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Patient Perceptions of Readmission Risk: An Exploratory Survey
Recent years have seen a proliferation of programs designed to prevent readmissions, including patient education initiatives, financial assistance programs, postdischarge services, and clinical personnel assigned to help patients navigate their posthospitalization clinical care. Although some strategies do not require direct patient participation (such as timely and effective handoffs between inpatient and outpatient care teams), many rely upon a commitment by the patient to participate in the postdischarge care plan. At our hospital, we have found that only about 2/3 of patients who are offered transitional interventions (such as postdischarge phone calls by nurses or home nursing through a “transition guide” program) receive the intended interventions, and those who do not receive them are more likely to be readmitted.1 While limited patient uptake may relate, in part, to factors that are difficult to overcome, such as inadequate housing or phone service, we have also encountered patients whose values, beliefs, or preferences about their care do not align with those of the care team. The purposes of this exploratory study were to (1) assess patient attitudes surrounding readmission, (2) ascertain whether these attitudes are associated with actual readmission, and (3) determine whether patients can estimate their own risk of readmission.
METHODS
From January 2014 to September 2016, we circulated surveys to patients on internal medicine nursing units who were being discharged home within 24 hours. Blank surveys were distributed to nursing units by the researchers. Unit clerks and support staff were educated on the purpose of the project and asked to distribute surveys to patients who were identified by unit case managers or nurses as slated for discharge. Staff members were not asked to help with or supervise survey completion. Surveys were generally filled out by patients, but we allowed family members to assist patients if needed, and to indicate so with a checkbox. There were no exclusion criteria. Because surveys were distributed by clinical staff, the received surveys can be considered a convenience sample. Patients were asked 5 questions with 4- or 5-point Likert scale responses:
(1) “How likely is it that you will be admitted to the hospital (have to stay in the hospital overnight) again within the next 30 days after you leave the hospital this time?” [answers ranging from “Very Unlikely (<5% chance)” to “Very Likely (>50% chance)”];
(2) “How would you feel about being rehospitalized in the next month?” [answers ranging from “Very sad, frustrated, or disappointed” to “Very happy or relieved”];
(3) “How much do you think that you personally can control whether or not you will be rehospitalized (based on what you do to take care of your body, take your medicines, and follow-up with your healthcare team)?” [answers ranging from “I have no control over whether I will be rehospitalized” to “I have complete control over whether I will be rehospitalized”];
(4) “Which of the options below best describes how you plan to follow the medical instructions after you leave the hospital?” [answers ranging from “I do NOT plan to do very much of what I am being asked to do by the doctors, nurses, therapists, and other members of the care team” to “I plan to do EVERYTHING I am being asked to do by the doctors, nurses, therapists and other members of the care team”]; and
(5) “Pick the item below that best describes YOUR OWN VIEW of the care team’s recommendations:” [answers ranging from “I DO NOT AGREE AT ALL that the best way to be healthy is to do exactly what I am being asked to do by the doctors, nurses, therapists, and other members of the care team” to “I FULLY AGREE that the best way to be healthy is to do exactly what I am being asked to do by the doctors, nurses, therapists, and other members of the care team”].
Responses were linked, based on discharge date and medical record number, to administrative data, including age, sex, race, payer, and clinical data. Subsequent hospitalizations to our hospital were ascertained from administrative data. We estimated expected risk of readmission using the all payer refined diagnosis related group coupled with the associated severity-of-illness (SOI) score, as we have reported previously.2-5 We restricted our analysis to patients who answered the question related to the likelihood of readmission. Logistic regression models were constructed using actual 30-day readmission as the dependent variable to determine whether patients could predict their own readmissions and whether patient attitudes and beliefs about their care were predictive of subsequent readmission. Patient survey responses were entered as continuous independent variables (ranging from 1-4 or 1-5, as appropriate). Multivariable logistic regression was used to determine whether patients could predict their readmissions independent of demographic variables and expected readmission rate (modeled continuously); we repeated this model after dichotomizing the patient’s estimate of the likelihood of readmission as either “unlikely” or “likely.” Patients with missing survey responses were excluded from individual models without imputation. The study was approved by the Johns Hopkins institutional review board.
RESULTS
Responses were obtained from 895 patients. Their median age was 56 years [interquartile range, 43-67], 51.4% were female, and 41.7% were white. Mean SOI was 2.53 (on a 1-4 scale), and median length-of-stay was representative for our medical service at 5.2 days (range, 1-66 days). Family members reported filling out the survey in 57 cases. The primary payer was Medicare in 40.7%, Medicaid in 24.9%, and other in 34.4%. A total of 138 patients (15.4%) were readmitted within 30 days. The Table shows survey responses and associated readmission rates. None of the attitudes related to readmission were predictive of actual readmission. However, patients were able to predict their own readmissions (P = .002 for linear trend). After adjustment for expected readmission rate, race, sex, age, and payer, the trend remained significant (P = .005). Other significant predictors of readmissions in this model included expected readmission rate (P = .002), age (P = .02), and payer (P = .002). After dichotomizing the patient estimate of readmission rate as “unlikely” (N = 581) or “likely” (N = 314), the unadjusted odds ratio associating a patient-estimated risk of readmission as “likely” with actual readmission was 1.8 (95% confidence interval, 1.2-2.5). The adjusted odds ratio (including the variables above) was 1.6 (1.1-2.4).
DISCUSSION
Our findings demonstrate that patients are able to quantify their own readmission risk. This was true even after adjustment for expected readmission rate, age, sex, race, and payer. However, we did not identify any patient attitudes, beliefs, or preferences related to readmission or discharge instructions that were associated with subsequent rehospitalization. Reassuringly, more than 80% of patients who responded to the survey indicated that they would be sad, frustrated, or disappointed should readmission occur. This suggests that most patients are invested in preventing rehospitalization. Also reassuring was that patients indicated that they agreed with the discharge care plan and intended to follow their discharge instructions.
The major limitation of this study is that it was a convenience sample. Surveys were distributed inconsistently by nursing unit staff, preventing us from calculating a response rate. Further, it is possible, if not likely, that those patients with higher levels of engagement were more likely to take the time to respond, enriching our sample with activated patients. Although we allowed family members to fill out surveys on behalf of patients, this was done in fewer than 10% of instances; as such, our data may have limited applicability to patients who are physically or cognitively unable to participate in the discharge process. Finally, in this study, we did not capture readmissions to other facilities.
We conclude that patients are able to predict their own readmissions, even after accounting for other potential predictors of readmission. However, we found no evidence to support the possibility that low levels of engagement, limited trust in the healthcare team, or nonchalance about being readmitted are associated with subsequent rehospitalization. Whether asking patients about their perceived risk of readmission might help target readmission prevention programs deserves further study.
Acknowledgments
Dr. Daniel J. Brotman had full access to the data in the study and takes responsibility for the integrity of the study data and the accuracy of the data analysis. The authors also thank the following individuals for their contributions: Drafting the manuscript (Brotman); revising the manuscript for important intellectual content (Brotman, Shihab, Tieu, Cheng, Bertram, Hoyer, Deutschendorf); acquiring the data (Brotman, Shihab, Tieu, Cheng, Bertram, Deutschendorf); interpreting the data (Brotman, Shihab, Tieu, Cheng, Bertram, Hoyer, Deutschendorf); and analyzing the data (Brotman). The authors thank nursing leadership and nursing unit staff for their assistance in distributing surveys.
Funding support: Johns Hopkins Hospitalist Scholars Program
Disclosures: The authors have declared no conflicts of interest.
1. Hoyer EH, Brotman DJ, Apfel A, et al. Improving outcomes after hospitalization: a prospective observational multi-center evaluation of care-coordination strategies on 30-day readmissions to Maryland hospitals. J Gen Int Med. 2017 (in press). PubMed
2. Oduyebo I, Lehmann CU, Pollack CE, et al. Association of self-reported hospital discharge handoffs with 30-day readmissions. JAMA Intern Med. 2013;173(8):624-629. PubMed
3. Hoyer EH, Needham DM, Atanelov L, Knox B, Friedman M, Brotman DJ. Association of impaired functional status at hospital discharge and subsequent rehospitalization. J Hosp Med. 2014;9(5):277-282. PubMed
4. Hoyer EH, Needham DM, Miller J, Deutschendorf A, Friedman M, Brotman DJ. Functional status impairment is associated with unplanned readmissions. Arch Phys Med Rehabil. 2013;94(10):1951-1958. PubMed
5. Hoyer EH, Odonkor CA, Bhatia SN, Leung C, Deutschendorf A, Brotman DJ. Association between days to complete inpatient discharge summaries with all-payer hospital readmissions in Maryland. J Hosp Med. 2016;11(6):393-400. PubMed
Recent years have seen a proliferation of programs designed to prevent readmissions, including patient education initiatives, financial assistance programs, postdischarge services, and clinical personnel assigned to help patients navigate their posthospitalization clinical care. Although some strategies do not require direct patient participation (such as timely and effective handoffs between inpatient and outpatient care teams), many rely upon a commitment by the patient to participate in the postdischarge care plan. At our hospital, we have found that only about 2/3 of patients who are offered transitional interventions (such as postdischarge phone calls by nurses or home nursing through a “transition guide” program) receive the intended interventions, and those who do not receive them are more likely to be readmitted.1 While limited patient uptake may relate, in part, to factors that are difficult to overcome, such as inadequate housing or phone service, we have also encountered patients whose values, beliefs, or preferences about their care do not align with those of the care team. The purposes of this exploratory study were to (1) assess patient attitudes surrounding readmission, (2) ascertain whether these attitudes are associated with actual readmission, and (3) determine whether patients can estimate their own risk of readmission.
METHODS
From January 2014 to September 2016, we circulated surveys to patients on internal medicine nursing units who were being discharged home within 24 hours. Blank surveys were distributed to nursing units by the researchers. Unit clerks and support staff were educated on the purpose of the project and asked to distribute surveys to patients who were identified by unit case managers or nurses as slated for discharge. Staff members were not asked to help with or supervise survey completion. Surveys were generally filled out by patients, but we allowed family members to assist patients if needed, and to indicate so with a checkbox. There were no exclusion criteria. Because surveys were distributed by clinical staff, the received surveys can be considered a convenience sample. Patients were asked 5 questions with 4- or 5-point Likert scale responses:
(1) “How likely is it that you will be admitted to the hospital (have to stay in the hospital overnight) again within the next 30 days after you leave the hospital this time?” [answers ranging from “Very Unlikely (<5% chance)” to “Very Likely (>50% chance)”];
(2) “How would you feel about being rehospitalized in the next month?” [answers ranging from “Very sad, frustrated, or disappointed” to “Very happy or relieved”];
(3) “How much do you think that you personally can control whether or not you will be rehospitalized (based on what you do to take care of your body, take your medicines, and follow-up with your healthcare team)?” [answers ranging from “I have no control over whether I will be rehospitalized” to “I have complete control over whether I will be rehospitalized”];
(4) “Which of the options below best describes how you plan to follow the medical instructions after you leave the hospital?” [answers ranging from “I do NOT plan to do very much of what I am being asked to do by the doctors, nurses, therapists, and other members of the care team” to “I plan to do EVERYTHING I am being asked to do by the doctors, nurses, therapists and other members of the care team”]; and
(5) “Pick the item below that best describes YOUR OWN VIEW of the care team’s recommendations:” [answers ranging from “I DO NOT AGREE AT ALL that the best way to be healthy is to do exactly what I am being asked to do by the doctors, nurses, therapists, and other members of the care team” to “I FULLY AGREE that the best way to be healthy is to do exactly what I am being asked to do by the doctors, nurses, therapists, and other members of the care team”].
Responses were linked, based on discharge date and medical record number, to administrative data, including age, sex, race, payer, and clinical data. Subsequent hospitalizations to our hospital were ascertained from administrative data. We estimated expected risk of readmission using the all payer refined diagnosis related group coupled with the associated severity-of-illness (SOI) score, as we have reported previously.2-5 We restricted our analysis to patients who answered the question related to the likelihood of readmission. Logistic regression models were constructed using actual 30-day readmission as the dependent variable to determine whether patients could predict their own readmissions and whether patient attitudes and beliefs about their care were predictive of subsequent readmission. Patient survey responses were entered as continuous independent variables (ranging from 1-4 or 1-5, as appropriate). Multivariable logistic regression was used to determine whether patients could predict their readmissions independent of demographic variables and expected readmission rate (modeled continuously); we repeated this model after dichotomizing the patient’s estimate of the likelihood of readmission as either “unlikely” or “likely.” Patients with missing survey responses were excluded from individual models without imputation. The study was approved by the Johns Hopkins institutional review board.
RESULTS
Responses were obtained from 895 patients. Their median age was 56 years [interquartile range, 43-67], 51.4% were female, and 41.7% were white. Mean SOI was 2.53 (on a 1-4 scale), and median length-of-stay was representative for our medical service at 5.2 days (range, 1-66 days). Family members reported filling out the survey in 57 cases. The primary payer was Medicare in 40.7%, Medicaid in 24.9%, and other in 34.4%. A total of 138 patients (15.4%) were readmitted within 30 days. The Table shows survey responses and associated readmission rates. None of the attitudes related to readmission were predictive of actual readmission. However, patients were able to predict their own readmissions (P = .002 for linear trend). After adjustment for expected readmission rate, race, sex, age, and payer, the trend remained significant (P = .005). Other significant predictors of readmissions in this model included expected readmission rate (P = .002), age (P = .02), and payer (P = .002). After dichotomizing the patient estimate of readmission rate as “unlikely” (N = 581) or “likely” (N = 314), the unadjusted odds ratio associating a patient-estimated risk of readmission as “likely” with actual readmission was 1.8 (95% confidence interval, 1.2-2.5). The adjusted odds ratio (including the variables above) was 1.6 (1.1-2.4).
DISCUSSION
Our findings demonstrate that patients are able to quantify their own readmission risk. This was true even after adjustment for expected readmission rate, age, sex, race, and payer. However, we did not identify any patient attitudes, beliefs, or preferences related to readmission or discharge instructions that were associated with subsequent rehospitalization. Reassuringly, more than 80% of patients who responded to the survey indicated that they would be sad, frustrated, or disappointed should readmission occur. This suggests that most patients are invested in preventing rehospitalization. Also reassuring was that patients indicated that they agreed with the discharge care plan and intended to follow their discharge instructions.
The major limitation of this study is that it was a convenience sample. Surveys were distributed inconsistently by nursing unit staff, preventing us from calculating a response rate. Further, it is possible, if not likely, that those patients with higher levels of engagement were more likely to take the time to respond, enriching our sample with activated patients. Although we allowed family members to fill out surveys on behalf of patients, this was done in fewer than 10% of instances; as such, our data may have limited applicability to patients who are physically or cognitively unable to participate in the discharge process. Finally, in this study, we did not capture readmissions to other facilities.
We conclude that patients are able to predict their own readmissions, even after accounting for other potential predictors of readmission. However, we found no evidence to support the possibility that low levels of engagement, limited trust in the healthcare team, or nonchalance about being readmitted are associated with subsequent rehospitalization. Whether asking patients about their perceived risk of readmission might help target readmission prevention programs deserves further study.
Acknowledgments
Dr. Daniel J. Brotman had full access to the data in the study and takes responsibility for the integrity of the study data and the accuracy of the data analysis. The authors also thank the following individuals for their contributions: Drafting the manuscript (Brotman); revising the manuscript for important intellectual content (Brotman, Shihab, Tieu, Cheng, Bertram, Hoyer, Deutschendorf); acquiring the data (Brotman, Shihab, Tieu, Cheng, Bertram, Deutschendorf); interpreting the data (Brotman, Shihab, Tieu, Cheng, Bertram, Hoyer, Deutschendorf); and analyzing the data (Brotman). The authors thank nursing leadership and nursing unit staff for their assistance in distributing surveys.
Funding support: Johns Hopkins Hospitalist Scholars Program
Disclosures: The authors have declared no conflicts of interest.
Recent years have seen a proliferation of programs designed to prevent readmissions, including patient education initiatives, financial assistance programs, postdischarge services, and clinical personnel assigned to help patients navigate their posthospitalization clinical care. Although some strategies do not require direct patient participation (such as timely and effective handoffs between inpatient and outpatient care teams), many rely upon a commitment by the patient to participate in the postdischarge care plan. At our hospital, we have found that only about 2/3 of patients who are offered transitional interventions (such as postdischarge phone calls by nurses or home nursing through a “transition guide” program) receive the intended interventions, and those who do not receive them are more likely to be readmitted.1 While limited patient uptake may relate, in part, to factors that are difficult to overcome, such as inadequate housing or phone service, we have also encountered patients whose values, beliefs, or preferences about their care do not align with those of the care team. The purposes of this exploratory study were to (1) assess patient attitudes surrounding readmission, (2) ascertain whether these attitudes are associated with actual readmission, and (3) determine whether patients can estimate their own risk of readmission.
METHODS
From January 2014 to September 2016, we circulated surveys to patients on internal medicine nursing units who were being discharged home within 24 hours. Blank surveys were distributed to nursing units by the researchers. Unit clerks and support staff were educated on the purpose of the project and asked to distribute surveys to patients who were identified by unit case managers or nurses as slated for discharge. Staff members were not asked to help with or supervise survey completion. Surveys were generally filled out by patients, but we allowed family members to assist patients if needed, and to indicate so with a checkbox. There were no exclusion criteria. Because surveys were distributed by clinical staff, the received surveys can be considered a convenience sample. Patients were asked 5 questions with 4- or 5-point Likert scale responses:
(1) “How likely is it that you will be admitted to the hospital (have to stay in the hospital overnight) again within the next 30 days after you leave the hospital this time?” [answers ranging from “Very Unlikely (<5% chance)” to “Very Likely (>50% chance)”];
(2) “How would you feel about being rehospitalized in the next month?” [answers ranging from “Very sad, frustrated, or disappointed” to “Very happy or relieved”];
(3) “How much do you think that you personally can control whether or not you will be rehospitalized (based on what you do to take care of your body, take your medicines, and follow-up with your healthcare team)?” [answers ranging from “I have no control over whether I will be rehospitalized” to “I have complete control over whether I will be rehospitalized”];
(4) “Which of the options below best describes how you plan to follow the medical instructions after you leave the hospital?” [answers ranging from “I do NOT plan to do very much of what I am being asked to do by the doctors, nurses, therapists, and other members of the care team” to “I plan to do EVERYTHING I am being asked to do by the doctors, nurses, therapists and other members of the care team”]; and
(5) “Pick the item below that best describes YOUR OWN VIEW of the care team’s recommendations:” [answers ranging from “I DO NOT AGREE AT ALL that the best way to be healthy is to do exactly what I am being asked to do by the doctors, nurses, therapists, and other members of the care team” to “I FULLY AGREE that the best way to be healthy is to do exactly what I am being asked to do by the doctors, nurses, therapists, and other members of the care team”].
Responses were linked, based on discharge date and medical record number, to administrative data, including age, sex, race, payer, and clinical data. Subsequent hospitalizations to our hospital were ascertained from administrative data. We estimated expected risk of readmission using the all payer refined diagnosis related group coupled with the associated severity-of-illness (SOI) score, as we have reported previously.2-5 We restricted our analysis to patients who answered the question related to the likelihood of readmission. Logistic regression models were constructed using actual 30-day readmission as the dependent variable to determine whether patients could predict their own readmissions and whether patient attitudes and beliefs about their care were predictive of subsequent readmission. Patient survey responses were entered as continuous independent variables (ranging from 1-4 or 1-5, as appropriate). Multivariable logistic regression was used to determine whether patients could predict their readmissions independent of demographic variables and expected readmission rate (modeled continuously); we repeated this model after dichotomizing the patient’s estimate of the likelihood of readmission as either “unlikely” or “likely.” Patients with missing survey responses were excluded from individual models without imputation. The study was approved by the Johns Hopkins institutional review board.
RESULTS
Responses were obtained from 895 patients. Their median age was 56 years [interquartile range, 43-67], 51.4% were female, and 41.7% were white. Mean SOI was 2.53 (on a 1-4 scale), and median length-of-stay was representative for our medical service at 5.2 days (range, 1-66 days). Family members reported filling out the survey in 57 cases. The primary payer was Medicare in 40.7%, Medicaid in 24.9%, and other in 34.4%. A total of 138 patients (15.4%) were readmitted within 30 days. The Table shows survey responses and associated readmission rates. None of the attitudes related to readmission were predictive of actual readmission. However, patients were able to predict their own readmissions (P = .002 for linear trend). After adjustment for expected readmission rate, race, sex, age, and payer, the trend remained significant (P = .005). Other significant predictors of readmissions in this model included expected readmission rate (P = .002), age (P = .02), and payer (P = .002). After dichotomizing the patient estimate of readmission rate as “unlikely” (N = 581) or “likely” (N = 314), the unadjusted odds ratio associating a patient-estimated risk of readmission as “likely” with actual readmission was 1.8 (95% confidence interval, 1.2-2.5). The adjusted odds ratio (including the variables above) was 1.6 (1.1-2.4).
DISCUSSION
Our findings demonstrate that patients are able to quantify their own readmission risk. This was true even after adjustment for expected readmission rate, age, sex, race, and payer. However, we did not identify any patient attitudes, beliefs, or preferences related to readmission or discharge instructions that were associated with subsequent rehospitalization. Reassuringly, more than 80% of patients who responded to the survey indicated that they would be sad, frustrated, or disappointed should readmission occur. This suggests that most patients are invested in preventing rehospitalization. Also reassuring was that patients indicated that they agreed with the discharge care plan and intended to follow their discharge instructions.
The major limitation of this study is that it was a convenience sample. Surveys were distributed inconsistently by nursing unit staff, preventing us from calculating a response rate. Further, it is possible, if not likely, that those patients with higher levels of engagement were more likely to take the time to respond, enriching our sample with activated patients. Although we allowed family members to fill out surveys on behalf of patients, this was done in fewer than 10% of instances; as such, our data may have limited applicability to patients who are physically or cognitively unable to participate in the discharge process. Finally, in this study, we did not capture readmissions to other facilities.
We conclude that patients are able to predict their own readmissions, even after accounting for other potential predictors of readmission. However, we found no evidence to support the possibility that low levels of engagement, limited trust in the healthcare team, or nonchalance about being readmitted are associated with subsequent rehospitalization. Whether asking patients about their perceived risk of readmission might help target readmission prevention programs deserves further study.
Acknowledgments
Dr. Daniel J. Brotman had full access to the data in the study and takes responsibility for the integrity of the study data and the accuracy of the data analysis. The authors also thank the following individuals for their contributions: Drafting the manuscript (Brotman); revising the manuscript for important intellectual content (Brotman, Shihab, Tieu, Cheng, Bertram, Hoyer, Deutschendorf); acquiring the data (Brotman, Shihab, Tieu, Cheng, Bertram, Deutschendorf); interpreting the data (Brotman, Shihab, Tieu, Cheng, Bertram, Hoyer, Deutschendorf); and analyzing the data (Brotman). The authors thank nursing leadership and nursing unit staff for their assistance in distributing surveys.
Funding support: Johns Hopkins Hospitalist Scholars Program
Disclosures: The authors have declared no conflicts of interest.
1. Hoyer EH, Brotman DJ, Apfel A, et al. Improving outcomes after hospitalization: a prospective observational multi-center evaluation of care-coordination strategies on 30-day readmissions to Maryland hospitals. J Gen Int Med. 2017 (in press). PubMed
2. Oduyebo I, Lehmann CU, Pollack CE, et al. Association of self-reported hospital discharge handoffs with 30-day readmissions. JAMA Intern Med. 2013;173(8):624-629. PubMed
3. Hoyer EH, Needham DM, Atanelov L, Knox B, Friedman M, Brotman DJ. Association of impaired functional status at hospital discharge and subsequent rehospitalization. J Hosp Med. 2014;9(5):277-282. PubMed
4. Hoyer EH, Needham DM, Miller J, Deutschendorf A, Friedman M, Brotman DJ. Functional status impairment is associated with unplanned readmissions. Arch Phys Med Rehabil. 2013;94(10):1951-1958. PubMed
5. Hoyer EH, Odonkor CA, Bhatia SN, Leung C, Deutschendorf A, Brotman DJ. Association between days to complete inpatient discharge summaries with all-payer hospital readmissions in Maryland. J Hosp Med. 2016;11(6):393-400. PubMed
1. Hoyer EH, Brotman DJ, Apfel A, et al. Improving outcomes after hospitalization: a prospective observational multi-center evaluation of care-coordination strategies on 30-day readmissions to Maryland hospitals. J Gen Int Med. 2017 (in press). PubMed
2. Oduyebo I, Lehmann CU, Pollack CE, et al. Association of self-reported hospital discharge handoffs with 30-day readmissions. JAMA Intern Med. 2013;173(8):624-629. PubMed
3. Hoyer EH, Needham DM, Atanelov L, Knox B, Friedman M, Brotman DJ. Association of impaired functional status at hospital discharge and subsequent rehospitalization. J Hosp Med. 2014;9(5):277-282. PubMed
4. Hoyer EH, Needham DM, Miller J, Deutschendorf A, Friedman M, Brotman DJ. Functional status impairment is associated with unplanned readmissions. Arch Phys Med Rehabil. 2013;94(10):1951-1958. PubMed
5. Hoyer EH, Odonkor CA, Bhatia SN, Leung C, Deutschendorf A, Brotman DJ. Association between days to complete inpatient discharge summaries with all-payer hospital readmissions in Maryland. J Hosp Med. 2016;11(6):393-400. PubMed
© 2018 Society of Hospital Medicine
The Johns Hopkins VTE Collaborative
Venous thromboembolism (VTE), which encompasses deep venous thrombosis and pulmonary embolism, is an important cause of preventable morbidity and mortality.[1] Each year it is estimated as many as 600,000 American's suffer VTE and as many as 100,000 die.[2] Consequently, patient safety and healthcare quality, accrediting organizations such as The Joint Commission, and federal agencies such as the Centers for Disease Control and Prevention and Agency for Healthcare Research and Quality (AHRQ) have made VTE prevention a priority.[3, 4, 5]
Despite widespread recognition that VTE prophylaxis is an important patient safety measure, poor performance is common. The ENDORSE (Epidemiologic International Day for the Evaluation of Patients at Risk for Venous Thromboembolism in the Acute Hospital Care Setting) study of over 68,000 hospitalized patients in 32 countries noted only 58.5% of surgical patients and 39.5% medical patients received American College of Chest Physicians (ACCP) guideline‐appropriate VTE prophylaxis.[6] In 2005, an audit of the surgical services at The Johns Hopkins Hospital found that only 33% of 322 randomly selected patients were prescribed prophylaxis consistent with the ACCP guidelines.
