Up in Flames: Antiplatelet Therapy in Patients with Stable Ischemic Heart Disease Receiving Anticoagulation for A-fib

Author(s)
Alina Kukin, PharmD
Zachary Noel, PharmD, BCCP

Reviewed By
David Parra, Pharm.D., BCPS
Reaghan Erickson, PharmD
Jennifer N. Clements, PharmD, BCPS, BCACP, CDE

Citation
Yasuda S, Kaikita K, Akao M, et al. Antithrombotic Therapy for Atrial Fibrillation with Stable Coronary Disease. N Engl J Med. 2019;381:1103-13.

The Problem

 

Antiplatelet therapy is considered a mainstay treatment for the prevention of recurrent cardiovascular events in patients with stable coronary artery disease (CAD).¹ Anticoagulation therapy is consider the cornerstone of therapy for most patients with atrial fibrillation (AF). AF and CAD are frequent comorbid conditions, occurring in 20-30% of patients with stable CAD. Unfortunately, combining antiplatelet and anticoagulation therapy increases the risk of major bleeding over 50% compared to anticoagulation alone.² Recent real-world observational data suggests that anticoagulation therapy can reduce cardiovascular event rates, particularly with the use of direct oral anticoagulants (DOACs).³ This begs the question: In patients with stable CAD and AF, is combination therapy necessary or is anticoagulation monotherapy sufficient?

 

What’s Known

 

For stroke prevention in AF, anticoagulation with a DOAC or warfarin is, without question, superior to antiplatelet therapy.^4,5 On the other hand, for patients with stable CAD (ie, >1 year since acute coronary syndrome or percutaneous coronary intervention (PCI)), long term single or dual antiplatelet therapy is indicated based on an assessment of ischemia and bleeding risk.¹ It’s unclear what is the best course of action in patients with AF and comorbid CAD.⁶ Current American College of Cardiology/American Heart Association (ACC/AHA) guidelines provide minimal guidance on whether to continue antiplatelet therapy in combination with anticoagulation in patients with stable CAD and AF.⁵ While the 2017 European Society of Cardiology guidelines recommend oral anticoagulation alone, there is little supporting evidence for this recommendation.⁷ Given the dearth of high-quality data, the AFIRE trial sought to determine whether a DOAC alone or antiplatelet therapy plus a DOAC provides the greatest net clinical benefit in patients with stable CAD and AF.

 

What’s New

 

The AFIRE trial was a multicenter, randomized, open-label, parallel-group study that compared rivaroxaban monotherapy to rivaroxaban plus antiplatelet therapy in patients with stable CAD and AF whose CHADS₂ score was ≥1. Stable CAD was defined as PCI or coronary-artery bypass grafting (CABG) at least one year prior to enrollment or angiographically confirmed CAD (stenosis of ≥50%) not requiring revascularization. Notable exclusion criteria included history of stent thrombosis, active tumor, poorly controlled hypertension (defined as systolic blood pressure ≥ 160 mmHg), or high-risk of coronary ischemic events based on lesion shape, lesion site, and type of stent.⁸

 

Rivaroxaban was dosed at 15 mg once daily if the patient’s creatinine clearance was ≥50 ml/min or 10 mg daily if the creatinine clearance was 15-49 ml/min. Antiplatelet therapy consisted of aspirin 81-100 mg daily or a P2Y₁₂ inhibitor. Choice of antiplatelet agent was at the discretion of the treating physician. The primary efficacy end point was the composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, or death from any cause. The primary safety end point was major bleeding as defined by the International Society on Thrombosis and Hemostasis (ISTH). The pre-specified follow-up period was 24-45 months.

 

Investigators randomized 2,236 Japanese patients to rivaroxaban or rivaroxaban plus an antiplatelet agent. Baseline patient characteristics were similar between groups (Table 1). In the combination group, 70% of patients received aspirin and 27% received a P2Y₁₂ inhibitor. The majority of patients on a P2Y₁₂ inhibitor received clopidogrel. Rivaroxaban 15 and 10 mg was prescribed to approximately 55% and 45% of patients, respectively. After a median of 24 months follow-up, the trial was stopped early due to higher all-cause mortality in the combination treatment group [1.85% v 3.37%; HR 0.55 (95% CI 0.38-0.81)] (Table 2).  Rivaroxaban monotherapy was noninferior to combination therapy for the primary efficacy endpoint [(4.14% v 5.75%; HR 0.72 (0.55-0.95)]. Post-hoc analyses demonstrated superiority for the primary efficacy endpoint, which was driven by reductions in hemorrhagic stroke and both cardiovascular and noncardiovascular death. Monotherapy also demonstrated superiority for ISTH major bleeding [1.62% v 2.76%; HR 0.59 (95% CI 0.39-0.89), p=0.01] (Table 2).

