Deep vein thrombosis landmark trials in prevention
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Editor(s)-In-Chief: The APEX Trial Investigators, C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Justine Cadet
Overview
Randomized trials have compared the efficacy and safety of antithrombins and anticoagulants in the prevention of deep vein thrombosis in the setting of surgical procedures and in the context of hospitalization for a medical illness.
Medically Ill Patients
MAGELLAN[1]
Purpose: This study evaluated if extended therapy with oral rivaroxaban can prevent blood clots in the leg and lung that can occur with patients hospitalized for acute medical illness, and compared these results with those of the standard enoxaparin dose and duration regimen. The safety of rivaroxaban also was studied.
Outcomes:
- Primary Outcome Measures: Composite of VTE (DVT and/or PE) and death (Time Frame: up to day 35)
- Secondary Outcome Measures: Individual components of the composite endpoint and other cardiovascular events. (Time Frame: 90 + 7 days)
ADOPT[2]
Background:The efficacy and safety of prolonging prophylaxis for venous thromboembolism in medically ill patients beyond hospital discharge remain uncertain. We hypothesized that extended prophylaxis with apixaban would be safe and more effective than short-term prophylaxis with enoxaparin.
Methods: In this double-blind, double-dummy, placebo-controlled trial, the researchers randomly assigned acutely ill patients who had congestive heart failure or respiratory failure or other medical disorders and at least one additional risk factor for venous thromboembolism and who were hospitalized with an expected stay of at least three days to receive apixaban, administered orally at a dose of 2.5 mg twice daily for 30 days, or enoxaparin, administered subcutaneously at a dose of 40 mg once daily for 6 to 14 days. The primary efficacy outcome was the 30-day composite of death related to venous thromboembolism, pulmonary embolism, symptomatic deep-vein thrombosis, or asymptomatic proximal-leg deep-vein thrombosis, as detected with the use of systematic bilateral compression ultrasonography on day 30. The primary safety outcome was bleeding. All efficacy and safety outcomes were independently adjudicated.
Results: A total of 6,528 subjects underwent randomization, 4495 of whom could be evaluated for the primary efficacy outcome--2211 in the apixaban group and 2284 in the enoxaparin group. Among the patients who could be evaluated, 2.71% in the apixaban group (60 patients) and 3.06% in the enoxaparin group (70 patients) met the criteria for the primary efficacy outcome (relative risk with apixaban, 0.87; 95% confidence interval [CI], 0.62 to 1.23; P=0.44). By day 30, major bleeding had occurred in 0.47% of the patients in the apixaban group (15 of 3184 patients) and in 0.19% of the patients in the enoxaparin group (6 of 3217 patients) (relative risk, 2.58; 95% CI, 1.02 to 7.24; P=0.04).
Conclusion: In medically ill patients, an extended course of thromboprophylaxis with apixaban was not superior to a shorter course with enoxaparin. Apixaban was associated with significantly more major bleeding events than was enoxaparin. (Funded by Bristol-Myers Squibb and Pfizer)
APEX[3]
Background: The safety of betrixaban will also be studied. The Apex study is a multicenter, randomized, active-controlled efficacy and safety study comparing extended duration Betrixaban with standard of care Enoxaparin for the prevention of venous thromboembolism in acute medically ill patients. The purpose of this study is to evaluate whether extended prophylaxis with oral betrixaban can prevent blood clots in the leg and lung that sometime occur in patients hospitalized for an acute medical illness and to compare these results with standard of care enoxaparin.
Total Hip Replacement
RECORD 1 Study[4]
Background: This phase 3 trial compared the efficacy and safety of rivaroxaban, an oral direct inhibitor of factor Xa, with those of enoxaparin for extended thromboprophylaxis in patients undergoing total hip arthroplasty.
Methods: In this randomized, double-blind study, the researchers assigned 4,541 patients to receive either 10 mg of oral rivaroxaban once daily, beginning after surgery, or 40 mg of enoxaparin subcutaneously once daily, beginning the evening before surgery, plus a placebo tablet or injection. The primary efficacy outcome was the composite of deep vein thrombosis (DVT) (either symptomatic or detected by bilateral venography if the patient was asymptomatic), nonfatal pulmonary embolism or death from any cause at 36 days (range, 30 to 42). The main secondary efficacy outcome was major venous thromboembolism (proximal deep-vein thrombosis, nonfatal PE or death from venous thromboembolism [VTE]). The primary safety outcome was major bleeding.
Results: A total of 3,153 patients were included in the superiority analysis (after 1,388 exclusions), and 4,433 were included in the safety analysis (after 108 exclusions). The primary efficacy outcome occurred in 18 of 1,595 patients (1.1%) in the rivaroxaban group and in 58 of 1558 patients (3.7%) in the enoxaparin group (absolute risk reduction, 2.6%; 95% confidence interval [CI], 1.5 to 3.7; P<0.001). Major VTE occurred in 4 of 1686 patients (0.2%) in the rivaroxaban group and in 33 of 1678 patients (2%) in the enoxaparin group (absolute risk reduction, 1.7%; 95% CI, 1.0 to 2.5; P<0.001). Major bleeding occurred in six of 2,209 patients (0.3%) in the rivaroxaban group and in two of 2,224 patients (0.1%) in the enoxaparin group (P=0.18).
Conclusions: A once-daily, 10-mg oral dose of rivaroxaban was significantly more effective for extended thromboprophylaxis than a once-daily, 40mg subcutaneous dose of enoxaparin in patients undergoing elective total hip arthroplasty. The two drugs had similar safety profiles.
