Are P2Y12 inhibitors superior to aspirin for long-term secondary prevention of cardiovascular disease?

KEYWORDS:

• cardiovascular disease
• secondary prevention
• antiplatelet agents
• aspirin
• P2Y12 receptor antagonists

1. Introduction

Aspirin remains the single most widely used antithrombotic treatment for long-term secondary prevention of cardiovascular (CV) disease, including coronary artery disease, peripheral arterial disease, and cerebrovascular disease. A meta-analysis assessing the benefit of aspirin in these populations found a 20% reduction in CV events [1]. Clopidogrel was the first P2Y12 inhibitor to be evaluated as an alternative to aspirin for long-term secondary prevention. In the initial trials, clopidogrel appeared to provide only a small incremental benefit and because it was much more expensive, it was not recommended or widely used for this indication. However, data from more recent randomized controlled trials (RCTs) and meta-analyses suggest that P2Y12 inhibitors are more effective and at least as safe or safer than aspirin. Now that these agents have become generic in most jurisdictions, we believe that P2Y12 inhibitors should become the preferred single agent antiplatelet therapy for long-term secondary prevention.

2. Pharmacology of aspirin and oral P2Y12 inhibitors

Key pharmacological features of aspirin and oral P2Y12 inhibitors are summarized in Table 1.

Table 1. Pharmacology of aspirin and oral P2Y12 inhibitors.

Agent	Mechanism of action	Prodrug	Time to onset	Half-life/time to offset	Notable adverse effects	Specific reversal agent	Cost
Aspirin*	COX-1 inhibitor (irreversible)	No	5 minutes	T1/2: 10–20 minutes Time to offset: 3 days	Hypersensitivity reactions, gastrointestinal upset, tinnitus	No	$
Clopidogrel	P2Y12 inhibitor (irreversible)	Yes (two step hepatic process; primarily CYP2C19)	2–8 hours	T1/2 (parent drug): 6 hours T1/2 (active metabolite): 30 minutes Time to offset: 5–7 days	Type IV hypersensitivity reactions, diarrhea	No	$
Prasugrel	P2Y12 inhibitor (irreversible)	Yes (two step; first via esterases, second via hepatic CYP3A)	30 minutes − 4 hours	T1/2 (parent drug): <5 minutes (rapidly hydrolyzed by esterases) T1/2 (active metabolite): 7 hours Time to offset: 7 days	Colonic neoplasms	No	$$
Ticagrelor	P2Y12 inhibitor (reversible)	No (both parent drug and metabolite are active)	30 minutes − 4 hours	T1/2 (parent drug): 7 hours T1/2 (active metabolite): 9 hours Time to offset: 3–5 days	Dyspnea, ventricular pauses	Bentracimab†	$$

*Can also be administered intravenously or rectally.

†Experimental; not approved for clinical use

2.1. Aspirin

Salicylate-containing plants have been used since ancient times for their pain-relieving properties. First synthesized in 1853, acetylsalicylic acid (ASA or aspirin) was shown many years later to block platelet cyclooxygenase-1 to prevent thromboxane A2 production, thereby reducing the risk of CV events.

2.2. P2Y12 inhibitors

Ticlopidine was approved for secondary stroke prevention in 1991 and thereafter for use in combination with aspirin to prevent stent thrombosis following percutaneous coronary intervention (PCI). Although effective, the drawbacks of ticlopidine included severe neutropenia and rarely aplastic anemia and thrombotic thrombocytopenic purpura, and it has since been withdrawn from many markets.

Clopidogrel is a second-generation oral P2Y12 inhibitor that was first approved in 1997. It is approved for multiple indications, including in combination with aspirin for acute coronary syndrome (ACS) with or without PCI and acute stroke or transient ischemic attack (TIA), as well as a single agent for long-term secondary prevention. Clopidogrel does not cause cytopenias, but like ticlopidine is a prodrug that requires two-step hepatic activation to form the active metabolite that binds to the P2Y12 receptor. This not only delays its onset of action but also results in substantial interindividual response variability due to genetic variants encoding the enzymes involved in clopidogrel metabolism.

