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Extended-Duration Venous Thromboembolism Prophylaxis in Acutely Ill Medical Patients With Recently Reduced Mobility: A Randomized Trial

Russell D. Hull, MBBS; Sebastian M. Schellong, MD; Victor F. Tapson, MD; Manuel Monreal, MD; Meyer-Michel Samama, MD, PharmD; Philippe Nicol, PhD; Eric Vicaut, MD, PhD; Alexander G.G. Turpie, MD; Roger D. Yusen, MD, MPH, EXCLAIM (Extended Prophylaxis for Venous ThromboEmbolism in Acutely Ill Medical Patients With Prolonged Immobilization) study
[+] Article and Author Information

For a list of the EXCLAIM study investigators, see Appendix 1.


From University of Calgary, Foothills Hospital, Calgary, Alberta, and McMaster University and HHSC McMaster Clinic, Hamilton, Ontario, Canada; Hospital Carl Gustav Carus, Dresden, Germany; Duke University Medical Center, Durham, North Carolina; Hospital Germans Trias i Pujol, Barcelona, Spain; Service d'Hématologie Biologique Hotel-Dieu and sanofi-aventis, Paris, France; and Washington University School of Medicine, St. Louis, Missouri.


Acknowledgment: The authors thank Min Chen and Genevieve Salette (sanofi-aventis) for their statistical analysis, Rachel Spice (Excerpta Medica) for providing editorial support, and Bruno Deslandes (sanofi-aventis) for critically reviewing the content.

Grant Support: By sanofi-aventis, which also funded editorial support.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M09-0393.

Reproducible Research Statement:Study protocol: See reference (11). Statistical code: Not available. Data set: Available on request from the EXCLAIM Steering Committee (e-mail, rdhull@ucalgary.ca).

Requests for Single Reprints: Russell D. Hull, MBBS, Thrombosis Research Unit, University of Calgary, Foothills Hospital, Room 601 South Tower, 1403 29th Street Northwest, Calgary, Alberta T2N 2T9, Canada; e-mail, rdhull@ucalgary.ca.

Current Author Addresses: Dr. Hull: Thrombosis Research Unit, University of Calgary, Foothills Hospital, Room 601 South Tower, 1403 29th Street Northwest, Calgary, Alberta T2N 2T9, Canada.

Dr. Schellong: Division of Angiology, University Hospital Carl Gustav Carus, Fetscherstraße 74, 01307 Dresden, Germany.

Dr. Tapson: Duke University Medical Center, Hanes House, Room 128, Durham, NC 27710.

Dr. Monreal: Carretera de Canyet s/n, Barcelona, 08916, Spain.

Dr. Samama: Départment d'Hématologie Biologique, Hôtel Dieu, 75181 Paris, France.

Dr. Nicol: sanofi-aventis, 174 Avenue de France, 75635 Paris Cedex 13, France.

Dr. Vicaut: Clinical Research Unit, Hôpital F. Widal, 200 Rue du Faubourg St-Denis, 75010 Paris, France.

Dr. Turpie: Hamilton General Hospital, 237 Barton Street East, Hamilton, Ontario L8I 2X2, Canada.

Dr. Yusen: Washington University School of Medicine, 660 South Euclid Avenue, Box 8052, St. Louis, MO 63110.

Author Contributions: Conception and design: R.D. Hull, S.M. Schellong, V.F. Tapson, M. Monreal, A.G.G. Turpie, R.D. Yusen.

Analysis and interpretation of the data: R.D. Hull, S.M. Schellong, V.F. Tapson, M.M. Samama, E. Vicaut, A.G.G. Turpie, R.D. Yusen.

Drafting of the article: R.D. Hull, M. Monreal, R.D. Yusen.

Critical revision of the article for important intellectual content: R.D. Hull, S.M. Schellong, V.F. Tapson, M. Monreal, M.M. Samama, A.G.G. Turpie, R.D. Yusen.

Final approval of the article: R.D. Hull, S.M. Schellong, V.F. Tapson, M. Monreal, M.M. Samama, A.G.G. Turpie, R.D. Yusen.

Provision of study materials or patients: R.D. Hull, S.M. Schellong, V.F. Tapson, M. Monreal, A.G.G. Turpie, R.D. Yusen.

