4 Atrial Fibrillation Studies Pharmacists Should Know About, Part 2

MARCH 09, 2018
Atrial fibrillation (AF) is an irregular and often rapid heart rate that can increase the risk of blood clots, stroke, heart failure, and other heart-related complications. Up to 6.1 million people in the United States are estimated to have AF, with this number expected to increase with the aging U.S population.
Studies show that AF increases a person’s risk for stroke by up to 5 times compared with those who don’t have AF. Additionally, more than 750,000 hospitalizations occur each year because of AF with the condition contributing to an estimated 130,000 deaths per year and $6 billion in medical costs.1
Over the years, a number of landmark clinical studies on the management of AF have been published, sharping how patients are treated. In Part 1,we covered 4 studies that every pharmacist should know about. In this article we will cover 4 additional studies. 
1. ACTIVE-W (2009)2
Oral anticoagulation therapy, such as warfarin, has been shown in studies to significantly reduce the risk of stroke in AF patients; however, it also increases the risk of major bleeding by about 70% compared with aspirin. To determine the value of an alternative regimen in this population researchers conducted a study to assess whether Plavix (clopidogrel) plus aspirin is noninferior to oral anticoagulation therapy for prevention of vascular events.
Patients were enrolled in the study if they had AF plus 1 or more risk factor for stroke, and were randomly assigned to receive open treatment with warfarin (target INR of 2.0 - 3.0) or clopidogrel 75 mg plus aspirin 75-100 mg per day. A total of 7455 patients were assessed for eligibility from centers in more than 30 countries, and 6,706 were ultimately randomized into the study. The primary outcome was first occurrence of stroke, non-CNS systemic embolus, myocardial infarction, or vascular death. The median follow-up duration was 1.28 years.
The study was terminated early due to clear evidence of superiority of warfarin therapy. There were 165 primary outcome events in patients on warfarin compared to 234 in those on clopidogrel plus aspirin (RR=1.44, 95% CI 1.18-1.76; p=0.0003). For patients not already on warfarin therapy at baseline, the risk of a primary outcome event was only moderately higher on clopidogrel plus aspirin; however, for those already on warfarin at entry the risk was much higher on clopidogrel plus aspirin. Rates of major hemorrhage were similar in the two groups although significantly more minor bleeds occurred with clopidogrel plus aspirin than with warfarin.
Warfarin is superior to clopidogrel plus aspirin for prevention of vascular events in patients with AF at high risk of stroke.
2. ARISTOTLE (2011)3
Eliquis (apixaban) is an oral factor Xa inhibitor that is FDA-approved to reduce the risk of stroke and systemic embolism in patients with non-valvular AF. The 2012 approval of Eliquis was based on 2 phase III clinical studies, 1 of which was ARISTOTLE.
The study was designed in a randomized, double-blind trial, double-dummy fashion and enrolled more than 18,000 patients with AF and at least 1 additional risk factor for stroke, from 1,034 clinical sites in 39 countries. Participants were randomly assigned to receive Eliquis 5 mg twice daily or warfarin with a target INR between 2.0 and 3.0. The primary outcome was ischemic or hemorrhagic stroke or systemic embolism. The trial was designed to test for non-inferiority, with key secondary objectives of testing for superiority with respect to the primary outcome and to the rates of major bleeding and death from any cause.
After a 1.8 year mean duration of follow-up, the rate of the primary outcome was shown to be 1.27% per year in the Eliquis group, as compared with 1.60% per year in the warfarin group (HR=0.79; 95% CI: 0.66 - 0.95; p<0.001 for non-inferiority; p=0.01 for superiority). This reduction was consistent across all major subgroups. The rate of major bleeding was 2.13% per year in the Eliquis group, as compared with 3.09% per year in the warfarin group (HR=0.69; 95% CI, 0.60-0.80; p<0.001), and the rates of death from any cause was 11% lower in those treated with Eliquis (3.52% versus 3.94%; p=0.047).
Eliquis is superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality in patients with AF.
3. AVERROES (2011)4
Following the results from ACTIVE-W and similar studies, researchers continued to look at alternative regimens to warfarin in patients with AF. AVERROES was specifically designed to determine the efficacy and safety of Eliquis as compared with aspirin for the treatment of patients with AF for whom vitamin
K antagonist therapy was considered unsuitable.
