• Thrombotic Disorders Clinical Trials

An extended course of thromboprophylaxis with apixaban did not reduce the risk of venous thromboembolism (VTE, which consists of pulmonary embolism (PE) and deep venous thrombosis [DVT]) and VTE-related death in medically ill patients compared with a shorter course of enoxaparin, according to findings from the Apixaban Dosing to Optimize Protection from Thrombosis trial [ADOPT; NCT00457002].

PE is one of the most preventable causes of death among hospitalized patients [Goldhaber SZ et al. Lancet 1999]. Recent improvements in inpatient thromboprophylaxis have reduced in-hospital mortality rates. Although average hospital stays are shortening, patients remain vulnerable to VTE-related complications after discharge [Ridker PM et al. N Engl J Med 2003]. The ADOPT trial evaluated whether extended thromboprophylaxis with a novel oral factor Xa anticoagulant, apixaban, compared with standard short-term treatment, would reduce the risk of VTE and VTE-related death in hospitalized medically ill patients.

The ADOPT trial enrolled 6528 patients who were hospitalized with congestive heart failure, acute respiratory failure, or other risk factors for VTE. Patients were randomly assigned to treatment with oral apixaban 2.5 mg twice daily for 30 days (n=3255) or subcutaneous enoxaparin 40 mg daily for 6 to 14 days (n=3273). Patients were evaluated with systemic compression ultrasonography at hospital discharge and on Day 30. The primary efficacy endpoint was the 30-day composite of death that was related to VTE, PE, symptomatic DVT, or asymptomatic proximal leg DVT.

Samuel Z. Goldhaber, MD, Senior Cardiologist, Brigham and Women's Hospital, Professor of Medicine, Harvard Medical School, Boston, Massachusetts, USA, presented findings from the ADOPT trial.

Overall, 2.71% of patients in the apixaban group and 3.06% of those in the enoxaparin group reached the primary endpoint by Day 30 (RR, 0.87; 95% CI, 0.62 to 1.23; p=0.44). This 13% reduction in events favored apixaban but did not achieve statistical significance. Apixaban did increase the risk of major bleeding compared with enoxaparin (0.47% vs 0.19%; RR, 2.53; p=0.04), but there were no deaths from bleeding and no intracranial hemorrhages.

“The ADOPT trial does not provide evidence to justify a policy of extended prophylaxis in a broad population of medically ill patients after hospital discharge,” Dr. Goldhaber said. However, findings from ADOPT illustrate the importance of effective thromboprophylaxis beyond hospital discharge. The cumulative risk of VTE and VTE-related death continued to increase during follow-up, particularly after thromboprophylaxis was discontinued.

In a secondary endpoint analysis, investigators examined outcomes during the postparenteral period, when blinded parenteral therapy was discontinued in the enoxaparin group and oral prophylaxis continued in the apixaban group. During this period, patients in the apixaban group had a 56% reduction in the risk of VTE-related death and symptomatic VTE compared with those in the enoxaparin group (95% CI, 0.19 to 1.00).

Several limitations of the study are worthy of consideration when interpreting the results. Because one-third of all protocol-mandated ultrasonography examinations were not obtained or nonevaluable, resulting in a high rate of patient exclusion from the efficacy analysis, the ADOPT trial had substantially less statistical power than initially planned. In addition, the study protocol mandated treatment with enoxaparin for at least 6 days and up to 14 days, even if patients were discharged earlier. This resulted in better efficacy with enoxaparin than would be expected in routine practice, in which VTE prophylaxis is discontinued at the time of hospital discharge. The Day 10 ultrasonography examination also distorted the natural history of DVT because of early identification and treatment of asymptomatic DVT. Despite these measures that went beyond standard practice, the number of primary endpoints in the control group increased steadily throughout the trial after enoxaparin was discontinued. These findings support further VTE prevention studies in high-risk populations.

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