Prasugrel and ticagrelor are third generation oral P2Y12 inhibitors. Prasugrel is a prodrug but requires only a single step hepatic activation to form the active metabolite that binds to the P2Y12 receptor and therefore has a more rapid onset of action than clopidogrel. Ticlopidine, clopidogrel, and prasugrel irreversibly block the P2Y12 receptor, thereby preventing the binding of adenosine diphosphate (ADP) which activates platelets. Ticagrelor is a direct-acting non-thienopyridine and the only oral P2Y12 receptor antagonist that reversibly inhibits the receptor.

In addition to their anti-platelet effects, P2Y12 inhibitors may also have off-target effects related to inhibition of extra-platelet P2Y12 receptors as well as P2Y12 receptor-independent activity, including increased adenosine levels. There is some evidence that P2Y12 receptor inhibitors modulate inflammation, stabilize atherosclerotic plaques, prevent vasoconstriction, reduce reperfusion injury [2], and improve endothelial function [3].

3. Randomized trials of P2Y12 inhibitors for long-term secondary prevention

3.1. Clopidogrel as an alternative to aspirin

The randomized, blinded, trial of clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE) compared clopidogrel 75 mg daily with aspirin 325 mg daily in 19,185 patients with previous stroke, myocardial infarction (MI), or symptomatic peripheral arterial disease (PAD). The results published in 1996 demonstrated that clopidogrel reduced the risk of the primary outcome, ischemic stroke, MI, or CV death by 8.7% (95% CI, 0.3–16.5%; p = 0.043) with no significant increase in bleeding. Pre-specified subgroup analyses suggested that clopidogrel produced greater benefits (p heterogeneity 0.042) in patients with PAD (RRR, 23.8%) than in those with previous stroke (RRR, 7.3%) or MI (RRR, −3.7%) [4]. In the Aspirin and Extended-Release Dipyridamole versus Clopidogrel for Recurrent Stroke (PRoFESS) trial involving patients within 90 days of acute stroke, clopidogrel did not significantly reduce recurrent stroke although it was associated with a lower rate of bleeding [5]. Because of the overall modest benefit of clopidogrel in CAPRIE and its higher cost, guidelines did not routinely recommend clopidogrel as a replacement for aspirin, except in patients with PAD [6].

The next generation of trials of clopidogrel tested its use in combination with aspirin in patients with recent elective PCI or ACS with or without PCI, and in patients with recent TIA or minor stroke. In these settings, multiple large trials consistently demonstrated a benefit of the combination over aspirin alone [7–12]. When tested for long-term secondary prevention, the Clopidogrel and Aspirin versus Aspirin Alone for the Prevention of Atherothrombotic Events (CHARISMA) trial found no overall benefit of the combination, but a pre-specified subgroup analysis suggested a clear benefit in patients with symptomatic disease [13].

With the advent of more potent P2Y12 inhibitors and growing concerns about the risk of bleeding with dual antiplatelet therapy, attention has shifted back to the potential for P2Y12 inhibitors to replace aspirin. With respect to clopidogrel, a post-hoc analysis of the Clopidogrel with Aspirin in Acute Minor Stroke or Transient Ischemic Attack (CHANCE) trial suggested that after completion of 21 days of DAPT or aspirin (n = 4,696), patients receiving clopidogrel monotherapy may achieve greater benefit from continuing clopidogrel in preference to aspirin monotherapy (HR, 0.72; 95% CI, 0.46–1.14; p = 0.16) although this result was not statistically significant [14]. Most recently, the Aspirin Versus Clopidogrel for Long-Term Maintenance Monotherapy After Percutaneous Coronary Intervention (HOST-EXAM) trial conducted at 37 South Korean sites in 5,438 patients with CAD who were 6–18 months post PCI found that clopidogrel substantially reduced the risk of CV death, non-fatal MI, ischemic stroke, readmission due to ACS and definite or probable stent thrombosis (RR, 0.68; 95% CI, 0.52–0.87; p = 0.003) as well as Bleeding Academic Research Consortium (BARC) type >3 major bleeding (HR, 0.63; 95% CI, 0.41–0.97; p = 0.035) [15]. The benefit of clopidogrel over aspirin persisted during a mean follow-up of 5.8 years [16]. Further, the HOST-EXAM results may underestimate the benefits in non-East Asian populations as East Asians have a higher prevalence of CYP2C19 loss of function alleles that may reduce the efficacy of clopidogrel.

