c levels than those who did not (7.9% vs 9.6%) and delivered fewer infants with major congenital anomalies (relative risk [RR]=0.36; 95% confidence interval [CI], 0.22–0.59).2 One limitation of this study was that preconception care was not consistently defined among the included studies.
A 10-year RCT evaluated the outcomes of 270 pregnancies in women who had received either intensive (SQ infusion or multiple daily injections) or conventional insulin regimens prior to pregnancy. Women were advised to use intensive therapy when they were trying to conceive, and all were changed to intensive therapy if pregnancy was confirmed. Women in the intensive therapy group had normal HbA1c levels for an average of 40 months before conception. Women receiving intensive therapy had lower mean HbA1c levels at conception (7.4 ± 1.3 SD vs 8.1 ± 1.7 SD) and fewer major congenital anomalies (0.7% vs 5.9%; number needed to treat=19) than did women in the conventional group. When infants with genetic malformations were excluded from the analysis, rates of congenital malformations were similar in women switched to intensive therapy either before or after conception (3.8% vs 3.6%). No differences were seen between neonatal mortality, spontaneous abortion rates, birth weights, Apgar scores, and hypocalcemia or hypoglycemia rates.3
When tight and very tight control of glucose in pregnant women with pregestational diabetes were compared in a Cochrane systematic review, rates of maternal hypoglycemia in the very tightly controlled group were higher (odds ratio [OR]=25.96; 95% CI, 4.91–137.26).5 An RCT of 118 women with pregestational diabetes compared 4-times-daily vs twice-daily doses of insulin. Infants born to women receiving 4-times-daily insulin had significantly lower rates of neonatal hypoglycemia (RR=0.17; 95% CI, 0.04–0.74). While the trend was toward improved neonatal metabolic effects in the trials, the clinical significance of these findings is not clear.
Whether or not treatment of gestational diabetes improves outcomes is uncertain. A Cochrane systematic review evaluating a small number of trials, with variable quality and inconsistent outcome measures, compared dietary management to routine care in gestational diabetics. While fewer infants with birth weights >4000 g were delivered in the diet therapy group (OR=0.78; 95% CI, 0.45–1.35), the results were not statistically significant. No other important clinical differences were found.6
Another Cochrane systematic review evaluated the effects of dietary treatment of women with impaired glucose tolerance and gestational diabetes. Three trials with a total of 223 women with impaired glucose tolerance found a significant reduction in the rate of neonatal hypoglycemia (RR=0.25; 95% CI, 0.07–0.86). There was no significant change in the rates of cesarean section (RR=0.86; 95% CI, 0.51–1.45), admission to the special care nursery (RR=0.49; 95% CI, 0.19–1.24), or birth weights greater than the 90th percentile (RR=0.55; 95% CI, 0.19–1.61). Inadequate power may well account for the failure to reach significance in these outcomes.7
Recommendations from others
The American College of Obstetrics and Gynecology (ACOG) recommends that women with pregestational diabetes maintain fasting plasma glucose levels between 60–90 mg/dL and 2-hour postprandial levels <120 mg/dL.8 For women with gestational diabetes who are not controlled within these targets on dietary therapy alone, ACOG recommends the additional of insulin therapy.9
The American Diabetes Association recommends that women with pregestational diabetes maintain capillary plasma glucose levels of 80–110 mg/dL before and <155 mg/dL 2 hours after meals before pregnancy and while trying to conceive.10 The ADA does not list target glucose levels for women with pregestational diabetes once they become pregnant. The ADA recommends the use of diet and insulin therapy to maintain preprandial plasma glucose levels of <105 mg/dL and 2-hour postprandial levels below <130 mg/dL in gestational diabetes.11
Glucose control makes a difference for pregnancy outcomes in type I diabetes
Linda French, MD
Michigan State University, East Lansing
It is well accepted that glucose control makes a difference for pregnancy outcomes in women with type 1 diabetes. Since similar studies have not been done in women with preexisting type 2 diabetes, we have to assume that the risk is also high for them. Preconception counseling about glucose control is so important for women with diabetes. Fortunately, because they generally have routine visits for their chronic care, we have an opportunity to initiate discussion of glucose control in relationship to pregnancy planning. Routine diabetes care visits also give us the opportunity to discuss other important preconception topics.