Achieving defect‐free VTE prevention requires attention to each step in the process: (1) assessment of both VTE and bleeding risk, (2) prescription of risk‐appropriate VTE prophylaxis, and (3) administration of risk‐appropriate VTE prophylaxis. In 2005, to improve our VTE prevention performance at Johns Hopkins Hospital, the Center for Innovations organized a VTE Collaborative of 2 physicians, 1 nurse, and 1 pharmacist dedicated to VTE quality improvement. Since then, the group has grown dramatically, adding a clinical informatics expert and numerous other members and coming under the auspices of The Armstrong Institute for Patient Safety. Recognizing that many, though not all, VTEs are potentially preventable,[7, 8] the mission of the Johns Hopkins VTE Collaborative is to ensure that all hospitalized patients receive risk‐appropriate, best‐practice VTE prophylaxis. This article chronicles the innovative strategies that the Johns Hopkins VTE Collaborative has employed over the past decade to improve our hospital's performance in VTE prevention (Table 1).
|
| Strategies to improve VTE prophylaxis ordering |
| Paper‐based patient risk assessment forms (before computer order entry) |
| Mandatory evidence‐based specialty‐specific computer clinical decision support smart order sets |
| Group data and competitions |
| 1‐on‐1 provider feedback |
| Pay for performance |
| Individualized feedback with resident scorecards |
| Strategies to improve VTE prophylaxis administration |
| Identification of missed doses as a major contributor to preventable VTE |
| Identification of physician, nurse and patient contributors to missed doses |
| Collaboration with patients to create patient‐centered educational materials |
| Novel web‐based module for nursing education |
| Real‐time missed doses alert |
| Targeted 1‐on‐1 patient education |
ENSURING EVERY PATIENT IS PRESCRIBED RISK‐APPROPRIATE PROPHYLAXIS
With the support of hospital leadership, the VTE Collaborative held a series of events in 2005 with medical and surgical providers to review the current evidence supporting VTE prophylaxis and achieve consensus on appropriate practice based upon the 2004 ACCP VTE Prophylaxis Guideline. The result was the development of 5 evidence‐based, paper VTE prophylaxis order sets that guided the ordering provider on the assessment of VTE and bleeding risk and facilitated the selection of risk‐appropriate VTE prophylaxis. Because there were no validated VTE or bleeding risk assessment tools at the time we developed our order sets, we used specialty‐specific VTE risk factors derived from the 2004 ACCP Guideline. To identify patients inappropriate for pharmacologic prophylaxis, we used exclusion criteria derived from contemporary randomized clinical trials of pharmacologic prophylaxis in the target populations (ie, active bleeding, abnormal activated partial thromboplastin time not due to a lupus inhibitor) or mutually agreed upon thresholds after discussion with individual provider groups (platelet count <50,000/L). On the Johns Hopkins Hospital inpatient acute rehabilitation unit, introduction of the paper order sets increased adherence with ACCP guidelines from 27% to 98% (P < 0.0001) and reduced symptomatic VTE from 49 per 1000 admissions to 8 per 1000 admissions (P = 0.0001).[9] This study demonstrated that paper order sets used consistently by a dedicated group of providers can result in sustained improvements in practice. Paper order sets remain a low‐tech, easy‐to‐implement strategy that can be applied in any healthcare setting. Other services also saw improvements in risk‐appropriate prophylaxis prescription. In a follow‐up cross‐sectional analysis of the surgical services at Johns Hopkins, we found that appropriate VTE prophylaxis prescription improved from 33% to 62% in a sample of 226 patients. Unfortunately, paper order sets had several disadvantages including (1) the inherent difficulty of making them a mandatory part of the admission or transfer process, (2) their existence outside the usual clinical workflow, and (3) the labor‐ and time‐intensive data collection that made it difficult to provide credible, timely performance reports to providers and leadership.
These disadvantages and our adoption of a computerized provider order entry system prompted us to pursue the development and implementation of mandatory, evidence‐based, specialty‐specific computerized clinical decision support (CCDS) VTE prophylaxis order sets. Using the Translating Research Into Practice approach to quality improvement,[10] we collaborated with providers to design 16 different evidence‐based specialty‐specific CCDS VTE order sets. These CCDS VTE order sets, which are imbedded in the specialty‐specific admission and transfer order sets, assist providers in assessing patients' VTE and bleeding risk factors and provide evidence‐based risk‐appropriate VTE prophylaxis (see Supporting Figure 1 in the online version of this article). Individual patient data are saved in an administrative database and can be easily aggregated for research analyses and quality improvement/performance reporting. A detailed discussion of our strategy for change is discussed in Streiff et al.[11] Because pharmacologic prophylaxis is not appropriate for every patient, and not all VTE are preventable, even with perfect prophylaxis, the goals of our collaborative are to ensure that every patient is ordered VTE prophylaxis consistent with their risk profile (risk‐appropriate prophylaxis) and to eliminate preventable episodes of VTE (VTE that occurs in the setting of suboptimal prophylaxis). In a prepost quasi‐experimental study of 1599 trauma patients, the CCDS VTE order set increased risk‐appropriate prophylaxis prescription from 66.2% to 84.4% (P < .001) and reduced the incidence of potentially preventable harm from VTE from 1% to 0.17% (P = 0.04) (Figure 1).[12] On the medical service, the CCDS VTE order set improved risk‐appropriate VTE prophylaxis prescription from 65.6% to 90.1% (P < 0.0001) and reduced the incidence of potentially preventable harm attributable to VTE from 1.1% to 0% (P = 0.001). There was no increase in major bleeding (International Society of Thrombosis and Hemostasis definition: hemoglobin decline of 2 grams/dL or transfusion of 2 or more units of blood or bleeding into a critical organ such as brain, gastrointestinal tract, or eye) postorder set implementation (0.3% vs 0.1%, P = 0.625) or all‐cause mortality (1.3% vs 2.0%, P = 0.285).[13]
These order sets demonstrated that CCDS tools can lead to significant improvements in prescribing practices and reductions in preventable harm from VTE without increasing the risk of major bleeding complications. In addition to improving the quality of care, the order sets also improved the consistency of care. In a retrospective analysis, we found that implementation of CCDS VTE order sets eliminated racial disparities in prescribing practices. In the preimplementation group, risk‐appropriate VTE prophylaxis was prescribed for 70.1% of black patients and 56.6% of white patients on the trauma service (P = 0.025) and 69.5% of black patients and 61.7% of white patients on the medical service (P = 0.015). After implementation of the CCDS VTE order sets, care improved for all patients such that the previously observed disparities were eliminated (trauma service 84.5% vs 85.5%, P = 0.99 and medical service 91.8% vs 88.0%, P = 0.082).[14] These data indicate that standardizing care can potentially eliminate disparities in clinical practice.
Although implementation of mandatory evidence‐based, specialty‐specific CDSS VTE order sets led to substantial improvements in VTE prophylaxis ordering, high performance was not uniform across our institution. On the medical service, substantial disparities in adherence to order set recommendations existed. On the housestaff services, over 90% of patients consistently received risk‐appropriate VTE prophylaxis compared with only 85% on the hospitalist service. Examination of individual provider performance found that some providers only ordered risk‐appropriate prophylaxis 50% of the time, whereas others were doing so 98% of the time. To address this disparity, we conducted a retrospective analysis of a prospective performance improvement project conducted on the Johns Hopkins Hospitalist service studying the impact of individualized hospitalist attending feedback on VTE prevention practices. During the preintervention period (January 2009December 2010), guideline‐adherent VTE prophylaxis was ordered for 86% (95% confidence interval [CI]: 85%‐88%) of patients. Six months after initiation of direct face‐to‐face provider feedback (January 2011June 2011), guideline‐adherent VTE prophylaxis rates rose to 90% (95% CI: 88‐93). Subsequently (July 2011December 2012), a pay‐for‐performance (P4P) initiative was added to direct face‐to‐face provider feedback. During the P4P initiative, provider incentive per relative value unit (RVU) was progressively increased with increasing performance on provision of risk‐appropriate VTE prophylaxis (adherence <80% = no bonus to $0.50 per RVU for adherence 95%). During this period, prescription of guideline‐adherent prophylaxis rose to 94% (95% CI: 93%‐96%).[15] These initiatives transformed the hospitalist unit from a consistently low‐performance unit to a high‐performance unit.
Similar findings were noted on the trauma service. Although the original plan was to provide feedback to attending trauma surgeons, that plan changed when we found that performance was driven entirely by resident practice; residents write the VTE prophylaxis orders, which is then attributed to attending performance. Resident performance varied widely; 42 of 75 (56%) residents on the trauma service ordered risk‐appropriate prophylaxis for 100% of their patients. In contrast, 7 (9.3%) residents never ordered optimal prophylaxis for any of their patients.[16] To motivate all residents to prescribe optimal prophylaxis, we developed an individualized resident VTE prophylaxis scorecard (Figure 2). This prospective cohort study of 2420 patients and 49 general surgery residents compared resident VTE prophylaxis performance on the general surgery service during 3 periods: period 1 (baseline, July 2013September 2013), period 2 (surgery resident scorecard, October 2013December 2013), period 3 (resident scorecard plus individualized 1‐on‐1 coaching, January 2014March 2014). At baseline, 89.4% of patients were prescribed appropriate VTE prophylaxis, and only 45% of residents prescribed risk‐appropriate prophylaxis for all their patients. During the scorecard period, 95.4% of patients were prescribed risk‐appropriate VTE prophylaxis (P < 0.001). During the scorecard plus coaching period, risk‐appropriate prophylaxis rose to 96.4%. These prescribing practice changes were durable. During the 15 months prior to issuing scorecards, 88.0% of patients (3718/4226) were prescribed risk‐appropriate prophylaxis. After implementation, 95.8% of patients (3799/3966) were prescribed risk‐appropriate prophylaxis (P < 0.001) (see Supporting Figure 2 in the online version of this article). During the baseline period, 7 of 865 patients (0.81%) had a VTE during their hospital stay, of which 3 (0.35%) were potentially preventable. In contrast, none of the 3 of 784 patients who suffered VTE during the postimplementation period had a potentially preventable event (0.35% vs 0%, P = 0.046).[17] These studies demonstrate that providing physicians with their own specific data can be a powerful tool for performance improvement that may be applicable to many other quality and safety measures. Our group recently received funding from the AHRQ to scale this work to other residents, nurse practitioners, physician assistants, and attending physicians (1R01HS024547, Individualized Performance Feedback on Venous Thromboembolism Prevention Practice).
IMPROVING VTE PROPHYLAXIS ADMINISTRATION
Ordering VTE prophylaxis does not ensure its administration. We conducted a retrospective review of electronic administration records of 10,526 consecutive patients admitted over a 7‐month period at The Johns Hopkins Hospital. Twelve percent of the over 100,000 ordered doses of VTE prophylaxis were not administered, and the proportion of nonadministered doses on individual floors varied 5‐fold from 5.4% to 26.9%. The proportion of nonadministered doses was significantly higher on medical floors compared with all other services (17.5% vs 8.1%, odds ratio [OR]: 2.1 [95% CI: 2.0‐2.2]). Patient or family member refusal was the most common cause for nonadministered doses of VTE prophylaxis accounting for 59% of all missed doses. Eight percent of patients missed more than half their prescribed doses, and 5% of patients missed over 75% of ordered doses of VTE prophylaxis. Consistent with the Pareto principle, over 80% of the missed doses of prophylaxis were accounted for by just 20% of the patients.[18] A retrospective analysis of hospital‐acquired VTE at Johns Hopkins found that 39% of events occurred in patients who missed 1 or more doses of appropriate VTE prophylaxis.[19] Louis et al. noted that nonadministration of 1 dose of VTE prophylaxis was associated with a significant increase in risk for hospital acquired VTE.[20] These data indicate the need for more aggressive interventions to reduce missed doses to improve VTE prevention.
To fully understand the root causes of VTE prophylaxis non‐administration, we conducted a series of studies examining each of the participants in the VTE prevention care pathway, physicians, nurses, and patients. In a survey of 122 resident physicians, we found significant differences in clinical practice between medicine and surgery residents. Medicine residents were more likely to believe that VTE prophylaxis was overprescribed, and that it was appropriate for nurses to make judgement calls about whether patients needed the prophylaxis that was prescribed.[21] In a mixed methods study that included a written survey and qualitative observations of nursing practice, we found that some nurses presented pharmacologic VTE prophylaxis injections as optional to patients. Furthermore, nurses on units where nonadministration was higher were more likely to believe that VTE prophylaxis was prescribed for patients unnecessarily, and that they could use their clinical judgement to determine when it was appropriate to omit doses of pharmacologic prophylaxis.[22] Our team also examined patient preferences in regard to VTE prophylaxis. In a survey of 227 consecutive medical and surgical inpatients, we found that 60% of patients would prefer an oral route of administration if available. Patients with a preference for a parenteral route of administration (27.5%) were less likely to refuse prophylaxis (37.5% vs 51.3%, P < 0.0001).[23] These findings underscore the fact that unit culture, nursing attitudes and beliefs, and patient preferences have an important influence on medication administration, and that nursepatient communication is an important target for modifying adherence.
PATIENT‐CENTERED APPROACHES TO IMPROVE VTE PROPHYLAXIS ADMINISTRATION
To address nurse‐ and patient‐related factors that influence VTE prophylaxis administration, we applied for and received a Patient Centered Outcomes Research Institute contract to develop patient‐centered interventions to engage and empower patients to take an active role in their preventive care. To achieve these aims, we partnered with 3 national patient advocacy organizations, the National Blood Clot Alliance, the North American Thrombosis Forum, and ClotCare, as well as our local Johns Hopkins Patient and Family Advisory Council. Using a modified Delphi method, we engaged patient stakeholders from the 4 collaborating organizations to build consensus on patient‐centered VTE education methods. Input from this Delphi assessment was used to build educational materials including paper brochures published in 8 different languages and a 10‐minute educational video filmed by an Oscar‐winning documentary director featuring both clinicians and patients relating their VTE experience and the importance of VTE prevention.[24] These educational materials are available for public use (
ENGAGING TRAINEES IN MULTIDISCIPLINARY PATIENT SAFETY/QUALITY IMPROVEMENT INITIATIVES
Trainees from many healthcare‐related disciplines have played a critical role in our quest to improve VTE prevention. Over the past 10 years, we have mentored countless medical students, public health graduate students, nursing students, residents, and postdoctoral fellows in research projects that have resulted in numerous high‐quality publications. Trainees have helped to dispel staff concerns about patient falls in connection of intermittent pneumatic compression devices,[25] identify the weaknesses of current publicly reported VTE measures,[26, 27, 28, 29] identify opportunities to improve VTE prevention practices within clinical specialties,[30, 31, 32] define the role of surveillance bias in VTE outcomes reporting,[33, 34, 35] discover and fully explore the important problem of missed doses of VTE prophylaxis,[18, 21, 22, 23, 36] and summarize knowledge about VTE prevention via systematic reviews and meta‐analyses.[37, 38, 39] These collaborations have been a classic win‐win. The mentees learn critical skills while growing their curriculum vitae with contributions to the literature, allowing them to progress in their careers (ie, obtain a residency match, faculty positions). The faculty have leveraged this work to obtain over $3 million in extramural funding to develop interventions to study and improve the quality of VTE preventive care for hospitalized patients.
In healthcare, we have not yet achieved defect‐free VTE prevention; however, we have a better understanding of the path to accomplishing this goal. In this article we describe our goal of zero harm from VTE and our learning journey to realize that goal. Although the journey never ends, a critical ingredient to the success of our program has been the multidisciplinary nature of our VTE collaborative team. The combination of expertise from medicine, surgery, nursing, pharmacy, clinical informatics, and public health has facilitated the development of innovative strategies to improve VTE prevention that integrate seamlessly into clinical workflow. The approach used for VTE can be applied to eliminate other types of harms.
Disclosures
Mr. Lau, Dr. Streiff, and Dr. Haut are supported by a grant from the Agency for Healthcare Research and Quality (1R01HS024547) titled Individualized Performance Feedback on Venous Thromboembolism Prevention Practice and a contract from the Patient‐Centered Outcomes Research Institute titled Preventing Venous Thromboembolism: Empowering Patients and Enabling Patient‐Centered Care via Health Information Technology (CE‐12‐11‐4489). Mr. Lau is supported by the Institute for Excellence in Education Berkheimer Faculty Education Scholar Grant and a contract (AD‐1306‐03980) from the Patient‐Centered Outcomes Research Institute titled Patient Centered Approaches to Collect Sexual Orientation/Gender Identity Information in the Emergency Department. Ms. Hobson has given expert witness testimony in various medical malpractice cases. Dr. Streiff has received research funding from Portola and Janssen; consulted for Bio2Medical, CSL Behring, Merck, and Janssen HealthCare; and has given expert witness testimony in various medical malpractice cases. Dr. Haut receives royalties from Lippincott, Williams, and Wilkins for a book titled Avoiding Common ICU Errors. Dr. Haut is a paid consultant and speaker for the Preventing Avoidable Venous ThromboembolismEvery Patient, Every Time VHA/Vizient IMPERATIV Advantage Performance Improvement Collaborative. Dr. Haut is a paid consultant and speaker for the Illinois Surgical Quality Improvement Collaborative. All other authors report no disclosures.
- , . Thromboprophylaxis in nonsurgical patients. Hematology Am Soc Hematol Educ Program. 2012;2012:631–637.
- Office of the Surgeon General (US); National Heart, Lung, and Blood Institute (US). The Surgeon General's Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism. Rockville, MD: Office of the Surgeon General; 2008.
- , . Prevention of venous thromboembolism: brief update review. In: Making Health Care Safer II: An Updated Critical Analysis of the Evidence for Patient Safety Practices. Rockville, MD: Agency for Healthcare Research and Quality; 2013.
- , , , et al. The top patient safety strategies that can be encouraged for adoption now. Ann Intern Med. 2013;158:365–368.
- , . Practices to prevent venous thromboembolism: a brief review. BMJ Qual Saf. 2014;23:187–195.
- , , , et al. Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross‐sectional study. Lancet. 2008;371:387–394.
- , . The CMS ruling on venous thromboembolism after total knee or hip arthroplasty: weighing risks and benefits. JAMA. 2009;301:1063–1065.
- , , , et al. ICD‐9 code‐based venous thromboembolism performance targets fail to measure up. Am J Med Qual. 2016;31(5):448–453.
- , , , , . Evidence‐based venous thromboembolism prophylaxis is associated with a six‐fold decrease in numbers of symptomatic venous thromboembolisms in rehabilitation inpatients. PM R. 2011;3:1111–1115.e1.
- , , . Translating evidence into practice: a model for large scale knowledge translation. BMJ. 2008;337:a1714.
- , , , et al. Lessons from the Johns Hopkins Multi‐Disciplinary Venous Thromboembolism (VTE) Prevention Collaborative. BMJ. 2012;344:e3935.
- , , , et al. Improved prophylaxis and decreased rates of preventable harm with the use of a mandatory computerized clinical decision support tool for prophylaxis for venous thromboembolism in trauma. Arch Surg. 2012;147:901–907.
- , , , et al. Impact of a venous thromboembolism prophylaxis “smart order set”: improved compliance, fewer events. Am J Hematol. 2013;88(7):545–549.
- , , , et al. Eliminating health care disparities with mandatory clinical decision support: the venous thromboembolism (VTE) example. Med Care. 2015;53:18–24.
- , , , et al. Use of provider‐level dashboards and pay‐for‐performance in venous thromboembolism prophylaxis. J Hosp Med. 2015;10:172–178.
- , , , , , . Attending physician performance measure scores and resident physicians' ordering practices. JAMA Surg. 2015;150:813–814.
- , , , et al. Individualized performance feedback to surgical residents improves appropriate venous thromboembolism prophylaxis prescription and reduces potentially preventable VTE: a prospective cohort study [published online November 25, 2015]. Ann Surg. doi: 10.1097/SLA.0000000000001512.
- , , , et al. Patterns of non‐administration of ordered doses of venous thromboembolism prophylaxis: implications for novel intervention strategies. PLoS One. 2013;8:e66311.
- , , , et al. Preventability of hospital‐acquired venous thromboembolism. JAMA Surg. 2015;150(9):912–915.
- , , , et al. Correlation of missed doses of enoxaparin with increased incidence of deep vein thrombosis in trauma and general surgery patients. JAMA Surg. 2014;149:365–370.
- , , , et al. Prescriber knowledge and attitudes regarding non‐administration of prescribed pharmacologic venous thromboembolism prophylaxis [published online May 21, 2016]. J Thromb Thrombolysis. doi:10.1007/s11239-016-1378-8.
- , , , et al. Hidden barriers to delivery of pharmacological venous thromboembolism prophylaxis: the role of nursing beliefs and practices. J Patient Saf. 2016;12:63–68.
- , , , et al. Patient preferences regarding pharmacologic venous thromboembolism prophylaxis. J Hosp Med. 2015;10:108–111.
- , , , et al. Patient preferences for receiving education on venous thromboembolism prevention—a survey of stakeholder organizations. PLoS One. 2016;11:e0152084.
- , , , , , . Are sequential compression devices commonly associated with in‐hospital falls? A myth‐busters review using the patient safety net database. J Patient Saf. 2011;7:77–79.
- , , , , . No association between hospital‐reported perioperative venous thromboembolism prophylaxis and outcome rates in publicly reported data. JAMA Surg. 2014;149:400–401.
- , , , , . Linking processes and outcomes: a key strategy to prevent and report harm from venous thromboembolism in surgical patients. JAMA Surg. 2013;148:299–300.
- , , , et al. Hazards of benchmarking complications with the National Trauma Data Bank: numerators in search of denominators. J Trauma. 2008;64:273–277; discussion 277–279.
- , , , et al. Is the meaningful use venous thromboembolism VTE‐6 measure meaningful? A retrospective analysis of one hospital's VTE‐6 cases. Jt Comm J Qual Patient Saf. 2016;42(9):410–416.
- , , , et al. Is venous thromboembolism in colorectal surgery patients preventable or inevitable? One institution's experience. J Am Coll Surg. 2013;216:395–401.e1.
- , , , et al. Venous thromboembolic prophylaxis after a hepatic resection: patterns of care among liver surgeons. HPB (Oxford). 2014;16:892–898.
- , , , et al. Defining incidence and risk factors of venous thromboembolism after hepatectomy. J Gastrointest Surg. 2014;18:1116–1124.
- , , , et al. Can increased incidence of deep vein thrombosis (DVT) be used as a marker of quality of care in the absence of standardized screening? The potential effect of surveillance bias on reported DVT rates after trauma. J Trauma. 2007;63:1132–1135; discussion 1135–1137.
- , . Surveillance bias in outcomes reporting. JAMA. 2011;305:2462–2463.
- , , , et al. Surveillance bias and deep vein thrombosis in the national trauma data bank: the more we look, the more we find. J Trauma. 2008;64:932–936; discussion 936–937.
- , , , et al. Nonadministration of thromboprophylaxis in hospitalized patients with HIV: a missed opportunity for prevention? J Hosp Med. 2014;9:215–220.
- , , , et al. Pharmacologic and mechanical prophylaxis of venous thromboembolism among special populations. Comparative effectiveness review No. 116. Prepared by the Johns Hopkins University Evidence‐based Practice Center under Contract No. 290‐2007‐10061‐I.) AHRQ Publication No. 13‐EHC082–1. Rockville, MD: Agency for Healthcare Research and Quality; 2013.
- , , , et al. Pharmacologic and mechanical strategies for preventing venous thromboembolism after bariatric surgery: a systematic review and meta‐analysis. JAMA Surg. 2013;148:675–686.
- , , , et al. The effectiveness of prophylactic inferior vena cava filters in trauma patients: a systematic review and meta‐analysis. JAMA Surg. 2014;149:194–202.
Venous thromboembolism (VTE), which encompasses deep venous thrombosis and pulmonary embolism, is an important cause of preventable morbidity and mortality.[1] Each year it is estimated as many as 600,000 American's suffer VTE and as many as 100,000 die.[2] Consequently, patient safety and healthcare quality, accrediting organizations such as The Joint Commission, and federal agencies such as the Centers for Disease Control and Prevention and Agency for Healthcare Research and Quality (AHRQ) have made VTE prevention a priority.[3, 4, 5]
Despite widespread recognition that VTE prophylaxis is an important patient safety measure, poor performance is common. The ENDORSE (Epidemiologic International Day for the Evaluation of Patients at Risk for Venous Thromboembolism in the Acute Hospital Care Setting) study of over 68,000 hospitalized patients in 32 countries noted only 58.5% of surgical patients and 39.5% medical patients received American College of Chest Physicians (ACCP) guideline‐appropriate VTE prophylaxis.[6] In 2005, an audit of the surgical services at The Johns Hopkins Hospital found that only 33% of 322 randomly selected patients were prescribed prophylaxis consistent with the ACCP guidelines.
