Elliott R. Haut, MD

Patients with human immunodeficiency virus (HIV) are at a 2‐ to 10‐fold greater risk for venous thromboembolism (VTE) compared with the general population.[1] Although antiphospholipid antibodies and protein S deficiency have often been cited as reasons for the thrombophilia associated with HIV, previous studies have also documented an increased risk of VTE with declining CD4+ cell count.[2, 3, 4, 5, 6, 7, 8] Worsening immune function places HIV patients at increased risk for opportunistic and nonopportunistic infections and malignancies, all independently associated with an increased risk of VTE.[5, 9, 10, 11, 12] Although increasing use of antiretroviral therapy has greatly decreased these sequelae, these complications of HIV infection are associated with an increased frequency of hospitalization.[13, 14, 15, 16] HIV infection and associated inflammation has been implicated in cardiovascular conditions such as cardiomyopathy, pulmonary hypertension, and myocardial infarction.[17, 18] Additionally, progression of HIV infection appears to influence T‐cell activation and differentiation in a manner that leads to early immunosenescence in infected individuals.[19, 20]

VTE prophylaxis is effective.[21] Virtually all efforts to decrease VTE have been focused on improving the prescription of prophylaxis with varying degrees of success.[22] These interventions have been employed with the tacit assumption that medication prescribed for inpatients will always be administered. However, at our institution, recent research has demonstrated that a significant proportion of prescribed thromboprophylaxis doses are not administered to hospitalized patients.[23] Refusal by the patient or a family member was the most commonly documented reason for dose nonadministration. In addition, the rate of thromboprophylaxis nonadministration varied greatly between nursing units with distinct patient populations. We hypothesized that nonadministration of VTE prophylaxis may be more common in patients with HIV, and this phenomenon may contribute to their increased risk for VTE.

The purpose of this study was to determine if the proportion of nonadministered thromboprophylaxis is greater among hospitalized patients with HIV and to characterize documented reasons for dose nonadministration.

METHODS

This study was conducted at The Johns Hopkins Hospital (JHH), a large, urban, academic medical center in Baltimore, Maryland. This single‐center retrospective cohort study utilized an existing dataset containing dose administration data extracted from an electronic medication administration record (eMAR). This dataset included information for all prescribed doses of thromboprophylaxis (heparin 5000 U subcutaneously every 8 or 12 hours, heparin 7500 U subcutaneously every 12 hours, enoxaparin 30 mg subcutaneously every 12 hours, or enoxaparin 40 mg subcutaneously daily) for patients hospitalized on medicine units at JHH from November 2007 to December 2008. This time period follows the implementation of an electronic order set for VTE prophylaxis.[24, 25] Data available for each dose included drug name, dose, frequency, patient demographics, and whether or not the dose was administered. Each dose not administered included a reason for nonadministration, which was chosen from a dropdown menu of responses on the eMAR by the nurse at the time the dose was due. A separate electronic report was obtained from an internal administrative database, which identified all patients within the dose administration dataset who had the International Classification of Diseases, 9th Revision code 042 (HIV diagnosis). A report identifying patient history numbers with matching diagnostic code for HIV was appended to the dose administration dataset using a relational database (Microsoft Access; Microsoft Corp., Redmond, WA) prior to analysis. The dose administration data were obtained previously for a separate analysis.[23] Approval for this study was granted from the institutional review board of Johns Hopkins Medicine.

Our analytic plan included comparisons between patients with and without HIV on a dose, patient, and unit level. As JHH operates a nursing unit dedicated to the inpatient care of patients with HIV, we included analyses of dose characteristics between this unit and other medicine units. It should be noted that patients without a diagnosis of HIV are sometimes cared for on this unit. Therefore, the electronic medical record for each patient without the diagnosis code for HIV hospitalized on this unit was reviewed to determine HIV status. An analysis was performed comparing visit identification numbers with diagnosis codes to identify potential seroconversions during the study period. Although we planned to compare nonadministration and documented refusal of doses on the unit level, a lack of patients with HIV on a number of units limited our ability to perform these analyses.

RESULTS

During the 8‐month study period, 42,870 doses of thromboprophylaxis were prescribed during 4947 patient admissions to 13 individual medicine units. Overall, the diagnosis code for HIV was present in 12% of patient visits. The proportion of nonadministered doses per unit ranged from 6% to 27%, whereas the number of doses prescribed per unit ranged from 34 to 7301.

Patient characteristics were described on the visit level (Table 1). Patients with HIV were significantly younger, more often male and black, and had a longer length of stay compared with patients without HIV. Patients hospitalized on the HIV care unit had similar characteristics to the overall population of patients with HIV. It should be noted that not all patients cared for on this unit had a diagnosis of HIV, as patients from other medicine services are sometimes cared for in this location.

