Venous Thromboembolism Prophylaxis for Medical Service Mostly Cancer Patients at Hospital Discharge

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1 CLINICAL RESEARCH STUDY Venous Thromboembolism Prophylaxis for Medical Service Mostly Cancer Patients at Hospital Discharge John Fanikos, RPh, MBA, a Amanda Rao, BS, b Andrew C. Seger, PharmD, b Gregory Piazza, MD, MS, b Elaine Catapane, MED, MT, c Xiaohua Chen, MA, c Samuel Z. Goldhaber, MD b a Department of Pharmacy, Brigham and Women s Hospital, Boston, Mass; b Venous Thromboembolism Research Group, Cardiovascular Division, Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, Mass; c Harvard Clinical Research Institute, Boston, Mass. ABSTRACT OBJECTIVE: Many hospitalized Medical Service patients remain at high risk for venous thromboembolism (VTE) after hospital discharge. Our aim was to compare the effect of the use or omission of extended pharmacologic VTE prophylaxis after hospital discharge among Medical Service patients on the incidence of symptomatic deep vein thrombosis (DVT) or pulmonary embolism (PE) over the ensuing 3 months. METHODS: In this case-control study, we identified a case population of 461 patients for whom parenteral pharmacological VTE prophylaxis was prescribed to continue after discharge and matched them according to age, sex, and VTE risk score to a control group of 922 patients for whom VTE prophylaxis was not continued after discharge. RESULTS: The primary endpoint of symptomatic DVT or PE at 90 days occurred in 5.0% of patients receiving extended prophylaxis compared with 4.3% of patients who received no prophylaxis after discharge (P.58). Fewer patients were alive at 90 days in patients receiving extended pharmacologic VTE prophylaxis, compared with those who received no prophylaxis after discharge (56.8% vs 68.4%, P.001). Major bleeding, defined as those events requiring blood transfusion, medical, or surgical intervention, occurred more frequently in patients receiving extended VTE prophylaxis after discharge than in those patients who received no prophylaxis after discharge (3.9% vs 1.9%, P.03). CONCLUSION: Extended pharmacologic thromboprophylaxis in high-risk Medical Service patients did not reduce symptomatic DVT and PE in the ensuing 90 days after hospital discharge. There was a higher incidence of all-cause death and major bleeding episodes in patients receiving extended prophylaxis. Our observations do not support the routine use of extended VTE prophylaxis in Medical Service patients. Further research is needed to identify patients who may benefit from extended pharmacologic VTE prophylaxis and those who may have too great a bleeding risk Elsevier Inc. All rights reserved. The American Journal of Medicine (2011) 124, KEYWORDS: Acutely ill medical patients; Low-molecular-weight heparin; Prevention; Prophylaxis strategies; Unfractionated heparin; Venous thromboembolism Prevention of venous thromboembolism (VTE) has been segregated into 2 separate silos: hospitalized patients and outpatients. 1,2 Clinical trials have shown the benefit of pharmacologic thromboprophylaxis over placebo in reducing VTE in hospitalized Medical Service patients. 3-5 The duration of prophylaxis in these trials ranged from 6 to 14 days. Funding: This study was supported in part by sanofi-aventis, Inc. Gregory Piazza, MD is supported by a Research Career Development Award (K12 HL083786) from the National Heart, Lung, and Blood Institute (NHLBI). Conflicts of Interest: The authors of this article have disclosed the following industry relationships: John Fanikos, RPh, MBA, served as a consultant/advisory board participant for Bristol-Myers Squibb and Baxter Healthcare. Samuel Z. Goldhaber, MD receives research funds from sanofi-aventis, Eisai, Bristol-Myers Squibb, Johnson and Johnson, EKOS, and Boehringer-Ingelheim and is a consultant for sanofi-aventis, Eisai, Bristol-Myers Squibb, EKOS, Portola, Merck, and Boehringer-Ingelheim. Amanda Rao, BS, Andrew C. Seger, PharmD, Elaine Catapane, MED, MT (ASCP), and Xiaohua Chen, MA have no conflicts to disclose. Authorship: All authors participated in the data collection, analysis, and manuscript preparation. Requests for reprints should be addressed to Samuel Z. Goldhaber, MD, Cardiovascular Division, Brigham and Women s Hospital, 75 Francis Street, Boston, MA address: sgoldhaber@partners.org /$ -see front matter 2011 Elsevier Inc. All rights reserved. doi: /j.amjmed