Achieving defect‐free VTE prevention requires attention to each step in the process: (1) assessment of both VTE and bleeding risk, (2) prescription of risk‐appropriate VTE prophylaxis, and (3) administration of risk‐appropriate VTE prophylaxis. In 2005, to improve our VTE prevention performance at Johns Hopkins Hospital, the Center for Innovations organized a VTE Collaborative of 2 physicians, 1 nurse, and 1 pharmacist dedicated to VTE quality improvement. Since then, the group has grown dramatically, adding a clinical informatics expert and numerous other members and coming under the auspices of The Armstrong Institute for Patient Safety. Recognizing that many, though not all, VTEs are potentially preventable,[7, 8] the mission of the Johns Hopkins VTE Collaborative is to ensure that all hospitalized patients receive risk‐appropriate, best‐practice VTE prophylaxis. This article chronicles the innovative strategies that the Johns Hopkins VTE Collaborative has employed over the past decade to improve our hospital's performance in VTE prevention (Table 1).
|
| Strategies to improve VTE prophylaxis ordering |
| Paper‐based patient risk assessment forms (before computer order entry) |
| Mandatory evidence‐based specialty‐specific computer clinical decision support smart order sets |
| Group data and competitions |
| 1‐on‐1 provider feedback |
| Pay for performance |
| Individualized feedback with resident scorecards |
| Strategies to improve VTE prophylaxis administration |
| Identification of missed doses as a major contributor to preventable VTE |
| Identification of physician, nurse and patient contributors to missed doses |
| Collaboration with patients to create patient‐centered educational materials |
| Novel web‐based module for nursing education |
| Real‐time missed doses alert |
| Targeted 1‐on‐1 patient education |
ENSURING EVERY PATIENT IS PRESCRIBED RISK‐APPROPRIATE PROPHYLAXIS
With the support of hospital leadership, the VTE Collaborative held a series of events in 2005 with medical and surgical providers to review the current evidence supporting VTE prophylaxis and achieve consensus on appropriate practice based upon the 2004 ACCP VTE Prophylaxis Guideline. The result was the development of 5 evidence‐based, paper VTE prophylaxis order sets that guided the ordering provider on the assessment of VTE and bleeding risk and facilitated the selection of risk‐appropriate VTE prophylaxis. Because there were no validated VTE or bleeding risk assessment tools at the time we developed our order sets, we used specialty‐specific VTE risk factors derived from the 2004 ACCP Guideline. To identify patients inappropriate for pharmacologic prophylaxis, we used exclusion criteria derived from contemporary randomized clinical trials of pharmacologic prophylaxis in the target populations (ie, active bleeding, abnormal activated partial thromboplastin time not due to a lupus inhibitor) or mutually agreed upon thresholds after discussion with individual provider groups (platelet count <50,000/L). On the Johns Hopkins Hospital inpatient acute rehabilitation unit, introduction of the paper order sets increased adherence with ACCP guidelines from 27% to 98% (P < 0.0001) and reduced symptomatic VTE from 49 per 1000 admissions to 8 per 1000 admissions (P = 0.0001).[9] This study demonstrated that paper order sets used consistently by a dedicated group of providers can result in sustained improvements in practice. Paper order sets remain a low‐tech, easy‐to‐implement strategy that can be applied in any healthcare setting. Other services also saw improvements in risk‐appropriate prophylaxis prescription. In a follow‐up cross‐sectional analysis of the surgical services at Johns Hopkins, we found that appropriate VTE prophylaxis prescription improved from 33% to 62% in a sample of 226 patients. Unfortunately, paper order sets had several disadvantages including (1) the inherent difficulty of making them a mandatory part of the admission or transfer process, (2) their existence outside the usual clinical workflow, and (3) the labor‐ and time‐intensive data collection that made it difficult to provide credible, timely performance reports to providers and leadership.
These disadvantages and our adoption of a computerized provider order entry system prompted us to pursue the development and implementation of mandatory, evidence‐based, specialty‐specific computerized clinical decision support (CCDS) VTE prophylaxis order sets. Using the Translating Research Into Practice approach to quality improvement,[10] we collaborated with providers to design 16 different evidence‐based specialty‐specific CCDS VTE order sets. These CCDS VTE order sets, which are imbedded in the specialty‐specific admission and transfer order sets, assist providers in assessing patients' VTE and bleeding risk factors and provide evidence‐based risk‐appropriate VTE prophylaxis (see Supporting Figure 1 in the online version of this article). Individual patient data are saved in an administrative database and can be easily aggregated for research analyses and quality improvement/performance reporting. A detailed discussion of our strategy for change is discussed in Streiff et al.[11] Because pharmacologic prophylaxis is not appropriate for every patient, and not all VTE are preventable, even with perfect prophylaxis, the goals of our collaborative are to ensure that every patient is ordered VTE prophylaxis consistent with their risk profile (risk‐appropriate prophylaxis) and to eliminate preventable episodes of VTE (VTE that occurs in the setting of suboptimal prophylaxis). In a prepost quasi‐experimental study of 1599 trauma patients, the CCDS VTE order set increased risk‐appropriate prophylaxis prescription from 66.2% to 84.4% (P < .001) and reduced the incidence of potentially preventable harm from VTE from 1% to 0.17% (P = 0.04) (Figure 1).[12] On the medical service, the CCDS VTE order set improved risk‐appropriate VTE prophylaxis prescription from 65.6% to 90.1% (P < 0.0001) and reduced the incidence of potentially preventable harm attributable to VTE from 1.1% to 0% (P = 0.001). There was no increase in major bleeding (International Society of Thrombosis and Hemostasis definition: hemoglobin decline of 2 grams/dL or transfusion of 2 or more units of blood or bleeding into a critical organ such as brain, gastrointestinal tract, or eye) postorder set implementation (0.3% vs 0.1%, P = 0.625) or all‐cause mortality (1.3% vs 2.0%, P = 0.285).[13]
These order sets demonstrated that CCDS tools can lead to significant improvements in prescribing practices and reductions in preventable harm from VTE without increasing the risk of major bleeding complications. In addition to improving the quality of care, the order sets also improved the consistency of care. In a retrospective analysis, we found that implementation of CCDS VTE order sets eliminated racial disparities in prescribing practices. In the preimplementation group, risk‐appropriate VTE prophylaxis was prescribed for 70.1% of black patients and 56.6% of white patients on the trauma service (P = 0.025) and 69.5% of black patients and 61.7% of white patients on the medical service (P = 0.015). After implementation of the CCDS VTE order sets, care improved for all patients such that the previously observed disparities were eliminated (trauma service 84.5% vs 85.5%, P = 0.99 and medical service 91.8% vs 88.0%, P = 0.082).[14] These data indicate that standardizing care can potentially eliminate disparities in clinical practice.
Although implementation of mandatory evidence‐based, specialty‐specific CDSS VTE order sets led to substantial improvements in VTE prophylaxis ordering, high performance was not uniform across our institution. On the medical service, substantial disparities in adherence to order set recommendations existed. On the housestaff services, over 90% of patients consistently received risk‐appropriate VTE prophylaxis compared with only 85% on the hospitalist service. Examination of individual provider performance found that some providers only ordered risk‐appropriate prophylaxis 50% of the time, whereas others were doing so 98% of the time. To address this disparity, we conducted a retrospective analysis of a prospective performance improvement project conducted on the Johns Hopkins Hospitalist service studying the impact of individualized hospitalist attending feedback on VTE prevention practices. During the preintervention period (January 2009December 2010), guideline‐adherent VTE prophylaxis was ordered for 86% (95% confidence interval [CI]: 85%‐88%) of patients. Six months after initiation of direct face‐to‐face provider feedback (January 2011June 2011), guideline‐adherent VTE prophylaxis rates rose to 90% (95% CI: 88‐93). Subsequently (July 2011December 2012), a pay‐for‐performance (P4P) initiative was added to direct face‐to‐face provider feedback. During the P4P initiative, provider incentive per relative value unit (RVU) was progressively increased with increasing performance on provision of risk‐appropriate VTE prophylaxis (adherence <80% = no bonus to $0.50 per RVU for adherence 95%). During this period, prescription of guideline‐adherent prophylaxis rose to 94% (95% CI: 93%‐96%).[15] These initiatives transformed the hospitalist unit from a consistently low‐performance unit to a high‐performance unit.
Similar findings were noted on the trauma service. Although the original plan was to provide feedback to attending trauma surgeons, that plan changed when we found that performance was driven entirely by resident practice; residents write the VTE prophylaxis orders, which is then attributed to attending performance. Resident performance varied widely; 42 of 75 (56%) residents on the trauma service ordered risk‐appropriate prophylaxis for 100% of their patients. In contrast, 7 (9.3%) residents never ordered optimal prophylaxis for any of their patients.[16] To motivate all residents to prescribe optimal prophylaxis, we developed an individualized resident VTE prophylaxis scorecard (Figure 2). This prospective cohort study of 2420 patients and 49 general surgery residents compared resident VTE prophylaxis performance on the general surgery service during 3 periods: period 1 (baseline, July 2013September 2013), period 2 (surgery resident scorecard, October 2013December 2013), period 3 (resident scorecard plus individualized 1‐on‐1 coaching, January 2014March 2014). At baseline, 89.4% of patients were prescribed appropriate VTE prophylaxis, and only 45% of residents prescribed risk‐appropriate prophylaxis for all their patients. During the scorecard period, 95.4% of patients were prescribed risk‐appropriate VTE prophylaxis (P < 0.001). During the scorecard plus coaching period, risk‐appropriate prophylaxis rose to 96.4%. These prescribing practice changes were durable. During the 15 months prior to issuing scorecards, 88.0% of patients (3718/4226) were prescribed risk‐appropriate prophylaxis. After implementation, 95.8% of patients (3799/3966) were prescribed risk‐appropriate prophylaxis (P < 0.001) (see Supporting Figure 2 in the online version of this article). During the baseline period, 7 of 865 patients (0.81%) had a VTE during their hospital stay, of which 3 (0.35%) were potentially preventable. In contrast, none of the 3 of 784 patients who suffered VTE during the postimplementation period had a potentially preventable event (0.35% vs 0%, P = 0.046).[17] These studies demonstrate that providing physicians with their own specific data can be a powerful tool for performance improvement that may be applicable to many other quality and safety measures. Our group recently received funding from the AHRQ to scale this work to other residents, nurse practitioners, physician assistants, and attending physicians (1R01HS024547, Individualized Performance Feedback on Venous Thromboembolism Prevention Practice).
IMPROVING VTE PROPHYLAXIS ADMINISTRATION
Ordering VTE prophylaxis does not ensure its administration. We conducted a retrospective review of electronic administration records of 10,526 consecutive patients admitted over a 7‐month period at The Johns Hopkins Hospital. Twelve percent of the over 100,000 ordered doses of VTE prophylaxis were not administered, and the proportion of nonadministered doses on individual floors varied 5‐fold from 5.4% to 26.9%. The proportion of nonadministered doses was significantly higher on medical floors compared with all other services (17.5% vs 8.1%, odds ratio [OR]: 2.1 [95% CI: 2.0‐2.2]). Patient or family member refusal was the most common cause for nonadministered doses of VTE prophylaxis accounting for 59% of all missed doses. Eight percent of patients missed more than half their prescribed doses, and 5% of patients missed over 75% of ordered doses of VTE prophylaxis. Consistent with the Pareto principle, over 80% of the missed doses of prophylaxis were accounted for by just 20% of the patients.[18] A retrospective analysis of hospital‐acquired VTE at Johns Hopkins found that 39% of events occurred in patients who missed 1 or more doses of appropriate VTE prophylaxis.[19] Louis et al. noted that nonadministration of 1 dose of VTE prophylaxis was associated with a significant increase in risk for hospital acquired VTE.[20] These data indicate the need for more aggressive interventions to reduce missed doses to improve VTE prevention.
To fully understand the root causes of VTE prophylaxis non‐administration, we conducted a series of studies examining each of the participants in the VTE prevention care pathway, physicians, nurses, and patients. In a survey of 122 resident physicians, we found significant differences in clinical practice between medicine and surgery residents. Medicine residents were more likely to believe that VTE prophylaxis was overprescribed, and that it was appropriate for nurses to make judgement calls about whether patients needed the prophylaxis that was prescribed.[21] In a mixed methods study that included a written survey and qualitative observations of nursing practice, we found that some nurses presented pharmacologic VTE prophylaxis injections as optional to patients. Furthermore, nurses on units where nonadministration was higher were more likely to believe that VTE prophylaxis was prescribed for patients unnecessarily, and that they could use their clinical judgement to determine when it was appropriate to omit doses of pharmacologic prophylaxis.[22] Our team also examined patient preferences in regard to VTE prophylaxis. In a survey of 227 consecutive medical and surgical inpatients, we found that 60% of patients would prefer an oral route of administration if available. Patients with a preference for a parenteral route of administration (27.5%) were less likely to refuse prophylaxis (37.5% vs 51.3%, P < 0.0001).[23] These findings underscore the fact that unit culture, nursing attitudes and beliefs, and patient preferences have an important influence on medication administration, and that nursepatient communication is an important target for modifying adherence.
PATIENT‐CENTERED APPROACHES TO IMPROVE VTE PROPHYLAXIS ADMINISTRATION
To address nurse‐ and patient‐related factors that influence VTE prophylaxis administration, we applied for and received a Patient Centered Outcomes Research Institute contract to develop patient‐centered interventions to engage and empower patients to take an active role in their preventive care. To achieve these aims, we partnered with 3 national patient advocacy organizations, the National Blood Clot Alliance, the North American Thrombosis Forum, and ClotCare, as well as our local Johns Hopkins Patient and Family Advisory Council. Using a modified Delphi method, we engaged patient stakeholders from the 4 collaborating organizations to build consensus on patient‐centered VTE education methods. Input from this Delphi assessment was used to build educational materials including paper brochures published in 8 different languages and a 10‐minute educational video filmed by an Oscar‐winning documentary director featuring both clinicians and patients relating their VTE experience and the importance of VTE prevention.[24] These educational materials are available for public use (
ENGAGING TRAINEES IN MULTIDISCIPLINARY PATIENT SAFETY/QUALITY IMPROVEMENT INITIATIVES
Trainees from many healthcare‐related disciplines have played a critical role in our quest to improve VTE prevention. Over the past 10 years, we have mentored countless medical students, public health graduate students, nursing students, residents, and postdoctoral fellows in research projects that have resulted in numerous high‐quality publications. Trainees have helped to dispel staff concerns about patient falls in connection of intermittent pneumatic compression devices,[25] identify the weaknesses of current publicly reported VTE measures,[26, 27, 28, 29] identify opportunities to improve VTE prevention practices within clinical specialties,[30, 31, 32] define the role of surveillance bias in VTE outcomes reporting,[33, 34, 35] discover and fully explore the important problem of missed doses of VTE prophylaxis,[18, 21, 22, 23, 36] and summarize knowledge about VTE prevention via systematic reviews and meta‐analyses.[37, 38, 39] These collaborations have been a classic win‐win. The mentees learn critical skills while growing their curriculum vitae with contributions to the literature, allowing them to progress in their careers (ie, obtain a residency match, faculty positions). The faculty have leveraged this work to obtain over $3 million in extramural funding to develop interventions to study and improve the quality of VTE preventive care for hospitalized patients.
In healthcare, we have not yet achieved defect‐free VTE prevention; however, we have a better understanding of the path to accomplishing this goal. In this article we describe our goal of zero harm from VTE and our learning journey to realize that goal. Although the journey never ends, a critical ingredient to the success of our program has been the multidisciplinary nature of our VTE collaborative team. The combination of expertise from medicine, surgery, nursing, pharmacy, clinical informatics, and public health has facilitated the development of innovative strategies to improve VTE prevention that integrate seamlessly into clinical workflow. The approach used for VTE can be applied to eliminate other types of harms.
Disclosures
Mr. Lau, Dr. Streiff, and Dr. Haut are supported by a grant from the Agency for Healthcare Research and Quality (1R01HS024547) titled Individualized Performance Feedback on Venous Thromboembolism Prevention Practice and a contract from the Patient‐Centered Outcomes Research Institute titled Preventing Venous Thromboembolism: Empowering Patients and Enabling Patient‐Centered Care via Health Information Technology (CE‐12‐11‐4489). Mr. Lau is supported by the Institute for Excellence in Education Berkheimer Faculty Education Scholar Grant and a contract (AD‐1306‐03980) from the Patient‐Centered Outcomes Research Institute titled Patient Centered Approaches to Collect Sexual Orientation/Gender Identity Information in the Emergency Department. Ms. Hobson has given expert witness testimony in various medical malpractice cases. Dr. Streiff has received research funding from Portola and Janssen; consulted for Bio2Medical, CSL Behring, Merck, and Janssen HealthCare; and has given expert witness testimony in various medical malpractice cases. Dr. Haut receives royalties from Lippincott, Williams, and Wilkins for a book titled Avoiding Common ICU Errors. Dr. Haut is a paid consultant and speaker for the Preventing Avoidable Venous ThromboembolismEvery Patient, Every Time VHA/Vizient IMPERATIV Advantage Performance Improvement Collaborative. Dr. Haut is a paid consultant and speaker for the Illinois Surgical Quality Improvement Collaborative. All other authors report no disclosures.
Venous thromboembolism (VTE), which encompasses deep venous thrombosis and pulmonary embolism, is an important cause of preventable morbidity and mortality.[1] Each year it is estimated as many as 600,000 American's suffer VTE and as many as 100,000 die.[2] Consequently, patient safety and healthcare quality, accrediting organizations such as The Joint Commission, and federal agencies such as the Centers for Disease Control and Prevention and Agency for Healthcare Research and Quality (AHRQ) have made VTE prevention a priority.[3, 4, 5]
Despite widespread recognition that VTE prophylaxis is an important patient safety measure, poor performance is common. The ENDORSE (Epidemiologic International Day for the Evaluation of Patients at Risk for Venous Thromboembolism in the Acute Hospital Care Setting) study of over 68,000 hospitalized patients in 32 countries noted only 58.5% of surgical patients and 39.5% medical patients received American College of Chest Physicians (ACCP) guideline‐appropriate VTE prophylaxis.[6] In 2005, an audit of the surgical services at The Johns Hopkins Hospital found that only 33% of 322 randomly selected patients were prescribed prophylaxis consistent with the ACCP guidelines.
Achieving defect‐free VTE prevention requires attention to each step in the process: (1) assessment of both VTE and bleeding risk, (2) prescription of risk‐appropriate VTE prophylaxis, and (3) administration of risk‐appropriate VTE prophylaxis. In 2005, to improve our VTE prevention performance at Johns Hopkins Hospital, the Center for Innovations organized a VTE Collaborative of 2 physicians, 1 nurse, and 1 pharmacist dedicated to VTE quality improvement. Since then, the group has grown dramatically, adding a clinical informatics expert and numerous other members and coming under the auspices of The Armstrong Institute for Patient Safety. Recognizing that many, though not all, VTEs are potentially preventable,[7, 8] the mission of the Johns Hopkins VTE Collaborative is to ensure that all hospitalized patients receive risk‐appropriate, best‐practice VTE prophylaxis. This article chronicles the innovative strategies that the Johns Hopkins VTE Collaborative has employed over the past decade to improve our hospital's performance in VTE prevention (Table 1).
|
| Strategies to improve VTE prophylaxis ordering |
| Paper‐based patient risk assessment forms (before computer order entry) |
| Mandatory evidence‐based specialty‐specific computer clinical decision support smart order sets |
| Group data and competitions |
| 1‐on‐1 provider feedback |
| Pay for performance |
| Individualized feedback with resident scorecards |
| Strategies to improve VTE prophylaxis administration |
| Identification of missed doses as a major contributor to preventable VTE |
| Identification of physician, nurse and patient contributors to missed doses |
| Collaboration with patients to create patient‐centered educational materials |
| Novel web‐based module for nursing education |
| Real‐time missed doses alert |
| Targeted 1‐on‐1 patient education |
ENSURING EVERY PATIENT IS PRESCRIBED RISK‐APPROPRIATE PROPHYLAXIS
With the support of hospital leadership, the VTE Collaborative held a series of events in 2005 with medical and surgical providers to review the current evidence supporting VTE prophylaxis and achieve consensus on appropriate practice based upon the 2004 ACCP VTE Prophylaxis Guideline. The result was the development of 5 evidence‐based, paper VTE prophylaxis order sets that guided the ordering provider on the assessment of VTE and bleeding risk and facilitated the selection of risk‐appropriate VTE prophylaxis. Because there were no validated VTE or bleeding risk assessment tools at the time we developed our order sets, we used specialty‐specific VTE risk factors derived from the 2004 ACCP Guideline. To identify patients inappropriate for pharmacologic prophylaxis, we used exclusion criteria derived from contemporary randomized clinical trials of pharmacologic prophylaxis in the target populations (ie, active bleeding, abnormal activated partial thromboplastin time not due to a lupus inhibitor) or mutually agreed upon thresholds after discussion with individual provider groups (platelet count <50,000/L). On the Johns Hopkins Hospital inpatient acute rehabilitation unit, introduction of the paper order sets increased adherence with ACCP guidelines from 27% to 98% (P < 0.0001) and reduced symptomatic VTE from 49 per 1000 admissions to 8 per 1000 admissions (P = 0.0001).[9] This study demonstrated that paper order sets used consistently by a dedicated group of providers can result in sustained improvements in practice. Paper order sets remain a low‐tech, easy‐to‐implement strategy that can be applied in any healthcare setting. Other services also saw improvements in risk‐appropriate prophylaxis prescription. In a follow‐up cross‐sectional analysis of the surgical services at Johns Hopkins, we found that appropriate VTE prophylaxis prescription improved from 33% to 62% in a sample of 226 patients. Unfortunately, paper order sets had several disadvantages including (1) the inherent difficulty of making them a mandatory part of the admission or transfer process, (2) their existence outside the usual clinical workflow, and (3) the labor‐ and time‐intensive data collection that made it difficult to provide credible, timely performance reports to providers and leadership.
These disadvantages and our adoption of a computerized provider order entry system prompted us to pursue the development and implementation of mandatory, evidence‐based, specialty‐specific computerized clinical decision support (CCDS) VTE prophylaxis order sets. Using the Translating Research Into Practice approach to quality improvement,[10] we collaborated with providers to design 16 different evidence‐based specialty‐specific CCDS VTE order sets. These CCDS VTE order sets, which are imbedded in the specialty‐specific admission and transfer order sets, assist providers in assessing patients' VTE and bleeding risk factors and provide evidence‐based risk‐appropriate VTE prophylaxis (see Supporting Figure 1 in the online version of this article). Individual patient data are saved in an administrative database and can be easily aggregated for research analyses and quality improvement/performance reporting. A detailed discussion of our strategy for change is discussed in Streiff et al.[11] Because pharmacologic prophylaxis is not appropriate for every patient, and not all VTE are preventable, even with perfect prophylaxis, the goals of our collaborative are to ensure that every patient is ordered VTE prophylaxis consistent with their risk profile (risk‐appropriate prophylaxis) and to eliminate preventable episodes of VTE (VTE that occurs in the setting of suboptimal prophylaxis). In a prepost quasi‐experimental study of 1599 trauma patients, the CCDS VTE order set increased risk‐appropriate prophylaxis prescription from 66.2% to 84.4% (P < .001) and reduced the incidence of potentially preventable harm from VTE from 1% to 0.17% (P = 0.04) (Figure 1).[12] On the medical service, the CCDS VTE order set improved risk‐appropriate VTE prophylaxis prescription from 65.6% to 90.1% (P < 0.0001) and reduced the incidence of potentially preventable harm attributable to VTE from 1.1% to 0% (P = 0.001). There was no increase in major bleeding (International Society of Thrombosis and Hemostasis definition: hemoglobin decline of 2 grams/dL or transfusion of 2 or more units of blood or bleeding into a critical organ such as brain, gastrointestinal tract, or eye) postorder set implementation (0.3% vs 0.1%, P = 0.625) or all‐cause mortality (1.3% vs 2.0%, P = 0.285).[13]
These order sets demonstrated that CCDS tools can lead to significant improvements in prescribing practices and reductions in preventable harm from VTE without increasing the risk of major bleeding complications. In addition to improving the quality of care, the order sets also improved the consistency of care. In a retrospective analysis, we found that implementation of CCDS VTE order sets eliminated racial disparities in prescribing practices. In the preimplementation group, risk‐appropriate VTE prophylaxis was prescribed for 70.1% of black patients and 56.6% of white patients on the trauma service (P = 0.025) and 69.5% of black patients and 61.7% of white patients on the medical service (P = 0.015). After implementation of the CCDS VTE order sets, care improved for all patients such that the previously observed disparities were eliminated (trauma service 84.5% vs 85.5%, P = 0.99 and medical service 91.8% vs 88.0%, P = 0.082).[14] These data indicate that standardizing care can potentially eliminate disparities in clinical practice.
Although implementation of mandatory evidence‐based, specialty‐specific CDSS VTE order sets led to substantial improvements in VTE prophylaxis ordering, high performance was not uniform across our institution. On the medical service, substantial disparities in adherence to order set recommendations existed. On the housestaff services, over 90% of patients consistently received risk‐appropriate VTE prophylaxis compared with only 85% on the hospitalist service. Examination of individual provider performance found that some providers only ordered risk‐appropriate prophylaxis 50% of the time, whereas others were doing so 98% of the time. To address this disparity, we conducted a retrospective analysis of a prospective performance improvement project conducted on the Johns Hopkins Hospitalist service studying the impact of individualized hospitalist attending feedback on VTE prevention practices. During the preintervention period (January 2009December 2010), guideline‐adherent VTE prophylaxis was ordered for 86% (95% confidence interval [CI]: 85%‐88%) of patients. Six months after initiation of direct face‐to‐face provider feedback (January 2011June 2011), guideline‐adherent VTE prophylaxis rates rose to 90% (95% CI: 88‐93). Subsequently (July 2011December 2012), a pay‐for‐performance (P4P) initiative was added to direct face‐to‐face provider feedback. During the P4P initiative, provider incentive per relative value unit (RVU) was progressively increased with increasing performance on provision of risk‐appropriate VTE prophylaxis (adherence <80% = no bonus to $0.50 per RVU for adherence 95%). During this period, prescription of guideline‐adherent prophylaxis rose to 94% (95% CI: 93%‐96%).[15] These initiatives transformed the hospitalist unit from a consistently low‐performance unit to a high‐performance unit.
