Lifelong Aspirin for All in the Secondary Prevention of Chronic Coronary Syndrome: Still Sacrosanct or Is Reappraisal Warranted?

Alan P. Jacobsen, MB, BCh, BAO; Inbar Raber, MD; Cian P. McCarthy, MB, BCh, BAO; Roger S. Blumenthal, MD; Deepak L. Bhatt, MD, MPH; Ronan W. Cusack, BM, BS, BSc; Patrick W.J.C. Serruys, MD, PhD; William Wijns, MD, PhD; John W. McEvoy, MB, BCh, BAO, MHS


Circulation. 2020;142(16):1579-1590. 

In This Article

Contemporary Trials of Aspirin Discontinuation in Select Secondary Prevention

Patients With CCS Without Atrial Fibrillation

The COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies) sought to determine whether low-dose rivaroxaban, with or without standard antiplatelet therapy, would reduce CVD events in patients with stable atherosclerotic vascular disease.[32–34] COMPASS enrolled 27 400 patients with documented coronary artery disease (90% of participants) or peripheral vascular disease and randomized them using a factorial design to aspirin 100 mg alone, aspirin 100 mg with rivaroxaban 2.5 mg twice daily, or rivaroxaban 5 mg twice daily alone (ie, the latter group did not receive aspirin). Of note, the full anticoagulant dose of rivaroxaban for atrial fibrillation in patients with normal renal function is 20 mg daily in the United States and Europe and 15 mg daily in Asia.

The primary outcome of cardiovascular death, stroke, or MI occurred in 379 (4.1%) of the aspirin plus rivaroxaban group, 448 (4.9%) of the rivaroxaban alone group, and 496 (5.4%) of the aspirin alone group. Adverse CVD events were significantly reduced in the aspirin plus rivaroxaban group compared with those taking aspirin only. Rivaroxaban (5 mg twice daily) alone compared with aspirin alone did not significantly reduce major adverse cardiovascular events in COMPASS (hazard ratio [HR], 0.90 [95% CI, 0.79–1.03]; P=0.12) but did increase major bleeding (2.8% versus 1.9%; HR, 1.51 [95% CI, 1.25–1.84]; P<0.001). Thus, the HR point estimate of 0.9 for major adverse cardiovascular events was also in favor of rivaroxaban alone versus aspirin alone, although with more major bleeding.

The recent European Society of Cardiology guideline on CCS states that either low-dose rivaroxaban or P2Y12 inhibitors should be considered for long-term secondary prevention among patients >1 year out from their index MI who are at high risk for ischemic events but without high bleeding risk.[19] This new European Society of Cardiology recommendation assumes baseline aspirin use and all current international guidelines continue to recommend lifelong aspirin use for patients with CCS.

Patients With CCS After Percutaneous Coronary Intervention

An alternative strategy to year-long dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) is the early introduction of single antiplatelet therapy (SAPT) with more potent P2Y12 inhibitors (eg, stopping aspirin 3 months after PCI). Whereas this specific clinical scenario has been reviewed in more detail previously,[35,36] a number of new studies[37–39] have emerged in this area (Table 2).[20–23] STOPDAPT-2 (Short and Optimal Duration of Dual Antiplatelet Therapy After Everolimus-Eluting Cobalt-Chromium Stent 2)[22] and SMART-CHOICE (Smart Angioplasty Research Team: Comparison Between P2Y12 Antagonist Monotherapy Versus Dual Antiplatelet Therapy in Patients Undergoing Implantation of Coronary Drug-Eluting Stents),[23] both published in early 2019, found that clopidogrel monotherapy after an initial 1 or 3 months, respectively, of DAPT (ie, early discontinuation of aspirin) in lower risk patients after PCI was associated with lower rates of bleeding and no increase in ischemic events. Although the 2018 SMART-DATE trial (Smart Angioplasty Research Team: Safety of 6-Month Duration of Dual Antiplatelet Therapy After Percutaneous Coronary Intervention in Patients With Acute Coronary Syndromes) did not support an early SAPT strategy, this study only enrolled individuals who underwent PCI in the setting of ACS and excluded patients with CCS.[40]