Overall, 17% of prescribed prophylaxis doses were not administered. A greater proportion of prescribed doses were not administered to patients with HIV compared with patients without HIV (23.5% vs 16.1%, OR: 1.59, 95% CI: 1.49‐1.70, P<0.001) (Table 2). Using a GEE and univariate regression, HIV diagnosis was associated with nonadministration of doses (OR: 1.37, 95% CI: 1.17‐1.60, P<0.001) (Table 3). Race, age, length of stay, and drug (heparin vs enoxaparin) were each associated with nonadministration. There was no significant association between nonadministration and sex, marital status, or payor. When stratified by nursing unit, there was substantial variation in the proportion of nonadministered doses between units. Within each unit, the proportion of doses not administered varied when stratified by HIV status. For example, on unit A, the proportion of doses not administered was greater for patients with HIV compared with patients without HIV (33.3% vs 12.9%, OR: 3.38, 95% CI: 2.61 to 4.37, P<0.001) (Figure 1). However, on unit K, the proportion of doses not administered to patients with HIV was 2‐fold less than in patients without HIV (7.2% vs 14.3%, OR: 0.47, 95% CI: 0.30‐0.74, P<0.001). Unit‐level analysis was not possible in regression models due to drastic imbalance in the prevalence of HIV across units. When comparing doses prescribed in the HIV care unit to all other medicine units, the proportion not administered (23.9% vs 16.3%, OR: 1.61, 95% CI: 1.49‐1.73, P<0.001) closely resembled the values seen when comparing patients with and without HIV hospital wide (23.5% vs 16.1%). However, when doses on the HIV care unit were stratified by HIV status, the doses not administered were 2‐fold greater, as a proportion, for patients with HIV compared with those without HIV (26.4% vs 13.1%, OR: 2.39, 95% CI: 1.93‐2.96, P<0.001).

Figure 1

The results of the multivariate regression analyses with GEE are displayed in Table 4. HIV diagnosis, non‐African American race, and heparin (as compared with enoxaparin) were associated with increased likelihood of nonadministration. Increasing age and increasing length of stay were associated with decreased likelihood of nonadministration by a small but significant amount.

The most commonly documented reason for nonadministration was refusal by the patient or family member (66% of all doses not administered). The second most common reason, patient condition not appropriate, accounted for an additional 10% of doses. Across all nursing units, the proportion of prescribed doses that were documented as refused was significantly greater for patients with HIV compared with patients without HIV (16.5% vs 10.6%, OR: 1.66, 95% CI: 1.54‐1.80, P<0.0001) (Table 2). Using the GEE and multivariate regression, HIV diagnosis, non‐African American race, and heparin were associated with increased risk of documented dose refusal. Age and length of stay were inversely related to the likelihood of documented dose refusal. When all administered doses were excluded from the analysis, the association between these variables and documented dose refusal were not as strong. Age and length of stay remained significantly inversely related; however, the other factors were no longer significantly positively associated with documented dose refusal.

Within the HIV care unit, the proportion of prescribed doses documented as refused was greater for patients with HIV compared with patients without HIV (18.1% vs 6.8%, OR: 3.01, 95% CI: 2.28‐3.99, P<0.0001). For all other medicine units, the proportion of nonadministered doses documented as refused was also greater for patients with HIV compared with patients without HIV (13.7% vs 10.7%, OR: 1.32, 95% CI: 1.16‐1.51, P<0.0001).

DISCUSSION

We have identified that nonadministration of thromboprophylaxis was more common among patients with HIV at our institution. Substantial variation in the proportion of doses not administered existed on the nursing unit level, as well as within each unit when stratified by HIV status. This disparity in dose administration was observed on the HIV care unit as well, as the proportion not administered was about 2‐fold greater for patients with HIV compared with those without HIV. Documented dose refusal appeared to account for the majority of nonadministered doses in our cohort. Our analysis also demonstrated that HIV diagnosis is significantly associated with both dose nonadministration and documented dose refusal at our institution.

Medication refusal is a well‐recognized phenomenon among hospitalized patients. A recent study of medication administration in hospitalized patients in the United Kingdom noted that refusal accounted for about 45% of omitted doses.[26] Fanikos et al. also found that documented refusal of doses contributed significantly to the overall number of VTE prophylaxis doses not administered to patients.[27] In our study, the proportion of nonadministered doses documented as refused by the patient or family member was significantly greater in patients with HIV than in patients without HIV across all units. Interestingly, the difference was greater on the HIV care unit when doses were stratified by HIV status. This observation leads us to hypothesize that specific hospital care environments may influence dose nonadministration and refusal rates among our patient population.

Based on regression analyses, increasing age and length of stay were associated with a decreased likelihood of any particular dose not being administered and with any particular dose being documented as refused. It is important to note that our GEE did not take into account date or time of each dose, and therefore we cannot make conclusions as to the likelihood of dose nonadministration or refusal of doses in relation to each other on a time scale. One cannot assume that a dose due later in a hospital course was more or less likely to be given than a dose due on the first hospital day. Although we did not expect these findings, one can hypothesize that patients who are older or have longer stays may be perceived to have more severe illness, and therefore greater need for prophylaxis, from nursing staff and others involved in their care. The associations were small but significant and warrant future investigation.