Similar findings were noted on the trauma service. Although the original plan was to provide feedback to attending trauma surgeons, that plan changed when we found that performance was driven entirely by resident practice; residents write the VTE prophylaxis orders, which is then attributed to attending performance. Resident performance varied widely; 42 of 75 (56%) residents on the trauma service ordered risk‐appropriate prophylaxis for 100% of their patients. In contrast, 7 (9.3%) residents never ordered optimal prophylaxis for any of their patients.[16] To motivate all residents to prescribe optimal prophylaxis, we developed an individualized resident VTE prophylaxis scorecard (Figure 2). This prospective cohort study of 2420 patients and 49 general surgery residents compared resident VTE prophylaxis performance on the general surgery service during 3 periods: period 1 (baseline, July 2013September 2013), period 2 (surgery resident scorecard, October 2013December 2013), period 3 (resident scorecard plus individualized 1‐on‐1 coaching, January 2014March 2014). At baseline, 89.4% of patients were prescribed appropriate VTE prophylaxis, and only 45% of residents prescribed risk‐appropriate prophylaxis for all their patients. During the scorecard period, 95.4% of patients were prescribed risk‐appropriate VTE prophylaxis (P < 0.001). During the scorecard plus coaching period, risk‐appropriate prophylaxis rose to 96.4%. These prescribing practice changes were durable. During the 15 months prior to issuing scorecards, 88.0% of patients (3718/4226) were prescribed risk‐appropriate prophylaxis. After implementation, 95.8% of patients (3799/3966) were prescribed risk‐appropriate prophylaxis (P < 0.001) (see Supporting Figure 2 in the online version of this article). During the baseline period, 7 of 865 patients (0.81%) had a VTE during their hospital stay, of which 3 (0.35%) were potentially preventable. In contrast, none of the 3 of 784 patients who suffered VTE during the postimplementation period had a potentially preventable event (0.35% vs 0%, P = 0.046).[17] These studies demonstrate that providing physicians with their own specific data can be a powerful tool for performance improvement that may be applicable to many other quality and safety measures. Our group recently received funding from the AHRQ to scale this work to other residents, nurse practitioners, physician assistants, and attending physicians (1R01HS024547, Individualized Performance Feedback on Venous Thromboembolism Prevention Practice).
IMPROVING VTE PROPHYLAXIS ADMINISTRATION
Ordering VTE prophylaxis does not ensure its administration. We conducted a retrospective review of electronic administration records of 10,526 consecutive patients admitted over a 7‐month period at The Johns Hopkins Hospital. Twelve percent of the over 100,000 ordered doses of VTE prophylaxis were not administered, and the proportion of nonadministered doses on individual floors varied 5‐fold from 5.4% to 26.9%. The proportion of nonadministered doses was significantly higher on medical floors compared with all other services (17.5% vs 8.1%, odds ratio [OR]: 2.1 [95% CI: 2.0‐2.2]). Patient or family member refusal was the most common cause for nonadministered doses of VTE prophylaxis accounting for 59% of all missed doses. Eight percent of patients missed more than half their prescribed doses, and 5% of patients missed over 75% of ordered doses of VTE prophylaxis. Consistent with the Pareto principle, over 80% of the missed doses of prophylaxis were accounted for by just 20% of the patients.[18] A retrospective analysis of hospital‐acquired VTE at Johns Hopkins found that 39% of events occurred in patients who missed 1 or more doses of appropriate VTE prophylaxis.[19] Louis et al. noted that nonadministration of 1 dose of VTE prophylaxis was associated with a significant increase in risk for hospital acquired VTE.[20] These data indicate the need for more aggressive interventions to reduce missed doses to improve VTE prevention.
To fully understand the root causes of VTE prophylaxis non‐administration, we conducted a series of studies examining each of the participants in the VTE prevention care pathway, physicians, nurses, and patients. In a survey of 122 resident physicians, we found significant differences in clinical practice between medicine and surgery residents. Medicine residents were more likely to believe that VTE prophylaxis was overprescribed, and that it was appropriate for nurses to make judgement calls about whether patients needed the prophylaxis that was prescribed.[21] In a mixed methods study that included a written survey and qualitative observations of nursing practice, we found that some nurses presented pharmacologic VTE prophylaxis injections as optional to patients. Furthermore, nurses on units where nonadministration was higher were more likely to believe that VTE prophylaxis was prescribed for patients unnecessarily, and that they could use their clinical judgement to determine when it was appropriate to omit doses of pharmacologic prophylaxis.[22] Our team also examined patient preferences in regard to VTE prophylaxis. In a survey of 227 consecutive medical and surgical inpatients, we found that 60% of patients would prefer an oral route of administration if available. Patients with a preference for a parenteral route of administration (27.5%) were less likely to refuse prophylaxis (37.5% vs 51.3%, P < 0.0001).[23] These findings underscore the fact that unit culture, nursing attitudes and beliefs, and patient preferences have an important influence on medication administration, and that nursepatient communication is an important target for modifying adherence.
PATIENT‐CENTERED APPROACHES TO IMPROVE VTE PROPHYLAXIS ADMINISTRATION
To address nurse‐ and patient‐related factors that influence VTE prophylaxis administration, we applied for and received a Patient Centered Outcomes Research Institute contract to develop patient‐centered interventions to engage and empower patients to take an active role in their preventive care. To achieve these aims, we partnered with 3 national patient advocacy organizations, the National Blood Clot Alliance, the North American Thrombosis Forum, and ClotCare, as well as our local Johns Hopkins Patient and Family Advisory Council. Using a modified Delphi method, we engaged patient stakeholders from the 4 collaborating organizations to build consensus on patient‐centered VTE education methods. Input from this Delphi assessment was used to build educational materials including paper brochures published in 8 different languages and a 10‐minute educational video filmed by an Oscar‐winning documentary director featuring both clinicians and patients relating their VTE experience and the importance of VTE prevention.[24] These educational materials are available for public use (
ENGAGING TRAINEES IN MULTIDISCIPLINARY PATIENT SAFETY/QUALITY IMPROVEMENT INITIATIVES
Trainees from many healthcare‐related disciplines have played a critical role in our quest to improve VTE prevention. Over the past 10 years, we have mentored countless medical students, public health graduate students, nursing students, residents, and postdoctoral fellows in research projects that have resulted in numerous high‐quality publications. Trainees have helped to dispel staff concerns about patient falls in connection of intermittent pneumatic compression devices,[25] identify the weaknesses of current publicly reported VTE measures,[26, 27, 28, 29] identify opportunities to improve VTE prevention practices within clinical specialties,[30, 31, 32] define the role of surveillance bias in VTE outcomes reporting,[33, 34, 35] discover and fully explore the important problem of missed doses of VTE prophylaxis,[18, 21, 22, 23, 36] and summarize knowledge about VTE prevention via systematic reviews and meta‐analyses.[37, 38, 39] These collaborations have been a classic win‐win. The mentees learn critical skills while growing their curriculum vitae with contributions to the literature, allowing them to progress in their careers (ie, obtain a residency match, faculty positions). The faculty have leveraged this work to obtain over $3 million in extramural funding to develop interventions to study and improve the quality of VTE preventive care for hospitalized patients.
In healthcare, we have not yet achieved defect‐free VTE prevention; however, we have a better understanding of the path to accomplishing this goal. In this article we describe our goal of zero harm from VTE and our learning journey to realize that goal. Although the journey never ends, a critical ingredient to the success of our program has been the multidisciplinary nature of our VTE collaborative team. The combination of expertise from medicine, surgery, nursing, pharmacy, clinical informatics, and public health has facilitated the development of innovative strategies to improve VTE prevention that integrate seamlessly into clinical workflow. The approach used for VTE can be applied to eliminate other types of harms.
Disclosures
Mr. Lau, Dr. Streiff, and Dr. Haut are supported by a grant from the Agency for Healthcare Research and Quality (1R01HS024547) titled Individualized Performance Feedback on Venous Thromboembolism Prevention Practice and a contract from the Patient‐Centered Outcomes Research Institute titled Preventing Venous Thromboembolism: Empowering Patients and Enabling Patient‐Centered Care via Health Information Technology (CE‐12‐11‐4489). Mr. Lau is supported by the Institute for Excellence in Education Berkheimer Faculty Education Scholar Grant and a contract (AD‐1306‐03980) from the Patient‐Centered Outcomes Research Institute titled Patient Centered Approaches to Collect Sexual Orientation/Gender Identity Information in the Emergency Department. Ms. Hobson has given expert witness testimony in various medical malpractice cases. Dr. Streiff has received research funding from Portola and Janssen; consulted for Bio2Medical, CSL Behring, Merck, and Janssen HealthCare; and has given expert witness testimony in various medical malpractice cases. Dr. Haut receives royalties from Lippincott, Williams, and Wilkins for a book titled Avoiding Common ICU Errors. Dr. Haut is a paid consultant and speaker for the Preventing Avoidable Venous ThromboembolismEvery Patient, Every Time VHA/Vizient IMPERATIV Advantage Performance Improvement Collaborative. Dr. Haut is a paid consultant and speaker for the Illinois Surgical Quality Improvement Collaborative. All other authors report no disclosures.
- , . Thromboprophylaxis in nonsurgical patients. Hematology Am Soc Hematol Educ Program. 2012;2012:631–637.
- Office of the Surgeon General (US); National Heart, Lung, and Blood Institute (US). The Surgeon General's Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism. Rockville, MD: Office of the Surgeon General; 2008.
- , . Prevention of venous thromboembolism: brief update review. In: Making Health Care Safer II: An Updated Critical Analysis of the Evidence for Patient Safety Practices. Rockville, MD: Agency for Healthcare Research and Quality; 2013.
- , , , et al. The top patient safety strategies that can be encouraged for adoption now. Ann Intern Med. 2013;158:365–368.
- , . Practices to prevent venous thromboembolism: a brief review. BMJ Qual Saf. 2014;23:187–195.
- , , , et al. Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross‐sectional study. Lancet. 2008;371:387–394.
- , . The CMS ruling on venous thromboembolism after total knee or hip arthroplasty: weighing risks and benefits. JAMA. 2009;301:1063–1065.
- , , , et al. ICD‐9 code‐based venous thromboembolism performance targets fail to measure up. Am J Med Qual. 2016;31(5):448–453.
- , , , , . Evidence‐based venous thromboembolism prophylaxis is associated with a six‐fold decrease in numbers of symptomatic venous thromboembolisms in rehabilitation inpatients. PM R. 2011;3:1111–1115.e1.
- , , . Translating evidence into practice: a model for large scale knowledge translation. BMJ. 2008;337:a1714.
- , , , et al. Lessons from the Johns Hopkins Multi‐Disciplinary Venous Thromboembolism (VTE) Prevention Collaborative. BMJ. 2012;344:e3935.
- , , , et al. Improved prophylaxis and decreased rates of preventable harm with the use of a mandatory computerized clinical decision support tool for prophylaxis for venous thromboembolism in trauma. Arch Surg. 2012;147:901–907.
- , , , et al. Impact of a venous thromboembolism prophylaxis “smart order set”: improved compliance, fewer events. Am J Hematol. 2013;88(7):545–549.
- , , , et al. Eliminating health care disparities with mandatory clinical decision support: the venous thromboembolism (VTE) example. Med Care. 2015;53:18–24.
- , , , et al. Use of provider‐level dashboards and pay‐for‐performance in venous thromboembolism prophylaxis. J Hosp Med. 2015;10:172–178.
- , , , , , . Attending physician performance measure scores and resident physicians' ordering practices. JAMA Surg. 2015;150:813–814.
- , , , et al. Individualized performance feedback to surgical residents improves appropriate venous thromboembolism prophylaxis prescription and reduces potentially preventable VTE: a prospective cohort study [published online November 25, 2015]. Ann Surg. doi: 10.1097/SLA.0000000000001512.
- , , , et al. Patterns of non‐administration of ordered doses of venous thromboembolism prophylaxis: implications for novel intervention strategies. PLoS One. 2013;8:e66311.
- , , , et al. Preventability of hospital‐acquired venous thromboembolism. JAMA Surg. 2015;150(9):912–915.
- , , , et al. Correlation of missed doses of enoxaparin with increased incidence of deep vein thrombosis in trauma and general surgery patients. JAMA Surg. 2014;149:365–370.
- , , , et al. Prescriber knowledge and attitudes regarding non‐administration of prescribed pharmacologic venous thromboembolism prophylaxis [published online May 21, 2016]. J Thromb Thrombolysis. doi:10.1007/s11239-016-1378-8.
- , , , et al. Hidden barriers to delivery of pharmacological venous thromboembolism prophylaxis: the role of nursing beliefs and practices. J Patient Saf. 2016;12:63–68.
- , , , et al. Patient preferences regarding pharmacologic venous thromboembolism prophylaxis. J Hosp Med. 2015;10:108–111.
- , , , et al. Patient preferences for receiving education on venous thromboembolism prevention—a survey of stakeholder organizations. PLoS One. 2016;11:e0152084.
- , , , , , . Are sequential compression devices commonly associated with in‐hospital falls? A myth‐busters review using the patient safety net database. J Patient Saf. 2011;7:77–79.
- , , , , . No association between hospital‐reported perioperative venous thromboembolism prophylaxis and outcome rates in publicly reported data. JAMA Surg. 2014;149:400–401.
- , , , , . Linking processes and outcomes: a key strategy to prevent and report harm from venous thromboembolism in surgical patients. JAMA Surg. 2013;148:299–300.
- , , , et al. Hazards of benchmarking complications with the National Trauma Data Bank: numerators in search of denominators. J Trauma. 2008;64:273–277; discussion 277–279.
- , , , et al. Is the meaningful use venous thromboembolism VTE‐6 measure meaningful? A retrospective analysis of one hospital's VTE‐6 cases. Jt Comm J Qual Patient Saf. 2016;42(9):410–416.
- , , , et al. Is venous thromboembolism in colorectal surgery patients preventable or inevitable? One institution's experience. J Am Coll Surg. 2013;216:395–401.e1.
- , , , et al. Venous thromboembolic prophylaxis after a hepatic resection: patterns of care among liver surgeons. HPB (Oxford). 2014;16:892–898.
- , , , et al. Defining incidence and risk factors of venous thromboembolism after hepatectomy. J Gastrointest Surg. 2014;18:1116–1124.
- , , , et al. Can increased incidence of deep vein thrombosis (DVT) be used as a marker of quality of care in the absence of standardized screening? The potential effect of surveillance bias on reported DVT rates after trauma. J Trauma. 2007;63:1132–1135; discussion 1135–1137.
- , . Surveillance bias in outcomes reporting. JAMA. 2011;305:2462–2463.
- , , , et al. Surveillance bias and deep vein thrombosis in the national trauma data bank: the more we look, the more we find. J Trauma. 2008;64:932–936; discussion 936–937.
- , , , et al. Nonadministration of thromboprophylaxis in hospitalized patients with HIV: a missed opportunity for prevention? J Hosp Med. 2014;9:215–220.
- , , , et al. Pharmacologic and mechanical prophylaxis of venous thromboembolism among special populations. Comparative effectiveness review No. 116. Prepared by the Johns Hopkins University Evidence‐based Practice Center under Contract No. 290‐2007‐10061‐I.) AHRQ Publication No. 13‐EHC082–1. Rockville, MD: Agency for Healthcare Research and Quality; 2013.
- , , , et al. Pharmacologic and mechanical strategies for preventing venous thromboembolism after bariatric surgery: a systematic review and meta‐analysis. JAMA Surg. 2013;148:675–686.
- , , , et al. The effectiveness of prophylactic inferior vena cava filters in trauma patients: a systematic review and meta‐analysis. JAMA Surg. 2014;149:194–202.
- , . Thromboprophylaxis in nonsurgical patients. Hematology Am Soc Hematol Educ Program. 2012;2012:631–637.
- Office of the Surgeon General (US); National Heart, Lung, and Blood Institute (US). The Surgeon General's Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism. Rockville, MD: Office of the Surgeon General; 2008.
- , . Prevention of venous thromboembolism: brief update review. In: Making Health Care Safer II: An Updated Critical Analysis of the Evidence for Patient Safety Practices. Rockville, MD: Agency for Healthcare Research and Quality; 2013.
- , , , et al. The top patient safety strategies that can be encouraged for adoption now. Ann Intern Med. 2013;158:365–368.
- , . Practices to prevent venous thromboembolism: a brief review. BMJ Qual Saf. 2014;23:187–195.
- , , , et al. Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross‐sectional study. Lancet. 2008;371:387–394.
- , . The CMS ruling on venous thromboembolism after total knee or hip arthroplasty: weighing risks and benefits. JAMA. 2009;301:1063–1065.
- , , , et al. ICD‐9 code‐based venous thromboembolism performance targets fail to measure up. Am J Med Qual. 2016;31(5):448–453.
- , , , , . Evidence‐based venous thromboembolism prophylaxis is associated with a six‐fold decrease in numbers of symptomatic venous thromboembolisms in rehabilitation inpatients. PM R. 2011;3:1111–1115.e1.
- , , . Translating evidence into practice: a model for large scale knowledge translation. BMJ. 2008;337:a1714.
- , , , et al. Lessons from the Johns Hopkins Multi‐Disciplinary Venous Thromboembolism (VTE) Prevention Collaborative. BMJ. 2012;344:e3935.
- , , , et al. Improved prophylaxis and decreased rates of preventable harm with the use of a mandatory computerized clinical decision support tool for prophylaxis for venous thromboembolism in trauma. Arch Surg. 2012;147:901–907.
- , , , et al. Impact of a venous thromboembolism prophylaxis “smart order set”: improved compliance, fewer events. Am J Hematol. 2013;88(7):545–549.
- , , , et al. Eliminating health care disparities with mandatory clinical decision support: the venous thromboembolism (VTE) example. Med Care. 2015;53:18–24.
- , , , et al. Use of provider‐level dashboards and pay‐for‐performance in venous thromboembolism prophylaxis. J Hosp Med. 2015;10:172–178.
- , , , , , . Attending physician performance measure scores and resident physicians' ordering practices. JAMA Surg. 2015;150:813–814.
- , , , et al. Individualized performance feedback to surgical residents improves appropriate venous thromboembolism prophylaxis prescription and reduces potentially preventable VTE: a prospective cohort study [published online November 25, 2015]. Ann Surg. doi: 10.1097/SLA.0000000000001512.
- , , , et al. Patterns of non‐administration of ordered doses of venous thromboembolism prophylaxis: implications for novel intervention strategies. PLoS One. 2013;8:e66311.
- , , , et al. Preventability of hospital‐acquired venous thromboembolism. JAMA Surg. 2015;150(9):912–915.
- , , , et al. Correlation of missed doses of enoxaparin with increased incidence of deep vein thrombosis in trauma and general surgery patients. JAMA Surg. 2014;149:365–370.
- , , , et al. Prescriber knowledge and attitudes regarding non‐administration of prescribed pharmacologic venous thromboembolism prophylaxis [published online May 21, 2016]. J Thromb Thrombolysis. doi:10.1007/s11239-016-1378-8.
- , , , et al. Hidden barriers to delivery of pharmacological venous thromboembolism prophylaxis: the role of nursing beliefs and practices. J Patient Saf. 2016;12:63–68.
- , , , et al. Patient preferences regarding pharmacologic venous thromboembolism prophylaxis. J Hosp Med. 2015;10:108–111.
- , , , et al. Patient preferences for receiving education on venous thromboembolism prevention—a survey of stakeholder organizations. PLoS One. 2016;11:e0152084.
- , , , , , . Are sequential compression devices commonly associated with in‐hospital falls? A myth‐busters review using the patient safety net database. J Patient Saf. 2011;7:77–79.
- , , , , . No association between hospital‐reported perioperative venous thromboembolism prophylaxis and outcome rates in publicly reported data. JAMA Surg. 2014;149:400–401.
- , , , , . Linking processes and outcomes: a key strategy to prevent and report harm from venous thromboembolism in surgical patients. JAMA Surg. 2013;148:299–300.
- , , , et al. Hazards of benchmarking complications with the National Trauma Data Bank: numerators in search of denominators. J Trauma. 2008;64:273–277; discussion 277–279.
- , , , et al. Is the meaningful use venous thromboembolism VTE‐6 measure meaningful? A retrospective analysis of one hospital's VTE‐6 cases. Jt Comm J Qual Patient Saf. 2016;42(9):410–416.
- , , , et al. Is venous thromboembolism in colorectal surgery patients preventable or inevitable? One institution's experience. J Am Coll Surg. 2013;216:395–401.e1.
- , , , et al. Venous thromboembolic prophylaxis after a hepatic resection: patterns of care among liver surgeons. HPB (Oxford). 2014;16:892–898.
- , , , et al. Defining incidence and risk factors of venous thromboembolism after hepatectomy. J Gastrointest Surg. 2014;18:1116–1124.
- , , , et al. Can increased incidence of deep vein thrombosis (DVT) be used as a marker of quality of care in the absence of standardized screening? The potential effect of surveillance bias on reported DVT rates after trauma. J Trauma. 2007;63:1132–1135; discussion 1135–1137.
- , . Surveillance bias in outcomes reporting. JAMA. 2011;305:2462–2463.
- , , , et al. Surveillance bias and deep vein thrombosis in the national trauma data bank: the more we look, the more we find. J Trauma. 2008;64:932–936; discussion 936–937.
- , , , et al. Nonadministration of thromboprophylaxis in hospitalized patients with HIV: a missed opportunity for prevention? J Hosp Med. 2014;9:215–220.
- , , , et al. Pharmacologic and mechanical prophylaxis of venous thromboembolism among special populations. Comparative effectiveness review No. 116. Prepared by the Johns Hopkins University Evidence‐based Practice Center under Contract No. 290‐2007‐10061‐I.) AHRQ Publication No. 13‐EHC082–1. Rockville, MD: Agency for Healthcare Research and Quality; 2013.
- , , , et al. Pharmacologic and mechanical strategies for preventing venous thromboembolism after bariatric surgery: a systematic review and meta‐analysis. JAMA Surg. 2013;148:675–686.
- , , , et al. The effectiveness of prophylactic inferior vena cava filters in trauma patients: a systematic review and meta‐analysis. JAMA Surg. 2014;149:194–202.
© 2016 Society of Hospital Medicine
Review of VTE Prophylaxis Strategies
Venous thromboembolism (VTE), including deep venous thrombosis (DVT) and pulmonary embolism (PE), is estimated to affect 900,000 Americans each year and is a cause of significant morbidity and mortality with associated high healthcare costs.[1] Accordingly, the comparative effectiveness and safety of interventions for the prevention and treatment of VTE are among the national priorities for comparative effectiveness research.[2] Whereas we have evidence‐based guidelines for the prophylaxis of VTE in the general population, there are no guidelines informing the care of select patient populations. Select populations are those patients in whom there is decisional uncertainty about the optimal choice, timing, and dose of VTE prophylaxis. Not only do these patients have an increased risk of DVT and PE, but most are also at high risk of bleeding, the most important complication of VTE prophylaxis.[3, 4, 5, 6]
The objectives of this systematic review were to define the comparative effectiveness and safety of pharmacologic and mechanical strategies for VTE prevention in some of these select medical populations including obese patients, patients on concomitant antiplatelet therapy, patients with renal insufficiency, patients who are underweight, and patients with coagulopathy due to liver disease.