The TWILIGHT trial (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention) enrolled 9006 participants after undergoing PCI who had already received aspirin and ticagrelor for an initial 3 months.[20,41,42] If no ischemic or bleeding event had occurred, participants were randomized in a double-blind fashion to ongoing DAPT or ticagrelor monotherapy for 12 months longer. The indication for PCI was CCS in ≈35% of those enrolled and, in this CCS subgroup, the incidence of the primary end point of Bleeding Academic Research Consortium type 2, 3, or 5 bleeding was 4.8% in the ticagrelor monotherapy group and 6.2% in the DAPT group (HR, 0.76 [95% CI, 0.54–1.06]). The incidence of a composite of death from any cause, nonfatal MI, or nonfatal stroke was 3.1% in the monotherapy group and 2.9% in the DAPT group (HR, 1.06 [95% CI, 0.67–1.67]). The results in CCS and ACS patients combined are provided in Table 2.

GLOBAL LEADERS (A Clinical Study Comparing Two Forms of Antiplatelet Therapy After Stent Implantation) randomized 15 968 participants who had undergone PCI for stable coronary artery disease (53% of participants) or ACS (47% of participants) to either 1 month of dual antiplatelet with ticagrelor and aspirin followed by 23 months of ticagrelor monotherapy (experimental group) or to standard dual antiplatelet therapy (ie, with aspirin and clopidogrel [if stable coronary artery disease] or aspirin and ticagrelor [if recent ACS] for 12 months, followed by aspirin monotherapy for another 12 months).[21] At 2 years, the primary outcome of death or nonfatal new Q-wave MI occurred in 3.81% of the experimental group compared with 4.37% of the standard therapy group (rate ratio, 0.87 [95% CI, 0.75–1.01]; Table 2). Among the CCS subgroup, the primary end point occurred in 157 of 4230 of the experimental group and 180 of 4251 of the standard therapy group (rate ratio, 0.87 [95% CI, 0.71–1.08]). There was no significant difference in major bleeding. Post hoc analyses suggested net benefit for the experimental intervention among the subgroup who had undergone complex or multivessel PCI (51% and 49% of these subgroups had CCS, respectively).[43,44]

Patients With CCS and Atrial Fibrillation who Require PCI

The WOEST (What is the Optimal Antiplatelet and Anticoagulant Therapy in Patients With Oral Anticoagulation and Coronary Stenting), PIONEER AF-PCI (Prevention of Bleeding in Patients With Atrial Fibrillation Undergoing PCI), and RE-DUAL trials (Dual Antithrombotic Therapy With Dabigatran After PCI in Atrial Fibrillation) assessed the effects of discontinuing aspirin and varying the anticoagulants used in individuals with atrial fibrillation after ACS or clinically indicated PCI (Table 3).[12,45–48] A 2018 meta-analysis including these 3 trials found that dual antithrombotic therapy with an anticoagulant and single antiplatelet P2Y12 agent decreased the risk of TIMI (Thrombolysis in Myocardial Infarction) minor or major bleeds compared with triple therapy (4.3% versus 9%; HR, 0.53 [95% credible interval, 0.36–0.85; I2=42.9%), without any difference in major adverse cardiovascular events.[49] Triple therapy in this context comprised an anticoagulant, an antiplatelet P2Y12 agent, and aspirin. The PCI indication was CCS in ≈50% of participants in this analysis.