 

Table 1. Notable Baseline Characteristics

Characteristic*	Monotherapy (n=1107)	Combination Therapy (n=1108)
Age, years, mean      ≥ 75 years	74.3 52.6%	74.4 52.4%
Male gender	79.0%	79.1%
Previous stroke	13.4%	15.8%
Previous myocardial infarction	34.7%	35.5%
Previous PCI	70.6%	70.7%
Previous CABG	11.3%	11.5%
Type of atrial fibrillation      Paroxysmal      Persistent      Permanent	53.8% 14.8% 31.3%	52.3% 15.8% 31.9%
Creatinine clearance, mean      < 30      30-50      ≥ 50	62.8 mL/min 5.1% 28.5% 66.4%	61.7 mL/min 5.8% 28.2% 66.0%
Receiving proton-pump inhibitors	59.9%	62.6%
CHA2DS2-VASc score, median	4	4
HAS-BLED score, median	2	2

*Numbers are represented as number (percentage) unless otherwise stated
CABG: coronary-artery bypass grafting, PCI: percutaneous coronary intervention

 

Table 2. Efficacy and Safety Outcomes

	Monotherapy (n=1107)	Combination Therapy (n=1108)	Hazard Ratio (95% CI)	p-value
Cardiovascular events or all-cause mortality	4.14%	5.75%	0.72 (0.55–0.95)	<0.001#
Major bleeding	1.62%	2.76%	0.59 (0.39–0.89)	0.01**
Cardiovascular event      Ischemic stroke      Hemorrhagic stroke      MI      Unstable angina*      Systemic embolism	0.96% 0.18% 0.59% 0.59% 0.09%	1.31% 0.60% 0.37% 0.84% 0.05%	0.73 (0.42–1.29) 0.30 (0.10–0.92) 1.60 (0.67–3.87) 0.71 (0.35–1.44) 1.97 (0.18–21.73)
Death	1.85%	3.37%	0.55 (0.38-0.81)	0.01**
Any bleeding	7.22%	12.72%	0.58 (0.47–0.71)	0.01**

Numbers are represented as number (percentage) unless otherwise stated
MI: myocardial infarction
*requiring revascularization
^#p-value for noninferiority using one-sided alpha of 0.025 with a noninferiority margin of 1.46 based on a modified intention to treat population
^**p-value for superiority 

 

Our Critical Appraisal

 

The results of the AFIRE trial provide valuable insight about the relative risks and benefits of two different strategies for treating patients with stable CAD and AF. The trial was a prospective, multicenter, randomized study and, unlike prior studies in this population, was powered for the primary endpoint.⁹ The majority of patients in the trial had a history of PCI and the median CHA₂DS₂-VASc score was 4, representing a patient population that was at a moderate-high risk for thromboembolic events. Overall, patients included in the trial had a low-moderate bleeding risk.

 

Limitations of the AFIRE trial must be scrutinized before generalizing the results. Perhaps the most noteworthy limitation is the exclusively Japanese population enrolled in the trial. The dose of rivaroxaban used in AFIRE was lower than the FDA-recommended dosing for AF in the United States. This dosing stems from pharmacokinetic modeling data showing similar drug concentrations in Japanese individuals receiving rivaroxaban 15 mg as Caucasian individuals receiving 20 mg.¹⁰   Aside from differences in drug metabolism and dosing, it is unclear if other genetic, environmental, and lifestyle factors influenced the response to therapy.  

 

Other limitations of the trial include the open-label design, which may have introduced reporting bias. In addition, patients could be excluded at the treating physician’s discretion based on lesion and stent characteristics; however, the number of patients excluded for this reason was quite low. Only 35% of patients had a history of myocardial infarction and patients with a history of stent thrombosis were excluded, thus the results probably should not be applied to patients at high-risk of recurrent coronary events. Other considerations include the relatively few patients that had other indications for aspirin (ie, stroke, peripheral artery disease), high-use of proton-pump inhibitors, lack of information on adherence to the study medications, and changes in the study’s primary efficacy endpoint after enrollment had started. While the primary efficacy endpoint was based on a modified intention-to-treat analysis, a per-protocol analysis showed similar findings.  The reduction in both cardiovascular and noncardiovascular death was observed, and the authors did not attempt to establish a biological explanation for these findings. It is plausible that the reductions in death were due to chance alone, or that early termination of the trial overestimated the difference.

 

The Bottom Line

 

In Japanese patients with stable CAD and AF, rivaroxaban monotherapy resulted in fewer major bleeding events in comparison to combination therapy and was non-inferior in terms of a composite of MACE outcomes. Surprisingly, rivaroxaban monotherapy was associated with a significantly lower rate of all-cause mortality – for which there is not clear explanation.  While it is plausible that similar results would be observed with apixaban use, other anticoagulants (dabigatran and warfarin) would likely produce different outcomes. Importantly, while rivaroxaban has reduced metabolism necessitating a lower dose in Japanese patients, rivaroxaban should be given in a 20mg dose in most patients unless a dose reduction is indicated based on renal function.

 

The Key Points

• In Japanese patients with stable CAD and AF, anticoagulation monotherapy with rivaroxaban reduces the rate of major bleeding compared to combination therapy but does not result in an increased risk of cardiovascular events.
• Whether these results can be applied to other anticoagulants is unknown. It is likely that similar results would be observed with other Xa inhibitors (i.e. apixaban). Additional studies are needed to confirm this.
• Rivaroxaban dosing should be based on US FDA approved dosing guidelines.