To our knowledge, this is the first investigation comparing the proportion of nonadministered doses of thromboprophylaxis between patients with and without HIV. Our data show that nonadministered doses and refused doses of thromboprophylaxis are more frequent among patients with HIV. In addition, we noted that nonadministration was more common on the dedicated HIV care unit compared with other units. We cannot currently offer a clear explanation for the disparity observed between units, and more specifically, within the HIV care unit. However, it is possible that a unique culture of care and provider‐specific factors may contribute.

Our study was limited by a number of factors. Seroconversion among patients during the study period was possible; however, our analysis revealed only 2 instances among nearly 4000 unique patients. A more significant limitation was the level of analysis allowed by the dataset. We examined dose characteristics on a dose and unit level, but the ability to analyze doses based on the prescriber and nurse level may have provided valuable insight into the specific reasons behind the observations presented here. Additionally, the specific unit assigned to a given dose in our dataset represented the discharge location for the corresponding patient, making it possible that some amount of nonadministered doses may be attributed to the incorrect unit. However, we do not believe that unit‐to‐unit transfers would be frequent enough to influence the overall results. In addition, we did not link nonadministration of thromboprophylaxis with VTE events, as these data were not present in the current dataset. Although this is a limitation of the current study, we believe that the notion that missed doses of thromboprophylaxis place patients at higher risk for VTE is plausible, as the efficacy of thromboprophylaxis is well established.[28, 29, 30] It is important to note that the reason for nonadministration selected by the nurse on the eMAR may not always represent the only reason or even the true reason for dose nonadministration. It is possible that dose refusal may be over‐represented in our sample, in part due to inaccurate documentation. Recent investigations at JHH have identified varying attitudes on the part of the patient and the nurse regarding thromboprophylaxis. A questionnaire and interview of patients showed a large knowledge gap regarding thromboprophylaxis, with many individuals unable to explain its role or significance in their medical care.[31] A common theme was also observed in a survey of nurses regarding VTE prophylaxis: doses were sometimes considered optional for reasons such as ambulation status, perceived severity of illness, or reason for hospitalization. Some nurses also reported that after an initial refused dose, they may continue to document subsequent doses as refused, sometimes without offering the dose to the patient.[32] As variation in practice was observed between individual nurses, it is also likely that the culture of care may vary between units, influencing thromboprophylaxis nonadministration rates as well as documentation of doses as refused. The dose‐level data used for the GEE analyses did not include date and time of administration, which limited the ability of the GEE to more completely account for autocorrelation.

To further investigate the findings of this and related studies, we intend to more closely analyze data at multiple levels with the goal of identifying an appropriate and feasible target for intervention. Additionally, further investigation should be performed with the goal of determining the relationship between decreased exposure to thromboprophylaxis and VTE. However, as patients with HIV appear to be at increased risk of VTE, ensuring that thromboprophylaxis is delivered appropriately and consistently should be an important goal for all who provide care to this population.

Patients with human immunodeficiency virus (HIV) are at a 2‐ to 10‐fold greater risk for venous thromboembolism (VTE) compared with the general population.[1] Although antiphospholipid antibodies and protein S deficiency have often been cited as reasons for the thrombophilia associated with HIV, previous studies have also documented an increased risk of VTE with declining CD4+ cell count.[2, 3, 4, 5, 6, 7, 8] Worsening immune function places HIV patients at increased risk for opportunistic and nonopportunistic infections and malignancies, all independently associated with an increased risk of VTE.[5, 9, 10, 11, 12] Although increasing use of antiretroviral therapy has greatly decreased these sequelae, these complications of HIV infection are associated with an increased frequency of hospitalization.[13, 14, 15, 16] HIV infection and associated inflammation has been implicated in cardiovascular conditions such as cardiomyopathy, pulmonary hypertension, and myocardial infarction.[17, 18] Additionally, progression of HIV infection appears to influence T‐cell activation and differentiation in a manner that leads to early immunosenescence in infected individuals.[19, 20]

VTE prophylaxis is effective.[21] Virtually all efforts to decrease VTE have been focused on improving the prescription of prophylaxis with varying degrees of success.[22] These interventions have been employed with the tacit assumption that medication prescribed for inpatients will always be administered. However, at our institution, recent research has demonstrated that a significant proportion of prescribed thromboprophylaxis doses are not administered to hospitalized patients.[23] Refusal by the patient or a family member was the most commonly documented reason for dose nonadministration. In addition, the rate of thromboprophylaxis nonadministration varied greatly between nursing units with distinct patient populations. We hypothesized that nonadministration of VTE prophylaxis may be more common in patients with HIV, and this phenomenon may contribute to their increased risk for VTE.