2 1144 The American Journal of Medicine, Vol 124, No 12, December 2011 Yet, with the current emphasis on shortened lengths of hospital stay and rapid patient transitions, the concept of inpatient versus ambulatory care becomes blurred, and the optimal duration of thromboprophylaxis remains unknown. Furthermore, underutilization of VTE prophylaxis remains a problem in the care of hospitalized patients. 6-8 Data suggest that as many as 28% of at-risk Medical Service patients stop receiving prophylaxis before hospital discharge. 6 While few data exist on VTE prophylaxis practices in atrisk Medical Service patients in the immediate hospital predischarge and early postdischarge periods, patients may remain at risk for VTE and VTE-related death at the time of hospital discharge. 9 Therefore, we performed a nested case-control study and compared the use or omission of VTE extended pharmacologic prophylaxis after hospital discharge among a cohort of at-risk patients. Our primary endpoint was development of symptomatic deep vein thrombosis (DVT) or pulmonary embolism (PE) over the ensuing 3 months. CLINICAL SIGNIFICANCE METHODS Brigham and Women s Hospital has information technology that integrates medical, laboratory, nursing, and pharmacy patient data from hospitalization and subsequent outpatient evaluations. For all hospitalized patients, the computer system calculates a daily previously validated VTE risk score based upon 8 common VTE risk factors, each weighted according to a point scale. 10 Major risk factors (cancer, prior VTE, and hypercoagulability) are assigned 3 points each, while major surgery is assigned 2 points, and minor risk factors (age, obesity, bed rest, and female hormone replacement therapy and oral contraceptive use) are assigned 1 point each. We used the computer system to screen patients from May 2000 through March We identified a case group of 461 consecutive hospitalized Medical Service patients with a discharge VTE risk score of 3 or more score points where inpatient-prescribed parenteral pharmacological VTE prophylaxis with low-molecular-weight heparin or unfractionated heparin (UFH) was ordered to continue after hospital discharge. We matched this case group by age, sex, and risk score to a control group of 922 hospitalized medically ill patients with a discharge VTE risk score of 3 or more score points in whom prescribed inpatient low-molecularweight heparin or UFH VTE prophylaxis was not continued after discharge. Extended thromboprophylaxis after hospital discharge in Medical Service patients did not reduce symptomatic venous thromboembolism over the ensuing 90 days. All-cause death and major bleeding at 90 days were more frequent in those Medical Service patients receiving extended thromboprophylaxis after hospital discharge than in those who did not receive thromboprophylaxis. Our findings do not support routine prescribing of pharmacologic thromboprophylaxis in Medical Service patients after hospital discharge. We completed 90-day follow-up on study patients by identifying endpoints after hospitalization through our health systems computerized longitudinal medical record. Within our integrated health care system, any patient encounter across 6 hospitals, 17 ambulatory clinics, and numerous private practices is recorded in the longitudinal medical record. We captured all subsequent hospitalizations, office visits, including discharge summaries and clinicians notes; laboratory tests; medical treatments; and diagnostic procedures, regardless of the facility or office location. The Social Security Death Index was used to identify patients who died during the 90-day period. We utilized the Centers for Disease Control and Prevention s National Death Index to validate mortality outcomes. This database uses input from the US, the District of Columbia, and Puerto Rico. Cause of death is reported as a single International Classification of Diseases and Related Health Problems, 10 th Revision code. The primary endpoint was the incidence of symptomatic VTE confirmed by imaging within 90 days of hospital discharge. Safety endpoints included all-cause mortality, major bleeding episodes, and adverse drug reactions within 90 days of hospital discharge. We defined major bleeding as any bleeding episode that required blood transfusion of more than 2 units, a medical intervention to reverse anticoagulant effect, or surgical intervention. We completed 90-day follow-up for 99.0% of the study patients. There were 3 patients in the group receiving extended prophylaxis and 11 patients in the group receiving no extended prophylaxis for whom 90-day follow-up was not completed. Based upon our previous study in high-risk patients that included a high proportion of cancer patients, we assumed that the VTE rate in those not receiving extended prophylaxis after discharge would be 8.3% during the 90-day postdischarge period. 