3.2. Prasugrel and ticagrelor as alternatives to aspirin

The third-generation P2Y12 inhibitors, prasugrel and ticagrelor, were first tested as alternatives to clopidogrel as part of a dual antiplatelet strategy in patients with recent ACS. Among those undergoing PCI, these agents demonstrated substantial benefits albeit at the cost of increased bleeding [17,18], whereas in medically treated patients there was no benefit of prasugrel compared with clopidogrel [19]. Similarly, in patients with recent minor-moderate non-cardioembolic stroke or TIA, the combination of ticagrelor and aspirin provided no benefits over aspirin alone and increased bleeding [20].

Potent P2Y12 inhibitors have since been compared head to head with aspirin or with clopidogrel for long-term secondary prevention. GLOBAL LEADERS was an open-label trial of 15,968 patients that compared ticagrelor plus aspirin for 1 month, followed by ticagrelor monotherapy for 23 months versus aspirin plus clopidogrel (75 mg daily for stable CAD) or ticagrelor (90 mg twice daily for ACS) for 12 months, followed by aspirin monotherapy for 12 months after implantation of a drug-eluting stent [21]. In a landmark analysis confined to events beyond 12 months, ticagrelor monotherapy compared with aspirin reduced the secondary composite outcome of all-cause death, MI, and stroke (HR, 0.74; 95% CI, 0.58–0.96; p = 0.022) at the cost of increased BARC 3 or 5 bleeding (HR, 1.89; 95% CI, 1.03–3.45; p = 0.005) [22].

The Ticagrelor versus Aspirin in Acute Stroke or Transient Ischemic Attack (SOCRATES) trial compared ticagrelor 90 mg twice daily with aspirin 100 mg daily in 13,199 patients with recent high-risk TIA or minor stroke. Ticagrelor did not reduce the primary end point, a composite of stroke, MI, or death within 90 days (HR, 0.89; 95% CI, 0.78–1.01; p = 0.07) and did not increase Platelet inhibition and Patient Outcomes (PLATO) major bleeding (HR, 0.83; 95% CI, 0.52–1.34; p = 0.45) [23]. In a study involving symptomatic PAD patients, ticagrelor was not superior to clopidogrel for CV event prevention and was associated with similar rates of major bleeding [24].

4. Meta-analyses

The results of the randomized trials comparing a P2Y12 inhibitor versus aspirin for long-term secondary prevention have been pooled in several meta-analyses. One of the earliest was a 2020 meta-analysis by Chiarito and colleagues which included nine trials (n = 42,108) and found that a P2Y12 inhibitor compared with aspirin reduced the risk of MI (OR, 0.81; 95% CI, 0.66-0.99), but not stroke (OR, 0.93; 95% CI, 0.82–1.06), all-cause death (OR, 0.98; 95% CI, 0.89–1.08) or vascular death (OR, 0.97; 95% CI, 0.86–1.09) and did not increase major bleeding (OR, 0.90; 95% CI, 0.74–1.10) [25]. Six of the nine included trials compared ticlopidine with aspirin, and these analyses did not include the HOST-EXAM trial which at the time had not yet been completed, or the data from secondary landmark analyses of the GLOBAL LEADERS and CHANCE trials. In 2022, Aggarwal et al. published a meta-analysis of nine trials (n = 61,623) comparing clopidogrel or ticagrelor with aspirin, including GLOBAL LEADERS, HOST-EXAM, and CHANCE, thereby adding an additional 20,000 patients to the analyses presented by Chiarito et al. The results demonstrated that a P2Y12 inhibitor compared with aspirin reduced the risk of major adverse CV events (MACE) (RR, 0.89; 95% CI, 0.84-0.95), including MI (RR, 0.81%, 95% CI, 0.71-0.92), but not stroke (RR, 0.85; 95% CI, 0.73–1.01) or all-cause mortality (RR, 1.01; 95% CI, 0.92–1.11) and did not increase major bleeding (RR, 0.94; 95% CI, 0.72–1.22) [26]. Several other meta-analyses have produced similar results [27,28].