Statistical expertise: R.D. Hull, S.M. Schellong, E. Vicaut, R.D. Yusen.

Administrative, technical, or logistic support: S.M. Schellong, P. Nicol.

Collection and assembly of data: R.D. Hull, V.F. Tapson, M. Monreal, M.M. Samama, A.G.G. Turpie, P. Nicol, R.D. Yusen.


Ann Intern Med. 2010;153(1):8-18. doi:10.7326/0003-4819-153-1-201007060-00004
Text Size: A A A

Background: Extended-duration low-molecular-weight heparin has been shown to prevent venous thromboembolism (VTE) in high-risk surgical patients.

Objective: To evaluate the efficacy and safety of extended-duration enoxaparin thromboprophylaxis in acutely ill medical patients.

Design: Randomized, parallel, placebo-controlled trial. Randomization was computer-generated. Allocation was centralized. Patients, caregivers, and outcome assessors were blinded to group assignment. (ClinicalTrials.gov registration number: NCT00077753)

Setting: 370 sites in 20 countries across North and South America, Europe, and Asia.

Patients: Acutely ill medical patients 40 years or older with recently reduced mobility (bed rest or sedentary without [level 1] or with [level 2] bathroom privileges). Eligibility criteria for patients with level 2 immobility were amended to include only those who had additional VTE risk factors (age >75 years, history of VTE, or active or previous cancer) after interim analyses suggested lower-than-expected VTE rates.

Intervention: Enoxaparin, 40 mg/d subcutaneously (2975 patients), or placebo (2988 patients), for 28 ± 4 days after receiving open-label enoxaparin for an initial 10 ± 4 days.

Measurements: Incidence of VTE up to day 28 and of major bleeding events up to 48 hours after the last study treatment dose.

Results: Extended-duration enoxaparin reduced VTE incidence compared with placebo (2.5% vs. 4%; absolute risk difference favoring enoxaparin, −1.53% [95.8% CI, −2.54% to −0.52%]). Enoxaparin increased major bleeding events (0.8% vs. 0.3%; absolute risk difference favoring placebo, 0.51% [95% CI, 0.12% to 0.89%]). The benefits of extended-duration enoxaparin seemed to be restricted to women, patients older than 75 years, and those with level 1 immobility.

Limitation: Estimates of efficacy and safety for the overall trial population are difficult to interpret because of the change in eligibility criteria during the trial.

Conclusion: Use of extended-duration enoxaparin reduces VTE more than it increases major bleeding events in acutely ill medical patients with level 1 immobility, those older than 75 years, and women.

Primary Funding Source: Sanofi-aventis.

Figures

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Figure 1.
Study flow diagram.

Numbers are reported for the total study population, followed by the number of patients enrolled before and after the eligibility criteria were amended.

* Includes 1 patient who did not receive enoxaparin during the open-label phase of the trial but received it during the double-blind phase and 23 patients (12 enoxaparin recipients and 11 placebo recipients; 22 preamendment [11 enoxaparin recipients and 11 placebo recipients], 1 postamendment [1 enoxaparin recipient]) for whom immobility classification data were missing or immobility-level classification was absent.

† Includes 22 patients (21 preamendment [10 enoxaparin recipients and 11 placebo recipients] and 1 postamendment [enoxaparin recipient]) who had missing immobility-level data or no immobility-level classification.

‡ Reasons include incompatible digital format, incomplete scans, and insufficient quality of scans.

§ No ultrasonography, reason not known, 65 (48; 17); evaluated outside of time window, 5 (4; 1); not sent for central reading, 43 (23; 20); not evaluable centrally, 100 (56; 44); not read centrally because of technical problems, 19 (8; 11).

∥ No ultrasonography, reason not known, 53 (38; 15); evaluated outside of time window, 2 (2; 0); not sent for central reading, 40 (20; 20); not evaluable centrally, 96 (44; 52); not read centrally because of technical problems, 24 (10; 14).

¶ Adverse event, 76 (60; 16); lost during follow-up, 6 (5; 1); died, 25 (17; 8); discontinued study participation, 61 (52; 9); progressive disease, 14 (11; 3); other, 76 (57; 19).

