4 Atrial Fibrillation Studies Pharmacists Should Know About

MARCH 06, 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. Here are 4 that every pharmacist should know about. We will cover 4 more studies in a second article. 
1. SPAF (1991)2
Coumadin (warfarin) was initially approved as an anticoagulant in 1954 by the FDA. It wasn’t until 37 years later the results of a large scale clinical trial would be published to better understand warfarin’s role in reducing ischemic stroke and systemic embolism in patients with AF.
SPAF was a randomized, multicenter, clinical trial that enrolled 1330 inpatients and outpatients aged 18 years and older with constant or intermittent AF. Those with a prosthetic heart value or with a stroke or transient ischemic attack with the previous 24 months were excluded from the study due to their perceived needs for antithrombic therapy (and therefore unable to be assigned placebo). Patients were categorized as warfarin eligible or ineligible and then randomized to receive warfarin (adjusted to an INR between 2.0 and 4.5), aspirin 325 mg, or placebo (group 1) or aspirin 325 mg or placebo (group 2). The primary outcome was prevention of ischemic stroke and systemic embolism.
The mean follow-up was 1.3 years, although the placebo arm was terminated early when the superiority of both warfarin and aspirin relative to placebo was established. The data showed that patients on warfarin experienced a significant 67% relative risk reduction in the rate of the primary outcome as compared to placebo (2.3% versus 7.4% per year; p=0.01). Those on aspirin experienced a 42% reduction as compared to patients taking placebo (3.6% versus 6.3% per year; p=0.02). Notably, the study did not directly compare warfarin to aspirin since their efficacy was not known at time of the study. The risk of significant bleeding did not differ significantly between the groups ranging from 1.4% to 1.6%.
With its publication SPAF became the first large scale study to show benefit of antithrombotic therapy in reducing the risk of ischemic stroke and systemic embolism in patients with AF. Following SPAF and several other subsequent trials, anticoagulation became standard of care for stroke prevention in eligible patients with non-valvular AF.
Aspirin and warfarin are both effective in reducing ischemic stroke and systemic embolism in patients with AF although warfarin appears to demonstrate a better protective effect.
2. CHADS2 Index Validation (2001)3
By the year 2000, there was agreement that antithrombotic therapy can be effective in AF patients to reduce the risk of stroke; however, there was little agreement on how to predict the risk of a future stroke. As a result, investigators pooled data from a number of trials to develop a unified stroke classification scheme, CHADS2 index, and then conducted a retrospective study to assess the validity of the tool.
The study used data from the National Registry of AF (NRAF) consisting of 1733 Medicare beneficiaries aged 65 to 95 years who had nonrheumatic AF and were not prescribed warfarin at hospital discharge. The study outcome was hospitalization for ischemic stroke as determined by Medicare claims data using CHADS2 index and two existing classification schemes. The investigators set a minimum of 365 days of follow-up claims for all Medicare beneficiaries.
During 2121 patient-years of follow-up, 94 patients were readmitted to the hospital for ischemic stroke. The 2 existing classification schemes predicted stroke better than chance; however, with a c statistic of 0.82 (95% CI, 0.80-0.84), the CHADS2 index was the most accurate predictor of stroke. The authors stated that using CHADS2 may be helpful in guiding clinical decision making for antithromtoic therapy.
In 2009, a refined classification called CHA2DS2-VASc was introduced to better stratify risk in AF patients.
The CHADS2 index is an effective tool to quantify risk of stroke for patients who have AF and may aid in selection of antithrombotic therapy.
3. AFFIRM (2002)4
Although AF has historically been the most common sustained cardiac arrhythmia, until 2002 the optimal management strategy between rate-control and rhythm-control was not yet fully defined. With its publication, AFFIRM became the first and largest study to compare rate and rhythm control strategies for the treatment of AF.
The study was designed as a randomized, multicenter comparison study of 4060 individuals aged 65 years and older with AF and a high risk of stroke or death. Participants were assigned to one of two groups: (1) rhythm control strategy consisting of several antiarrhythmic drugs chosen by the treating physician and cardioversion as necessary or (2) rate-control strategy through beta blockers, calcium-channel blockers, and digoxin. The primary end point was overall mortality.
Data results showed that more deaths occurred in the rhythm-control group than in the rate-control group (356 versus 310), although the difference in mortality did not reach statistical significance (HR = 1.15; p=0.08). The rates of the composite end point of death, disabling stroke, disabling anoxic encephalopathy, major bleeding, or cardiac arrest were also similar in the two groups. More patients in the rhythm-control group than in the rate-control group were hospitalized (80.1% vs 73%; p <0.001) and there were more adverse drug effects in the rhythm-control group as well.
In patients with AF, there was no significant difference between rhythm-control and rate-control strategies although the latter trended towards better survival and demonstrated better on some secondary endpoints.
4. RELY (2009)5
Before 2009, warfarin was the anticoagulant of choice in preventing thromboembolic stroke among patients with AF due to its documented effectiveness and relatively inexpensive cost. However, warfarin also presents a number of food and drug interactions, requires regular laboratory monitoring, and increases the risk of major bleeds. RELY was a large scale study that looked to compare the effectiveness of Pradaxa (dabigatran), a novel oral direct thrombin inhibitor, to warfarin in terms of stroke risk and the risk of major bleeding in patients in AF.
The study was a non-inferiority trial that randomly assigned 18,113 patients who had AF and an increased risk of stroke to receive fixed doses of Pradaxa 110 mg or 150 mg twice daily or adjusted-dose warfarin. Patients were recruited from 951 clinical centers in 44 countries. Reasons for exclusion include the presence of a severe heart-valve disorder, stroke within 14 days or severe stroke within 6 months before screening. The median duration of the follow-up period was 2 years. The primary outcome was stroke or systemic embolism.
The rate of the primary outcome was 1.69% per year in the warfarin group as compared with 1.53% per year in the group that received 110 mg of Pradaxa and 1.11% per year in the group that received 150 mg of Pradaxa (p<0.001 for both comparisons). In addition to both doses being non-inferior to warfarin, the 150 mg dose was shown to demonstrate superiority (RR=0.66; 95% CI: 0.53-0.82; p<0.0001).The rate of major bleeding was 3.36% per year in the warfarin group, as compared with 2.71% per year in the group receiving 110 mg of Pradaxa (p=0.003) and 3.11% per year in the group receiving 150 mg of Pradaxa (p=0.31). The mortality rate was lower in both Pradaxa groups although neither reached statistical significance (p=0.13 for the 110 mg dose and 0.051 for 150 mg dose).
Following the study’s publication, the FDA approved the 150 mg Pradaxa dose for use in non-valvular AF.
Pradaxa 110 mg and 150 mg twice daily is non-inferior to warfarin. The 150 dose was superior to warfarin with respect to stroke or systemic embolism.
  1. Atrial Fibrillation Fact Sheet. Centers for Disease Control and Prevention. . Accessed February 18, 2018.
  2. SPAF Investigators. Stroke Prevention in Atrial Fibrillation Study. Final results. Circulation. 1991. 84(2):527-39.
  3. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA. 2001 Jun 13;285(22):2864-70.
  4. Wyse DG, Waldo AL, DiMarco JP, et al. A Comparison of Rate Control and Rhythm Control in Patients with Atrial Fibrillation. N Engl J Med. 2002. 347(23):1825-1833.
  5. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009. 361(12):1139-51.

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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