The PANTHER patient-level meta-analysis was presented at the European Society of Cardiology meeting in Barcelona in August 2022. These analyses included seven trials that compared clopidogrel, prasugrel, or ticagrelor with aspirin in 24,325 patients with CAD (including HOST-EXAM and Ticagrelor Alone Versus Dual Antiplatelet Therapy From 1 Month After Drug-Eluting Coronary Stenting (GLASSY), a pre-specified GLOBAL LEADERS ancillary study including 7,585 patients from the 20 top-enrolling participating sites with central adjudication) [29,30]. Fifty-six percent of those included had a history of MI, 70% prior cardiac revascularization, 7% prior stroke, and 9% PAD. P2Y12 inhibitor treatment compared with aspirin reduced the composite of MI, stroke, and CV death (HR, 0.88; 95% CI, 0.79-0.97; p = 0.012), including MI (HR, 0.77; 95% CI, 0.66–0.90; P < 0.001) and definite or probable stent thrombosis (HR, 0.46; 95% CI, 0.23–0.92, p = 0.028), but did not significantly reduce stroke (HR, 0.84; 95% CI, 0.70–1.02; p = 0.076) or CV death (HR, 1.02; 95% CI, 0.86–1.20; p = 0.82). There was also a significant reduction in gastrointestinal bleeding (HR, 0.75; 95% CI, 0.57–0.97; p = 0.027) and hemorrhagic stroke (HR, 0.43; 95% CI, 0.23–0.83; p = 0.012) although overall major bleeding was not significantly reduced (HR, 0.87; 95% CI, 0.70–1.09; p = 0.23). Subgroup analyses demonstrated consistent benefits regardless of age, clinical presentation (ACS vs. stable CAD), history of diabetes, MI, stroke, or PAD, baseline bleeding risk, or prior use of proton pump inhibitors. Patients at the highest baseline risk including those with prior MI and polyvascular disease (prior stroke or PAD) derived the greatest absolute benefit from P2Y12 therapy.

5. Summary of the evidence and implications for practice

Taken together, the available evidence indicates a clear benefit of single agent antiplatelet therapy with a P2Y12 inhibitor over aspirin in chronic CAD, with reductions in risk of MI and stent thrombosis, and similar or reduced bleeding. P2Y12 inhibitors also appear to be superior to aspirin in patients with symptomatic PAD based on the subgroup data from CAPRIE. The evidence for a benefit of P2Y12 inhibitors over aspirin in patients with recent transient ischemic attacks or strokes is less conclusive, but clopidogrel reduces bleeding compared with the combination of aspirin and dipyridamole.

Based on these data, we suggest that either ticagrelor or clopidogrel should now be preferred over aspirin for long-term secondary prevention in patients with CAD who are treated with single agent antiplatelet therapy, whereas clopidogrel should be the preferred P2Y12 inhibitor in patients with PAD and in those with prior stroke or TIA. Possible additional considerations in the choice of antiplatelet agent include the pharmacological profile of individual antiplatelet drugs and concerns regarding adherence. In patients with CAD, ticagrelor may be preferred over clopidogrel in the highest risk patients and in patients who have experienced breakthrough events during clopidogrel therapy because it is the most potent, as well as in patients with known CYP2C19 polymorphisms associated with reduced response to clopidogrel. Clopidogrel may be favored in patients with heart failure, chronic obstructive pulmonary disease, asthma, anemia, or other conditions associated with breathlessness in whom ticagrelor-associated dyspnea, if it occurs, may be less well tolerated and lead to diagnostic uncertainty. As a once daily medication, clopidogrel may be preferred over twice daily ticagrelor if adherence to more frequent dosing is a concern. As prescription medications, P2Y12 inhibitors may also be perceived by patients as more important than aspirin (which is readily available over the counter) and adherence can typically be more easily monitored through dispensing records.

6. Unresolved issues

Additional randomized controlled trials are needed to further evaluate optimal long-term antithrombotic therapy in patients with chronic CV disease, particularly patients with peripheral arterial disease who are not candidates for dual-pathway inhibition and those with a history of stroke or TIA. Further studies are also required to assess the efficacy and safety of P2Y12 inhibitors in additional, non-East Asian populations who may derive additional benefits with these agents as compared to aspirin.

Declaration of interest

S. Carlin has received honoraria from BMS/Pfizer, and advisory board fees from AZ and Servier. J. Eikelboom has received honoraria and/or research support from Anthos, AZ, Bayer, BI, BMS, DSI, Ionis, Janssen, Pfizer, Servier, and USV. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

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