- Allopurinol • Lopurin, Zyloprim
- Amitriptyline • Elavil, Endep
- Benzbromarone • Urinorm
- Botulinim toxin A • Botox
- Clindamycin • Cleocin
- Fluoxetine • Prozac
- Fluticasone • Flovent
- Gabapentin • Neurontin
- Metronidazole (intravaginal) • MetroGel
- Probenecid • Benemid, Probalan
- Sumatriptan • Imitrex
- Tizanidine • Zanaflex
- Triamcinolone • Azmacort
- Valproate • Depacon
1. Vaarasmaki MS, Hartikainen A, Anttila M, Pramila S, Koivisto M. Factors predicting peri- and neonatal outcome in diabetic pregnancy. Early Hum Dev 2000;59:61-70.
2. Ray JG, O’Brien TE, Chan WS. Preconception care and the risk of congenital anomalies in the offspring of women with diabetes mellitus: a meta-analysis. QJM 2001;94:435-444.
3. Pregnancy outcomes in the Diabetes Control and Complications Trial. Am J Obstet Gynecol 1996;174:1343-1353.
4. Nachum Z, Ben-Shlomo I, Weiner E, Shalev E. Twice daily versus four times daily insulin dose regimens for diabetes in pregnancy. BMJ 1999;319:1223-1227.
5. Walkinshaw SA. Very tight versus tight control for diabetes in pregnancy (Cochrane Review). In: The Cochrane Library, Issue 4, 2003. Chichester, UK: John Wiley & Sons, Ltd. Last updated 2-15-1999. Accessed on January 4, 2004.
6. Walkinshaw SA. Dietary regulation for ‘gestational diabetes’ (Cochrane Review). In: The Cochrane Library, Issue 4, 2003. Chichester, UK: John Wiley & Sons, Ltd. Last updated 2-25-1999. Accessed on January 4, 2004.
7. West J, Walkinshaw SA. Treatments for gestational diabetes and impaired glucose tolerance in pregnancy (Cochrane Review). In: The Cochrane Library, Issue 4, 2003. Chichester, UK: John Wiley & Sons, Ltd. Last updated 9-12-2002. Accessed on January 4, 2004.
8. ACOG technical bulletin Diabetes and pregnancy. Number 200—December 1994 (replaces No. 92, May 1986). Committee on Technical Bulletins of the American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet 1995;48:331-339.
9. Gestational Diabetes. ACOG Pract Bull No. 30. American College of Obstetricians and Gynecologists. Obstet Gynecol 2001;98:525-538.
10. Preconception care of women with diabetes. Diabetes Care 2004;27 Suppl 1:S76-S78.Available at: care.diabetesjournals.org/cgi/content/full/27/suppl_1/s76. Accessed on January 4, 2004.
11. Gestational diabetes mellitus. Diabetes Care 2003;26 Suppl 1:S103-S105.Available at: care.diabetesjournals.org/cgi/content/full/26/suppl_1/s103. Accessed on January 4, 2004.
1. Vaarasmaki MS, Hartikainen A, Anttila M, Pramila S, Koivisto M. Factors predicting peri- and neonatal outcome in diabetic pregnancy. Early Hum Dev 2000;59:61-70.
2. Ray JG, O’Brien TE, Chan WS. Preconception care and the risk of congenital anomalies in the offspring of women with diabetes mellitus: a meta-analysis. QJM 2001;94:435-444.
