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Meeting Highlights: ESC Congress 2011
Apixaban Superior to Warfarin
The ARISTOTLE trial, designed to show noninferiority, went further and showed superiority of the oral factor Xa inhibitor apixaban to warfarin in preventing stroke and systemic embolism, major bleeding and death, in patients with AF.
This multisite, randomized, double-blind, double-dummy study enrolled 18,201 patients with AF and at least one additional risk factor for stroke. The apixaban group (n=9,120) received apixaban 5 mg twice daily; the warfarin group (n=9,081) received warfarin with a target INR 2.0 to 3.0. Treatment groups matched according to age (median 70 years), sex (65% male), geographic region, prior warfarin use (57%), CHADS2 score, qualifying risk factors and renal function. The primary objective was to determine whether apixaban is noninferior to warfarin in reducing ischemic or hemorrhagic stroke or systemic embolism in this patient population, and the primary safety outcome was major bleeding.
Compared with warfarin, over 1.8 years apixaban prevented 6 strokes, 15 major bleeds and 8 deaths per 1,000 patients treated, and reduced stroke and systemic embolism by 21% (p = 0.01), major bleeding by 31% (p < 0.001), and mortality by 11% (p = 0.047).
The study report is available at Granger CB, et al. N Engl J Med. 2011;365:981-992.
RESPONSE: Michael D. Ezekowitz, MD, (Thomas Jefferson Medical College, Philadelphia) responded to the report as the discussant, declaring a new era of reducing risk of stroke in patients with AF. Although warfarin was demonstrated to be effective, he said, the agent has been underutilized due to fear of bleeding—leading to the situation where physicians are more influenced by events that are induced (intracerebral hemorrhage) than events that are prevented.
Dr. Ezekowitz cited novel agents with different mechanisms of action, such as apixaban and dabigatran, that have been shown to be associated with much lower risk of intracranial and intracerebral hemorrhages. The consistency between the RE-LY trial of dabigatran and ARISTOTLE gives assurance that these results are valid, he said. The challenge going forward, said Ezekowitz, will be translating trial data into practice so that fewer patients are put at risk by permanent or even temporary discontinuation of anticoagulation.
Rivaroxaban in AF Patients With Renal Impairment
In a prespecified subset of patients with renal impairment in the ROCKET-AF trial, researchers found efficacy and safety of rivaroxaban compared with warfarin to be similar to those of the larger trial. The smaller study found a lower dose of rivaroxaban, an oral direct factor Xa inhibitor metabolized in the liver, to be as safe and effective as the higher dose used in the larger trial.
ROCKET-AF, a multisite, randomized, double-blind, double-dummy study, assigned 14,264 patients with AF to either rivaroxaban or warfarin (targeting an INR of 2.0 to 3.0). Patients with > 50 mL/min creatinine clearance (CrCl) assigned to rivaroxaban received 20 mg/day. The 2,950 patients with CrCl of 30 to 49 mL/min received 15 mg/day. The patients in this subset were older than those in the larger group (79 vs. 73 years, respectively) and had higher event rates in both the rivaroxaban and warfarin groups. Stroke or systemic embolism occurred in 2.32% per 100 patient-years with rivaroxaban vs. 2.77% with warfarin (HR 0.84; 95% CI 0.57 to 1.23). Major and clinically relevant nonmajor bleeding and intracranial bleeding were similar in the two drug groups, while fatal bleeding occurred less often with rivaroxaban (0.28% per 100 patient-years) than with warfarin (0.74% per 100 patient years; p = 0.047).
RESPONSE: Stefan H. Hohnloser, MD, (JW Goethe University, Frankfurt, Germany), as discussant, pointed out that patients with chronic kidney disease have an increased risk of developing AF, and patients with AF and moderate to severe renal impairment face 3 times the risk of stroke or thromboembolism as those with normal renal function—regardless of treatment. In patients with moderate chronic kidney disease, rivaroxaban 15 mg/day was noninferior to warfarin with respect to stroke prevention. The rate of major and clinically nonrelevant bleeding in these patients was similar with the two drugs, but fewer fatal bleeding events occurred on rivaroxaban.
Hohnloser said that further study is needed to determine whether kidney function should be monitored over time to allow for anticoagulant dose adjustments and to examine anticoagulant use in patients with severe renal impairment or patients on renal replacement therapy. Finally, which of the new oral anticoagulants—rivaroxaban, apixaban or dabigatran—works best in patients with moderate kidney disease will be determined not only by efficacy and safety, he said, but also by health economy considerations, such as pricing of the products.
Dabigatran With Concomitant Use of Antiplatelets
In a post hoc analysis of subgroups of patients with AF participating in the RE-LY trial, those receiving dabigatran with concomitant antiplatelet therapy experienced higher rates of major bleeding—regardless of anticoagulant type or dose—than those not taking antiplatelet therapy.
The RE-LY trial, a multisite, randomized, double-blind, double-dummy study, compared two doses of the oral direct thrombin inhibitor dabigatran (110 mg [D110] and 150 mg [D150] twice daily) and dose-adjusted warfarin in 18,113 patients with AF. The study showed D150 to be superior to warfarin and D110 to be noninferior in preventing stroke and systemic embolism. D110 was superior to warfarin in terms of major hemorrhages, and D150 showed major bleeding rates similar to those of warfarin.
During the trial, 6,952 patients received concomitant aspirin or clopidogrel; investigators did not distinguish between monotherapy and dual antiplatelet therapy. Of these patients, those receiving D150 had fewer strokes and systemic embolisms than those on warfarin, but the rate was nonsignificantly higher than for those not taking antiplatelet agents.
Overall, the rates of major bleeding were higher for those on concomitant antiplatelet therapy (HR = 1.60; 95% CI = 1.41-1.81 after adjusting for age,
gender, warfarin experience, creatinine clearance and comorbidities), but the absolute risks were lowest with D110.
RESPONSE: Responding to the study report, Freek W. A. Verheugt, MD, (Onze Lieve Vrouwe Gasthuis, Amsterdam) noted that the addition of antiplatelet agents to anticoagulant therapy raises the risk of major bleeding by about 60% in clinical trials, and the increased risk is even greater in practice and with each additional agent. Yet, the benefit of anticoagulation for stroke prevention remains, with D110 demonstrating the lowest rates of major bleeding in these patients compared with warfarin and D150. Low-dose dabigatran seems to be a good anticoagulant for patients with AF who need antiplatelet therapy, said Verheugt, but this therapy needs to be confirmed in a new, prospective randomized trial against warfarin, with larger participant numbers. Future trials should also examine the use of dabigatran and warfarin patients requiring dual therapy.