** Adverse event, 85 (70; 15); lost during follow-up, 13 (9; 4); died, 32 (20; 12); discontinued study participation, 56 (36; 20); progressive disease, 15 (15; 0); other, 62 (45; 17).

†† 21 patients were excluded from the immobility subgroups (20 preamendment [9 enoxaparin recipients and 11 placebo recipients] and 1 postamendment [enoxaparin recipient]) because immobility-level data were missing or immobility-level classification was absent.

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Appendix Figure 1.
Relative risk for VTE across specific patient subgroups during the double-blind treatment period.

Assessed in the total efficacy population. NYHA = New York Heart Association; OR = odds ratio; VTE = venous thromboembolism.

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Appendix Figure 2.
Changes in thePvalue, by VTE incidence in the placebo group.

The area below the horizontal dashed line represents the region of statistical significance. VTE = venous thromboembolism.

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Tables

References

Letters

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Comments

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Extended-duration of venous thromboembolism prophylaxis.
Posted on July 21, 2010
Jose A. Nieto
Hospital Virgen de la Luz. Cuenca. Spain
Conflict of Interest: None Declared

TO THE EDITOR: In an excellent EXCLAIM study1 (July 4th issue), Hull and co-workers reported on the benefits of a fixed dose of 40 mg enoxaparin on the extended-duration of thromboembolism prophylaxis for patients with level 1 immobility, women and patients older than 75 years. We hypothesize that the better outcomes observed in the last two groups are dependent on the weight-adjusted enoxaparin administered.

According to the RIETE (Registro Informatizado de Enfermedad Tromboembolica) registry data, women (older than 40 years) diagnosed with venous thromboembolism weighed significantly less than men (mean, 70,5 vs 77,5 kg, respectively; p<0,001), and patients older than 75 years weighed significantly less than those who are younger (mean, 76,7 vs. 69,6; p<0,001). As a consequence, a 10% fluctuation in the weight- adjusted enoxaparin administered may occur.

By applying the weight of 26.888 RIETE patients to this study, the benefit in the primary efficacy end point (defined as the absolute risk difference) in the EXCLAIM patients correlated very closely (R=0.97; p=0.03) with the weight-adjusted enoxaparin administered. The greatest benefit (5.37%)occurs in women older than 75 years (mean weight, 67.1 kg) that receive 59.6 IU/kg enoxaparin while the lowest benefit (-0.34%) are in men younger than 75 years old (mean weight, 79.2 kg) that receive 50.5 IU/kg. In an intermediate position are men older than 75 years (absolute risk difference 2.62%) and women younger than 75 years (absolute risk difference 1.20%), The mean weight and the weight-adjusted enoxaparin administered in the last two groups are the same (73.5 Kg; 54.4 IU).

References.

1.Hull RS, Schellong SM, Tapson VF et al. Extended duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility. Ann Intern Med 2010; 153:8-18.

Conflict of Interest:

None declared

Risks and benefits of extended antithrombotic prophylaxis in patients antiplatelet agents-free
Posted on July 27, 2010
Francesco Dentali
Department of Clinical Medicine, University of Insubria, Varese
Conflict of Interest: None Declared

To the editor: In the large randomized controlled trial (RCT) performed by Hull and colleagues (1), extended-duration prophylaxis with subcutaneous enoxaparin in comparison with short-duration prophylaxis reduces the incidence of the primary efficacy end point-defined as the composite of symptomatic or asymptomatic deep venous thrombosis (DVT), symptomatic pulmonary embolism (PE), or fatal PE in patients requiring total bed rest or being sedentary without bathroom privileges, in those older than 75 years, and in women; on the other hand, the primary safety end point defined as the incidence of major hemorrhagic complications, during and up to 48 hours after the double-blind treatment period was significantly greater in the extended-duration enoxaparin group than the placebo group although the observed absolute differences in risk for VTE and major bleeding events suggest a favourable benefit-to-risk ratio in these patients. Conversely to the orthopedic and general surgical patients (2,3), extended -duration prophylaxis is still underused in medical patients. Besides the lack of compelling evidence on the efficacy of antithrombotic prophylaxis (4) this was probably due to the fear of haemorrhagic complications. Although caution is necessary in the interpretation of these results due to the amendment in original protocol, findings of this RCT encourage the use of antithrombotic prophylaxis beyond the established 6-14 days (5). However, this potential benefit is partially counterbalanced by an increased risk of haemorrhagic complication. To better stratify bleeding risk and module prophylaxis duration, bleeding risk factors should be identified. In the RCT performed by Hull and colleagues, only 7% of patients received antiplatelet agents for 1 day or longer and, conversely, more than 30% of the total episodes of major bleeding occurred in this subgroup of patients. Since the risk of major bleeding complication is increased in patients receiving antiplatelet agents, it would be of great interest to know if extended-duration prophylaxis with enoxaparin still reduces the risk of VTE compared to placebo without increasing the risk of major bleeding complication in patients antiplatelet agents-free.

