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This blog was originally posted to iForumRx on 01/03/2020. The original commentary, as well as a podcast discussing the trial, can be found here.
Authors: Alina Kukin, PharmD and Zachary R. Noel, PharmD
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?
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.
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
|Combination Therapy (n=1108)|
|Age, years, mean
≥ 75 years
|Previous myocardial infarction||34.7%||35.5%|
|Type of atrial fibrillation
|Creatinine clearance, mean
|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
|Combination Therapy (n=1108)||Hazard Ratio (95% CI)||
|Cardiovascular events or all-cause mortality||
|Numbers are represented as number (percentage) unless otherwise stated
MI: myocardial infarction
#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.
Alina Kukin, PharmD
Zachary R. Noel, PharmD, BCCP
- Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation. 2012;126(25). doi:10.1161/CIR.0b013e318277d6a0
- Steinberg BA, Kim S, Piccini JP, et al. Use and Associated Risks of Concomitant Aspirin Therapy With Oral Anticoagulation in Patients With Atrial Fibrillation: Insights From the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Registry. Circulation. 2013;128(7):721-728. doi:10.1161/CIRCULATIONAHA.113.002927
- Lee CJ-Y, Gerds TA, Carlson N, et al. Risk of Myocardial Infarction in Anticoagulated Patients With Atrial Fibrillation. J Am Coll Cardiol. 2018;72(1):17-26. doi:10.1016/j.jacc.2018.04.036
- Lip GYH, Banerjee A, Boriani G, et al. Antithrombotic Therapy for Atrial Fibrillation: CHEST Guideline and Expert Panel Report. CHEST. 2018;154(5):1121-1201. doi:10.1016/j.chest.2018.07.040
- January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation. Heart Rhythm. 2019;16(8):e66-e93. doi:10.1016/j.hrthm.2019.01.024
- Angiolillo DJ, Goodman SG, Bhatt DL, et al. Antithrombotic Therapy in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention: A North American Perspective—2016 Update. Circ Cardiovasc Interv. 2016;9(11). doi:10.1161/CIRCINTERVENTIONS.116.004395
- Valgimigli M, Bueno H, Byrne RA, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS. Eur Heart J. 2018;39(3):213-260. doi:10.1093/eurheartj/ehx419
- Yasuda S, Kaikita K, Ogawa H, et al. Atrial fibrillation and ischemic events with rivaroxaban in patients with stable coronary artery disease (AFIRE): Protocol for a multicenter, prospective, randomized, open-label, parallel group study. Int J Cardiol. 2018;265:108-112. doi:10.1016/j.ijcard.2018.04.131
- Matsumura-Nakano Y, Shizuta S, Komasa A, et al. Open-Label Randomized Trial Comparing Oral Anticoagulation With and Without Single Antiplatelet Therapy in Patients With Atrial Fibrillation and Stable Coronary Artery Disease Beyond 1 Year After Coronary Stent Implantation: OAC-ALONE Study. Circulation. 2019;139(5):604-616. doi:10.1161/CIRCULATIONAHA.118.036768
- Tanigawa T, Kaneko M, Hashizume K, et al. Model-based dose selection for phase III rivaroxaban study in Japanese patients with non-valvular atrial fibrillation. Drug Metab Pharmacokinet. 2013;28(1):59-70.
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