The AUGUSTUS trial (Antithrombotic Therapy After Acute Coronary Syndrome or PCI in Atrial Fibrillation) randomized 4614 participants with atrial fibrillation who were taking P2Y12 inhibitors,[12] in a 2×2 fashion, to standard dosing apixaban versus a vitamin K antagonist and to low-dose aspirin versus placebo. Approximately 93% of participants received clopidogrel, 6% ticagrelor, and 1% prasugrel as the P2Y12 inhibitor. The indication for P2Y12 inhibitors was elective PCI for 38.8% of participants. In the overall sample, major or clinically relevant nonmajor bleeding was noted in 10.5% of the apixaban group as compared with 14.7% in the vitamin K antagonist group (HR, 0.69 [95% CI, 0.58–0.81]; P<0.001 for both noninferiority and superiority) and in 16.1% of those receiving aspirin as compared with 9% of those receiving placebo (HR, 1.89 [95% CI, 1.59–2.24]; P<0.001). A subgroup analysis demonstrated similar major or clinically significant nonmajor bleeding in the aspirin or placebo groups, regardless of whether the indication at enrollment was ACS or CCS (Pinteraction=0.48). A 2019 meta-analysis that incorporated AUGUSTUS reported that strategies omitting aspirin resulted in less bleeding, including intracranial bleeding, without significant differences in cardiovascular events.[50]

ENTRUST-AF PCI (Edoxaban-Based Versus Vitamin K Antagonist–Based Antithrombotic Regimen After Successful Coronary Stenting in Patients With Atrial Fibrillation), published in mid-2019, enrolled 1506 participants with atrial fibrillation who had undergone PCI for CCS (48% of participants) or ACS (52%) to either edoxaban 60 mg daily with a P2Y12 inhibitor or triple therapy (warfarin with aspirin plus a P2Y12 inhibitor).[48] The primary outcome was a composite of major and clinically relevant nonmajor bleeding at 12 months, which occurred in 128 (17%) of the edoxaban group and 152 (20%) of the vitamin K–dependent anticoagulant group (HR, 0.83 [95 CI 0.65–1.05]; P=0.0010 for noninferiority; P=0.1154 for superiority). The main efficacy outcome, a composite of cardiovascular death, stroke, systemic embolic events, MI, and definite stent thrombosis, occurred in 49 (7%) of the edoxaban plus P2Y12 group and 46 (6%) of the triple therapy group (HR for edoxaban, 1.06 [95% CI 0.71–1.69]). Whether these results differed by ACS or CCS at baseline has yet to be published.

Patients With CCS and Atrial Fibrillation but Without Recent PCI

European guidelines recommend discontinuation of SAPT in patients who continue to be treated with an oral anticoagulant (OAC) 1 year after either ACS or PCI.[51] Published in 2019, OAC-ALONE (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) was a noninferiority trial comparing oral anticoagulant alone with SAPT plus OAC in patients with atrial fibrillation beyond 1 year after PCI.[52] The trial was terminated early because of slow enrollment. The OAC was warfarin in 75.2% of participants and the antiplatelet was aspirin in 86% or clopidogrel in 14%. The primary end point, a composite of all-cause mortality, MI, stroke, or systemic embolism, occurred in 54 patients (15.7%) in the OAC-only group and in 47 patients (13.6%) in the combined SAPT plus OAC group (HR, 1.16 [95% CI, 0.79–1.72]; P=0.20 for noninferiority [despite an upper bound to the noninferiority margin being set at 1.5). Major bleeding occurred in 27 (7.8%) and 36 (10.4%) patients, respectively (HR, 0.73 [95% CI, 0.44–1.20]).

OAC-ALONE was followed closely by another noninferiority trial, AFIRE (Atrial Fibrillation and Ischemic Events with Rivaroxaban), in patients with CCS and atrial fibrillation.[53] A total of 2236 Asian patients were randomized to monotherapy with rivaroxaban 15 mg daily or combination therapy with rivaroxaban plus an antiplatelet agent chosen at the discretion of the treating physician (70.2% aspirin, 26.8% P2Y12 inhibitor). The primary efficacy end point was major adverse cardiovascular events and the primary safety end point was major bleeding. The trial was stopped early because of increased mortality in the combination group. Rivaroxaban monotherapy was noninferior to combination therapy for the primary efficacy end point with event rates of 4.14% and 5.75% per patient-year, respectively (HR, 0.72 [95% CI, 0.55–0.95]; P<0.001 for noninferiority). A post hoc analysis of the primary safety end point, which was not prespecified, demonstrated superiority of monotherapy.