3. Pregnancy outcomes in the Diabetes Control and Complications Trial. Am J Obstet Gynecol 1996;174:1343-1353.
4. Nachum Z, Ben-Shlomo I, Weiner E, Shalev E. Twice daily versus four times daily insulin dose regimens for diabetes in pregnancy. BMJ 1999;319:1223-1227.
5. Walkinshaw SA. Very tight versus tight control for diabetes in pregnancy (Cochrane Review). In: The Cochrane Library, Issue 4, 2003. Chichester, UK: John Wiley & Sons, Ltd. Last updated 2-15-1999. Accessed on January 4, 2004.
6. Walkinshaw SA. Dietary regulation for ‘gestational diabetes’ (Cochrane Review). In: The Cochrane Library, Issue 4, 2003. Chichester, UK: John Wiley & Sons, Ltd. Last updated 2-25-1999. Accessed on January 4, 2004.
7. West J, Walkinshaw SA. Treatments for gestational diabetes and impaired glucose tolerance in pregnancy (Cochrane Review). In: The Cochrane Library, Issue 4, 2003. Chichester, UK: John Wiley & Sons, Ltd. Last updated 9-12-2002. Accessed on January 4, 2004.
8. ACOG technical bulletin Diabetes and pregnancy. Number 200—December 1994 (replaces No. 92, May 1986). Committee on Technical Bulletins of the American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet 1995;48:331-339.
9. Gestational Diabetes. ACOG Pract Bull No. 30. American College of Obstetricians and Gynecologists. Obstet Gynecol 2001;98:525-538.
10. Preconception care of women with diabetes. Diabetes Care 2004;27 Suppl 1:S76-S78.Available at: care.diabetesjournals.org/cgi/content/full/27/suppl_1/s76. Accessed on January 4, 2004.
11. Gestational diabetes mellitus. Diabetes Care 2003;26 Suppl 1:S103-S105.Available at: care.diabetesjournals.org/cgi/content/full/26/suppl_1/s103. Accessed on January 4, 2004.
Evidence-based answers from the Family Physicians Inquiries Network
Is there a role for theophylline in treating patients with asthma?
With adults, oral theophylline may help lower the dosage of inhaled steroids needed to control chronic asthma. It offers no benefit for acute asthma exacerbations. For children, intravenous aminophylline may improve the clinical course of severe asthma attacks. Side effects and toxicity limit use of these medications in most settings. (Grade of recommendation: A, based on systematic reviews and randomized control trials [RCTs]).
Evidence summary
Several systematic reviews help clarify theophylline’s role in asthma management. When compared with placebo in the management of acute exacerbations, theophylline confers no added benefit to beta-agonist therapy (with or without steroids) in improving pulmonary function or reducing hospitalization rates. Side effects occurred more often in the theophylline group: palpitations/arrhythmias (OR = 2.9; 95% CI: 1.5 to 5.7) and vomiting (OR = 4.2; 95% CI: 2.4 to 7.4).1 For moderately severe asthma in patients already receiving inhaled corticosteroids (ICS), theophylline as maintenance therapy equaled long-acting beta-2-agonists in increasing FEV 1 and PEFR, but was less effective in controlling night time symptoms. Use of long-acting beta-agonists resulted in fewer side effects (RR = 0.38; 95%CI: 0.25-0.57).2 When added to low-dose ICS for maintenance, theophylline was as effective as high-dose ICS alone in improving FEV 1 , decreasing day and night symptoms, and reducing the need for rescue medications and the incidence of attacks. This suggests theophylline has utility as a steroid sparing agent.3
