For years, Pharma have been itching to prove a benefit of extended chemoprophylaxis against DVT / PE in medically ill patients after hospital discharge. Three weeks or more of enoxaparin after surgical knee or hip replacement is standard care, since it reduces the high risk of serious venous thromboembolism with a relatively low risk of serious bleeding events. Although medically ill patients are also at risk for DVT/PE post-discharge, no benefit from extended prophylaxis has been shown. Bristol-Myers Squibb and Pfizer are the latest to seek a sales-boosting new indication for a novel anticoagulant, but their ADOPT trial, just published in the New England Journal, showed giving apixaban post-discharge in medically ill patients didn’t reduce serious DVT/PE, but did cause excessive bleeding.
BMS-Pfizer are not the first Pharmas to stumble on this particular path. In Sanofi-Aventis’s 2010 EXCLAIM trial, ~28 days of enoxaparin after discharge for medical illness prevented serious VTE (about a 1.5% absolute risk reduction, a number needed to treat of ~70), but at the price of a 0.5% absolute increase in major bleeding (a number needed to harm of 200). Most of the events enoxaparin prevented were symptomatic proximal DVTs (which would likely have been detected and treated anyway). Enoxaparin did prevent 1 or 2 fatal pulmonary emboli at 90 days, among almost 6,000 patients in the trial. However, there were also 4 intracranial bleeds and one fatal hemorrhage in the enoxaparin-treated group. (This arguable equipoise didn’t prevent breathless reviews by prominent academics in the press about the promise of enoxaparin for this new indication, however.)
Bayer then jumped in with its new drug rivaroxaban, pitted against enoxaparin in medical patients in the 2011 MAGELLAN trial. Rivaroxaban for 30 days post discharge was no more effective than enoxaparin for 10 days at clot prevention, but rivaroxaban did cause excess bleeding.
Here, Bristol-Myers Squibb and Pfizer entered the game with their new oral direct inhibitor of factor Xa, apixaban, publishing results of their ADOPT trial on extended thromboprophylaxis of medically ill patients in the New England Journal this month by P.I. Samuel Goldhaber. Apixaban already has FDA indications for thromboprophylaxis after joint replacement, and for stroke prevention in people with atrial fibrillation.
Investigators gave apixaban for 30 days or or enoxaparin for 6-14 days (double-dummy) to 4,495 patients going home after admissions for congestive heart failure, respiratory illnesses, or inflammatory bowel disease.
Equal numbers developed potentially serious VTE (proximal DVT or PE) — 2.7% taking apixaban vs. 3% taking enoxaparin, p=0.44. However, major bleeding occurred in 0.5% of those taking apixaban and only 0.2% of those taking enoxaparin, a 30 day relative risk of 2.6 for major bleeding on apixaban.
Clinical Takeaway: Heparin prophylaxis during the hospital stay remains the standard of care for most acutely ill medical patients. The American College of Physicians recently warned that patients at low risk for VTE or high risk for bleeding may even be harmed by low-dose heparin, and physicians should therefore prescribe mechanical or thromboprophylaxis on an individual basis. The 3% rate of serious VTE at 30 days seen here, and rates of 5% seen in EXCLAIM (which included those detected by surveillance ultrasound) reinforces the importance of thromboprophylaxis for all medically ill patients without contraindications, while they are in the hospital.
Goldhaber GZ et al (the ADOPT Trial Investigators). Apixaban versus Enoxaparin for Thromboprophylaxis in Medically Ill Patients. N Engl J Med 2011;365:2167-2177.