11 We estimated that extending prophylaxis beyond discharge would result in a 40% reduction in event rates to 4.5%. We estimated that the sample size, with a power of 0.80 and a 2-sided alpha of 0.05, and an allocation ratio of 1:2, would require recruitment of approximately 387 case patients and 767 control patients. 12 We aimed for a study enrollment of 1300 patients, to allow for 146 patients who may have been lost to follow-up. Differences between groups were examined with the Fisher s exact or chi-squared tests for comparison of proportions, analysis of variance for continuous variables, and Kruskal-Wallis test for categorical data. The primary analysis was performed using Peto s formula for the difference

3 Fanikos et al VTE Prophylaxis at Discharge 1145 between the intervention group and the control group in the Kaplan-Meier estimates of freedom from VTE on day 90. The log-rank test was used to estimate the cumulative probability of the primary endpoint in the intervention and control groups. Multivariate logistic regression analysis was used to identify independent predictors of VTE and death using the variables length of hospital stay, age, sex, and prior hospitalization within 30 days. We included variables from the univariate analysis that were significant to the 0.05 level in the regression model. A stepwise backward elimination procedure was used by excluding variables from the model that did not maintain P values of.05. All reported P values are 2-tailed. All statistical analyses were performed using Statistic Analysis System software version 8.0 (SAS Institute Inc., Cary, NC). Our study was approved by the Partners Healthcare System Human Research Committee. The U.S. National Institutes of Health Registry ( identifies our study as NCT RESULTS Study groups were well matched in terms of age, sex, discharge diagnosis, and VTE risk scores (Table 1). However, the duration of hospitalization was longer in the group receiving extended prophylaxis compared with the group receiving no extended prophylaxis (9.1 days vs 5.7 days, P.001). VTE risk factors and comorbidities at hospital discharge are listed in Table 2. There was a significantly higher percent of patients with the comorbidities of nonpulmonary infection, recent hospitalization, and brain and other cancers in the group receiving extended prophylaxis than the group receiving no extended prophylaxis. There were more patients with leukemia in the group receiving no extended prophylaxis (Table 2). All patients received parenteral pharmacologic VTE prophylaxis while hospitalized. The mean duration of inpatient prophylaxis was longer in the group receiving extended prophylaxis (9.7 days vs 5.3 days, P.001). In the group receiving extended prophylaxis, the most commonly prescribed pharmacologic strategy was enoxaparin (67.5%), followed by UFH (31.2%) and fondaparinux (0.9%) (Table 3). The primary endpoint of symptomatic VTE at 90 days occurred in 23 patients receiving extended pharmacologic VTE prophylaxis (5.0%), compared with 39 patients in the group that received no prophylactic measures after discharge (4.3%, P.58) (Table 4). Kaplan-Meier estimates of the absence of venous thromboembolism at 90 days were 93.3% (95% confidence interval [CI], 90.3%-96.4%) and 94.9% (95% CI, 93.2%-96.6%), respectively (P.30) (Figure). Of the 23 case patients Table 1 Baseline Patient Characteristics Patient Characteristic Extended Prophylaxis at Discharge (n 461) No Extended Prophylaxis at Discharge (n 922) P Value Age, years Mean SD (461) (922).87 Age 75 years 28.4% (131/461) 28.1% (259/922).90 Male 42.3% (195/461) 42.3% (390/922) 1.00 Female 57.7% (266/461) 57.7% (532/922) 1.00 Race American Indian or Alaska 0% (0/461) 0.22% (2/922).56 Native Asian 1.5% (7/461) 1.8% (17/922).83 White 80.7% (372/461) 82.2% (758/922).51 Hispanic or Latino 3.5% (16/461) 4.7% (43/922).33 Black or African American 12.8% (59/461) 10.2% (94/922).15 Unknown or not recorded 1.5% (7/461) 0.87% (8/922).28 BMI Mean SD (368) (736).35 Length of stay, days Mean SD (461) (922).001 Discharge diagnosis Cardiovascular disease 8.9% (41/461) 8.1% (75/922).68 Pulmonary disease 7.8% (36/461) 11.2% (103/922).06 Gastrointestinal disease 5.6% (26/461) 8.5% (78/922).07 Neurologic disease 4.6% (21/461) 2.9% (27/922).12 Cancer 45.8% (211/461) 44.0% (406/922).57 Renal disease 2.6% (12/461) 2.9% (27/922).86 Other medical illness 24.7% (114/461) 22.3% (206/922).34 BMI body mass index.