The purpose of this study was to determine if the proportion of nonadministered thromboprophylaxis is greater among hospitalized patients with HIV and to characterize documented reasons for dose nonadministration.

METHODS

This study was conducted at The Johns Hopkins Hospital (JHH), a large, urban, academic medical center in Baltimore, Maryland. This single‐center retrospective cohort study utilized an existing dataset containing dose administration data extracted from an electronic medication administration record (eMAR). This dataset included information for all prescribed doses of thromboprophylaxis (heparin 5000 U subcutaneously every 8 or 12 hours, heparin 7500 U subcutaneously every 12 hours, enoxaparin 30 mg subcutaneously every 12 hours, or enoxaparin 40 mg subcutaneously daily) for patients hospitalized on medicine units at JHH from November 2007 to December 2008. This time period follows the implementation of an electronic order set for VTE prophylaxis.[24, 25] Data available for each dose included drug name, dose, frequency, patient demographics, and whether or not the dose was administered. Each dose not administered included a reason for nonadministration, which was chosen from a dropdown menu of responses on the eMAR by the nurse at the time the dose was due. A separate electronic report was obtained from an internal administrative database, which identified all patients within the dose administration dataset who had the International Classification of Diseases, 9th Revision code 042 (HIV diagnosis). A report identifying patient history numbers with matching diagnostic code for HIV was appended to the dose administration dataset using a relational database (Microsoft Access; Microsoft Corp., Redmond, WA) prior to analysis. The dose administration data were obtained previously for a separate analysis.[23] Approval for this study was granted from the institutional review board of Johns Hopkins Medicine.

Our analytic plan included comparisons between patients with and without HIV on a dose, patient, and unit level. As JHH operates a nursing unit dedicated to the inpatient care of patients with HIV, we included analyses of dose characteristics between this unit and other medicine units. It should be noted that patients without a diagnosis of HIV are sometimes cared for on this unit. Therefore, the electronic medical record for each patient without the diagnosis code for HIV hospitalized on this unit was reviewed to determine HIV status. An analysis was performed comparing visit identification numbers with diagnosis codes to identify potential seroconversions during the study period. Although we planned to compare nonadministration and documented refusal of doses on the unit level, a lack of patients with HIV on a number of units limited our ability to perform these analyses.

RESULTS

During the 8‐month study period, 42,870 doses of thromboprophylaxis were prescribed during 4947 patient admissions to 13 individual medicine units. Overall, the diagnosis code for HIV was present in 12% of patient visits. The proportion of nonadministered doses per unit ranged from 6% to 27%, whereas the number of doses prescribed per unit ranged from 34 to 7301.

Patient characteristics were described on the visit level (Table 1). Patients with HIV were significantly younger, more often male and black, and had a longer length of stay compared with patients without HIV. Patients hospitalized on the HIV care unit had similar characteristics to the overall population of patients with HIV. It should be noted that not all patients cared for on this unit had a diagnosis of HIV, as patients from other medicine services are sometimes cared for in this location.

Overall, 17% of prescribed prophylaxis doses were not administered. A greater proportion of prescribed doses were not administered to patients with HIV compared with patients without HIV (23.5% vs 16.1%, OR: 1.59, 95% CI: 1.49‐1.70, P<0.001) (Table 2). Using a GEE and univariate regression, HIV diagnosis was associated with nonadministration of doses (OR: 1.37, 95% CI: 1.17‐1.60, P<0.001) (Table 3). Race, age, length of stay, and drug (heparin vs enoxaparin) were each associated with nonadministration. There was no significant association between nonadministration and sex, marital status, or payor. When stratified by nursing unit, there was substantial variation in the proportion of nonadministered doses between units. Within each unit, the proportion of doses not administered varied when stratified by HIV status. For example, on unit A, the proportion of doses not administered was greater for patients with HIV compared with patients without HIV (33.3% vs 12.9%, OR: 3.38, 95% CI: 2.61 to 4.37, P<0.001) (Figure 1). However, on unit K, the proportion of doses not administered to patients with HIV was 2‐fold less than in patients without HIV (7.2% vs 14.3%, OR: 0.47, 95% CI: 0.30‐0.74, P<0.001). Unit‐level analysis was not possible in regression models due to drastic imbalance in the prevalence of HIV across units. When comparing doses prescribed in the HIV care unit to all other medicine units, the proportion not administered (23.9% vs 16.3%, OR: 1.61, 95% CI: 1.49‐1.73, P<0.001) closely resembled the values seen when comparing patients with and without HIV hospital wide (23.5% vs 16.1%). However, when doses on the HIV care unit were stratified by HIV status, the doses not administered were 2‐fold greater, as a proportion, for patients with HIV compared with those without HIV (26.4% vs 13.1%, OR: 2.39, 95% CI: 1.93‐2.96, P<0.001).

Figure 1

The results of the multivariate regression analyses with GEE are displayed in Table 4. HIV diagnosis, non‐African American race, and heparin (as compared with enoxaparin) were associated with increased likelihood of nonadministration. Increasing age and increasing length of stay were associated with decreased likelihood of nonadministration by a small but significant amount.

The most commonly documented reason for nonadministration was refusal by the patient or family member (66% of all doses not administered). The second most common reason, patient condition not appropriate, accounted for an additional 10% of doses. Across all nursing units, the proportion of prescribed doses that were documented as refused was significantly greater for patients with HIV compared with patients without HIV (16.5% vs 10.6%, OR: 1.66, 95% CI: 1.54‐1.80, P<0.0001) (Table 2). Using the GEE and multivariate regression, HIV diagnosis, non‐African American race, and heparin were associated with increased risk of documented dose refusal. Age and length of stay were inversely related to the likelihood of documented dose refusal. When all administered doses were excluded from the analysis, the association between these variables and documented dose refusal were not as strong. Age and length of stay remained significantly inversely related; however, the other factors were no longer significantly positively associated with documented dose refusal.

Within the HIV care unit, the proportion of prescribed doses documented as refused was greater for patients with HIV compared with patients without HIV (18.1% vs 6.8%, OR: 3.01, 95% CI: 2.28‐3.99, P<0.0001). For all other medicine units, the proportion of nonadministered doses documented as refused was also greater for patients with HIV compared with patients without HIV (13.7% vs 10.7%, OR: 1.32, 95% CI: 1.16‐1.51, P<0.0001).

DISCUSSION

We have identified that nonadministration of thromboprophylaxis was more common among patients with HIV at our institution. Substantial variation in the proportion of doses not administered existed on the nursing unit level, as well as within each unit when stratified by HIV status. This disparity in dose administration was observed on the HIV care unit as well, as the proportion not administered was about 2‐fold greater for patients with HIV compared with those without HIV. Documented dose refusal appeared to account for the majority of nonadministered doses in our cohort. Our analysis also demonstrated that HIV diagnosis is significantly associated with both dose nonadministration and documented dose refusal at our institution.

Medication refusal is a well‐recognized phenomenon among hospitalized patients. A recent study of medication administration in hospitalized patients in the United Kingdom noted that refusal accounted for about 45% of omitted doses.[26] Fanikos et al. also found that documented refusal of doses contributed significantly to the overall number of VTE prophylaxis doses not administered to patients.[27] In our study, the proportion of nonadministered doses documented as refused by the patient or family member was significantly greater in patients with HIV than in patients without HIV across all units. Interestingly, the difference was greater on the HIV care unit when doses were stratified by HIV status. This observation leads us to hypothesize that specific hospital care environments may influence dose nonadministration and refusal rates among our patient population.

Based on regression analyses, increasing age and length of stay were associated with a decreased likelihood of any particular dose not being administered and with any particular dose being documented as refused. It is important to note that our GEE did not take into account date or time of each dose, and therefore we cannot make conclusions as to the likelihood of dose nonadministration or refusal of doses in relation to each other on a time scale. One cannot assume that a dose due later in a hospital course was more or less likely to be given than a dose due on the first hospital day. Although we did not expect these findings, one can hypothesize that patients who are older or have longer stays may be perceived to have more severe illness, and therefore greater need for prophylaxis, from nursing staff and others involved in their care. The associations were small but significant and warrant future investigation.

To our knowledge, this is the first investigation comparing the proportion of nonadministered doses of thromboprophylaxis between patients with and without HIV. Our data show that nonadministered doses and refused doses of thromboprophylaxis are more frequent among patients with HIV. In addition, we noted that nonadministration was more common on the dedicated HIV care unit compared with other units. We cannot currently offer a clear explanation for the disparity observed between units, and more specifically, within the HIV care unit. However, it is possible that a unique culture of care and provider‐specific factors may contribute.

Our study was limited by a number of factors. Seroconversion among patients during the study period was possible; however, our analysis revealed only 2 instances among nearly 4000 unique patients. A more significant limitation was the level of analysis allowed by the dataset. We examined dose characteristics on a dose and unit level, but the ability to analyze doses based on the prescriber and nurse level may have provided valuable insight into the specific reasons behind the observations presented here. Additionally, the specific unit assigned to a given dose in our dataset represented the discharge location for the corresponding patient, making it possible that some amount of nonadministered doses may be attributed to the incorrect unit. However, we do not believe that unit‐to‐unit transfers would be frequent enough to influence the overall results. In addition, we did not link nonadministration of thromboprophylaxis with VTE events, as these data were not present in the current dataset. Although this is a limitation of the current study, we believe that the notion that missed doses of thromboprophylaxis place patients at higher risk for VTE is plausible, as the efficacy of thromboprophylaxis is well established.[28, 29, 30] It is important to note that the reason for nonadministration selected by the nurse on the eMAR may not always represent the only reason or even the true reason for dose nonadministration. It is possible that dose refusal may be over‐represented in our sample, in part due to inaccurate documentation. Recent investigations at JHH have identified varying attitudes on the part of the patient and the nurse regarding thromboprophylaxis. A questionnaire and interview of patients showed a large knowledge gap regarding thromboprophylaxis, with many individuals unable to explain its role or significance in their medical care.[31] A common theme was also observed in a survey of nurses regarding VTE prophylaxis: doses were sometimes considered optional for reasons such as ambulation status, perceived severity of illness, or reason for hospitalization. Some nurses also reported that after an initial refused dose, they may continue to document subsequent doses as refused, sometimes without offering the dose to the patient.[32] As variation in practice was observed between individual nurses, it is also likely that the culture of care may vary between units, influencing thromboprophylaxis nonadministration rates as well as documentation of doses as refused. The dose‐level data used for the GEE analyses did not include date and time of administration, which limited the ability of the GEE to more completely account for autocorrelation.

To further investigate the findings of this and related studies, we intend to more closely analyze data at multiple levels with the goal of identifying an appropriate and feasible target for intervention. Additionally, further investigation should be performed with the goal of determining the relationship between decreased exposure to thromboprophylaxis and VTE. However, as patients with HIV appear to be at increased risk of VTE, ensuring that thromboprophylaxis is delivered appropriately and consistently should be an important goal for all who provide care to this population.

Patients with human immunodeficiency virus (HIV) are at a 2‐ to 10‐fold greater risk for venous thromboembolism (VTE) compared with the general population.[1] Although antiphospholipid antibodies and protein S deficiency have often been cited as reasons for the thrombophilia associated with HIV, previous studies have also documented an increased risk of VTE with declining CD4+ cell count.[2, 3, 4, 5, 6, 7, 8] Worsening immune function places HIV patients at increased risk for opportunistic and nonopportunistic infections and malignancies, all independently associated with an increased risk of VTE.[5, 9, 10, 11, 12] Although increasing use of antiretroviral therapy has greatly decreased these sequelae, these complications of HIV infection are associated with an increased frequency of hospitalization.[13, 14, 15, 16] HIV infection and associated inflammation has been implicated in cardiovascular conditions such as cardiomyopathy, pulmonary hypertension, and myocardial infarction.[17, 18] Additionally, progression of HIV infection appears to influence T‐cell activation and differentiation in a manner that leads to early immunosenescence in infected individuals.[19, 20]

VTE prophylaxis is effective.[21] Virtually all efforts to decrease VTE have been focused on improving the prescription of prophylaxis with varying degrees of success.[22] These interventions have been employed with the tacit assumption that medication prescribed for inpatients will always be administered. However, at our institution, recent research has demonstrated that a significant proportion of prescribed thromboprophylaxis doses are not administered to hospitalized patients.[23] Refusal by the patient or a family member was the most commonly documented reason for dose nonadministration. In addition, the rate of thromboprophylaxis nonadministration varied greatly between nursing units with distinct patient populations. We hypothesized that nonadministration of VTE prophylaxis may be more common in patients with HIV, and this phenomenon may contribute to their increased risk for VTE.

The purpose of this study was to determine if the proportion of nonadministered thromboprophylaxis is greater among hospitalized patients with HIV and to characterize documented reasons for dose nonadministration.

METHODS

This study was conducted at The Johns Hopkins Hospital (JHH), a large, urban, academic medical center in Baltimore, Maryland. This single‐center retrospective cohort study utilized an existing dataset containing dose administration data extracted from an electronic medication administration record (eMAR). This dataset included information for all prescribed doses of thromboprophylaxis (heparin 5000 U subcutaneously every 8 or 12 hours, heparin 7500 U subcutaneously every 12 hours, enoxaparin 30 mg subcutaneously every 12 hours, or enoxaparin 40 mg subcutaneously daily) for patients hospitalized on medicine units at JHH from November 2007 to December 2008. This time period follows the implementation of an electronic order set for VTE prophylaxis.[24, 25] Data available for each dose included drug name, dose, frequency, patient demographics, and whether or not the dose was administered. Each dose not administered included a reason for nonadministration, which was chosen from a dropdown menu of responses on the eMAR by the nurse at the time the dose was due. A separate electronic report was obtained from an internal administrative database, which identified all patients within the dose administration dataset who had the International Classification of Diseases, 9th Revision code 042 (HIV diagnosis). A report identifying patient history numbers with matching diagnostic code for HIV was appended to the dose administration dataset using a relational database (Microsoft Access; Microsoft Corp., Redmond, WA) prior to analysis. The dose administration data were obtained previously for a separate analysis.[23] Approval for this study was granted from the institutional review board of Johns Hopkins Medicine.