Intravenous aminophylline does appear to be clinically beneficial for children with severe exacerbations, defined as an FEV 1 of 35%-40% of predicted value. Critically ill children receiving aminophylline in addition to usual care exhibited an improved FEV 1 at 24 hours (mean difference = 8.4%; 95% CI: 0.82 to 15.92) and reduced symptom scores at 6 hours.4 The largest RCT of aminophylline in children demonstrated a reduced intubation rate (NNT = 14 CI: 7.8-77).5 Children receiving aminophylline experienced more vomiting (RR = 3.69; 95%CI: 2.15-6.33). Treatment with aminophylline did not reduce length of hospital stay or the number of rescue nebulizers needed (Table).4
TABLE
Theophylline use in asthma
| Adults | Children | |
|---|---|---|
| Acute Treatment | No added benefit to corticosteroids and beta-agonist therapy; increased GI and cardiac side effects. | 24 hours of IV aminophylline improves symptom scores without reducing LOS or nebulizer requirements; may reduce intubation |
| Maintenance Therapy | ||
| Mild | No clinical benefit | Not recommended |
| Moderate | Performs worse than long-acting beta-agonists and has more side effects; may limit the need for high-dose ICS if not using long beta agonists. | No advantage over long-acting beta agonists when added to ICS. More side effects |
| Severe | Same for moderate; does not limit the need for oral corticosteroids in this setting. | Same as moderate |
| LOS = length of stay; ICS = inhaled corticosteroids. | ||
Recommendations from others
Three evidence-supported guidelines concur that theophylline has a limited role as maintenance therapy for moderate-to-severe persistent asthma when symptom control with ICS alone is not adequate. Much stronger evidence supports the use of long-acting beta-2-agonists or leukotriene modifiers in this setting.6-8 The guidelines do not recommend using theophylline to treat acute asthma exacerbations; nor do they address using theophylline in children.
Read a Clinical Commentary by M. Lee Chambliss, MD, MSPH, at www.fpin.org.
1. Wilson AJ, Gibson, PG, Coughlan J. The Cochrane Library, Issue 2, 2002. Oxford: Update Software.
2. Parameswaran K, Belda J, Rowe BH. The Cochrane Library, Issue 2, 2002. Oxford: Update Software.
3. Evans DJ, Taylor DA, Zetterstrom O, et al. N Engl J Med 1997;337:1412-8.
4. Mitra A, Bassler D, Ducharme FM. The Cochrane Library, Issue 2, 2002. Oxford: Update Software.
5. Yung M, South M. Arch Dis Child 1998;79:405-410.
6. Management of Chronic Asthma. Evidence Report/Technology Assessment. Number 44. AHQR Publication Number 01-E043, September 2001.
7. Global Initiative for Asthma, National Heart, Lung and Blood Institute, (U.S.)/World Health Organization. 1995 Jan (revised 1998).
8. Expert Panel Report 2:Guidelines for the diagnosis and management of asthma. National Asthma Education and Prevention Program/National Heart, Lung and Blood Institute (U.S.). 1997 Jul, (reprinted 1998 Apr, 1999 Mar).
With adults, oral theophylline may help lower the dosage of inhaled steroids needed to control chronic asthma. It offers no benefit for acute asthma exacerbations. For children, intravenous aminophylline may improve the clinical course of severe asthma attacks. Side effects and toxicity limit use of these medications in most settings. (Grade of recommendation: A, based on systematic reviews and randomized control trials [RCTs]).