REFERENCES

1.Hull RD, Schellong SM, Tapson VF, Monreal M, Samama MM, Nicol P, et al; EXCLAIM (Extended Prophylaxis for Venous ThromboEmbolism in Acutely Ill Medical Patients With Prolonged Immobilization) study. Extended- duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med. 2010;153:8-18.

2.Rasmussen MS, Jorgensen LN, Wille-Jorgensen P, Nielsen JD, Horn A, Mohn AC, et al; FAME Investigators. Prolonged prophylaxis with dalteparin to prevent late thromboembolic complications in patients undergoing major abdominal surgery: a multicenter randomized open-label study. J Thromb Haemost. 2006;4:2384-90.

3.Eikelboom JW, Quinlan DJ, Douketis JD. Extended-duration prophylaxis against venous thromboembolism after total hip or knee replacement: a metaanalysis of the randomised trials. Lancet. 2001;358:9- 15.

4.Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR, et al; American College of Chest Physicians. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:381S-453S.

5.Dentali F, Douketis JD, Gianni M, Lim W, Crowther MA. Meta- analysis: anticoagulant prophylaxis to prevent symptomatic venous thromboembolism in hospitalized medical patients. Ann Intern Med. 2007;146:278-88.

Conflict of Interest:

None declared

Extended-duration venous thromboembolism prophylaxis for medical patients.
Posted on July 28, 2010
Michael P. Carson
Jersey Shore University Medical Center
Conflict of Interest: None Declared

TO THE EDITOR: In the EXCLAIM study (July 6th issue), Hull and co- workers reported the results of their large trial evaluating extended VTE prophylaxis for hospitalized medical patients. It was nice to see transparent reporting of the limitations stated in the abstract and the balanced presentation in their discussion section. We reviewed this article at our resident run journal club and would appreciate feedback from the authors regarding a) the reason for reporting non-adjudicated data in Tables 2 and 3, and b) why they seemed to downplay the risk of major bleeding episodes by stating in the discussion that the rate was "similar to those seen in previous studies of short-term VTE prophylaxis in medical patients". When the difference in the rate of major hemorrhage was equal to 1/3 of the absolute decrease in VTE it seems that a comparing the risk, but not the "benefit-risk" ratio, to historical studies is not warranted. Based on the primary efficacy and safety outcomes, the number needed to treat (NNT) to prevent one VTE is 67, the NNT to "cause" a major hemorrhage is 200, and the NNT to prevent VTE without a major hemorrhage is 100. Perhaps this is fuel for the authors' next project, but it would be interesting to know if a cost analysis was constructed comparing the cost of administering the medication for a month to prevent VTE events vs. the cost associated with managing the complications of major hemorrhages.

Reference.

1.Hull RS, Schellong SM, Tapson VF et al. Extended duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility. Ann Intern Med 2010; 153:8-18.

Conflict of Interest:

None declared

Response to Annals of Internal Medicine correspondence
Posted on September 20, 2010
Russell D. Hull
From University of Calgary, Foothills Hospital, Calgary, Alberta, and McMaster University and HHSC M
Conflict of Interest: None Declared

We thank Dr. Dentali and colleagues for highlighting bleeding risk as a key factor in the decision to provide extended-duration anticoagulant prophylaxis. Stratification of patients according to bleeding risk would enable clinicians to clearly identify those more likely to experience hemorrhagic complications. Since few major bleeding events occurred in this study (N=35), we cannot accurately develop a predictive model. The EXCLAIM study demonstrated an increased risk for bleeding events in patients who received antiplatelet therapy.1 This population also had higher VTE event rates compared with antiplatelet-free patients (31/324 [9.6%] vs. 130/4671 [2.8%]; p<.0001). However, we recommend cautious interpretation of these results since the medical characteristics of these two populations may vary greatly and result in different baseline risk for VTE and bleeding.

