A Closer Look at Dual vs Triple Therapy After PCI in Atrial Fibrillation

Until recently, the standard antithrombotic treatment strategy for patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) consisted of “triple” therapy with anticoagulation and dual antiplatelet therapy with aspirin and a P2Y₁₂ inhibitor. Due to a high risk of major bleeding associated with this regimen (up to 3-fold higher compared to oral anticoagulation alone or antiplatelet therapy), researchers began investigating the effects of omitting aspirin in favor of “dual” therapy with anticoagulation and a P2Y₁₂ inhibitor.¹

In a report published in April 2021 in the American Journal of Cardiology, Christopher P. Cannon, MD, professor of medicine at Harvard Medical School and senior physician in the Cardiovascular Division at Brigham and Women’s Hospital in Boston, described the results of several randomized clinical trials (RCTs) supporting the benefits of dual therapy in terms of reduced bleeding risk with no significant increase in ischemic events.¹

In the first study to compare triple vs double therapy in patients undergoing PCI (the WOEST trial), individuals with AF comprised approximately two-thirds of the sample. The results showed that patients randomized to double therapy with a vitamin K antagonist (VKA) and a P2Y₁₂ inhibitor demonstrated significantly lower bleeding rates and fewer ischemic events compared to patients assigned to triple therapy.²

Subsequently, the PIONEER18 AF-PCI trial investigated the effects of double vs triple therapy using a non–vitamin K antagonist oral anticoagulant (NOAC) among AF patients undergoing PCI. Participants were randomly assigned to 1 of 3 interventions: dual therapy with rivaroxaban 15 mg plus a P2Y₁₂ inhibitor; rivaroxaban 2.5 mg twice daily plus a P2Y₁₂ inhibitor; or VKA plus a P2Y₁₂ inhibitor and aspirin.³ (Dr Cannon noted that the anticoagulation dose used in the dual-therapy group was 75% of the full dose, and this strategy has not been evaluated for its impact on stroke risk.¹)

The findings revealed a lower bleeding risk in the dual-therapy and low-dose rivaroxaban triple-therapy arms compared to the VKA triple-therapy arm (16.8% vs 18.0% vs 26.7%, P <.001).³

The RE-DUAL-PCI trial compared double therapy with dabigatran 110 mg or 150 mg twice daily to triple therapy with VKA. According to the results, both dual-therapy groups showed significant reductions in International Society on Thrombosis and Haemostasis (ISTH) major or clinically relevant nonmajor bleeding compared to the triple-therapy group (HR, 0.52 [95% CI, 0.42-0.63] for dabigatran 110 mg and HR, 0.72 [95% CI, 0.58-0.88] for dabigatran 150 mg).

Additionally, lower rates of intracranial hemorrhage were observed in the double-therapy groups compared to the triple-therapy group, and further analysis demonstrated no difference between dual and triple therapy in rates of thrombotic events or mortality.⁴

In the AUGUSTUS trial, investigators examined different treatment regimens in AF patients who underwent PCI and/or presented with acute coronary syndrome.⁵ They “compared regimens with both VKA and apixaban in a 2 ´ 2 factorial design to either apixaban or VKA, and then to either a P2Y12 inhibitor with aspirin or placebo.”¹ Lower rates of ISTH major bleeding and clinically relevant nonmajor bleeding were noted with apixaban vs VKA (HR, 0.69; 95% CI, 0.58-0.81).  

There was a reduced risk of death or hospitalization with apixaban vs VKA (23.5% vs 27.4%; HR, 0.83 [95% CI, 0.74-0.93]; P =.002) with a similar incidence of ischemic events between these regimens. An increased composite rate of bleeding was observed with aspirin compared to placebo (HR, 1.89; 95% CI, 1.59-2.24). In an analysis of stent thrombosis at 6 months, no significant difference was found between groups.¹

The ENTRUST-AF PCI trial compared a regimen of edoxaban and clopidogrel to a regimen of VKA, clopidogrel, and aspirin in patients with AF undergoing PCI.⁶ The investigators found no significant reduction in the dual- vs triple-therapy groups (17% vs 20%; HR, 0.83 [95% CI, 0.65-1.05]; P =.0010 for noninferiority, P =.12 for superiority).