Our analytic plan included comparisons between patients with and without HIV on a dose, patient, and unit level. As JHH operates a nursing unit dedicated to the inpatient care of patients with HIV, we included analyses of dose characteristics between this unit and other medicine units. It should be noted that patients without a diagnosis of HIV are sometimes cared for on this unit. Therefore, the electronic medical record for each patient without the diagnosis code for HIV hospitalized on this unit was reviewed to determine HIV status. An analysis was performed comparing visit identification numbers with diagnosis codes to identify potential seroconversions during the study period. Although we planned to compare nonadministration and documented refusal of doses on the unit level, a lack of patients with HIV on a number of units limited our ability to perform these analyses.

RESULTS

During the 8‐month study period, 42,870 doses of thromboprophylaxis were prescribed during 4947 patient admissions to 13 individual medicine units. Overall, the diagnosis code for HIV was present in 12% of patient visits. The proportion of nonadministered doses per unit ranged from 6% to 27%, whereas the number of doses prescribed per unit ranged from 34 to 7301.

Patient characteristics were described on the visit level (Table 1). Patients with HIV were significantly younger, more often male and black, and had a longer length of stay compared with patients without HIV. Patients hospitalized on the HIV care unit had similar characteristics to the overall population of patients with HIV. It should be noted that not all patients cared for on this unit had a diagnosis of HIV, as patients from other medicine services are sometimes cared for in this location.

Overall, 17% of prescribed prophylaxis doses were not administered. A greater proportion of prescribed doses were not administered to patients with HIV compared with patients without HIV (23.5% vs 16.1%, OR: 1.59, 95% CI: 1.49‐1.70, P<0.001) (Table 2). Using a GEE and univariate regression, HIV diagnosis was associated with nonadministration of doses (OR: 1.37, 95% CI: 1.17‐1.60, P<0.001) (Table 3). Race, age, length of stay, and drug (heparin vs enoxaparin) were each associated with nonadministration. There was no significant association between nonadministration and sex, marital status, or payor. When stratified by nursing unit, there was substantial variation in the proportion of nonadministered doses between units. Within each unit, the proportion of doses not administered varied when stratified by HIV status. For example, on unit A, the proportion of doses not administered was greater for patients with HIV compared with patients without HIV (33.3% vs 12.9%, OR: 3.38, 95% CI: 2.61 to 4.37, P<0.001) (Figure 1). However, on unit K, the proportion of doses not administered to patients with HIV was 2‐fold less than in patients without HIV (7.2% vs 14.3%, OR: 0.47, 95% CI: 0.30‐0.74, P<0.001). Unit‐level analysis was not possible in regression models due to drastic imbalance in the prevalence of HIV across units. When comparing doses prescribed in the HIV care unit to all other medicine units, the proportion not administered (23.9% vs 16.3%, OR: 1.61, 95% CI: 1.49‐1.73, P<0.001) closely resembled the values seen when comparing patients with and without HIV hospital wide (23.5% vs 16.1%). However, when doses on the HIV care unit were stratified by HIV status, the doses not administered were 2‐fold greater, as a proportion, for patients with HIV compared with those without HIV (26.4% vs 13.1%, OR: 2.39, 95% CI: 1.93‐2.96, P<0.001).

Figure 1

The results of the multivariate regression analyses with GEE are displayed in Table 4. HIV diagnosis, non‐African American race, and heparin (as compared with enoxaparin) were associated with increased likelihood of nonadministration. Increasing age and increasing length of stay were associated with decreased likelihood of nonadministration by a small but significant amount.

The most commonly documented reason for nonadministration was refusal by the patient or family member (66% of all doses not administered). The second most common reason, patient condition not appropriate, accounted for an additional 10% of doses. Across all nursing units, the proportion of prescribed doses that were documented as refused was significantly greater for patients with HIV compared with patients without HIV (16.5% vs 10.6%, OR: 1.66, 95% CI: 1.54‐1.80, P<0.0001) (Table 2). Using the GEE and multivariate regression, HIV diagnosis, non‐African American race, and heparin were associated with increased risk of documented dose refusal. Age and length of stay were inversely related to the likelihood of documented dose refusal. When all administered doses were excluded from the analysis, the association between these variables and documented dose refusal were not as strong. Age and length of stay remained significantly inversely related; however, the other factors were no longer significantly positively associated with documented dose refusal.

Within the HIV care unit, the proportion of prescribed doses documented as refused was greater for patients with HIV compared with patients without HIV (18.1% vs 6.8%, OR: 3.01, 95% CI: 2.28‐3.99, P<0.0001). For all other medicine units, the proportion of nonadministered doses documented as refused was also greater for patients with HIV compared with patients without HIV (13.7% vs 10.7%, OR: 1.32, 95% CI: 1.16‐1.51, P<0.0001).