4 1146 The American Journal of Medicine, Vol 124, No 12, December 2011 Table 2 Venous Thromboembolism Risk Factors and Comorbidities at Hospital Discharge Patient Characteristic Extended Prophylaxis at Discharge (n 461) No Extended Prophylaxis at Discharge (n 922) P Value Risk score for venous thromboembolism - % 3 Points 28.6% (132/461) 29.3% (270/922).85 4 Points 44.9% (207/461) 45.1% (416/922).95 5 Points 10.6% (49/461) 10.8% (100/922).93 6 Points 8.7% (40/461) 7.6% (70/922).53 7 Points 5.9% (27/461) 5.7% (53/922) Points 1.30% (6/461) 1.41% (13/922) 1.00 Discharge comorbidities Age 70 years 1 point score 43.8% (202/461) 44.5% (410/922).86 Bed rest 1 point score 12.8% (59/461) 10.6% (98/922).24 Obesity (BMI 29) 1 point score 24.3% (112/461) 25.0% (230/922).84 Oral contraceptives or hormone replacement 1 0.4% (2/461) 1.4% (13/922).17 point score Surgery/trauma 4 weeks - 2 points score 0.2% (1/461) 0.2% (2/922) 1.00 Prior VTE - 3 points score 24.7% (114/461) 24.5% (226/922).95 Thrombophilia - 3 points score 2.4% (11/461) 1.4% (13/922).20 Active cancer - 3 points score 86.3% (398/461) 86.7% (799/922).87 Lung 17.8% (82/461) 15.7% (145/922).36 GI (includes hepatic, pancreatic) 14.1% (65/461) 17.4% (160/922).14 Genitourinary 14.1% (65/461) 16.8% (155/922).21 Lymphoma 8.9% (41/461) 7.8% (72/922).53 Breast 7.8% (36/461) 7.6% (70/922).92 Leukemia 2.0% (9/461) 5.9% (54/922).001 Head and neck 2.8% (13/461) 3.7% (34/922).44 Sarcoma 2.2% (10/461) 3.5% (32/922).24 Brain 4.8% (22/461) 1.0% (9/922).001 Melanoma 3.0% (14/461) 1.7% (16/922).12 Mesothelioma 0.7% (3/461) 0.9% (8/922).76 Other 8.2% (38/461) 5.2% (48/922).03 Chronic obstructive pulmonary disease* 12.6% (58/461) 12.2% (112/922).86 Congestive heart failure* 11.7% (54/461) 9.3% (86/922).19 Nonpulmonary infection* 35.4% (163/461) 24.1% (222/922).001 Coronary artery disease* 22.3% (103/461) 19.6% (181/922).26 Hospitalized 30 days before current admission* 28.6% (132/461) 20.5% (189/922).001 BMI body mass index; VTE venous thromboembolism. *Indicates a VTE risk factor with no (0) point score. developing VTE at 90 days after hospital discharge, 19 patients (6.1%) received enoxaparin 40 mg once daily and 4 patients (2.7%) received UFH 5000 units twice daily. There were fewer patients alive at 90 days in the group receiving extended pharmacologic VTE prophylaxis, compared with the group that received no prophylaxis after discharge (56.8% vs 68.4%, P.001). In multivariate analysis, extended pharmacologic prophylaxis (odds ratio [OR] 1.58; 95% CI, ; P.001), male sex (OR 1.45; 95% CI, ; P.001), and age (OR 1.01; 95% CI, ; P.002) remained independent predictors of death. There was no difference in the incidence of malignancy-related deaths (185 patients, 92%) in patients receiving extended prophylaxis at discharge compared with those receiving no extended prophylaxis at discharge (268 patients, 89.6%) (Table 5). There was no difference between the groups in patients who died from all other causes (6.5% vs 6.7%, P 1.0). Major bleeding occurred more frequently in patients receiving extended prophylaxis than in patients who received no prophylaxis after discharge (3.9% vs 1.9%, P.03). Bleeding that required medical intervention occurred more frequently in patients receiving extended prophylaxis after discharge compared with the group that received no prophylaxis after discharge (2.2% vs 0.7%, P.03). The frequency of bleeding that required transfusion of more than 2 units of blood was similar in patients receiving extended prophylaxis and those patients who received no prophylaxis after discharge (1.7% vs 0.8%, P.11). Bleeding requiring surgical intervention was rare and was not statistically different between the 2 groups. There was no difference in the