For the main efficacy outcome – a composite of cardiovascular disease (CVD), stroke, systemic embolic event, myocardial infarction, or definite stent thrombosis – annualized event rates were 7.3% for dual therapy vs 6.9% for triple therapy (HR, 1.06; 95% CI, 0.71-1.69). “Thus, the findings were generally consistent, but this was the first trial that did not show a statistically significant lower rate of bleeding with de-escalation in antithrombotic therapy,” Dr Cannon wrote.

In a meta-analysis of these 5 RCTs (N=11,542), dual therapy with a NOAC plus a P2Y₁₂ inhibitor demonstrated significantly lower rates of Thrombolysis in Myocardial Infarction (TIMI) major bleeding and intracranial hemorrhage, with no significant between-group differences in the risk of ischemic events or stent thrombosis.^7,1

Although the results of these trials generally support the superiority of dual vs triple therapy for most patients, higher-risk individuals have shown small trends toward an elevated risk of stent thrombosis. Accordingly, the North American Consensus on Antithrombotic Therapy in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention currently recommends “dual therapy as the ‘default’ regimen, but that risk stratification be used to help inform the decision on potentially using a brief period of triple therapy in selected high ischemic risk patients.”⁸

For these patients, a regimen of triple therapy for 1 month post-PCI may be appropriate. “Investigators are now looking at use of risk scores to try to identify the subset of high ischemic risk patients who might most likely benefit from a short course of triple therapy,” according to Dr Cannon.¹

Additional studies have also demonstrated a favorable benefit:risk ratio with the use of oral anticoagulation alone at 1 year post-PCI. “Thus, while dropping aspirin at varying times post-PCI has become an attractive strategy in many patient groups, careful patient selection and individualized assessment of the risk:benefit balance is warranted,” he concluded.¹

Disclosures

Dr Cannon reported various industry relationships, including those related to grant funding as well as consulting and advisory roles, which are listed within the full text of his paper.¹

References

1. Cannon CP. Role and timing of aspirin therapy following PCI in patients with atrial fibrillation. Am J Cardiol. 2021;144(Suppl 1):S32-S39. doi:10.1016/j.amjcard.2020.12.017
2. Dewilde WJ, Oirbans T, Verheugt FW, et al; WOEST Study investigators. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet. 2013;381(9872):1107-1115. doi:10.1016/S0140-6736(12)62177-1
3. Gibson CM, Mehran R, Bode C, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med. 2016;375(25):2423-2434. doi:10.1056/NEJMoa1611594
4. Cannon CP, Bhatt DL, Oldgren J, et al; RE-DUAL PCI Steering Committee and Investigators. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med. 2017;377(16):1513-1524. doi:10.1056/NEJMoa1708454
5. Lopes RD, Heizer G, Aronson R, et al; AUGUSTUS Investigators. Antithrombotic therapy after acute coronary syndrome or PCI in atrial fibrillation. N Engl J Med. 2019;380(16):1509-1524. doi:10.1056/NEJMoa1817083
6. Vranckx P, Valgimigli M, Eckardt L, et al. Edoxaban-based versus vitamin K antagonist-based antithrombotic regimen after successful coronary stenting in patients with atrial fibrillation (ENTRUST-AF PCI): a randomised, open-label, phase 3b trial. Lancet. 2019;394(10206):1335-1343. doi:10.1016/S0140-6736(19)31872-0
7. Lopes RD, Hong H, Harskamp RE, et al. Optimal antithrombotic regimens for patients with atrial fibrillation undergoing percutaneous coronary intervention: an updated network meta-analysis. JAMA Cardiol. 2020;5(5):582-589. doi:10.1001/jamacardio.2019.6175
8. Angiolillo DJ, Bhatt DL, Cannon CP, et al. Antithrombotic therapy in patients with atrial fibrillation treated with oral anticoagulation undergoing percutaneous coronary intervention: A North American perspective: 2021 Update. Circulation. 2021;143(6):583-596. doi:10.1161/CIRCULATIONAHA.120.050438