DISCUSSION

We have identified that nonadministration of thromboprophylaxis was more common among patients with HIV at our institution. Substantial variation in the proportion of doses not administered existed on the nursing unit level, as well as within each unit when stratified by HIV status. This disparity in dose administration was observed on the HIV care unit as well, as the proportion not administered was about 2‐fold greater for patients with HIV compared with those without HIV. Documented dose refusal appeared to account for the majority of nonadministered doses in our cohort. Our analysis also demonstrated that HIV diagnosis is significantly associated with both dose nonadministration and documented dose refusal at our institution.

Medication refusal is a well‐recognized phenomenon among hospitalized patients. A recent study of medication administration in hospitalized patients in the United Kingdom noted that refusal accounted for about 45% of omitted doses.[26] Fanikos et al. also found that documented refusal of doses contributed significantly to the overall number of VTE prophylaxis doses not administered to patients.[27] In our study, the proportion of nonadministered doses documented as refused by the patient or family member was significantly greater in patients with HIV than in patients without HIV across all units. Interestingly, the difference was greater on the HIV care unit when doses were stratified by HIV status. This observation leads us to hypothesize that specific hospital care environments may influence dose nonadministration and refusal rates among our patient population.

Based on regression analyses, increasing age and length of stay were associated with a decreased likelihood of any particular dose not being administered and with any particular dose being documented as refused. It is important to note that our GEE did not take into account date or time of each dose, and therefore we cannot make conclusions as to the likelihood of dose nonadministration or refusal of doses in relation to each other on a time scale. One cannot assume that a dose due later in a hospital course was more or less likely to be given than a dose due on the first hospital day. Although we did not expect these findings, one can hypothesize that patients who are older or have longer stays may be perceived to have more severe illness, and therefore greater need for prophylaxis, from nursing staff and others involved in their care. The associations were small but significant and warrant future investigation.

To our knowledge, this is the first investigation comparing the proportion of nonadministered doses of thromboprophylaxis between patients with and without HIV. Our data show that nonadministered doses and refused doses of thromboprophylaxis are more frequent among patients with HIV. In addition, we noted that nonadministration was more common on the dedicated HIV care unit compared with other units. We cannot currently offer a clear explanation for the disparity observed between units, and more specifically, within the HIV care unit. However, it is possible that a unique culture of care and provider‐specific factors may contribute.

Our study was limited by a number of factors. Seroconversion among patients during the study period was possible; however, our analysis revealed only 2 instances among nearly 4000 unique patients. A more significant limitation was the level of analysis allowed by the dataset. We examined dose characteristics on a dose and unit level, but the ability to analyze doses based on the prescriber and nurse level may have provided valuable insight into the specific reasons behind the observations presented here. Additionally, the specific unit assigned to a given dose in our dataset represented the discharge location for the corresponding patient, making it possible that some amount of nonadministered doses may be attributed to the incorrect unit. However, we do not believe that unit‐to‐unit transfers would be frequent enough to influence the overall results. In addition, we did not link nonadministration of thromboprophylaxis with VTE events, as these data were not present in the current dataset. Although this is a limitation of the current study, we believe that the notion that missed doses of thromboprophylaxis place patients at higher risk for VTE is plausible, as the efficacy of thromboprophylaxis is well established.[28, 29, 30] It is important to note that the reason for nonadministration selected by the nurse on the eMAR may not always represent the only reason or even the true reason for dose nonadministration. It is possible that dose refusal may be over‐represented in our sample, in part due to inaccurate documentation. Recent investigations at JHH have identified varying attitudes on the part of the patient and the nurse regarding thromboprophylaxis. A questionnaire and interview of patients showed a large knowledge gap regarding thromboprophylaxis, with many individuals unable to explain its role or significance in their medical care.[31] A common theme was also observed in a survey of nurses regarding VTE prophylaxis: doses were sometimes considered optional for reasons such as ambulation status, perceived severity of illness, or reason for hospitalization. Some nurses also reported that after an initial refused dose, they may continue to document subsequent doses as refused, sometimes without offering the dose to the patient.[32] As variation in practice was observed between individual nurses, it is also likely that the culture of care may vary between units, influencing thromboprophylaxis nonadministration rates as well as documentation of doses as refused. The dose‐level data used for the GEE analyses did not include date and time of administration, which limited the ability of the GEE to more completely account for autocorrelation.

To further investigate the findings of this and related studies, we intend to more closely analyze data at multiple levels with the goal of identifying an appropriate and feasible target for intervention. Additionally, further investigation should be performed with the goal of determining the relationship between decreased exposure to thromboprophylaxis and VTE. However, as patients with HIV appear to be at increased risk of VTE, ensuring that thromboprophylaxis is delivered appropriately and consistently should be an important goal for all who provide care to this population.

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]

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.

Figure 1

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.

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]

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.

Figure 1

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.

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]

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.

Figure 1

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.