The trial was conducted as a double-blind, double-dummy study at 522 centers in 36 countries. A total of 5,599 patients with AF, who were at increased risk for stroke and for whom vitamin K antagonist therapy was unsuitable, were randomly assigned to receive Eliquis (at a dose of 5 mg twice daily) or aspirin (81 to 324 mg per day), to determine whether Eliquis was superior. The primary outcome was the occurrence of stroke or systemic embolism. The mean follow up period was 1.1 years.
The data and safety monitoring board recommended early termination of the study due to a clear benefit shown in favor of Eliquis. There were 51 primary outcome events among patients assigned to Eliquis and 113 among those assigned to aspirin (HR = 0.45; 95% CI: 0.32-0.62; p<0.001). The rates of death were 3.5% per year in the Eliquis group and 4.4% per year in the aspirin group, although the comparison did not reach statistical significance (HR = 0.79; 95% CI: 0.62-1.02; p=0.07). Cases of major bleeding were similar between the two groups. The risk of a first hospitalization for cardiovascular causes was reduced with Eliquis, as compared with aspirin (12.6% per year vs. 15.9% per year; p<0.001). The treatment effects were consistent among important subgroups.
In patients with AF who were unsuitable candidates for anticoagulation with a vitamin K antagonist, Eliquis significantly reduced the risk of stroke and systemic embolism without increasing the risk of major bleeding when compared to aspirin.
4. ROCKET-AF (2011)5,6
Xarelto (rivaroxaban) is a factor Xa inhibitor approved by the FDA in 2011 for stroke prevention in patients with AF. Its approval was based in-part due from results of ROCKET-AF, a multicenter, randomized, double-blind, double-dummy trial designed to compare once-daily oral Xarelto with dose-adjusted warfarin for the prevention of stroke and systemic embolism in patients with non-valvular AF.
More than 14,000 patients with non-valvular AF, who were at increased risk for stroke, were randomly assigned to receive either Xarelto 20 mg or dose-adjusted warfarin. The study was designed to whether Xarelto was non-inferior to warfarin. The primary efficacy end point was the composite of stroke (ischemic or hemorrhagic) and systemic embolism.
After a mean follow-up of 2 years, the primary end point was shown to occur in 188 patients in the Xarelto group and in 241 in the warfarin group (HR = 0.79; 95% CI: 0.66 - 0.96; p<0.001). In a secondary analysis, Xarelto failed to demonstrate superiority to warfarin (p=0.12). There were no major differences in the rate of major and non-major clinically relevant bleeding between the groups although there were significant reductions in intracranial hemorrhage (0.5% vs. 0.7%; p=0.02) and fatal bleeding (0.2% vs. 0.5%; p=0.003) in the Xarelto group.
Study results received sharp criticism in 2016 when it was revealed that investigators had used faulty INR monitoring devices in the warfarin control group. An FDA analysis later that year, however, revealed that the clinical trial results were not significantly affected by the device.
Among patients with non-valvular AF, rivaroxaban is non-inferior to warfarin in preventing stroke or systemic embolism.
  1. Atrial Fibrillation Fact Sheet. Centers for Disease Control and Prevention. www.cdc.gov/dhdsp/data_statistics/fact_sheets/fs_atrial_fibrillation.htm. Accessed February 18, 2018.
  2. Connolly SJ, Yusuf S, Camm J, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet. 2006. 367(9526):1903-12.
  3. Granger CB, Alexander JH, McMurray, JV, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011. 365(11):981-982.
  4. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011. 364(9):806-817.
  5. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. N Engl J Med. 2011. 365(10):883-891.
  6. FDA analyses conclude that Xarelto clinical trial results were not affected by faulty monitoring device. U.S. Food & Drug Administration. October 11, 2016. www.fda.gov/Drugs/DrugSafety/ucm524678.htm. Accessed March 8, 1018.

Timothy O'Shea, PharmD
Timothy O'Shea, PharmD
Timothy O'Shea, PharmD, is a Clinical Pharmacist working at a large health insurance plan on the east coast. Additionally he works per diem at a retail pharmacy chain. He graduated from MCPHS University - Boston in 2015 and subsequently completed a PGY-1 Managed Care Pharmacy Residency. His professional interests include pharmacy legislation and managed care pharmacy. He can be followed on Twitter at @toshea125.
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