Dr. Nieto and colleagues raised an interesting discussion point. They hypothesized that weight and therefore use of weight-adjusted enoxaparin may result in improved anticoagulant efficacy, and this suggests that weight may have been a causal factor in the favourable benefit-to-risk ratio of extended-duration prophylaxis compared to placebo observed in female patients and the elderly. A post hoc analysis suggested that patients receiving extended-duration enoxaparin who were ?70kg did have slightly greater absolute efficacy differences compared with the >70 kg subgroup in both female patients (-3.0% vs. -2.4%) and the elderly (-5.1% vs. -3.1%). However, this cannot explain all the benefit in favour of female and elderly patients as suggested by the multivariate analysis that demonstrated a nonstatistically significant interaction between treatment and weight (p = 0.353).

We would like to confirm that all efficacy and safety data shown in Tables 2 and 3 of the manuscript underwent adjudication. The table footnotes refer to selected outcomes that were not adjudicated when the final interim analysis was performed, though the outcomes were adjudicated prior to study completion.

We acknowledge Dr. Carson and colleagues' comment regarding the comparison of absolute risk for bleeding when evaluating the EXCLAIM results alongside short-term prophylaxis studies. This was intended to provide context for the bleeding rates associated with extended-duration thromboprophylaxis (similar to those observed with short-term prophylaxis regimens) rather than downplaying the risks. We find it difficult to compare the benefit-to-risk ratio among trials that used different designs.1-4 However, compared with PREVENT's standard-duration regimen, EXCLAIM's extended-duration thromboprophylaxis had similar or more favorable absolute risk reductions in VTE (-2.71% [women], -4.25% [age>75 years], -2.18% [level 1 immobility] vs. -2.4%) and absolute risk increases in major bleeding (+0.66% [women], +0.24% [age>75 years], +0.51% [level 1 immobility ] vs. +0.54%).1,4. Moreover, EXCLAIM demonstrated a statistically and clinically significant reduction in symptomatic VTE that previous trials of thromboprophylaxis in acutely ill medical patients have not shown.1-4

References

1. Hull RD, Schellong SM, Tapson VF, Monreal M, Samama MM, Nicol P, et al; EXCLAIM (Extended Prophylaxis for Venous ThromboEmbolism in Acutely Ill Medical Patients With Prolonged Immobilization) study. Extended- duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med. 2010;153:8-18.

2. Samama MM, Cohen AT, Darmon JY, Desjardins L, Eldor A, Janbon C, et al. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group. N Engl J Med. 1999;341:793- 800.

3. Cohen AT, Davidson BL, Gallus AS, et al.; ARTEMIS Investigators. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. Br Med J. 2006;332:325-9.

4. Leizorovicz A, Cohen AT, Turpie AG, Olsson CG, Vaitkus PT, Goldhaber SZ; PREVENT Medical Thromboprophylaxis Study Group. Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. Circulation. 2004;110:874 -9.

Conflict of Interest:

None declared

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Summary for Patients

Do the Benefits of Prolonged Low-Molecular-Weight Heparin Treatment Outweigh the Harms in Hospitalized Patients Who Are Bedbound?

The summary below is from the full report titled “Extended-Duration Venous Thromboembolism Prophylaxis in Acutely Ill Medical Patients With Recently Reduced Mobility. A Randomized Trial.” It is in the 6 July 2010 issue of Annals of Internal Medicine (volume 153, pages 8-18). The authors are R.D. Hull, S.M. Schellong, V.F. Tapson, M. Monreal, M.M. Samama, P. Nicol, E. Vicaut, A.G. Turpie, and R.D. Yusen, for the EXCLAIM (Extended Prophylaxis for Venous ThromboEmbolism in Acutely Ill Medical Patients With Prolonged Immobilization) study.

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