5 Fanikos et al VTE Prophylaxis at Discharge 1147 Table 3 Extended Venous Thromboembolism Prophylaxis After Hospital Discharge Measure Extended Prophylaxis at Discharge (n 461) Any pharmacologic prophylaxis 100% (461/461) Any enoxaparin 67.5% (311/461) Enoxaparin 40 mg injected once 66.8% (308/461) daily Enoxaparin 30 mg injected once 0.4% (2/461) daily Enoxaparin other daily regimen 0.2% (1/461) Any unfractionated heparin 31.2% (146/461) Unfractionated heparin 5000 units 15.4% (71/461) injected twice daily Unfractionated heparin 5000 units 14.5% (67/461) injected three times daily Unfractionated heparin other 1.7% (8/461) daily regimen Any fondaparinux 0.9% (4/461) Fondaparinux 2.5 mg injected 0.9% (4/461) once daily incidence of gastrointestinal bleeding (1.7% vs 2.3%, P.58) or intracranial bleeding (0.4% vs 0.2%, P.61) between patients receiving extended prophylaxis and those receiving no prophylaxis after discharge. There were no differences in other adverse drug reactions between the 2 groups. DISCUSSION We found that extended VTE pharmacologic prophylaxis after hospital discharge in at-risk Medical Service patients did not reduce symptomatic DVT or PE over the ensuing 90 days. Furthermore, all-cause mortality and major bleeding at 90 days were more frequent in those receiving extended VTE pharmacologic prophylaxis after hospital discharge. Of the patients who died within 90 days, malignancy was the most common cause of death, occurring in more than 90% of patients. In the Extended Clinical Prophylaxis in Acutely Ill Medical Patients (EXCLAIM) Trial, VTE prophylaxis was evaluated after hospital discharge in high-risk medical patients with heart failure, respiratory insufficiency, infection, or reduced mobility. 13 There was a reduction in VTE among those patients receiving extended postdischarge prophylaxis with enoxaparin 40 mg daily. However, EXCLAIM changed enrollment eligibility midway through the study and made the inclusion criteria for immobility more restrictive. 13 In EXCLAIM, extended-duration enoxaparin significantly reduced VTE at 28 days from 4.0% in the placebo group to 2.5% in the enoxaparin group. Similar to our study findings, major hemorrhage at 30 days was significantly greater in extended-duration prophylaxis patients compared with the placebo group. The Multicenter, randomized, Parallel Group Efficacy and Safety for the Prevention of VTE in Hospitalized Medically ill Patients Comparing rivaroxaban With Enoxaparin (MAGELLAN) Trial compared oral rivaroxaban 10 mg once daily for 35 days to enoxaparin 40 mg once daily Table 4 Endpoints of Venous Thromboembolism, Death, Bleeding, and Adverse Events in Patients with Follow-up at 90 Days Patient Characteristic Extended Prophylaxis at Discharge (n 458) No Extended Prophylaxis at Discharge (n 911) P Value VTE (within 90 days) - % Yes 5.0% (23/458) 4.3% (39/911).58 No 95.0% (435/458) 95.7% (872/911).58 DVT 3.3% (15/458) 2.6% (24/911).49 Any upper extremity 1.1% (5/458) 1.0% (9/911) 1.0 Any proximal with calf 0.7% (3/458) 0.8% (7/911) 1.0 Any proximal without calf 0.9% (4/458) 0.4% (4/911).45 Any calf only 0.7% (3/458) 0.3% (3/911).41 Other 0% (0/458) 0.1% (1/911) 1.0 PE 1.7% (8/458) 1.2% (11/911).47 Both DVT PE 0% (0/458) 0.4% (4/911).31 Alive at 90 days 56.8% (260/458) 68.4% (623/911).001 Major bleeding (within 90 days) 3.9% (18/458) 1.9% (17/911).03 Blood transfusion ( 2 units) 1.7% (8/458) 0.8% (7/911).11 Surgical intervention 0% (0/458) 0.4% (4/911).31 Medical intervention 2.2% (10/458) 0.7% (6/911).03 Adverse drug reaction (within 90 days) 0% (0/458) 0.2% (2/911).55 DVT deep vein thrombosis; PE pulmonary embolism; VTE venous thromboembolism.