METHODS
The methods for this comparative effectiveness review (CER) follow the guidelines suggested in the Agency for Healthcare Research and Quality (AHRQ) Methods Guide for Effectiveness and Comparative Effectiveness Reviews.[7] The protocol was publically posted.[8]
Search Strategy
We searched MEDLINE, EMBASE, and SCOPUS through August 2011, CINAHL, International Pharmaceutical Abstracts,
Study Selection
We reviewed titles followed by abstracts to identify randomized controlled trials (RCTs) or observational studies with comparison groups reporting on the effectiveness or safety of VTE prevention in our populations. Two investigators independently reviewed abstracts, and we excluded the abstracts if both investigators agreed that the article met 1 or more of the exclusion criteria. We included only English‐language articles that evaluated the effectiveness of pharmacological or mechanical interventions that have been approved for clinical use in the United States. To be eligible, the studies must have addressed relevant key questions in the population of our interest. We resolved disagreements by consensus. We used DistillerSR (Evidence Partners Inc., Ottawa, Ontario, Canada), a Web‐based database management program to manage the review process. Two investigators assessed the risk of bias in each study independently, using the Downs and Black instrument for observational studies and trials.[10]
Data Synthesis
For each select population, we created detailed evidence tables containing the information abstracted from the eligible studies. After synthesizing the evidence, we graded the quantity, quality, and consistency of the best available evidence for each select population by adapting an evidence‐grading scheme recommended in the Methods Guide for Conducting Comparative Effectiveness Reviews.[7]
RESULTS
We identified 30,902 unique citations and included 9 studies (Figure 1). There were 5 RCTs with relevant subgroups and 4 observational studies (Table 1). Two studies reported on the risk of bleeding in patients given pharmacologic prophylaxis while they are concomitantly taking nonsteroidal anti‐inflammatory drugs (NSAIDS) or antiplatelet agents/aspirin, 1 RCT and 1 prospective observational study reported on obese patients, and 5 studies described outcomes of patients with renal insufficiency (see Supporting Information, Table 1, in the online version of this article). No study tested prophylaxis in underweight patients or those with liver disease.
| Study | Arm, n | Total VTE (DVT and PE) | Bleeding | Other Outcomes | |
|---|---|---|---|---|---|
| |||||
| Obese patients | |||||
| Kucher et al., 2005[11] | Arm 1 (dalteparin), 558 | 2.8% (95% CI: 1.34.3) | 0% | Mortality at 21 days: 4.6% | |
| Arm 2 (placebo), 560 | 4.3% (95% CI: 2.56.2) | 0.7% | Mortality at 21 days: 2.7% | ||
| Freeman et al., [12] | Arm 1 (fixed‐dose enoxaparin), 11 | NR | NR | Peak anti‐factor Xa level 19 % | |
| Arm 2 (lower‐dose enoxaparin), 9 | NR | NR | Peak anti‐factor Xa level 32 % | ||
| Arm 3 (higher‐dose enoxaparin), 11 | NR | NR | Peak anti‐factor Xa level 86 % | ||
| Patients on antiplatelet agents | |||||
| Eriksson et al., 2012[14] | Arm 1 (rivaroxaban), 563 | NR | 20 (3.6%), rate ratio for use vs nonuse: 1.32 (95% CI: 0.85‐2.05) | NR | |
| Arm 2 (enoxaparin/placebo), 526 | NR | 17 (3.2%), rate ratio for use vs nonuse: 1.40 (95% CI: 0.87‐2.25) | NR | ||
| Friedman et al., 2012[15] | Arm 2 (150 mg dabigatran, no ASA), 1149 | NR | 11 (1.0%)a | NR | |
| Arm 5 (150 mg dabigatran+ASA), 128 | NR | 2 (1.6%)a | NR | ||
| Arm 3 (enoxaparin, no ASA), 1167 | NR | 14 (1.2%)a | NR | ||
| Arm 6 (enoxaparin+ASA), 132 | NR | 4 (3.0%) | NR | ||
| 150 mg dabigatran compared with enoxaparinNo concomitant ASA therapy | NR | RR: 0.82 (95% CI: 0.37‐1.84) | NR | ||
| 150 mg dabigatran compared with enoxaparinWith concomitant ASA therapy | NR | RR: 0.55 (95% CI: 0.11‐2.78) | NR | ||
| Patients with renal insufficiency | |||||
| Bauersachs et al., 2011[16] | Arm 2 (GFR <30), 92 | Total DVT: 11.11%; Total PE: 0% | Major bleeding: 4/92 (4.35%), minor bleeding: 9/92 (9.78%) | Mortality: 5.81% | |
| Mah et al., 2007[17] | Arm 2 (tinzaparin), 27 | NR | Major bleeding: 2/27 (7.4%), minor bleeding: 3/27 (11.1%) | Factor Xa level: AF: CmaxD8/Cmax D1=1.05 | |
| Arm 3 (enoxaparin), 28 | NR | Major bleeding: 1/28 (3.6%), minor bleeding: 3/28 (10.7%) | Factor Xa level: AF: CmaxD8/Cmax D1=1.22 | ||
| Dahl et al., 2012[18] | Arm 1 (enoxaparin), 332 | Major VTE: 8 (9.0%) | Major bleeding: 6 (4.7%) | Infections and infestations: 25 (7.5%), Wound infection: 4 (1.2%) | |
| Arm 2 (dabigatran), 300 | Major VTE: 3 (4.3%) | Major bleeding: 0 (0%) | Infections and infestations: 21 (7.0%), Wound Infection: 3 (1.0%) | ||
| Shorr et al., 2012[19] | Arm 1 (enoxaparin, CrCL 60 mL/min), 353 | Total VTE: 17/275 (6.2%) | Major bleeding: 0/351 (0%) | NR | |
| Arm 2 (desirudin, CrCL 60 mL/min), 353 | Total VTE: 13/284 (4.3%) | Major bleeding: 2/349 (0.27%) | NR | ||
| Arm 3 (enoxaparin, CrCL 4559 mL/min), 369 | Total VTE: 18/282 (6.2%) | Major bleeding: 1/365 (0.27%) | NR | ||
| Arm 4 (desirudin, CrCL 4559 mL/min), 395 | Total VTE: 17/303 (5.6%) | Major bleeding: 1/393 (0.25%) | NR | ||
| Arm 5 (enoxaparin, CrCL <45 mL/min), 298 | Total VTE: 24/216 (11.1%) | Major bleeding: 1/294 (0.34%) | NR | ||
| Arm 6 (desirudin, CrCL <45 mL/min), 279 | Total VTE: 7/205 (3.4%) | Major bleeding: 5/275 (1.82%) | NR | ||
| Elsaid et al., 2012[20] | Arm 1 (enoxaparin, CrCL 60 mL/min), 17 | NR | Major bleeding: 2 (11.8%) | NR | |
| Arm 2 (enoxaparin, CrCL 3059 mL/min), 86 | NR | Major bleeding: 9 (10.5%) | NR | ||
| Arm 3 (enoxaparin, CrCL 30 mL/min), 53 | NR | Major bleeding: 10 (18.9%) | NR | ||
| Arm 4 (UFH, CrCL 60 mL/min), 19 | NR | Major bleeding: 2 (10.5%) | NR | ||
| Arm 5 (UFH, CrCL 3059 mL/min), 99 | NR | Major bleeding: 3 (3%) | NR | ||
| Arm 6 (UFH, CrCL 30 mL/min), 49 | NR | Major bleeding: 2 (4.1%) | NR | ||
Obese Patients
We found 1 subgroup analysis of an RCT (total 3706 patients, 2563 nonobese and 1118 obese patients) that reported on the comparative effectiveness and safety of fixed low‐dose dalteparin 5000 IU/day compared to placebo among 1118 hospitalized medically ill patients with body mass indices (BMI) greater than 30 kg/m2.11 Neither group received additional concurrent prophylactic therapies. The 3 most prevalent medical diagnoses prompting hospitalization were congestive heart failure, respiratory failure, and infectious diseases. Compression ultrasound was performed in all patients by day 21 of hospitalization. The primary end point was the composite of VTE, fatal PE, and sudden death, and secondary end points included DVT, bleeding, and thrombocytopenia by day 21 (Table 1). In obese patients, the primary end point occurred in 2.8% (95% confidence interval [CI]: 1.34.3) of the dalteparin group and in 4.3% (95% CI: 2.56.2) of the placebo group (relative risk [RR]: 0.64; 95% CI: 0.32‐1.28). In nonobese patients, the primary end point occurred in 2.8% (95% CI: 1.8‐3.8) and 5.2% (95% CI: 3.9‐6.6) of the dalteparin and placebo groups, respectively (RR: 0.53; 95% CI: 0.34‐0.82). When weight was modeled as a continuous variable, no statistically significant interaction between weight and dalteparin efficacy was observed (P=0.97). The authors calculated the RR in predefined BMI subgroups and found that dalteparin was effective in reducing VTE in patients with BMIs up to 40, with RRs of <1.0 for all (approximate range, 0.20.8). However, a fixed dose of dalteparin 5000 IU/day was not better than placebo for individuals with BMI >40 kg/m2. There was no significant difference in mortality or major hemorrhage by day 21 between treatment and placebo groups.
Freeman and colleagues prospectively assigned 31 medically ill patients with extreme obesity (BMI >40 kg/m2) to 1 of 3 dosing regimens of enoxaparin: a fixed dose of 40 mg daily enoxaparin (control group, n=11), enoxaparin at 0.4 mg/kg (n=9), or enoxaparin at 0.5 mg/kg (n=11).[12] The average BMI of the entire cohort was 62.1 kg/m2 (range, 40.582.4). All patients had anti‐factor Xa levels drawn on the day of enrollment and daily for 3 days (Table 2). The relationship between anti‐factor Xa levels and clinical efficacy of low‐molecular weight heparin (LMWH) in VTE prophylaxis is still unclear; however, an anti‐factor Xa level of 0.2 to 0.5 IU/mL, measured 4 hours after the fourth dose of LMWH, is the target level recommended for VTE prophylaxis.[13] Patients who received weight‐based enoxaparin at 0.5mg/kg achieved target anti‐factor Xa level 86% of the time compared to 32% of the time in those receiving 0.4 mg/kg and 19% of the time for those in the fixed‐dose group (P<0.001). No clinical outcomes were reported in this study.
| Intervention | Outcome | Risk of Bias | Evidence Statement and Magnitude of Effect |
|---|---|---|---|
| |||
| Patients on antiplatelet agents | |||
| Rivaroxaban vs enoxaparin | Major bleeding | Low | Insufficient to support no difference in rates of major bleeding with prophylactic rivaroxaban or enoxaparin in patients concomitantly treated with antiplatelet agents; 3.6% vs 3.25% |
| Dabigatran vs enoxaparin | Major bleeding | Low | Insufficient to support no difference in rates of major bleeding with prophylactic dabigatran or enoxaparin in patients concomitantly treated with aspirin; 1.6% vs 3.0% |
| Obese patients | |||
| Dalteparin vs placebo | VTE | Moderate | Insufficient evidence for effectiveness of dalteparin vs placebo in reducing total VTE in obese patients; 2.8% vs 4.3%, RR: 0.64, 95% CI: 0.32‐1.28 |
| Dalteparin vs placebo | Mortality | Moderate | Insufficient evidence for effectiveness of dalteparin vs placebo in reducing mortality in obese patients; 9.9% vs 8.6%, P=0.36 |
| Dalteparin vs placebo | Major bleeding | Moderate | Insufficient evidence for safety of dalteparin vs placebo in reducing major bleeding in obese patients; 0% vs 0.7%, P>0.99 |
| Enoxaparin 40 mg daily vs 0.4 mg/kg | Percentage of patients achieving target anti‐factor Xa level | Moderate | Insufficient evidence for effectiveness of enoxaparin 40 mg daily versus 0.4 mg/kg in achieving peak anti‐factor Xa level in obese patients; 19% vs 32%, P=NR |
| Enoxaparin 40 mg daily vs 0.5 mg/kg | Percentage of patients achieving target anti‐factor Xa level | Moderate | Insufficient evidence for effectiveness of enoxaparin 40 mg daily versus 0.5 mg/kg in achieving peak anti‐factor Xa level in obese patients; 19% vs 86%, P<0.001 |
| Enoxaparin 0.4 mg/kg vs 0.5 mg/kg | Percentage of patients achieving target anti‐factor Xa level | Moderate | Insufficient evidence for effectiveness of enoxaparin 0.4 mg/kg versus 0.5 mg/kg in achieving peak anti‐factor Xa level in obese patients; 32% vs 86%, P=NR |
| Patients with renal insufficiency | |||
| Tinzaparin vs enoxaparin | VTE | High | Insufficient evidence about superiority of either drug for preventing VTE in patients with renal insufficiency, 0/27 vs 0/28* |
| Tinzaparin vs enoxaparin | Bleeding | High | Insufficient evidence about safety of either drug in patients with renal insufficiency; 5/27 vs 4/28, P=0.67 |
| Dabigatran vs enoxaparin | VTE | Moderate | Insufficient evidence for effectiveness of dabigatran in reducing VTE in severe renal compromise patients vs enoxaparin; 4.3% vs 9%, OR: 0.48, 95% CI: 0.13‐1.73, P=0.271 |
| Dabigatran vs enoxaparin | Bleeding | Moderate | Insufficient evidence for safety of dabigatran vs enoxaparin in patients with renal impairment; 0 vs 4.7%, P=0.039 |
| Desirudin vs enoxaparin | VTE | Moderate | Insufficient evidence for effectiveness of desirudin vs enoxaparin in reducing VTE in patients with renal impairment; 4.9% vs 7.6%, P=0.019 |
| Desirudin vs enoxaparin | Bleeding | Moderate | Insufficient evidence for safety of desirudin vs enoxaparin in patients with renal impairment; 0.8% vs 0.2%, P=0.109 |
| Enoxaparin vs UFH | Bleeding | High | Insufficient evidence for increased risk of bleeding with enoxaparin vs unfractionated heparin in patients with all levels of renal impairment, 13.5% vs 4.2%, RR: 3.2, 95% CI: 1.47.3; and for the subgroup of patients with creatinine clearance <30 mL/min; 18.9% vs 4.1%, RR: 4.68, 95% CI: 1.120.6 |
| UFH in severe renal compromise vs all other renal status (undifferentiated) | VTE | Moderate | Insufficient evidence regarding differential benefit of unfractionated heparin by renal function; 2.6% of patients had a VTE event |
| UFH in severe renal compromise vs all other renal status (undifferentiated) | Bleeding | Moderate | Insufficient evidence for differential harm from unfractionated heparin by renal function; 13 events in 92 patients |
Patients on Antiplatelet Drugs
We did not find studies that directly looked at the comparative effectiveness of VTE prophylaxis in patients who were on antiplatelet drugs including aspirin. However, there were 2 studies that looked at the risk of bleeding in patients who received VTE pharmacologic prophylaxis while concurrently taking antiplatelet agents including aspirin. Both studies used pooled data from large phase III trials.
The study by Eriksson et al. used data from the RECORD (Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism) trial where over 12,000 patients undergoing elective total knee or hip replacement were randomized to receive VTE prophylaxis with oral rivaroxaban or subcutaneous enoxaparin.[14] Nine percent of participants in each arm (563 in rivaroxaban and 526 in enoxaparin/placebo) were concomitantly using antiplatelet agents or aspirin at least once during the at risk period, defined as starting at day 1 of surgery up to 2 days after the last intake of the study drug. The only end point evaluated was bleeding, and the authors found no statistically significant bleeding difference among the 2 arms (Table 1). Any bleeding event in the rivaroxaban with antiplatelets or aspirin arm was found in 20 (3.6%) patients, whereas in those on enoxaparin/placebo with antiplatelets or aspirin arm it was 17 (3.2%). The relative rate of bleeding among users versus nonusers of antiplatelet drugs or aspirin was 1.32 (95% CI: 0.85‐2.05) in the rivaroxaban group and 1.40 (95% CI: 0.87‐2.25) in the enoxaparin arm (Table 1).
Friedman et al. used pooled data from the RE‐MODEL, RENOVATE, and REMOBILIZE trials, where patients who were undergoing hip or knee arthroplasty were randomized to 220 mg of dabigatran once daily, 150 mg of dabigatran once daily (we focused on this lower dosage as this is the only available dose used in the US), 40 mg of enoxaparin once daily, or 30 mg of enoxaparin twice a day.[15] Of the 8135 patients, 4.7% were on concomitant aspirin. The baseline characteristics of those on aspirin were similar to the other enrollees. The primary outcome was major bleeding events requiring transfusion, symptomatic internal bleeding, or bleeding requiring surgery. Among patients receiving 150 mg of dabigatran, bleeding events with and without concomitant aspirin occurred in 1.6% and 1.0%, respectively (odds ratio [OR]: 1.64; 95% CI: 0.36‐7.49; P=0.523). The percentages of participants with bleeding who received enoxaparin, with and without aspirin, were 3.0% and 1.2%, respectively (OR: 2.57; 95% CI: 0.83‐7.94; P=0.101). The RR of bleeding on dabigatran compared to enoxaparin with and without aspirin therapy was 0.55 (95% CI: 0.11‐2.78) and 0.82 (95% CI: 0.37‐1.84), respectively (Table 1).
Patients With Renal Insufficiency
We found 5 studies that evaluated the comparative effectiveness and safety of pharmacologic prophylaxis for prevention of VTE in patients with acute kidney injury, moderate renal insufficiency, severe renal insufficiency not undergoing dialysis, or patients receiving dialysis. Four studies were RCTs,[16, 17, 18, 19] and 1 used a cohort design assessing separate cohorts before and after a quality improvement intervention.[20] Bauersachs and colleagues conducted an RCT comparing unfractionated heparin at 5000 IU, 3 times daily to certoparin, which is not approved in the United States and is not further discussed here.[16] The rate of DVT among patients treated with unfractionated heparin in patients with a glomerular filtration rate >30 mL/min was marginally lower than those with severe renal dysfunction (10.3 vs 11.1%) (Table 1).
Patients with severe renal dysfunction who received 5000 IU of unfractionated heparin 3 times a day were at increased risk of all bleeds (RR: 3.4; 95% CI: 2.05.9), major bleeds (RR: 7.3; 95% CI: 3.316), and minor bleeds (RR: 2.6; 95% CI: 1.4‐4.9) compared to patients treated with unfractionated heparin without severe renal dysfunction.[16]
A randomized trial by Mah and colleagues compared drug accumulation and anti‐Xa activity in elderly patients with renal dysfunction (defined as a glomerular filtration rate of 20 to 50 mL/min) who received either tinzaparin at 4500 IU once daily or enoxaparin at 4000 IU once daily.[17] Enoxaparin accumulated to a greater extent from day 1 to day 8 than did tinzaparin; the ratio of maximum concentration on day 8 compared to day 1 was 1.22 for enoxaparin and 1.05 for tinzaparin (P=0.016). No VTE events were reported in patients who received tinzaparin or enoxaparin. There was no statistical difference in the incidence of bleeding events between patients receiving tinzaparin (5, including 2 major events) and enoxaparin (4, including 3 major events, P=0.67) (Table 1).
The trial by Dahl and colleagues randomly assigned patients who were over 75 years of age and/or who had moderate renal dysfunction (defined as creatinine clearance between 30 and 49 mL/min) to receive enoxaparin 40 mg daily or dabigatran 150 mg daily.[18] There was no significant difference in the rate of major VTE events between patients receiving dabigatran (4.3%) and enoxaparin (9%) (OR: 0.48; 95% CI: 0.13‐1.73; P=0.271) (Table 1). The rate of major bleeding was significantly higher among patients randomly assigned to receive enoxaparin (4.7%) versus dabigatran (0%) (P=0.039).[18]
Shorr and colleagues published a post hoc subgroup analysis of a multicenter trial in which orthopedic patients were randomly assigned to receive desirudin 15 mg twice daily or enoxaparin 40 mg once daily.[19] Evaluable patients (1565 of the 2079 patients randomized in the trial) receiving desirudin experienced a significantly lower rate of major VTE compared with patients receiving enoxaparin (4.9% vs 7.6%, P=0.019). This relationship was particularly pronounced for evaluable patients whose creatinine clearance was between 30 and 44 mL/min. In evaluable patients with this degree of renal dysfunction, 11% of patients taking enoxaparin compared to 3.4% of those taking desirudin had a major VTE (OR: 3.52; 95% CI: 1.48‐8.4; P=0.004). There was no significant difference in the rates of major bleeding among a subset of patients assessed for safety outcomes (2078 of the 2079 patients randomized in the trial) who received desirudin (0.8%) or enoxaparin (0.2%) (Table 1).
Elsaid and Collins assessed VTE and bleeding events associated with the use of unfractionated heparin 5000U either 2 or 3 times daily and enoxaparin 30 mg once or twice daily across patients stratified by renal function (creatinine clearance <30, 3059, and 60 mL/min). The investigators made assessments before and after a quality improvement intervention that was designed to eliminate the use of enoxaparin in patients whose creatinine clearance was <30 mL/min. No VTE events were reported. Patients receiving enoxaparin were significantly more likely to experience a major bleeding episode compared with patients receiving unfractionated heparin (overall rates for all levels of renal function: 13.5% vs 4. 2%; RR: 3.2; 95% CI: 1.47.3) (Table 2). This association was largely driven by the subgroup of patients with a creatinine clearance <30 mL/min. For this subgroup with severe renal insufficiency, patients receiving enoxaparin were significantly more likely to have a bleed compared with patients receiving unfractionated heparin (18.9% vs 4.1%; RR: 4.68; 95% CI: 1.120.6) (Tables 1 and 2). There was no difference in the bleeding rates for patients whose creatinine clearances were >60 mL/min.[20]
Strength of Evidence
Obese Patients
Overall, we found that the strength of evidence was insufficient regarding the composite end point of DVT, PE, and sudden death, and the outcomes of mortality and bleeding (Table 2). This was based on a paucity of available data, and a moderate risk of bias in the reviewed studies. Additionally, 92% of the enrolled patients in the studies were white, limiting the generalizability of the results to other ethnic groups.
Patients on Antiplatelets
The strength of evidence was insufficient in the studies reviewed here to conclude that there is no difference in rates of bleeding in patients who are concomitantly taking antiplatelet drugs while getting VTE prophylaxis with rivaroxaban, dabigatran, or enoxaparin. We based this rating because of the imprecision of results and unknown consistencies across multiple studies.
Patients With Renal Insufficiency
One RCT had a high risk of bias for our key question because data from only 1 study arm were useful for our review.[16] The other RCTs were judged to have a moderate risk of bias. The analyses led by Dahl and Shorr[18, 19] were based on post hoc (ie, not prespecified) analysis of data from RCTs. Additionally, outcomes in the Shorr et al. trial were reported for evaluable subpopulations of the cohort that was initially randomized in the clinical trial.
We rated the strength of evidence as insufficient to know the comparative effectiveness and safety of pharmacologic prophylaxis for prevention of VTE during hospitalization of patients with acute kidney injury, moderate renal insufficiency, severe renal insufficiency not undergoing dialysis, and patients receiving dialysis. We based this rating on the risk of bias associated with published studies and a lack of consistent evidence regarding associations that were reported. Similarly, we rated the strength of evidence as insufficient that 5000 U of unfractionated heparin 3 times daily increases the risk of major and minor bleeding events in patients with severely compromised renal function compared to this dose in patients without severely compromised renal function. We based this rating on a high risk of bias of included studies and inconsistent evidence. Likewise, we rated the strength of evidence as insufficient that enoxaparin significantly increases the risk of major bleeding compared with unfractionated heparin in patients with severe renal insufficiency. We based this rating on a high risk of bias and inconsistent published evidence.
We similarly found insufficient evidence to guide treatment decisions for patients with renal insufficiency. Our findings are consistent with other recent reviews. The American College of Chest Physicians (ACCP) practice guidelines[21] make dosing recommendations for the therapeutic use of enoxaparin. However, their assessment is that the data are insufficient to make direct recommendations about prophylaxis. Their assessment of the indirect evidence regarding bioaccumulation and increased anti‐factor Xa levels are consistent with ours. The ACCP guidelines also suggest that decreased clearance of enoxaparin has been associated with increased risk of bleeding events for patients with severe renal insufficiency. However, the cited study[20] compares patients with and without severe renal dysfunction who received the same therapy. Therefore, it is not possible to determine the additional risk conveyed by enoxaparin therapy, that is, above the baseline increased risk of bleeding among patients with renal insufficiency, particularly those receiving an alternate pharmacologic VTE prevention strategy, such as unfractionated heparin.
DISCUSSION
We found that the evidence was very limited about prevention of VTE in these select and yet prevalent patient populations. Despite the fact that there is an increasing number of obese patients and patients who are on antiplatelet therapies, most clinical practice guidelines do not address the care of these populations, which may be entirely appropriate given the state of the evidence.
The ACCP practice guidelines[21] suggest using a higher dose of enoxaparin for the prevention of VTE in obese patients. The subgroup analysis by Kucher et al.[11] showed effect attenuation of dalteparin when given at a fixed dose of 5000 IU/mL to patients with a BMI of >40 kg/m2. The Freeman study[12] showed that extremely obese patients (average BMI >62.1 kg/m2) who are given a fixed dose of enoxaparin achieved target anti‐factor Xa levels significantly less often than those who received a higher dose of enoxaparin. The 2 separate findings, although not conclusive, lend some credence to the current ACCP guidelines.[21]
The studies we reviewed on VTE prophylaxis in patients who are concomitantly on antiplatelets including aspirin reported no major increased risk of bleeding; however, in the Friedman et al. study,[15] 3.0% of patients who were put on enoxaparin while still on aspirin had a bleeding event compared to 1.2% of those on enoxaparin alone. This difference is not statistically significant but is a trend possibly worth noting, especially when one looks at the lower RR of bleeding at 0.55 compared to 0.82 when dabigatran is compared with enoxaparin with and without concomitant aspirin therapy, respectively (Table 1). The highest dose of aspirin used in either of the studies was 160 mg/day, and neither study addressed other potent antiplatelets such as clopidogrel or ticlopidine separately, which limits the generalizability of the finding to all antiplatelets. Current ACCP guidelines do not recommend aspirin as a sole option for the prevention of VTE in orthopedic surgery patients.[22] Concerns remain among clinicians that antiplatelets, including aspirin, on their own are unlikely to be fully effective to thwart venous thrombotic processes for most patients, and yet the risk of bleeding is not fully known when these agents are combined with other anticoagulants for VTE prophylaxis.
Our review has several limitations, including the possibility that we may have missed some observational studies, as the identification of relevant observational studies in electronic searches is more challenging than that of RCTs. The few studies made it impossible to quantitatively pool results. These results, however, have important implications, namely that additional research on the comparative effectiveness and safety of pharmacologic and mechanical strategies to prevent VTE is needed for the optimal care of these patient subgroups. This might be achieved with trials dedicated to enrolling these patients or prespecified subgroup analyses within larger trials. Observational data may be appropriate as long as attention is paid to confounding.
APPENDIX
MEDLINE Search Strategy
((pulmonary embolism[mh] OR PE[tiab] OR Pulmonary embolism[tiab] OR thromboembolism[mh] OR thromboembolism[tiab] OR thromboembolisms[tiab] OR Thrombosis[mh] OR thrombosis[tiab] OR DVT[tiab] OR VTE[tiab] OR clot[tiab]) AND (Anticoagulants[mh] OR Anticoagulants[tiab] OR Anticoagulant[tiab] OR thrombin inhibitors[tiab] OR Aspirin[mh] or aspirin[tiab] OR aspirins[tiab] or clopidogrel[nm] OR clopidogrel[tiab] OR Plavix[tiab] or ticlopidine[mh] or ticlopidine[tiab]OR ticlid[tiab] OR prasugrel[nm]Or prasugrel[tiab]OR effient[tiab]OR ticagrelor[NM] OR ticagrelor[tiab]OR Brilinta[tiab] OR cilostazol[NM] OR cilostazol[tiab]OR pletal[tiab] OR warfarin[mh]OR warfarin[tiab]OR coumadin[tiab] OR coumadine[tiab] OR Dipyridamole[mh]OR dipyridamole[tiab]OR persantine[tiab] OR dicoumarol[MH] OR dicoumarol[tiab] OR dicumarol[tiab] OR Dextran sulfate[mh] OR dextran sulfate[tiab] ORthrombin inhibitors[tiab] OR thrombin inhibitor[tiab] OR heparin[mh] OR Heparin[tiab] OR Heparins[tiab] OR LMWH[tiab] OR LDUH[tiab] OR Enoxaparin[mh] OR Enoxaparin[tiab] OR Lovenox[tiab] OR Dalteparin[tiab] OR Fragmin[tiab] OR Tinzaparin[tiab] OR innohep[tiab] OR Nadroparin[tiab] OR Fondaparinux[nm] OR Fondaparinux[tiab] OR Arixtra[tiab] OR Idraparinux[nm] OR Idraparinux[tiab] OR Rivaroxaban[nm] OR Rivaroxaban[tiab] OR novastan[tiab] OR Desirudin[nm] OR Desirudin[tiab] OR Iprivask[tiab]OR direct thrombin inhibitor[tiab] OR Argatroban[nm] OR Argatroban[tiab] OR Acova[tiab] OR Bivalirudin[nm] OR Bivalirudin[tiab] OR Angiomax[tiab] OR Lepirudin[nm] OR Lepirudin[tiab] OR Refludan[tiab] OR Dabigatran[nm] OR Dabigatran[tiab] OR Pradaxa[tiab] OR factor xa[mh] OR factor Xa[tiab] OR vena cava filters[mh] OR filters[tiab] OR filter[tiab] OR compression stockings[mh] OR intermittent pneumatic compression devices[mh] OR compression [tiab] OR Venous foot pump[tiab])) AND(prevent*[tiab] OR prophyla*[tiab] OR prevention and control[subheading]) NOT (animals[mh] NOT humans[mh]) NOT (editorial[pt] OR comment[pt]) NOT ((infant[mh] OR infant[tiab] OR child[mh] OR child[tiab] OR children[tiab] OR adolescent[mh] OR adolescent[tiab] OR teen‐age[tiab] OR pediatric[tiab] OR perinatal[tiab]) NOT (adult[tiab] OR adults[tiab] OR adult[mh])) NOT (mechanical valve[tiab] OR heart valve[tiab] OR atrial fibrillation[mh] OR atrial fibrillation[tiab] OR thrombophilia[mh] OR thrombophilia[tiab] OR pregnancy[mh])
- , , . Estimated annual number of incident and recurrent, non‐fatal and fatal venous thromboembolism (VTE) events in the US. Blood. 2005;106:910.
- Institute of Medicine. Institute of Medicine. Initial National Priorities for Comparative Effectiveness Research. Washington, DC: National Academies Press; 2009.
- Lovenox (enoxaparin sodium injection for subcutaneous and intravenous use: prescribing information). Bridgewater, NJ: SanofiAventis; 2011. Available at: http://products.sanofi.us/lovenox/lovenox.html. Accessed October 17, 2012.
- Innohep (tinzaparin sodium injection). Ballerup, Denmark: LEO Pharmaceutical Products; 2008. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/020484s011lbl.pdf. Accessed October 17, 2012.
- Leizorovicz A. Tinzaparin compared to unfractionated heparin for initial treatment of deep vein thrombosis in very elderly patients with renal insufficiency‐ the IRIS trial. [50th ASH Annual Meeting and Exposition abstract 434]. Blood. 2008;11:112.
- Fragmin (dalteparin sodium injection). New York, NY: Pfizer Inc.; 2007. Available at: http://www.pfizer.com/files/products/uspi_fragmin.pdf. Accessed October 17, 2012.
- Methods guide for effectiveness and comparative effectiveness reviews. Rockville, MD: Agency for Healthcare Research and Quality; August 2011. AHRQ publication No. 10 (11)‐EHC063‐EF. Available at: http://www.effectivehealthcare.ahrq.gov. Accessed October 17, 2012.
- Comparative effectiveness of pharmacologic and mechanical prophylaxis of venous thromboembolism among special populations. Available at: http://effectivehealthcare.ahrq.gov/ehc/products/341/928/VTE‐Special‐Populations_Protocol_20120112.pdf. Accessed April 17, 2012.
- , , , et al. Comparative effectiveness of pharmacologic and mechanical prophylaxis of venous thromboembolism among special populations. Evidence Report/Technology Assessment (AHRQ). Available at: http://effectivehealthcare.ahrq.gov/ehc/products/341/1501/venous‐thromboembolism‐special‐populations‐report‐130529.pdf. 2013.
- , . The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non‐randomised studies of health care interventions. J Epidemiol Community Health. 1998;52(6):377–384.
- , , , et al. Efficacy and safety of fixed low‐dose dalteparin in preventing venous thromboembolism among obese or elderly hospitalized patients: a subgroup analysis of the PREVENT trial. Arch Intern Med. 2005;165(3):341–345.
- , , , . Prospective comparison of three enoxaparin dosing regimens to achieve target anti‐factor Xa levels in hospitalized, medically ill patients with extreme obesity. Am J Hematol. 2012;87(7):740–743.
- , , . Effect of prophylactic dalteparin on anti‐factor xa levels in morbidly obese patients after bariatric surgery. Obes Surg. 2010;20(4):487–491.
- , , , , . Concomitant use of medication with antiplatelet effects in patients receiving either rivaroxaban or enoxaparin after total hip or knee arthroplasty. Thromb Res. 2012;130(2):147–151.
- , , , , , . Dabigatran etexilate and concomitant use of non‐steroidal anti‐inflammatory drugs or acetylsalicylic acid in patients undergoing total hip and total knee arthroplasty: No increased risk of bleeding. Thromb Haemost. 2012;108(1):183–190.
- , , , et al. CERTIFY: prophylaxis of venous thromboembolism in patients with severe renal insufficiency. Thromb Haemost. 2011;105(6):981–988.
- , , , et al. Tinzaparin and enoxaparin given at prophylactic dose for eight days in medical elderly patients with impaired renal function: a comparative pharmacokinetic study. Thromb Haemost. 2007;97(4):581–586.
- , , , , , . Thromboprophylaxis in patients older than 75 years or with moderate renal impairment undergoing knee or hip replacement surgery [published correction appears in Int Orthop. 2012;36(5):1113]. Int Orthop. 2012;36(4):741–748.
- , , , . Impact of stage 3B chronic kidney disease on thrombosis and bleeding outcomes after orthopedic surgery in patients treated with desirudin or enoxaparin: insights from a randomized trial. J Thromb Haemost. 2012;10(8):1515–1520.
- , . Initiative to improve thromboprophylactic enoxaparin exposure in hospitalized patients with renal impairment. Am J Health Syst Pharm. 2012;69(5):390–396.
- , , , , ; American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel. Executive summary: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence‐based clinical practice guidelines. Chest. 2012;141(2 suppl):7S–47S.
- , . Aspirin for the prophylaxis of venous thromboembolic events in orthopedic surgery patients: a comparison of the AAOS and ACCP guidelines with review of the evidence. Ann Pharmacother. 2013;47(1):63–74.
Venous thromboembolism (VTE), including deep venous thrombosis (DVT) and pulmonary embolism (PE), is estimated to affect 900,000 Americans each year and is a cause of significant morbidity and mortality with associated high healthcare costs.[1] Accordingly, the comparative effectiveness and safety of interventions for the prevention and treatment of VTE are among the national priorities for comparative effectiveness research.[2] Whereas we have evidence‐based guidelines for the prophylaxis of VTE in the general population, there are no guidelines informing the care of select patient populations. Select populations are those patients in whom there is decisional uncertainty about the optimal choice, timing, and dose of VTE prophylaxis. Not only do these patients have an increased risk of DVT and PE, but most are also at high risk of bleeding, the most important complication of VTE prophylaxis.[3, 4, 5, 6]
The objectives of this systematic review were to define the comparative effectiveness and safety of pharmacologic and mechanical strategies for VTE prevention in some of these select medical populations including obese patients, patients on concomitant antiplatelet therapy, patients with renal insufficiency, patients who are underweight, and patients with coagulopathy due to liver disease.
METHODS
The methods for this comparative effectiveness review (CER) follow the guidelines suggested in the Agency for Healthcare Research and Quality (AHRQ) Methods Guide for Effectiveness and Comparative Effectiveness Reviews.[7] The protocol was publically posted.[8]
Search Strategy
We searched MEDLINE, EMBASE, and SCOPUS through August 2011, CINAHL, International Pharmaceutical Abstracts,
Study Selection
We reviewed titles followed by abstracts to identify randomized controlled trials (RCTs) or observational studies with comparison groups reporting on the effectiveness or safety of VTE prevention in our populations. Two investigators independently reviewed abstracts, and we excluded the abstracts if both investigators agreed that the article met 1 or more of the exclusion criteria. We included only English‐language articles that evaluated the effectiveness of pharmacological or mechanical interventions that have been approved for clinical use in the United States. To be eligible, the studies must have addressed relevant key questions in the population of our interest. We resolved disagreements by consensus. We used DistillerSR (Evidence Partners Inc., Ottawa, Ontario, Canada), a Web‐based database management program to manage the review process. Two investigators assessed the risk of bias in each study independently, using the Downs and Black instrument for observational studies and trials.[10]
Data Synthesis
For each select population, we created detailed evidence tables containing the information abstracted from the eligible studies. After synthesizing the evidence, we graded the quantity, quality, and consistency of the best available evidence for each select population by adapting an evidence‐grading scheme recommended in the Methods Guide for Conducting Comparative Effectiveness Reviews.[7]
RESULTS
We identified 30,902 unique citations and included 9 studies (Figure 1). There were 5 RCTs with relevant subgroups and 4 observational studies (Table 1). Two studies reported on the risk of bleeding in patients given pharmacologic prophylaxis while they are concomitantly taking nonsteroidal anti‐inflammatory drugs (NSAIDS) or antiplatelet agents/aspirin, 1 RCT and 1 prospective observational study reported on obese patients, and 5 studies described outcomes of patients with renal insufficiency (see Supporting Information, Table 1, in the online version of this article). No study tested prophylaxis in underweight patients or those with liver disease.
| Study | Arm, n | Total VTE (DVT and PE) | Bleeding | Other Outcomes | |
|---|---|---|---|---|---|
| |||||
| Obese patients | |||||
| Kucher et al., 2005[11] | Arm 1 (dalteparin), 558 | 2.8% (95% CI: 1.34.3) | 0% | Mortality at 21 days: 4.6% | |
| Arm 2 (placebo), 560 | 4.3% (95% CI: 2.56.2) | 0.7% | Mortality at 21 days: 2.7% | ||
| Freeman et al., [12] | Arm 1 (fixed‐dose enoxaparin), 11 | NR | NR | Peak anti‐factor Xa level 19 % | |
| Arm 2 (lower‐dose enoxaparin), 9 | NR | NR | Peak anti‐factor Xa level 32 % | ||
| Arm 3 (higher‐dose enoxaparin), 11 | NR | NR | Peak anti‐factor Xa level 86 % | ||
| Patients on antiplatelet agents | |||||
| Eriksson et al., 2012[14] | Arm 1 (rivaroxaban), 563 | NR | 20 (3.6%), rate ratio for use vs nonuse: 1.32 (95% CI: 0.85‐2.05) | NR | |
| Arm 2 (enoxaparin/placebo), 526 | NR | 17 (3.2%), rate ratio for use vs nonuse: 1.40 (95% CI: 0.87‐2.25) | NR | ||
| Friedman et al., 2012[15] | Arm 2 (150 mg dabigatran, no ASA), 1149 | NR | 11 (1.0%)a | NR | |
| Arm 5 (150 mg dabigatran+ASA), 128 | NR | 2 (1.6%)a | NR | ||
| Arm 3 (enoxaparin, no ASA), 1167 | NR | 14 (1.2%)a | NR | ||
| Arm 6 (enoxaparin+ASA), 132 | NR | 4 (3.0%) | NR | ||
| 150 mg dabigatran compared with enoxaparinNo concomitant ASA therapy | NR | RR: 0.82 (95% CI: 0.37‐1.84) | NR | ||
| 150 mg dabigatran compared with enoxaparinWith concomitant ASA therapy | NR | RR: 0.55 (95% CI: 0.11‐2.78) | NR | ||
| Patients with renal insufficiency | |||||
| Bauersachs et al., 2011[16] | Arm 2 (GFR <30), 92 | Total DVT: 11.11%; Total PE: 0% | Major bleeding: 4/92 (4.35%), minor bleeding: 9/92 (9.78%) | Mortality: 5.81% | |
| Mah et al., 2007[17] | Arm 2 (tinzaparin), 27 | NR | Major bleeding: 2/27 (7.4%), minor bleeding: 3/27 (11.1%) | Factor Xa level: AF: CmaxD8/Cmax D1=1.05 | |
| Arm 3 (enoxaparin), 28 | NR | Major bleeding: 1/28 (3.6%), minor bleeding: 3/28 (10.7%) | Factor Xa level: AF: CmaxD8/Cmax D1=1.22 | ||
| Dahl et al., 2012[18] | Arm 1 (enoxaparin), 332 | Major VTE: 8 (9.0%) | Major bleeding: 6 (4.7%) | Infections and infestations: 25 (7.5%), Wound infection: 4 (1.2%) | |
| Arm 2 (dabigatran), 300 | Major VTE: 3 (4.3%) | Major bleeding: 0 (0%) | Infections and infestations: 21 (7.0%), Wound Infection: 3 (1.0%) | ||
| Shorr et al., 2012[19] | Arm 1 (enoxaparin, CrCL 60 mL/min), 353 | Total VTE: 17/275 (6.2%) | Major bleeding: 0/351 (0%) | NR | |
| Arm 2 (desirudin, CrCL 60 mL/min), 353 | Total VTE: 13/284 (4.3%) | Major bleeding: 2/349 (0.27%) | NR | ||
| Arm 3 (enoxaparin, CrCL 4559 mL/min), 369 | Total VTE: 18/282 (6.2%) | Major bleeding: 1/365 (0.27%) | NR | ||
| Arm 4 (desirudin, CrCL 4559 mL/min), 395 | Total VTE: 17/303 (5.6%) | Major bleeding: 1/393 (0.25%) | NR | ||
| Arm 5 (enoxaparin, CrCL <45 mL/min), 298 | Total VTE: 24/216 (11.1%) | Major bleeding: 1/294 (0.34%) | NR | ||
| Arm 6 (desirudin, CrCL <45 mL/min), 279 | Total VTE: 7/205 (3.4%) | Major bleeding: 5/275 (1.82%) | NR | ||
| Elsaid et al., 2012[20] | Arm 1 (enoxaparin, CrCL 60 mL/min), 17 | NR | Major bleeding: 2 (11.8%) | NR | |
| Arm 2 (enoxaparin, CrCL 3059 mL/min), 86 | NR | Major bleeding: 9 (10.5%) | NR | ||
| Arm 3 (enoxaparin, CrCL 30 mL/min), 53 | NR | Major bleeding: 10 (18.9%) | NR | ||
| Arm 4 (UFH, CrCL 60 mL/min), 19 | NR | Major bleeding: 2 (10.5%) | NR | ||
| Arm 5 (UFH, CrCL 3059 mL/min), 99 | NR | Major bleeding: 3 (3%) | NR | ||
| Arm 6 (UFH, CrCL 30 mL/min), 49 | NR | Major bleeding: 2 (4.1%) | NR | ||
Obese Patients
We found 1 subgroup analysis of an RCT (total 3706 patients, 2563 nonobese and 1118 obese patients) that reported on the comparative effectiveness and safety of fixed low‐dose dalteparin 5000 IU/day compared to placebo among 1118 hospitalized medically ill patients with body mass indices (BMI) greater than 30 kg/m2.11 Neither group received additional concurrent prophylactic therapies. The 3 most prevalent medical diagnoses prompting hospitalization were congestive heart failure, respiratory failure, and infectious diseases. Compression ultrasound was performed in all patients by day 21 of hospitalization. The primary end point was the composite of VTE, fatal PE, and sudden death, and secondary end points included DVT, bleeding, and thrombocytopenia by day 21 (Table 1). In obese patients, the primary end point occurred in 2.8% (95% confidence interval [CI]: 1.34.3) of the dalteparin group and in 4.3% (95% CI: 2.56.2) of the placebo group (relative risk [RR]: 0.64; 95% CI: 0.32‐1.28). In nonobese patients, the primary end point occurred in 2.8% (95% CI: 1.8‐3.8) and 5.2% (95% CI: 3.9‐6.6) of the dalteparin and placebo groups, respectively (RR: 0.53; 95% CI: 0.34‐0.82). When weight was modeled as a continuous variable, no statistically significant interaction between weight and dalteparin efficacy was observed (P=0.97). The authors calculated the RR in predefined BMI subgroups and found that dalteparin was effective in reducing VTE in patients with BMIs up to 40, with RRs of <1.0 for all (approximate range, 0.20.8). However, a fixed dose of dalteparin 5000 IU/day was not better than placebo for individuals with BMI >40 kg/m2. There was no significant difference in mortality or major hemorrhage by day 21 between treatment and placebo groups.
Freeman and colleagues prospectively assigned 31 medically ill patients with extreme obesity (BMI >40 kg/m2) to 1 of 3 dosing regimens of enoxaparin: a fixed dose of 40 mg daily enoxaparin (control group, n=11), enoxaparin at 0.4 mg/kg (n=9), or enoxaparin at 0.5 mg/kg (n=11).[12] The average BMI of the entire cohort was 62.1 kg/m2 (range, 40.582.4). All patients had anti‐factor Xa levels drawn on the day of enrollment and daily for 3 days (Table 2). The relationship between anti‐factor Xa levels and clinical efficacy of low‐molecular weight heparin (LMWH) in VTE prophylaxis is still unclear; however, an anti‐factor Xa level of 0.2 to 0.5 IU/mL, measured 4 hours after the fourth dose of LMWH, is the target level recommended for VTE prophylaxis.[13] Patients who received weight‐based enoxaparin at 0.5mg/kg achieved target anti‐factor Xa level 86% of the time compared to 32% of the time in those receiving 0.4 mg/kg and 19% of the time for those in the fixed‐dose group (P<0.001). No clinical outcomes were reported in this study.
| Intervention | Outcome | Risk of Bias | Evidence Statement and Magnitude of Effect |
|---|---|---|---|
| |||
| Patients on antiplatelet agents | |||
| Rivaroxaban vs enoxaparin | Major bleeding | Low | Insufficient to support no difference in rates of major bleeding with prophylactic rivaroxaban or enoxaparin in patients concomitantly treated with antiplatelet agents; 3.6% vs 3.25% |
| Dabigatran vs enoxaparin | Major bleeding | Low | Insufficient to support no difference in rates of major bleeding with prophylactic dabigatran or enoxaparin in patients concomitantly treated with aspirin; 1.6% vs 3.0% |
| Obese patients | |||
| Dalteparin vs placebo | VTE | Moderate | Insufficient evidence for effectiveness of dalteparin vs placebo in reducing total VTE in obese patients; 2.8% vs 4.3%, RR: 0.64, 95% CI: 0.32‐1.28 |
| Dalteparin vs placebo | Mortality | Moderate | Insufficient evidence for effectiveness of dalteparin vs placebo in reducing mortality in obese patients; 9.9% vs 8.6%, P=0.36 |
| Dalteparin vs placebo | Major bleeding | Moderate | Insufficient evidence for safety of dalteparin vs placebo in reducing major bleeding in obese patients; 0% vs 0.7%, P>0.99 |
| Enoxaparin 40 mg daily vs 0.4 mg/kg | Percentage of patients achieving target anti‐factor Xa level | Moderate | Insufficient evidence for effectiveness of enoxaparin 40 mg daily versus 0.4 mg/kg in achieving peak anti‐factor Xa level in obese patients; 19% vs 32%, P=NR |
| Enoxaparin 40 mg daily vs 0.5 mg/kg | Percentage of patients achieving target anti‐factor Xa level | Moderate | Insufficient evidence for effectiveness of enoxaparin 40 mg daily versus 0.5 mg/kg in achieving peak anti‐factor Xa level in obese patients; 19% vs 86%, P<0.001 |
| Enoxaparin 0.4 mg/kg vs 0.5 mg/kg | Percentage of patients achieving target anti‐factor Xa level | Moderate | Insufficient evidence for effectiveness of enoxaparin 0.4 mg/kg versus 0.5 mg/kg in achieving peak anti‐factor Xa level in obese patients; 32% vs 86%, P=NR |
| Patients with renal insufficiency | |||
| Tinzaparin vs enoxaparin | VTE | High | Insufficient evidence about superiority of either drug for preventing VTE in patients with renal insufficiency, 0/27 vs 0/28* |
| Tinzaparin vs enoxaparin | Bleeding | High | Insufficient evidence about safety of either drug in patients with renal insufficiency; 5/27 vs 4/28, P=0.67 |
| Dabigatran vs enoxaparin | VTE | Moderate | Insufficient evidence for effectiveness of dabigatran in reducing VTE in severe renal compromise patients vs enoxaparin; 4.3% vs 9%, OR: 0.48, 95% CI: 0.13‐1.73, P=0.271 |
| Dabigatran vs enoxaparin | Bleeding | Moderate | Insufficient evidence for safety of dabigatran vs enoxaparin in patients with renal impairment; 0 vs 4.7%, P=0.039 |
| Desirudin vs enoxaparin | VTE | Moderate | Insufficient evidence for effectiveness of desirudin vs enoxaparin in reducing VTE in patients with renal impairment; 4.9% vs 7.6%, P=0.019 |
| Desirudin vs enoxaparin | Bleeding | Moderate | Insufficient evidence for safety of desirudin vs enoxaparin in patients with renal impairment; 0.8% vs 0.2%, P=0.109 |
| Enoxaparin vs UFH | Bleeding | High | Insufficient evidence for increased risk of bleeding with enoxaparin vs unfractionated heparin in patients with all levels of renal impairment, 13.5% vs 4.2%, RR: 3.2, 95% CI: 1.47.3; and for the subgroup of patients with creatinine clearance <30 mL/min; 18.9% vs 4.1%, RR: 4.68, 95% CI: 1.120.6 |
| UFH in severe renal compromise vs all other renal status (undifferentiated) | VTE | Moderate | Insufficient evidence regarding differential benefit of unfractionated heparin by renal function; 2.6% of patients had a VTE event |
| UFH in severe renal compromise vs all other renal status (undifferentiated) | Bleeding | Moderate | Insufficient evidence for differential harm from unfractionated heparin by renal function; 13 events in 92 patients |
Patients on Antiplatelet Drugs
We did not find studies that directly looked at the comparative effectiveness of VTE prophylaxis in patients who were on antiplatelet drugs including aspirin. However, there were 2 studies that looked at the risk of bleeding in patients who received VTE pharmacologic prophylaxis while concurrently taking antiplatelet agents including aspirin. Both studies used pooled data from large phase III trials.
The study by Eriksson et al. used data from the RECORD (Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism) trial where over 12,000 patients undergoing elective total knee or hip replacement were randomized to receive VTE prophylaxis with oral rivaroxaban or subcutaneous enoxaparin.[14] Nine percent of participants in each arm (563 in rivaroxaban and 526 in enoxaparin/placebo) were concomitantly using antiplatelet agents or aspirin at least once during the at risk period, defined as starting at day 1 of surgery up to 2 days after the last intake of the study drug. The only end point evaluated was bleeding, and the authors found no statistically significant bleeding difference among the 2 arms (Table 1). Any bleeding event in the rivaroxaban with antiplatelets or aspirin arm was found in 20 (3.6%) patients, whereas in those on enoxaparin/placebo with antiplatelets or aspirin arm it was 17 (3.2%). The relative rate of bleeding among users versus nonusers of antiplatelet drugs or aspirin was 1.32 (95% CI: 0.85‐2.05) in the rivaroxaban group and 1.40 (95% CI: 0.87‐2.25) in the enoxaparin arm (Table 1).
Friedman et al. used pooled data from the RE‐MODEL, RENOVATE, and REMOBILIZE trials, where patients who were undergoing hip or knee arthroplasty were randomized to 220 mg of dabigatran once daily, 150 mg of dabigatran once daily (we focused on this lower dosage as this is the only available dose used in the US), 40 mg of enoxaparin once daily, or 30 mg of enoxaparin twice a day.[15] Of the 8135 patients, 4.7% were on concomitant aspirin. The baseline characteristics of those on aspirin were similar to the other enrollees. The primary outcome was major bleeding events requiring transfusion, symptomatic internal bleeding, or bleeding requiring surgery. Among patients receiving 150 mg of dabigatran, bleeding events with and without concomitant aspirin occurred in 1.6% and 1.0%, respectively (odds ratio [OR]: 1.64; 95% CI: 0.36‐7.49; P=0.523). The percentages of participants with bleeding who received enoxaparin, with and without aspirin, were 3.0% and 1.2%, respectively (OR: 2.57; 95% CI: 0.83‐7.94; P=0.101). The RR of bleeding on dabigatran compared to enoxaparin with and without aspirin therapy was 0.55 (95% CI: 0.11‐2.78) and 0.82 (95% CI: 0.37‐1.84), respectively (Table 1).
Patients With Renal Insufficiency
We found 5 studies that evaluated the comparative effectiveness and safety of pharmacologic prophylaxis for prevention of VTE in patients with acute kidney injury, moderate renal insufficiency, severe renal insufficiency not undergoing dialysis, or patients receiving dialysis. Four studies were RCTs,[16, 17, 18, 19] and 1 used a cohort design assessing separate cohorts before and after a quality improvement intervention.[20] Bauersachs and colleagues conducted an RCT comparing unfractionated heparin at 5000 IU, 3 times daily to certoparin, which is not approved in the United States and is not further discussed here.[16] The rate of DVT among patients treated with unfractionated heparin in patients with a glomerular filtration rate >30 mL/min was marginally lower than those with severe renal dysfunction (10.3 vs 11.1%) (Table 1).
Patients with severe renal dysfunction who received 5000 IU of unfractionated heparin 3 times a day were at increased risk of all bleeds (RR: 3.4; 95% CI: 2.05.9), major bleeds (RR: 7.3; 95% CI: 3.316), and minor bleeds (RR: 2.6; 95% CI: 1.4‐4.9) compared to patients treated with unfractionated heparin without severe renal dysfunction.[16]
A randomized trial by Mah and colleagues compared drug accumulation and anti‐Xa activity in elderly patients with renal dysfunction (defined as a glomerular filtration rate of 20 to 50 mL/min) who received either tinzaparin at 4500 IU once daily or enoxaparin at 4000 IU once daily.[17] Enoxaparin accumulated to a greater extent from day 1 to day 8 than did tinzaparin; the ratio of maximum concentration on day 8 compared to day 1 was 1.22 for enoxaparin and 1.05 for tinzaparin (P=0.016). No VTE events were reported in patients who received tinzaparin or enoxaparin. There was no statistical difference in the incidence of bleeding events between patients receiving tinzaparin (5, including 2 major events) and enoxaparin (4, including 3 major events, P=0.67) (Table 1).
The trial by Dahl and colleagues randomly assigned patients who were over 75 years of age and/or who had moderate renal dysfunction (defined as creatinine clearance between 30 and 49 mL/min) to receive enoxaparin 40 mg daily or dabigatran 150 mg daily.[18] There was no significant difference in the rate of major VTE events between patients receiving dabigatran (4.3%) and enoxaparin (9%) (OR: 0.48; 95% CI: 0.13‐1.73; P=0.271) (Table 1). The rate of major bleeding was significantly higher among patients randomly assigned to receive enoxaparin (4.7%) versus dabigatran (0%) (P=0.039).[18]
Shorr and colleagues published a post hoc subgroup analysis of a multicenter trial in which orthopedic patients were randomly assigned to receive desirudin 15 mg twice daily or enoxaparin 40 mg once daily.[19] Evaluable patients (1565 of the 2079 patients randomized in the trial) receiving desirudin experienced a significantly lower rate of major VTE compared with patients receiving enoxaparin (4.9% vs 7.6%, P=0.019). This relationship was particularly pronounced for evaluable patients whose creatinine clearance was between 30 and 44 mL/min. In evaluable patients with this degree of renal dysfunction, 11% of patients taking enoxaparin compared to 3.4% of those taking desirudin had a major VTE (OR: 3.52; 95% CI: 1.48‐8.4; P=0.004). There was no significant difference in the rates of major bleeding among a subset of patients assessed for safety outcomes (2078 of the 2079 patients randomized in the trial) who received desirudin (0.8%) or enoxaparin (0.2%) (Table 1).
Elsaid and Collins assessed VTE and bleeding events associated with the use of unfractionated heparin 5000U either 2 or 3 times daily and enoxaparin 30 mg once or twice daily across patients stratified by renal function (creatinine clearance <30, 3059, and 60 mL/min). The investigators made assessments before and after a quality improvement intervention that was designed to eliminate the use of enoxaparin in patients whose creatinine clearance was <30 mL/min. No VTE events were reported. Patients receiving enoxaparin were significantly more likely to experience a major bleeding episode compared with patients receiving unfractionated heparin (overall rates for all levels of renal function: 13.5% vs 4. 2%; RR: 3.2; 95% CI: 1.47.3) (Table 2). This association was largely driven by the subgroup of patients with a creatinine clearance <30 mL/min. For this subgroup with severe renal insufficiency, patients receiving enoxaparin were significantly more likely to have a bleed compared with patients receiving unfractionated heparin (18.9% vs 4.1%; RR: 4.68; 95% CI: 1.120.6) (Tables 1 and 2). There was no difference in the bleeding rates for patients whose creatinine clearances were >60 mL/min.[20]
Strength of Evidence
Obese Patients
Overall, we found that the strength of evidence was insufficient regarding the composite end point of DVT, PE, and sudden death, and the outcomes of mortality and bleeding (Table 2). This was based on a paucity of available data, and a moderate risk of bias in the reviewed studies. Additionally, 92% of the enrolled patients in the studies were white, limiting the generalizability of the results to other ethnic groups.
Patients on Antiplatelets
The strength of evidence was insufficient in the studies reviewed here to conclude that there is no difference in rates of bleeding in patients who are concomitantly taking antiplatelet drugs while getting VTE prophylaxis with rivaroxaban, dabigatran, or enoxaparin. We based this rating because of the imprecision of results and unknown consistencies across multiple studies.
Patients With Renal Insufficiency
One RCT had a high risk of bias for our key question because data from only 1 study arm were useful for our review.[16] The other RCTs were judged to have a moderate risk of bias. The analyses led by Dahl and Shorr[18, 19] were based on post hoc (ie, not prespecified) analysis of data from RCTs. Additionally, outcomes in the Shorr et al. trial were reported for evaluable subpopulations of the cohort that was initially randomized in the clinical trial.
We rated the strength of evidence as insufficient to know the comparative effectiveness and safety of pharmacologic prophylaxis for prevention of VTE during hospitalization of patients with acute kidney injury, moderate renal insufficiency, severe renal insufficiency not undergoing dialysis, and patients receiving dialysis. We based this rating on the risk of bias associated with published studies and a lack of consistent evidence regarding associations that were reported. Similarly, we rated the strength of evidence as insufficient that 5000 U of unfractionated heparin 3 times daily increases the risk of major and minor bleeding events in patients with severely compromised renal function compared to this dose in patients without severely compromised renal function. We based this rating on a high risk of bias of included studies and inconsistent evidence. Likewise, we rated the strength of evidence as insufficient that enoxaparin significantly increases the risk of major bleeding compared with unfractionated heparin in patients with severe renal insufficiency. We based this rating on a high risk of bias and inconsistent published evidence.
We similarly found insufficient evidence to guide treatment decisions for patients with renal insufficiency. Our findings are consistent with other recent reviews. The American College of Chest Physicians (ACCP) practice guidelines[21] make dosing recommendations for the therapeutic use of enoxaparin. However, their assessment is that the data are insufficient to make direct recommendations about prophylaxis. Their assessment of the indirect evidence regarding bioaccumulation and increased anti‐factor Xa levels are consistent with ours. The ACCP guidelines also suggest that decreased clearance of enoxaparin has been associated with increased risk of bleeding events for patients with severe renal insufficiency. However, the cited study[20] compares patients with and without severe renal dysfunction who received the same therapy. Therefore, it is not possible to determine the additional risk conveyed by enoxaparin therapy, that is, above the baseline increased risk of bleeding among patients with renal insufficiency, particularly those receiving an alternate pharmacologic VTE prevention strategy, such as unfractionated heparin.
DISCUSSION
We found that the evidence was very limited about prevention of VTE in these select and yet prevalent patient populations. Despite the fact that there is an increasing number of obese patients and patients who are on antiplatelet therapies, most clinical practice guidelines do not address the care of these populations, which may be entirely appropriate given the state of the evidence.
The ACCP practice guidelines[21] suggest using a higher dose of enoxaparin for the prevention of VTE in obese patients. The subgroup analysis by Kucher et al.[11] showed effect attenuation of dalteparin when given at a fixed dose of 5000 IU/mL to patients with a BMI of >40 kg/m2. The Freeman study[12] showed that extremely obese patients (average BMI >62.1 kg/m2) who are given a fixed dose of enoxaparin achieved target anti‐factor Xa levels significantly less often than those who received a higher dose of enoxaparin. The 2 separate findings, although not conclusive, lend some credence to the current ACCP guidelines.[21]
The studies we reviewed on VTE prophylaxis in patients who are concomitantly on antiplatelets including aspirin reported no major increased risk of bleeding; however, in the Friedman et al. study,[15] 3.0% of patients who were put on enoxaparin while still on aspirin had a bleeding event compared to 1.2% of those on enoxaparin alone. This difference is not statistically significant but is a trend possibly worth noting, especially when one looks at the lower RR of bleeding at 0.55 compared to 0.82 when dabigatran is compared with enoxaparin with and without concomitant aspirin therapy, respectively (Table 1). The highest dose of aspirin used in either of the studies was 160 mg/day, and neither study addressed other potent antiplatelets such as clopidogrel or ticlopidine separately, which limits the generalizability of the finding to all antiplatelets. Current ACCP guidelines do not recommend aspirin as a sole option for the prevention of VTE in orthopedic surgery patients.[22] Concerns remain among clinicians that antiplatelets, including aspirin, on their own are unlikely to be fully effective to thwart venous thrombotic processes for most patients, and yet the risk of bleeding is not fully known when these agents are combined with other anticoagulants for VTE prophylaxis.
Our review has several limitations, including the possibility that we may have missed some observational studies, as the identification of relevant observational studies in electronic searches is more challenging than that of RCTs. The few studies made it impossible to quantitatively pool results. These results, however, have important implications, namely that additional research on the comparative effectiveness and safety of pharmacologic and mechanical strategies to prevent VTE is needed for the optimal care of these patient subgroups. This might be achieved with trials dedicated to enrolling these patients or prespecified subgroup analyses within larger trials. Observational data may be appropriate as long as attention is paid to confounding.
APPENDIX
MEDLINE Search Strategy
((pulmonary embolism[mh] OR PE[tiab] OR Pulmonary embolism[tiab] OR thromboembolism[mh] OR thromboembolism[tiab] OR thromboembolisms[tiab] OR Thrombosis[mh] OR thrombosis[tiab] OR DVT[tiab] OR VTE[tiab] OR clot[tiab]) AND (Anticoagulants[mh] OR Anticoagulants[tiab] OR Anticoagulant[tiab] OR thrombin inhibitors[tiab] OR Aspirin[mh] or aspirin[tiab] OR aspirins[tiab] or clopidogrel[nm] OR clopidogrel[tiab] OR Plavix[tiab] or ticlopidine[mh] or ticlopidine[tiab]OR ticlid[tiab] OR prasugrel[nm]Or prasugrel[tiab]OR effient[tiab]OR ticagrelor[NM] OR ticagrelor[tiab]OR Brilinta[tiab] OR cilostazol[NM] OR cilostazol[tiab]OR pletal[tiab] OR warfarin[mh]OR warfarin[tiab]OR coumadin[tiab] OR coumadine[tiab] OR Dipyridamole[mh]OR dipyridamole[tiab]OR persantine[tiab] OR dicoumarol[MH] OR dicoumarol[tiab] OR dicumarol[tiab] OR Dextran sulfate[mh] OR dextran sulfate[tiab] ORthrombin inhibitors[tiab] OR thrombin inhibitor[tiab] OR heparin[mh] OR Heparin[tiab] OR Heparins[tiab] OR LMWH[tiab] OR LDUH[tiab] OR Enoxaparin[mh] OR Enoxaparin[tiab] OR Lovenox[tiab] OR Dalteparin[tiab] OR Fragmin[tiab] OR Tinzaparin[tiab] OR innohep[tiab] OR Nadroparin[tiab] OR Fondaparinux[nm] OR Fondaparinux[tiab] OR Arixtra[tiab] OR Idraparinux[nm] OR Idraparinux[tiab] OR Rivaroxaban[nm] OR Rivaroxaban[tiab] OR novastan[tiab] OR Desirudin[nm] OR Desirudin[tiab] OR Iprivask[tiab]OR direct thrombin inhibitor[tiab] OR Argatroban[nm] OR Argatroban[tiab] OR Acova[tiab] OR Bivalirudin[nm] OR Bivalirudin[tiab] OR Angiomax[tiab] OR Lepirudin[nm] OR Lepirudin[tiab] OR Refludan[tiab] OR Dabigatran[nm] OR Dabigatran[tiab] OR Pradaxa[tiab] OR factor xa[mh] OR factor Xa[tiab] OR vena cava filters[mh] OR filters[tiab] OR filter[tiab] OR compression stockings[mh] OR intermittent pneumatic compression devices[mh] OR compression [tiab] OR Venous foot pump[tiab])) AND(prevent*[tiab] OR prophyla*[tiab] OR prevention and control[subheading]) NOT (animals[mh] NOT humans[mh]) NOT (editorial[pt] OR comment[pt]) NOT ((infant[mh] OR infant[tiab] OR child[mh] OR child[tiab] OR children[tiab] OR adolescent[mh] OR adolescent[tiab] OR teen‐age[tiab] OR pediatric[tiab] OR perinatal[tiab]) NOT (adult[tiab] OR adults[tiab] OR adult[mh])) NOT (mechanical valve[tiab] OR heart valve[tiab] OR atrial fibrillation[mh] OR atrial fibrillation[tiab] OR thrombophilia[mh] OR thrombophilia[tiab] OR pregnancy[mh])
Venous thromboembolism (VTE), including deep venous thrombosis (DVT) and pulmonary embolism (PE), is estimated to affect 900,000 Americans each year and is a cause of significant morbidity and mortality with associated high healthcare costs.[1] Accordingly, the comparative effectiveness and safety of interventions for the prevention and treatment of VTE are among the national priorities for comparative effectiveness research.[2] Whereas we have evidence‐based guidelines for the prophylaxis of VTE in the general population, there are no guidelines informing the care of select patient populations. Select populations are those patients in whom there is decisional uncertainty about the optimal choice, timing, and dose of VTE prophylaxis. Not only do these patients have an increased risk of DVT and PE, but most are also at high risk of bleeding, the most important complication of VTE prophylaxis.[3, 4, 5, 6]
The objectives of this systematic review were to define the comparative effectiveness and safety of pharmacologic and mechanical strategies for VTE prevention in some of these select medical populations including obese patients, patients on concomitant antiplatelet therapy, patients with renal insufficiency, patients who are underweight, and patients with coagulopathy due to liver disease.
METHODS
The methods for this comparative effectiveness review (CER) follow the guidelines suggested in the Agency for Healthcare Research and Quality (AHRQ) Methods Guide for Effectiveness and Comparative Effectiveness Reviews.[7] The protocol was publically posted.[8]
Search Strategy
We searched MEDLINE, EMBASE, and SCOPUS through August 2011, CINAHL, International Pharmaceutical Abstracts,
Study Selection
We reviewed titles followed by abstracts to identify randomized controlled trials (RCTs) or observational studies with comparison groups reporting on the effectiveness or safety of VTE prevention in our populations. Two investigators independently reviewed abstracts, and we excluded the abstracts if both investigators agreed that the article met 1 or more of the exclusion criteria. We included only English‐language articles that evaluated the effectiveness of pharmacological or mechanical interventions that have been approved for clinical use in the United States. To be eligible, the studies must have addressed relevant key questions in the population of our interest. We resolved disagreements by consensus. We used DistillerSR (Evidence Partners Inc., Ottawa, Ontario, Canada), a Web‐based database management program to manage the review process. Two investigators assessed the risk of bias in each study independently, using the Downs and Black instrument for observational studies and trials.[10]
Data Synthesis
For each select population, we created detailed evidence tables containing the information abstracted from the eligible studies. After synthesizing the evidence, we graded the quantity, quality, and consistency of the best available evidence for each select population by adapting an evidence‐grading scheme recommended in the Methods Guide for Conducting Comparative Effectiveness Reviews.[7]
RESULTS
We identified 30,902 unique citations and included 9 studies (Figure 1). There were 5 RCTs with relevant subgroups and 4 observational studies (Table 1). Two studies reported on the risk of bleeding in patients given pharmacologic prophylaxis while they are concomitantly taking nonsteroidal anti‐inflammatory drugs (NSAIDS) or antiplatelet agents/aspirin, 1 RCT and 1 prospective observational study reported on obese patients, and 5 studies described outcomes of patients with renal insufficiency (see Supporting Information, Table 1, in the online version of this article). No study tested prophylaxis in underweight patients or those with liver disease.
| Study | Arm, n | Total VTE (DVT and PE) | Bleeding | Other Outcomes | |
|---|---|---|---|---|---|
| |||||
| Obese patients | |||||
| Kucher et al., 2005[11] | Arm 1 (dalteparin), 558 | 2.8% (95% CI: 1.34.3) | 0% | Mortality at 21 days: 4.6% | |
| Arm 2 (placebo), 560 | 4.3% (95% CI: 2.56.2) | 0.7% | Mortality at 21 days: 2.7% | ||
| Freeman et al., [12] | Arm 1 (fixed‐dose enoxaparin), 11 | NR | NR | Peak anti‐factor Xa level 19 % | |
| Arm 2 (lower‐dose enoxaparin), 9 | NR | NR | Peak anti‐factor Xa level 32 % | ||
| Arm 3 (higher‐dose enoxaparin), 11 | NR | NR | Peak anti‐factor Xa level 86 % | ||
| Patients on antiplatelet agents | |||||
| Eriksson et al., 2012[14] | Arm 1 (rivaroxaban), 563 | NR | 20 (3.6%), rate ratio for use vs nonuse: 1.32 (95% CI: 0.85‐2.05) | NR | |
| Arm 2 (enoxaparin/placebo), 526 | NR | 17 (3.2%), rate ratio for use vs nonuse: 1.40 (95% CI: 0.87‐2.25) | NR | ||
| Friedman et al., 2012[15] | Arm 2 (150 mg dabigatran, no ASA), 1149 | NR | 11 (1.0%)a | NR | |
| Arm 5 (150 mg dabigatran+ASA), 128 | NR | 2 (1.6%)a | NR | ||
| Arm 3 (enoxaparin, no ASA), 1167 | NR | 14 (1.2%)a | NR | ||
| Arm 6 (enoxaparin+ASA), 132 | NR | 4 (3.0%) | NR | ||
| 150 mg dabigatran compared with enoxaparinNo concomitant ASA therapy | NR | RR: 0.82 (95% CI: 0.37‐1.84) | NR | ||
| 150 mg dabigatran compared with enoxaparinWith concomitant ASA therapy | NR | RR: 0.55 (95% CI: 0.11‐2.78) | NR | ||
| Patients with renal insufficiency | |||||
| Bauersachs et al., 2011[16] | Arm 2 (GFR <30), 92 | Total DVT: 11.11%; Total PE: 0% | Major bleeding: 4/92 (4.35%), minor bleeding: 9/92 (9.78%) | Mortality: 5.81% | |
| Mah et al., 2007[17] | Arm 2 (tinzaparin), 27 | NR | Major bleeding: 2/27 (7.4%), minor bleeding: 3/27 (11.1%) | Factor Xa level: AF: CmaxD8/Cmax D1=1.05 | |
| Arm 3 (enoxaparin), 28 | NR | Major bleeding: 1/28 (3.6%), minor bleeding: 3/28 (10.7%) | Factor Xa level: AF: CmaxD8/Cmax D1=1.22 | ||
| Dahl et al., 2012[18] | Arm 1 (enoxaparin), 332 | Major VTE: 8 (9.0%) | Major bleeding: 6 (4.7%) | Infections and infestations: 25 (7.5%), Wound infection: 4 (1.2%) | |
| Arm 2 (dabigatran), 300 | Major VTE: 3 (4.3%) | Major bleeding: 0 (0%) | Infections and infestations: 21 (7.0%), Wound Infection: 3 (1.0%) | ||
| Shorr et al., 2012[19] | Arm 1 (enoxaparin, CrCL 60 mL/min), 353 | Total VTE: 17/275 (6.2%) | Major bleeding: 0/351 (0%) | NR | |
| Arm 2 (desirudin, CrCL 60 mL/min), 353 | Total VTE: 13/284 (4.3%) | Major bleeding: 2/349 (0.27%) | NR | ||
| Arm 3 (enoxaparin, CrCL 4559 mL/min), 369 | Total VTE: 18/282 (6.2%) | Major bleeding: 1/365 (0.27%) | NR | ||
| Arm 4 (desirudin, CrCL 4559 mL/min), 395 | Total VTE: 17/303 (5.6%) | Major bleeding: 1/393 (0.25%) | NR | ||
| Arm 5 (enoxaparin, CrCL <45 mL/min), 298 | Total VTE: 24/216 (11.1%) | Major bleeding: 1/294 (0.34%) | NR | ||
| Arm 6 (desirudin, CrCL <45 mL/min), 279 | Total VTE: 7/205 (3.4%) | Major bleeding: 5/275 (1.82%) | NR | ||
| Elsaid et al., 2012[20] | Arm 1 (enoxaparin, CrCL 60 mL/min), 17 | NR | Major bleeding: 2 (11.8%) | NR | |
| Arm 2 (enoxaparin, CrCL 3059 mL/min), 86 | NR | Major bleeding: 9 (10.5%) | NR | ||
| Arm 3 (enoxaparin, CrCL 30 mL/min), 53 | NR | Major bleeding: 10 (18.9%) | NR | ||
| Arm 4 (UFH, CrCL 60 mL/min), 19 | NR | Major bleeding: 2 (10.5%) | NR | ||
| Arm 5 (UFH, CrCL 3059 mL/min), 99 | NR | Major bleeding: 3 (3%) | NR | ||
| Arm 6 (UFH, CrCL 30 mL/min), 49 | NR | Major bleeding: 2 (4.1%) | NR | ||
Obese Patients
We found 1 subgroup analysis of an RCT (total 3706 patients, 2563 nonobese and 1118 obese patients) that reported on the comparative effectiveness and safety of fixed low‐dose dalteparin 5000 IU/day compared to placebo among 1118 hospitalized medically ill patients with body mass indices (BMI) greater than 30 kg/m2.11 Neither group received additional concurrent prophylactic therapies. The 3 most prevalent medical diagnoses prompting hospitalization were congestive heart failure, respiratory failure, and infectious diseases. Compression ultrasound was performed in all patients by day 21 of hospitalization. The primary end point was the composite of VTE, fatal PE, and sudden death, and secondary end points included DVT, bleeding, and thrombocytopenia by day 21 (Table 1). In obese patients, the primary end point occurred in 2.8% (95% confidence interval [CI]: 1.34.3) of the dalteparin group and in 4.3% (95% CI: 2.56.2) of the placebo group (relative risk [RR]: 0.64; 95% CI: 0.32‐1.28). In nonobese patients, the primary end point occurred in 2.8% (95% CI: 1.8‐3.8) and 5.2% (95% CI: 3.9‐6.6) of the dalteparin and placebo groups, respectively (RR: 0.53; 95% CI: 0.34‐0.82). When weight was modeled as a continuous variable, no statistically significant interaction between weight and dalteparin efficacy was observed (P=0.97). The authors calculated the RR in predefined BMI subgroups and found that dalteparin was effective in reducing VTE in patients with BMIs up to 40, with RRs of <1.0 for all (approximate range, 0.20.8). However, a fixed dose of dalteparin 5000 IU/day was not better than placebo for individuals with BMI >40 kg/m2. There was no significant difference in mortality or major hemorrhage by day 21 between treatment and placebo groups.
Freeman and colleagues prospectively assigned 31 medically ill patients with extreme obesity (BMI >40 kg/m2) to 1 of 3 dosing regimens of enoxaparin: a fixed dose of 40 mg daily enoxaparin (control group, n=11), enoxaparin at 0.4 mg/kg (n=9), or enoxaparin at 0.5 mg/kg (n=11).[12] The average BMI of the entire cohort was 62.1 kg/m2 (range, 40.582.4). All patients had anti‐factor Xa levels drawn on the day of enrollment and daily for 3 days (Table 2). The relationship between anti‐factor Xa levels and clinical efficacy of low‐molecular weight heparin (LMWH) in VTE prophylaxis is still unclear; however, an anti‐factor Xa level of 0.2 to 0.5 IU/mL, measured 4 hours after the fourth dose of LMWH, is the target level recommended for VTE prophylaxis.[13] Patients who received weight‐based enoxaparin at 0.5mg/kg achieved target anti‐factor Xa level 86% of the time compared to 32% of the time in those receiving 0.4 mg/kg and 19% of the time for those in the fixed‐dose group (P<0.001). No clinical outcomes were reported in this study.
| Intervention | Outcome | Risk of Bias | Evidence Statement and Magnitude of Effect |
|---|---|---|---|
| |||
| Patients on antiplatelet agents | |||
| Rivaroxaban vs enoxaparin | Major bleeding | Low | Insufficient to support no difference in rates of major bleeding with prophylactic rivaroxaban or enoxaparin in patients concomitantly treated with antiplatelet agents; 3.6% vs 3.25% |
| Dabigatran vs enoxaparin | Major bleeding | Low | Insufficient to support no difference in rates of major bleeding with prophylactic dabigatran or enoxaparin in patients concomitantly treated with aspirin; 1.6% vs 3.0% |
| Obese patients | |||
| Dalteparin vs placebo | VTE | Moderate | Insufficient evidence for effectiveness of dalteparin vs placebo in reducing total VTE in obese patients; 2.8% vs 4.3%, RR: 0.64, 95% CI: 0.32‐1.28 |
| Dalteparin vs placebo | Mortality | Moderate | Insufficient evidence for effectiveness of dalteparin vs placebo in reducing mortality in obese patients; 9.9% vs 8.6%, P=0.36 |
| Dalteparin vs placebo | Major bleeding | Moderate | Insufficient evidence for safety of dalteparin vs placebo in reducing major bleeding in obese patients; 0% vs 0.7%, P>0.99 |
| Enoxaparin 40 mg daily vs 0.4 mg/kg | Percentage of patients achieving target anti‐factor Xa level | Moderate | Insufficient evidence for effectiveness of enoxaparin 40 mg daily versus 0.4 mg/kg in achieving peak anti‐factor Xa level in obese patients; 19% vs 32%, P=NR |
| Enoxaparin 40 mg daily vs 0.5 mg/kg | Percentage of patients achieving target anti‐factor Xa level | Moderate | Insufficient evidence for effectiveness of enoxaparin 40 mg daily versus 0.5 mg/kg in achieving peak anti‐factor Xa level in obese patients; 19% vs 86%, P<0.001 |
| Enoxaparin 0.4 mg/kg vs 0.5 mg/kg | Percentage of patients achieving target anti‐factor Xa level | Moderate | Insufficient evidence for effectiveness of enoxaparin 0.4 mg/kg versus 0.5 mg/kg in achieving peak anti‐factor Xa level in obese patients; 32% vs 86%, P=NR |
| Patients with renal insufficiency | |||
| Tinzaparin vs enoxaparin | VTE | High | Insufficient evidence about superiority of either drug for preventing VTE in patients with renal insufficiency, 0/27 vs 0/28* |
| Tinzaparin vs enoxaparin | Bleeding | High | Insufficient evidence about safety of either drug in patients with renal insufficiency; 5/27 vs 4/28, P=0.67 |
| Dabigatran vs enoxaparin | VTE | Moderate | Insufficient evidence for effectiveness of dabigatran in reducing VTE in severe renal compromise patients vs enoxaparin; 4.3% vs 9%, OR: 0.48, 95% CI: 0.13‐1.73, P=0.271 |
| Dabigatran vs enoxaparin | Bleeding | Moderate | Insufficient evidence for safety of dabigatran vs enoxaparin in patients with renal impairment; 0 vs 4.7%, P=0.039 |
| Desirudin vs enoxaparin | VTE | Moderate | Insufficient evidence for effectiveness of desirudin vs enoxaparin in reducing VTE in patients with renal impairment; 4.9% vs 7.6%, P=0.019 |
| Desirudin vs enoxaparin | Bleeding | Moderate | Insufficient evidence for safety of desirudin vs enoxaparin in patients with renal impairment; 0.8% vs 0.2%, P=0.109 |
| Enoxaparin vs UFH | Bleeding | High | Insufficient evidence for increased risk of bleeding with enoxaparin vs unfractionated heparin in patients with all levels of renal impairment, 13.5% vs 4.2%, RR: 3.2, 95% CI: 1.47.3; and for the subgroup of patients with creatinine clearance <30 mL/min; 18.9% vs 4.1%, RR: 4.68, 95% CI: 1.120.6 |
| UFH in severe renal compromise vs all other renal status (undifferentiated) | VTE | Moderate | Insufficient evidence regarding differential benefit of unfractionated heparin by renal function; 2.6% of patients had a VTE event |
| UFH in severe renal compromise vs all other renal status (undifferentiated) | Bleeding | Moderate | Insufficient evidence for differential harm from unfractionated heparin by renal function; 13 events in 92 patients |
Patients on Antiplatelet Drugs
We did not find studies that directly looked at the comparative effectiveness of VTE prophylaxis in patients who were on antiplatelet drugs including aspirin. However, there were 2 studies that looked at the risk of bleeding in patients who received VTE pharmacologic prophylaxis while concurrently taking antiplatelet agents including aspirin. Both studies used pooled data from large phase III trials.