RECORD 2 Study[5]
Background: The researchers investigated the efficacy of rivaroxaban, an orally active direct factor Xa inhibitor, in preventing venous thrombosis after total knee arthroplasty.
Methods: In this randomized, double-blind trial, 2,531 patients who were to undergo total knee arthroplasty received either oral rivaroxaban, 10 mg once daily, beginning six to eight hours after surgery, or subcutaneous enoxaparin, 40 mg once daily, beginning 12 hours before surgery. The primary efficacy outcome was the composite of any deep vein thrombosis, nonfatal pulmonary embolism, or death from any cause within 13 to 17 days after surgery. Secondary efficacy outcomes included major venous thromboembolism (VTE) (i.e., proximal deep vein thrombosis, nonfatal pulmonary embolism or death related to venous thromboembolism) and symptomatic VTE. The primary safety outcome was major bleeding.
Results: The primary efficacy outcome occurred in 79 of 824 patients (9.6%) who received rivaroxaban and in 166 of 878 (18.9%) who received enoxaparin (absolute risk reduction, 9.2%; 95% confidence interval [CI], 5.9 to 12.4; P<0.001). Major VTE occurred in nine of 908 patients (1%) given rivaroxaban and 24 of 925 (2.6%) given enoxaparin (absolute risk reduction, 1.6%; 95% CI, 0.4 to 2.8; P=0.01). Symptomatic events occurred less frequently with rivaroxaban than with enoxaparin (P=0.005). Major bleeding occurred in 0.6% of patients in the rivaroxaban group and 0.5% of patients in the enoxaparin group. The incidence of drug-related adverse events, mainly gastrointestinal, was 12% in the rivaroxaban group and 13% in the enoxaparin group.
Conclusions: Rivaroxaban was superior to enoxaparin for thromboprophylaxis after total knee arthroplasty, with similar rates of bleeding.
Total Knee Replacement
RECORD 3 Study[6]
Background: The risk of venous thromboembolism (VTE) is high after total hip arthroplasty and could persist after hospital discharge. The researchers sought to compare the use of rivaroxaban for extended thromboprophylaxis with short-term thromboprophylaxis with enoxaparin.
Methods: 2,509 patients scheduled to undergo elective total hip arthroplasty were randomly assigned, stratified according to center, with a computer-generated randomization code, to receive oral rivaroxaban 10 mg once daily for 31-39 days (with placebo injection for 10-14 days; n=1,252), or enoxaparin 40 mg once daily subcutaneously for 10-14 days (with placebo tablet for 31-39 days; n=1,257). The primary efficacy outcome was the composite of deep vein thrombosis (DVT) (symptomatic or asymptomatic detected by mandatory, bilateral venography), non-fatal pulmonary embolism and all-cause mortality up to day 30-42. Analyses were done in the modified intention-to-treat population, which consisted of all patients who had received at least one dose of study medication, had undergone planned surgery, and had adequate assessment of thromboembolism.
Findings: The modified intention-to-treat population for the analysis of the primary efficacy outcome consisted of 864 patients in the rivaroxaban group and 869 in the enoxaparin group. The primary outcome occurred in 17 (2%) patients in the rivaroxaban group, compared with 81 (9.3%) in the enoxaparin group (absolute risk reduction 7.3%, 95% CI 5.2-9.4; p<0.0001). The incidence of any on-treatment bleeding was much the same in both groups (81 [6.6%] events in 1228 patients in the rivaroxaban safety population vs. 68 [5.5%] of 1229 patients in the enoxaparin safety population; p=0.25).
Interpretation: Extended thromboprophylaxis with rivaroxaban was significantly more effective than short-term enoxaparin plus placebo for the prevention of VTE, including symptomatic events, in patients undergoing total hip arthroplasty.
RECORD 4
References
- ↑ http://www.clinicaltrials.gov/ct2/show/NCT00571649?term=MAGELLAN&rank=1
- ↑ Goldhaber SZ, Leizorovicz A, Kakkar AK; et al. (2011). "Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients". N. Engl. J. Med. 365 (23): 2167–77. doi:10.1056/NEJMoa1110899. PMID 22077144. Unknown parameter
|month=ignored (help) - ↑ Cohen AT, Harrington R, Goldhaber SZ, Hull R, Gibson CM, Hernandez AF; et al. (2014). "The design and rationale for the Acute Medically Ill Venous Thromboembolism Prevention with Extended Duration Betrixaban (APEX) study". Am Heart J. 167 (3): 335–41. doi:10.1016/j.ahj.2013.11.006. PMID 24576517.
- ↑ Eriksson BI, Borris LC, Friedman RJ; et al. (2008). "Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty". N. Engl. J. Med. 358 (26): 2765–75. doi:10.1056/NEJMoa0800374. PMID 18579811. Unknown parameter
|month=ignored (help) - ↑ Lassen MR, Ageno W, Borris LC; et al. (2008). "Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty". N. Engl. J. Med. 358 (26): 2776–86. doi:10.1056/NEJMoa076016. PMID 18579812. Unknown parameter
|month=ignored (help) - ↑ Kakkar AK, Brenner B, Dahl OE; et al. (2008). "Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial". Lancet. 372 (9632): 31–9. doi:10.1016/S0140-6736(08)60880-6. PMID 18582928. Unknown parameter
|month=ignored (help)