6 1148 The American Journal of Medicine, Vol 124, No 12, December 2011 Figure Kaplan-Meier estimates of the freedom from deep vein thrombosis or pulmonary embolism in the extended prophylaxis after discharge and no prophylaxis after discharge groups. HR hazard ratio; VTE venous thromboembolism. for 10 days in acutely ill medical patients for prevention of VTE. 14 The primary efficacy endpoint was a composite of asymptomatic proximal DVT, symptomatic DVT, symptomatic nonfatal PE, and VTE-related death at 10 and 35 days. The incidence of the composite endpoint was noninferior at 10 days for rivaroxaban (2.7%) and enoxaparin (2.7%, P for noninferiority.0025). In contrast to our study results, the incidence of the composite endpoint at 35 days was reduced in the MAGELLAN group receiving 35 days of rivaroxaban (4.4%) compared with the group receiving 10 days of enoxaparin (5.7%, P for superiority.0025). MAGELLAN and our study found that extended anticoagulant prophylaxis increased the risk of major bleeding. Almost 90% of our patient population had malignancies. There is a 7-fold higher VTE rate in cancer patients than those patients hospitalized with other diseases. 15,16 VTE rates vary with each type of malignancy. The highest rates are associated with cancers of the kidney, stomach, pancreas, and brain. 17 The extent of cancer, type of chemotherapy, the presence of catheters, and underlying genetic and acquired thrombophilias all contribute to the development of VTE. Several studies have evaluated extended VTE prophylaxis in cancer patients with conflicting results. The Fragmin Advanced Malignancy Outcome Study (FAMOUS) trial evaluated dalteparin 5000 units once daily versus placebo over a 1-year period in patients with advanced malignancies. 18 The rates of symptomatic VTE were similar for dalteparin and placebo (2.4% vs 3.3%). There were no differences in major bleeding. The survival estimates for dalteparin and placebo at 1 year were not statistically different (46% vs 41%). However, for those patients with a better prognosis, survival at 2 years improved for those patients receiving dalteparin compared with placebo (78% vs 55%, P.03). The Prophylaxis of Thromboembolism During Chemotherapy (PROTECHT) study evaluated nadroparin 3800 units daily versus placebo, in conjunction with chemotherapy, over 4 months in patients with metastatic or locally advanced cancers. 19 Thromboembolism occurred in 2.0% of Table 5 Causes of Death Extended Prophylaxis at Discharge (n 201) No Extended Prophylaxis at Discharge (n 299) Malignancy related deaths - % 185 (92.0%) 268 (89.6%).44 Deaths from all other causes 13 (6.5%) 20 (6.7%) 1.00 Cardiovascular disease 4 (2.0%) 10 (3.3%).42 Respiratory disease 6 (3.0%) 2 (0.7%).07 Gastrointestinal disease 1 (0.5%) 1 (0.3%) 1.00 Intracranial hemorrhage 1 (0.5%) 1 (0.3%) 1.00 Other 1 (0.5%) 6 (2.0%).25 Missing 3 (1.5%) 11 (3.7%).17 P Value