Evidence summary
Several systematic reviews help clarify theophylline’s role in asthma management. When compared with placebo in the management of acute exacerbations, theophylline confers no added benefit to beta-agonist therapy (with or without steroids) in improving pulmonary function or reducing hospitalization rates. Side effects occurred more often in the theophylline group: palpitations/arrhythmias (OR = 2.9; 95% CI: 1.5 to 5.7) and vomiting (OR = 4.2; 95% CI: 2.4 to 7.4).1 For moderately severe asthma in patients already receiving inhaled corticosteroids (ICS), theophylline as maintenance therapy equaled long-acting beta-2-agonists in increasing FEV 1 and PEFR, but was less effective in controlling night time symptoms. Use of long-acting beta-agonists resulted in fewer side effects (RR = 0.38; 95%CI: 0.25-0.57).2 When added to low-dose ICS for maintenance, theophylline was as effective as high-dose ICS alone in improving FEV 1 , decreasing day and night symptoms, and reducing the need for rescue medications and the incidence of attacks. This suggests theophylline has utility as a steroid sparing agent.3
Intravenous aminophylline does appear to be clinically beneficial for children with severe exacerbations, defined as an FEV 1 of 35%-40% of predicted value. Critically ill children receiving aminophylline in addition to usual care exhibited an improved FEV 1 at 24 hours (mean difference = 8.4%; 95% CI: 0.82 to 15.92) and reduced symptom scores at 6 hours.4 The largest RCT of aminophylline in children demonstrated a reduced intubation rate (NNT = 14 CI: 7.8-77).5 Children receiving aminophylline experienced more vomiting (RR = 3.69; 95%CI: 2.15-6.33). Treatment with aminophylline did not reduce length of hospital stay or the number of rescue nebulizers needed (Table).4
TABLE
Theophylline use in asthma
| Adults | Children | |
|---|---|---|
| Acute Treatment | No added benefit to corticosteroids and beta-agonist therapy; increased GI and cardiac side effects. | 24 hours of IV aminophylline improves symptom scores without reducing LOS or nebulizer requirements; may reduce intubation |
| Maintenance Therapy | ||
| Mild | No clinical benefit | Not recommended |
| Moderate | Performs worse than long-acting beta-agonists and has more side effects; may limit the need for high-dose ICS if not using long beta agonists. | No advantage over long-acting beta agonists when added to ICS. More side effects |
| Severe | Same for moderate; does not limit the need for oral corticosteroids in this setting. | Same as moderate |
| LOS = length of stay; ICS = inhaled corticosteroids. | ||
Recommendations from others
Three evidence-supported guidelines concur that theophylline has a limited role as maintenance therapy for moderate-to-severe persistent asthma when symptom control with ICS alone is not adequate. Much stronger evidence supports the use of long-acting beta-2-agonists or leukotriene modifiers in this setting.6-8 The guidelines do not recommend using theophylline to treat acute asthma exacerbations; nor do they address using theophylline in children.
Read a Clinical Commentary by M. Lee Chambliss, MD, MSPH, at www.fpin.org.
With adults, oral theophylline may help lower the dosage of inhaled steroids needed to control chronic asthma. It offers no benefit for acute asthma exacerbations. For children, intravenous aminophylline may improve the clinical course of severe asthma attacks. Side effects and toxicity limit use of these medications in most settings. (Grade of recommendation: A, based on systematic reviews and randomized control trials [RCTs]).
Evidence summary
Several systematic reviews help clarify theophylline’s role in asthma management. When compared with placebo in the management of acute exacerbations, theophylline confers no added benefit to beta-agonist therapy (with or without steroids) in improving pulmonary function or reducing hospitalization rates. Side effects occurred more often in the theophylline group: palpitations/arrhythmias (OR = 2.9; 95% CI: 1.5 to 5.7) and vomiting (OR = 4.2; 95% CI: 2.4 to 7.4).1 For moderately severe asthma in patients already receiving inhaled corticosteroids (ICS), theophylline as maintenance therapy equaled long-acting beta-2-agonists in increasing FEV 1 and PEFR, but was less effective in controlling night time symptoms. Use of long-acting beta-agonists resulted in fewer side effects (RR = 0.38; 95%CI: 0.25-0.57).2 When added to low-dose ICS for maintenance, theophylline was as effective as high-dose ICS alone in improving FEV 1 , decreasing day and night symptoms, and reducing the need for rescue medications and the incidence of attacks. This suggests theophylline has utility as a steroid sparing agent.3
Intravenous aminophylline does appear to be clinically beneficial for children with severe exacerbations, defined as an FEV 1 of 35%-40% of predicted value. Critically ill children receiving aminophylline in addition to usual care exhibited an improved FEV 1 at 24 hours (mean difference = 8.4%; 95% CI: 0.82 to 15.92) and reduced symptom scores at 6 hours.4 The largest RCT of aminophylline in children demonstrated a reduced intubation rate (NNT = 14 CI: 7.8-77).5 Children receiving aminophylline experienced more vomiting (RR = 3.69; 95%CI: 2.15-6.33). Treatment with aminophylline did not reduce length of hospital stay or the number of rescue nebulizers needed (Table).4
TABLE
Theophylline use in asthma
| Adults | Children | |
|---|---|---|
| Acute Treatment | No added benefit to corticosteroids and beta-agonist therapy; increased GI and cardiac side effects. | 24 hours of IV aminophylline improves symptom scores without reducing LOS or nebulizer requirements; may reduce intubation |
| Maintenance Therapy | ||
| Mild | No clinical benefit | Not recommended |
| Moderate | Performs worse than long-acting beta-agonists and has more side effects; may limit the need for high-dose ICS if not using long beta agonists. | No advantage over long-acting beta agonists when added to ICS. More side effects |
| Severe | Same for moderate; does not limit the need for oral corticosteroids in this setting. | Same as moderate |
| LOS = length of stay; ICS = inhaled corticosteroids. | ||
Recommendations from others
Three evidence-supported guidelines concur that theophylline has a limited role as maintenance therapy for moderate-to-severe persistent asthma when symptom control with ICS alone is not adequate. Much stronger evidence supports the use of long-acting beta-2-agonists or leukotriene modifiers in this setting.6-8 The guidelines do not recommend using theophylline to treat acute asthma exacerbations; nor do they address using theophylline in children.
Read a Clinical Commentary by M. Lee Chambliss, MD, MSPH, at www.fpin.org.
1. Wilson AJ, Gibson, PG, Coughlan J. The Cochrane Library, Issue 2, 2002. Oxford: Update Software.
2. Parameswaran K, Belda J, Rowe BH. The Cochrane Library, Issue 2, 2002. Oxford: Update Software.
3. Evans DJ, Taylor DA, Zetterstrom O, et al. N Engl J Med 1997;337:1412-8.
4. Mitra A, Bassler D, Ducharme FM. The Cochrane Library, Issue 2, 2002. Oxford: Update Software.
5. Yung M, South M. Arch Dis Child 1998;79:405-410.
6. Management of Chronic Asthma. Evidence Report/Technology Assessment. Number 44. AHQR Publication Number 01-E043, September 2001.
7. Global Initiative for Asthma, National Heart, Lung and Blood Institute, (U.S.)/World Health Organization. 1995 Jan (revised 1998).
8. Expert Panel Report 2:Guidelines for the diagnosis and management of asthma. National Asthma Education and Prevention Program/National Heart, Lung and Blood Institute (U.S.). 1997 Jul, (reprinted 1998 Apr, 1999 Mar).
1. Wilson AJ, Gibson, PG, Coughlan J. The Cochrane Library, Issue 2, 2002. Oxford: Update Software.
2. Parameswaran K, Belda J, Rowe BH. The Cochrane Library, Issue 2, 2002. Oxford: Update Software.
3. Evans DJ, Taylor DA, Zetterstrom O, et al. N Engl J Med 1997;337:1412-8.
4. Mitra A, Bassler D, Ducharme FM. The Cochrane Library, Issue 2, 2002. Oxford: Update Software.
5. Yung M, South M. Arch Dis Child 1998;79:405-410.
6. Management of Chronic Asthma. Evidence Report/Technology Assessment. Number 44. AHQR Publication Number 01-E043, September 2001.
7. Global Initiative for Asthma, National Heart, Lung and Blood Institute, (U.S.)/World Health Organization. 1995 Jan (revised 1998).
8. Expert Panel Report 2:Guidelines for the diagnosis and management of asthma. National Asthma Education and Prevention Program/National Heart, Lung and Blood Institute (U.S.). 1997 Jul, (reprinted 1998 Apr, 1999 Mar).
Evidence-based answers from the Family Physicians Inquiries Network