The study by Eriksson et al. used data from the RECORD (Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism) trial where over 12,000 patients undergoing elective total knee or hip replacement were randomized to receive VTE prophylaxis with oral rivaroxaban or subcutaneous enoxaparin.[14] Nine percent of participants in each arm (563 in rivaroxaban and 526 in enoxaparin/placebo) were concomitantly using antiplatelet agents or aspirin at least once during the at risk period, defined as starting at day 1 of surgery up to 2 days after the last intake of the study drug. The only end point evaluated was bleeding, and the authors found no statistically significant bleeding difference among the 2 arms (Table 1). Any bleeding event in the rivaroxaban with antiplatelets or aspirin arm was found in 20 (3.6%) patients, whereas in those on enoxaparin/placebo with antiplatelets or aspirin arm it was 17 (3.2%). The relative rate of bleeding among users versus nonusers of antiplatelet drugs or aspirin was 1.32 (95% CI: 0.85‐2.05) in the rivaroxaban group and 1.40 (95% CI: 0.87‐2.25) in the enoxaparin arm (Table 1).
Friedman et al. used pooled data from the RE‐MODEL, RENOVATE, and REMOBILIZE trials, where patients who were undergoing hip or knee arthroplasty were randomized to 220 mg of dabigatran once daily, 150 mg of dabigatran once daily (we focused on this lower dosage as this is the only available dose used in the US), 40 mg of enoxaparin once daily, or 30 mg of enoxaparin twice a day.[15] Of the 8135 patients, 4.7% were on concomitant aspirin. The baseline characteristics of those on aspirin were similar to the other enrollees. The primary outcome was major bleeding events requiring transfusion, symptomatic internal bleeding, or bleeding requiring surgery. Among patients receiving 150 mg of dabigatran, bleeding events with and without concomitant aspirin occurred in 1.6% and 1.0%, respectively (odds ratio [OR]: 1.64; 95% CI: 0.36‐7.49; P=0.523). The percentages of participants with bleeding who received enoxaparin, with and without aspirin, were 3.0% and 1.2%, respectively (OR: 2.57; 95% CI: 0.83‐7.94; P=0.101). The RR of bleeding on dabigatran compared to enoxaparin with and without aspirin therapy was 0.55 (95% CI: 0.11‐2.78) and 0.82 (95% CI: 0.37‐1.84), respectively (Table 1).
Patients With Renal Insufficiency
We found 5 studies that evaluated the comparative effectiveness and safety of pharmacologic prophylaxis for prevention of VTE in patients with acute kidney injury, moderate renal insufficiency, severe renal insufficiency not undergoing dialysis, or patients receiving dialysis. Four studies were RCTs,[16, 17, 18, 19] and 1 used a cohort design assessing separate cohorts before and after a quality improvement intervention.[20] Bauersachs and colleagues conducted an RCT comparing unfractionated heparin at 5000 IU, 3 times daily to certoparin, which is not approved in the United States and is not further discussed here.[16] The rate of DVT among patients treated with unfractionated heparin in patients with a glomerular filtration rate >30 mL/min was marginally lower than those with severe renal dysfunction (10.3 vs 11.1%) (Table 1).
Patients with severe renal dysfunction who received 5000 IU of unfractionated heparin 3 times a day were at increased risk of all bleeds (RR: 3.4; 95% CI: 2.05.9), major bleeds (RR: 7.3; 95% CI: 3.316), and minor bleeds (RR: 2.6; 95% CI: 1.4‐4.9) compared to patients treated with unfractionated heparin without severe renal dysfunction.[16]
A randomized trial by Mah and colleagues compared drug accumulation and anti‐Xa activity in elderly patients with renal dysfunction (defined as a glomerular filtration rate of 20 to 50 mL/min) who received either tinzaparin at 4500 IU once daily or enoxaparin at 4000 IU once daily.[17] Enoxaparin accumulated to a greater extent from day 1 to day 8 than did tinzaparin; the ratio of maximum concentration on day 8 compared to day 1 was 1.22 for enoxaparin and 1.05 for tinzaparin (P=0.016). No VTE events were reported in patients who received tinzaparin or enoxaparin. There was no statistical difference in the incidence of bleeding events between patients receiving tinzaparin (5, including 2 major events) and enoxaparin (4, including 3 major events, P=0.67) (Table 1).
The trial by Dahl and colleagues randomly assigned patients who were over 75 years of age and/or who had moderate renal dysfunction (defined as creatinine clearance between 30 and 49 mL/min) to receive enoxaparin 40 mg daily or dabigatran 150 mg daily.[18] There was no significant difference in the rate of major VTE events between patients receiving dabigatran (4.3%) and enoxaparin (9%) (OR: 0.48; 95% CI: 0.13‐1.73; P=0.271) (Table 1). The rate of major bleeding was significantly higher among patients randomly assigned to receive enoxaparin (4.7%) versus dabigatran (0%) (P=0.039).[18]
Shorr and colleagues published a post hoc subgroup analysis of a multicenter trial in which orthopedic patients were randomly assigned to receive desirudin 15 mg twice daily or enoxaparin 40 mg once daily.[19] Evaluable patients (1565 of the 2079 patients randomized in the trial) receiving desirudin experienced a significantly lower rate of major VTE compared with patients receiving enoxaparin (4.9% vs 7.6%, P=0.019). This relationship was particularly pronounced for evaluable patients whose creatinine clearance was between 30 and 44 mL/min. In evaluable patients with this degree of renal dysfunction, 11% of patients taking enoxaparin compared to 3.4% of those taking desirudin had a major VTE (OR: 3.52; 95% CI: 1.48‐8.4; P=0.004). There was no significant difference in the rates of major bleeding among a subset of patients assessed for safety outcomes (2078 of the 2079 patients randomized in the trial) who received desirudin (0.8%) or enoxaparin (0.2%) (Table 1).
Elsaid and Collins assessed VTE and bleeding events associated with the use of unfractionated heparin 5000U either 2 or 3 times daily and enoxaparin 30 mg once or twice daily across patients stratified by renal function (creatinine clearance <30, 3059, and 60 mL/min). The investigators made assessments before and after a quality improvement intervention that was designed to eliminate the use of enoxaparin in patients whose creatinine clearance was <30 mL/min. No VTE events were reported. Patients receiving enoxaparin were significantly more likely to experience a major bleeding episode compared with patients receiving unfractionated heparin (overall rates for all levels of renal function: 13.5% vs 4. 2%; RR: 3.2; 95% CI: 1.47.3) (Table 2). This association was largely driven by the subgroup of patients with a creatinine clearance <30 mL/min. For this subgroup with severe renal insufficiency, patients receiving enoxaparin were significantly more likely to have a bleed compared with patients receiving unfractionated heparin (18.9% vs 4.1%; RR: 4.68; 95% CI: 1.120.6) (Tables 1 and 2). There was no difference in the bleeding rates for patients whose creatinine clearances were >60 mL/min.[20]
Strength of Evidence
Obese Patients
Overall, we found that the strength of evidence was insufficient regarding the composite end point of DVT, PE, and sudden death, and the outcomes of mortality and bleeding (Table 2). This was based on a paucity of available data, and a moderate risk of bias in the reviewed studies. Additionally, 92% of the enrolled patients in the studies were white, limiting the generalizability of the results to other ethnic groups.
Patients on Antiplatelets
The strength of evidence was insufficient in the studies reviewed here to conclude that there is no difference in rates of bleeding in patients who are concomitantly taking antiplatelet drugs while getting VTE prophylaxis with rivaroxaban, dabigatran, or enoxaparin. We based this rating because of the imprecision of results and unknown consistencies across multiple studies.
Patients With Renal Insufficiency
One RCT had a high risk of bias for our key question because data from only 1 study arm were useful for our review.[16] The other RCTs were judged to have a moderate risk of bias. The analyses led by Dahl and Shorr[18, 19] were based on post hoc (ie, not prespecified) analysis of data from RCTs. Additionally, outcomes in the Shorr et al. trial were reported for evaluable subpopulations of the cohort that was initially randomized in the clinical trial.
We rated the strength of evidence as insufficient to know the comparative effectiveness and safety of pharmacologic prophylaxis for prevention of VTE during hospitalization of patients with acute kidney injury, moderate renal insufficiency, severe renal insufficiency not undergoing dialysis, and patients receiving dialysis. We based this rating on the risk of bias associated with published studies and a lack of consistent evidence regarding associations that were reported. Similarly, we rated the strength of evidence as insufficient that 5000 U of unfractionated heparin 3 times daily increases the risk of major and minor bleeding events in patients with severely compromised renal function compared to this dose in patients without severely compromised renal function. We based this rating on a high risk of bias of included studies and inconsistent evidence. Likewise, we rated the strength of evidence as insufficient that enoxaparin significantly increases the risk of major bleeding compared with unfractionated heparin in patients with severe renal insufficiency. We based this rating on a high risk of bias and inconsistent published evidence.
We similarly found insufficient evidence to guide treatment decisions for patients with renal insufficiency. Our findings are consistent with other recent reviews. The American College of Chest Physicians (ACCP) practice guidelines[21] make dosing recommendations for the therapeutic use of enoxaparin. However, their assessment is that the data are insufficient to make direct recommendations about prophylaxis. Their assessment of the indirect evidence regarding bioaccumulation and increased anti‐factor Xa levels are consistent with ours. The ACCP guidelines also suggest that decreased clearance of enoxaparin has been associated with increased risk of bleeding events for patients with severe renal insufficiency. However, the cited study[20] compares patients with and without severe renal dysfunction who received the same therapy. Therefore, it is not possible to determine the additional risk conveyed by enoxaparin therapy, that is, above the baseline increased risk of bleeding among patients with renal insufficiency, particularly those receiving an alternate pharmacologic VTE prevention strategy, such as unfractionated heparin.
DISCUSSION
We found that the evidence was very limited about prevention of VTE in these select and yet prevalent patient populations. Despite the fact that there is an increasing number of obese patients and patients who are on antiplatelet therapies, most clinical practice guidelines do not address the care of these populations, which may be entirely appropriate given the state of the evidence.
The ACCP practice guidelines[21] suggest using a higher dose of enoxaparin for the prevention of VTE in obese patients. The subgroup analysis by Kucher et al.[11] showed effect attenuation of dalteparin when given at a fixed dose of 5000 IU/mL to patients with a BMI of >40 kg/m2. The Freeman study[12] showed that extremely obese patients (average BMI >62.1 kg/m2) who are given a fixed dose of enoxaparin achieved target anti‐factor Xa levels significantly less often than those who received a higher dose of enoxaparin. The 2 separate findings, although not conclusive, lend some credence to the current ACCP guidelines.[21]
The studies we reviewed on VTE prophylaxis in patients who are concomitantly on antiplatelets including aspirin reported no major increased risk of bleeding; however, in the Friedman et al. study,[15] 3.0% of patients who were put on enoxaparin while still on aspirin had a bleeding event compared to 1.2% of those on enoxaparin alone. This difference is not statistically significant but is a trend possibly worth noting, especially when one looks at the lower RR of bleeding at 0.55 compared to 0.82 when dabigatran is compared with enoxaparin with and without concomitant aspirin therapy, respectively (Table 1). The highest dose of aspirin used in either of the studies was 160 mg/day, and neither study addressed other potent antiplatelets such as clopidogrel or ticlopidine separately, which limits the generalizability of the finding to all antiplatelets. Current ACCP guidelines do not recommend aspirin as a sole option for the prevention of VTE in orthopedic surgery patients.[22] Concerns remain among clinicians that antiplatelets, including aspirin, on their own are unlikely to be fully effective to thwart venous thrombotic processes for most patients, and yet the risk of bleeding is not fully known when these agents are combined with other anticoagulants for VTE prophylaxis.
Our review has several limitations, including the possibility that we may have missed some observational studies, as the identification of relevant observational studies in electronic searches is more challenging than that of RCTs. The few studies made it impossible to quantitatively pool results. These results, however, have important implications, namely that additional research on the comparative effectiveness and safety of pharmacologic and mechanical strategies to prevent VTE is needed for the optimal care of these patient subgroups. This might be achieved with trials dedicated to enrolling these patients or prespecified subgroup analyses within larger trials. Observational data may be appropriate as long as attention is paid to confounding.
APPENDIX
MEDLINE Search Strategy
((pulmonary embolism[mh] OR PE[tiab] OR Pulmonary embolism[tiab] OR thromboembolism[mh] OR thromboembolism[tiab] OR thromboembolisms[tiab] OR Thrombosis[mh] OR thrombosis[tiab] OR DVT[tiab] OR VTE[tiab] OR clot[tiab]) AND (Anticoagulants[mh] OR Anticoagulants[tiab] OR Anticoagulant[tiab] OR thrombin inhibitors[tiab] OR Aspirin[mh] or aspirin[tiab] OR aspirins[tiab] or clopidogrel[nm] OR clopidogrel[tiab] OR Plavix[tiab] or ticlopidine[mh] or ticlopidine[tiab]OR ticlid[tiab] OR prasugrel[nm]Or prasugrel[tiab]OR effient[tiab]OR ticagrelor[NM] OR ticagrelor[tiab]OR Brilinta[tiab] OR cilostazol[NM] OR cilostazol[tiab]OR pletal[tiab] OR warfarin[mh]OR warfarin[tiab]OR coumadin[tiab] OR coumadine[tiab] OR Dipyridamole[mh]OR dipyridamole[tiab]OR persantine[tiab] OR dicoumarol[MH] OR dicoumarol[tiab] OR dicumarol[tiab] OR Dextran sulfate[mh] OR dextran sulfate[tiab] ORthrombin inhibitors[tiab] OR thrombin inhibitor[tiab] OR heparin[mh] OR Heparin[tiab] OR Heparins[tiab] OR LMWH[tiab] OR LDUH[tiab] OR Enoxaparin[mh] OR Enoxaparin[tiab] OR Lovenox[tiab] OR Dalteparin[tiab] OR Fragmin[tiab] OR Tinzaparin[tiab] OR innohep[tiab] OR Nadroparin[tiab] OR Fondaparinux[nm] OR Fondaparinux[tiab] OR Arixtra[tiab] OR Idraparinux[nm] OR Idraparinux[tiab] OR Rivaroxaban[nm] OR Rivaroxaban[tiab] OR novastan[tiab] OR Desirudin[nm] OR Desirudin[tiab] OR Iprivask[tiab]OR direct thrombin inhibitor[tiab] OR Argatroban[nm] OR Argatroban[tiab] OR Acova[tiab] OR Bivalirudin[nm] OR Bivalirudin[tiab] OR Angiomax[tiab] OR Lepirudin[nm] OR Lepirudin[tiab] OR Refludan[tiab] OR Dabigatran[nm] OR Dabigatran[tiab] OR Pradaxa[tiab] OR factor xa[mh] OR factor Xa[tiab] OR vena cava filters[mh] OR filters[tiab] OR filter[tiab] OR compression stockings[mh] OR intermittent pneumatic compression devices[mh] OR compression [tiab] OR Venous foot pump[tiab])) AND(prevent*[tiab] OR prophyla*[tiab] OR prevention and control[subheading]) NOT (animals[mh] NOT humans[mh]) NOT (editorial[pt] OR comment[pt]) NOT ((infant[mh] OR infant[tiab] OR child[mh] OR child[tiab] OR children[tiab] OR adolescent[mh] OR adolescent[tiab] OR teen‐age[tiab] OR pediatric[tiab] OR perinatal[tiab]) NOT (adult[tiab] OR adults[tiab] OR adult[mh])) NOT (mechanical valve[tiab] OR heart valve[tiab] OR atrial fibrillation[mh] OR atrial fibrillation[tiab] OR thrombophilia[mh] OR thrombophilia[tiab] OR pregnancy[mh])
- , , . Estimated annual number of incident and recurrent, non‐fatal and fatal venous thromboembolism (VTE) events in the US. Blood. 2005;106:910.
- Institute of Medicine. Institute of Medicine. Initial National Priorities for Comparative Effectiveness Research. Washington, DC: National Academies Press; 2009.
- Lovenox (enoxaparin sodium injection for subcutaneous and intravenous use: prescribing information). Bridgewater, NJ: SanofiAventis; 2011. Available at: http://products.sanofi.us/lovenox/lovenox.html. Accessed October 17, 2012.
- Innohep (tinzaparin sodium injection). Ballerup, Denmark: LEO Pharmaceutical Products; 2008. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/020484s011lbl.pdf. Accessed October 17, 2012.
- Leizorovicz A. Tinzaparin compared to unfractionated heparin for initial treatment of deep vein thrombosis in very elderly patients with renal insufficiency‐ the IRIS trial. [50th ASH Annual Meeting and Exposition abstract 434]. Blood. 2008;11:112.
- Fragmin (dalteparin sodium injection). New York, NY: Pfizer Inc.; 2007. Available at: http://www.pfizer.com/files/products/uspi_fragmin.pdf. Accessed October 17, 2012.
- Methods guide for effectiveness and comparative effectiveness reviews. Rockville, MD: Agency for Healthcare Research and Quality; August 2011. AHRQ publication No. 10 (11)‐EHC063‐EF. Available at: http://www.effectivehealthcare.ahrq.gov. Accessed October 17, 2012.
- Comparative effectiveness of pharmacologic and mechanical prophylaxis of venous thromboembolism among special populations. Available at: http://effectivehealthcare.ahrq.gov/ehc/products/341/928/VTE‐Special‐Populations_Protocol_20120112.pdf. Accessed April 17, 2012.
- , , , et al. Comparative effectiveness of pharmacologic and mechanical prophylaxis of venous thromboembolism among special populations. Evidence Report/Technology Assessment (AHRQ). Available at: http://effectivehealthcare.ahrq.gov/ehc/products/341/1501/venous‐thromboembolism‐special‐populations‐report‐130529.pdf. 2013.
- , . The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non‐randomised studies of health care interventions. J Epidemiol Community Health. 1998;52(6):377–384.
- , , , et al. Efficacy and safety of fixed low‐dose dalteparin in preventing venous thromboembolism among obese or elderly hospitalized patients: a subgroup analysis of the PREVENT trial. Arch Intern Med. 2005;165(3):341–345.
- , , , . Prospective comparison of three enoxaparin dosing regimens to achieve target anti‐factor Xa levels in hospitalized, medically ill patients with extreme obesity. Am J Hematol. 2012;87(7):740–743.
- , , . Effect of prophylactic dalteparin on anti‐factor xa levels in morbidly obese patients after bariatric surgery. Obes Surg. 2010;20(4):487–491.
- , , , , . Concomitant use of medication with antiplatelet effects in patients receiving either rivaroxaban or enoxaparin after total hip or knee arthroplasty. Thromb Res. 2012;130(2):147–151.
- , , , , , . Dabigatran etexilate and concomitant use of non‐steroidal anti‐inflammatory drugs or acetylsalicylic acid in patients undergoing total hip and total knee arthroplasty: No increased risk of bleeding. Thromb Haemost. 2012;108(1):183–190.
- , , , et al. CERTIFY: prophylaxis of venous thromboembolism in patients with severe renal insufficiency. Thromb Haemost. 2011;105(6):981–988.
- , , , et al. Tinzaparin and enoxaparin given at prophylactic dose for eight days in medical elderly patients with impaired renal function: a comparative pharmacokinetic study. Thromb Haemost. 2007;97(4):581–586.
- , , , , , . Thromboprophylaxis in patients older than 75 years or with moderate renal impairment undergoing knee or hip replacement surgery [published correction appears in Int Orthop. 2012;36(5):1113]. Int Orthop. 2012;36(4):741–748.
- , , , . Impact of stage 3B chronic kidney disease on thrombosis and bleeding outcomes after orthopedic surgery in patients treated with desirudin or enoxaparin: insights from a randomized trial. J Thromb Haemost. 2012;10(8):1515–1520.
- , . Initiative to improve thromboprophylactic enoxaparin exposure in hospitalized patients with renal impairment. Am J Health Syst Pharm. 2012;69(5):390–396.
- , , , , ; American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel. Executive summary: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence‐based clinical practice guidelines. Chest. 2012;141(2 suppl):7S–47S.
- , . Aspirin for the prophylaxis of venous thromboembolic events in orthopedic surgery patients: a comparison of the AAOS and ACCP guidelines with review of the evidence. Ann Pharmacother. 2013;47(1):63–74.
- , , . Estimated annual number of incident and recurrent, non‐fatal and fatal venous thromboembolism (VTE) events in the US. Blood. 2005;106:910.
- Institute of Medicine. Institute of Medicine. Initial National Priorities for Comparative Effectiveness Research. Washington, DC: National Academies Press; 2009.
- Lovenox (enoxaparin sodium injection for subcutaneous and intravenous use: prescribing information). Bridgewater, NJ: SanofiAventis; 2011. Available at: http://products.sanofi.us/lovenox/lovenox.html. Accessed October 17, 2012.
- Innohep (tinzaparin sodium injection). Ballerup, Denmark: LEO Pharmaceutical Products; 2008. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/020484s011lbl.pdf. Accessed October 17, 2012.
- Leizorovicz A. Tinzaparin compared to unfractionated heparin for initial treatment of deep vein thrombosis in very elderly patients with renal insufficiency‐ the IRIS trial. [50th ASH Annual Meeting and Exposition abstract 434]. Blood. 2008;11:112.
- Fragmin (dalteparin sodium injection). New York, NY: Pfizer Inc.; 2007. Available at: http://www.pfizer.com/files/products/uspi_fragmin.pdf. Accessed October 17, 2012.
- Methods guide for effectiveness and comparative effectiveness reviews. Rockville, MD: Agency for Healthcare Research and Quality; August 2011. AHRQ publication No. 10 (11)‐EHC063‐EF. Available at: http://www.effectivehealthcare.ahrq.gov. Accessed October 17, 2012.
- Comparative effectiveness of pharmacologic and mechanical prophylaxis of venous thromboembolism among special populations. Available at: http://effectivehealthcare.ahrq.gov/ehc/products/341/928/VTE‐Special‐Populations_Protocol_20120112.pdf. Accessed April 17, 2012.
- , , , et al. Comparative effectiveness of pharmacologic and mechanical prophylaxis of venous thromboembolism among special populations. Evidence Report/Technology Assessment (AHRQ). Available at: http://effectivehealthcare.ahrq.gov/ehc/products/341/1501/venous‐thromboembolism‐special‐populations‐report‐130529.pdf. 2013.
- , . The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non‐randomised studies of health care interventions. J Epidemiol Community Health. 1998;52(6):377–384.
- , , , et al. Efficacy and safety of fixed low‐dose dalteparin in preventing venous thromboembolism among obese or elderly hospitalized patients: a subgroup analysis of the PREVENT trial. Arch Intern Med. 2005;165(3):341–345.
- , , , . Prospective comparison of three enoxaparin dosing regimens to achieve target anti‐factor Xa levels in hospitalized, medically ill patients with extreme obesity. Am J Hematol. 2012;87(7):740–743.
- , , . Effect of prophylactic dalteparin on anti‐factor xa levels in morbidly obese patients after bariatric surgery. Obes Surg. 2010;20(4):487–491.
- , , , , . Concomitant use of medication with antiplatelet effects in patients receiving either rivaroxaban or enoxaparin after total hip or knee arthroplasty. Thromb Res. 2012;130(2):147–151.
- , , , , , . Dabigatran etexilate and concomitant use of non‐steroidal anti‐inflammatory drugs or acetylsalicylic acid in patients undergoing total hip and total knee arthroplasty: No increased risk of bleeding. Thromb Haemost. 2012;108(1):183–190.
- , , , et al. CERTIFY: prophylaxis of venous thromboembolism in patients with severe renal insufficiency. Thromb Haemost. 2011;105(6):981–988.
- , , , et al. Tinzaparin and enoxaparin given at prophylactic dose for eight days in medical elderly patients with impaired renal function: a comparative pharmacokinetic study. Thromb Haemost. 2007;97(4):581–586.
- , , , , , . Thromboprophylaxis in patients older than 75 years or with moderate renal impairment undergoing knee or hip replacement surgery [published correction appears in Int Orthop. 2012;36(5):1113]. Int Orthop. 2012;36(4):741–748.
- , , , . Impact of stage 3B chronic kidney disease on thrombosis and bleeding outcomes after orthopedic surgery in patients treated with desirudin or enoxaparin: insights from a randomized trial. J Thromb Haemost. 2012;10(8):1515–1520.
- , . Initiative to improve thromboprophylactic enoxaparin exposure in hospitalized patients with renal impairment. Am J Health Syst Pharm. 2012;69(5):390–396.
- , , , , ; American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel. Executive summary: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence‐based clinical practice guidelines. Chest. 2012;141(2 suppl):7S–47S.
- , . Aspirin for the prophylaxis of venous thromboembolic events in orthopedic surgery patients: a comparison of the AAOS and ACCP guidelines with review of the evidence. Ann Pharmacother. 2013;47(1):63–74.