7 Fanikos et al VTE Prophylaxis at Discharge 1149 nadroparin-treated patients compared with 3.9% treated with placebo (P.02). There were no differences in major bleeding. Survival at 1 year was similar between the 2 groups, 56.7% versus 59.3% in the nadroparin and placebo groups, respectively. The largest randomized trial to date, the Evaluation of AVE5026 in the Prevention of Venous Thromboembolism in Cancer Patients Undergoing Chemotherapy (SAVE ONCO) study, presented at the American Society of Clinical Oncology meeting in June 2011, evaluated semuloparin 20 mg once daily versus placebo in patients with metastatic or locally advanced cancers. 20 Semuloparin was initiated with a new chemotherapy course and continued until the regimen was changed. Thromboembolic events were reduced from 3.4% in the placebo group to 1.2% in the semuloparin group (P.001). Major bleeding did not differ between the semuloparin and placebo groups (1.2% vs 1.1%). Survival was not reported. As in our study, patients enrolled in these trials were afflicted with a wide variety of cancers, and thromboembolism rates were low. The American College of Chest Physicians recommend after-discharge thromboprophylaxis in patients requiring general or gynecologic surgery for cancer or those with a prior history of VTE. 21 Similarly, they recommend extending thromboprophylaxis after hip replacement, knee replacement, and hip fracture surgery, and continuing thromboprophylaxis in patients undergoing rehabilitation following major trauma or acute spinal cord injury. There are, however, no recommendations for extending thromboprophylaxis in patients with medical conditions and they recommend against the use of thromboprophylaxis for primary VTE prevention in patients receiving chemotherapy or hormone therapy. The National Comprehensive Cancer Network advocates extended out-of-hospital VTE prophylaxis in cancer patients after abdominal or pelvic surgery and in those high-risk outpatients on chemotherapy with combinations of risk factors. 22 VTE prophylaxis following hospital discharge may be a judicious strategy to prevent events in narrowly defined groups of patients. Studies focusing on specific cancer patient populations, with similar stage of disease progression, may facilitate determining which patients would benefit from extended pharmacologic prophylaxis without an increased bleeding risk. Our study must be interpreted in the context of its casecontrol design. While we matched patients by age, sex, and VTE risk score, we were not able to adjust for the variables of patient acuity, disease entity, or disease severity. For example, we did not adjust for the type of cancer, the stage of disease, the presence or absence of distal metastases, or projected life expectancy. Length of stay, the rate of prior hospitalization within 30 days, and the incidence of infection also were higher in the group receiving extended prophylaxis after discharge. Our observation of poorer outcomes in patients receiving extended pharmacologic VTE prophylaxis at discharge may reflect a more acutely ill population than the patients receiving no extended prophylaxis at discharge. The higher incidence of all-cause mortality and major bleeding episodes may further suggest underlying comorbid illness and medical frailty. Therefore, extended prophylaxis may be a proxy for patients who are particularly ill and destined for a high rate of adverse outcomes after hospital discharge. Our study suggests that symptomatic VTE rates were not different in Medical Service patients who received extended pharmacologic thromboprophylaxis after hospital discharge compared with those in whom extended pharmacological VTE prophylaxis was not continued after discharge. Furthermore, the increase in all-cause mortality and major bleeding does not support the routine prescribing of extended pharmacologic prophylaxis. There remains an unmet need to determine which risk factors, present among Medical Service patients before hospital discharge, identify a population that might warrant VTE prophylaxis. Future studies may require precise targeting of anticoagulant intensity and duration to specific levels of VTE and bleeding risk. References 1. Heit J, O Fallon M, Petterson TM, et al. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism. A populationbased study. Arch Intern Med. 2002;162: Goldhaber SZ. Outpatient venous thromboembolism. A common but often preventable public healthcare threat. Arch Intern Med. 2007;167: Samama MM, Cohen AT, Darmon JY, et al for the Prophylaxis in Medical Patients with Enoxaparin Study Group. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. N Engl J Med. 1999;341: Leizorovicz A, Cohen AT, Turpie AG, et al. Randomized placebocontrolled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. Circulation. 2004;110: Cohen AT, Davidson BL, Gallus AS, et al. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomized placebo controlled trial. BMJ. 2006;332: Yu HT, Dylan ML, Lin J, Dubois RW. Hospitals compliance with prophylaxis guidelines for venous thromboembolism. Am J Health Syst Pharm. 2007;64: Amin A, Stemkowski S, Lin J, et al. Thromboprophylaxis rates in US medical centers: success or failure? J Thromb Haemost. 2007;5: Cohen AT, Tapson VF, Bergmann JF, et al. Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross-sectional study. Lancet. 2008;371: Spencer FA, Lessard D, Emery C, et al. Venous thromboembolism in the outpatient setting. Arch Intern Med. 2007;167: Kucher N, Koo S, Quiroz R, et al. Electronic alerts prevent venous thromboembolism among hospitalized patients. N Engl J Med. 2005; 352: Fiumara K, Hurwitz S, Piazza G, et al. Multi-screen electronic alerts to augment venous thromboembolism prophylaxis. Thromb Haemost. 2010;103: Sahai H, Kurshid A. Formulae and tables for the determination of sample sizes and power in clinical trials for testing differences in proportions for the two-sample design: a review. Stat Med. 1996;15: Hull R, Schellong SM, Tapson VF, et al. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility. A randomized trial. Ann Intern Med. 2010; 153:8-18.

8 1150 The American Journal of Medicine, Vol 124, No 12, December Cohen AT, Spiro T, Büller H, et al. Rivaroxaban compared with enoxaparin for the prevention of venous thromboembolism in acutely ill medical patients. Presented at the American College of Cardiology Meeting, New Orleans, LA Abstract Heit JA, Silverstein MD, Mohr DN, et al. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med. 2000;160: Levitan N, Dowlati A, Remick SC, et al. Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy. Medicine. 1999;78: Lee AYY, Levine MN. Venous thromboembolism and cancer: risks and outcomes. Circulation. 2003;107:I-17-I Kakkar AK, Levine MN, Kadziola Z, et al. Low molecular weight heparin therapy with dalteparin, and survival in advanced cancer: the Fragmin Advanced Malignancy Outcome Study (FAMOUS). J Clin Oncol. 2004;22: Agnelli G, Gussoni G, Bianchini C, et al. Nadroparin for the prevention of thromboembolic events in ambulatory patients with metastatic or locally advanced solid cancer receiving chemotherapy: a randomized, placebo-controlled, double-blind study. Lancet Oncol. 2009;10: Agnelli G, George DJ, Fisher W, et al. The ultra-low molecular weight heparin semuloparin for prevention of venous thromboembolism in patients with cancer receiving chemotherapy: SAVE ONCO study. J Clin Oncol. 2011;29:LBA Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism. The 8th American College of Chest Physicians Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2008;133:381S- 453S. 22. Streiff MB, Bockenstedt PL, Cataland SR, et al. Venous thromboembolic disease. Clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2011;9: