Long-term clopidogrel for secondary prevention—towards resolution of complex problem?

The current guidelines recommend the use of dual antiplatelet therapy (DAPT) following an acute coronary syndrome (ACS) or percutaneous intervention (PCI) for ACS for 1 year and 6 months for chronic coronary syndrome (1,2). However, an individualized approach based on ischemic and bleeding risk for choice and duration of DAPT during the first-year post-PCI/ACS is many times practical (3,4). The guidelines also recommend lifelong use of single antiplatelet during the chronic maintenance phase which could be either aspirin or P2Y12 inhibitor (1,2). Aspirin monotherapy is usually the antiplatelet treatment of choice based on evidence-based data which is at least two decades old. However, according to recently published evidence, P2Y12 inhibitor monotherapy for long-term secondary prevention following PCI has emerged as a viable alternative (5-7).

While deciding the choice of antiplatelet agent for chronic maintenance phase, the patient’s bleeding risk and ischemic risk should always be kept in mind. As withdrawal of the antiplatelet agent for bleeding events might result in ischemic events, making the situation complicated. Since there has been a rise in complex PCI procedures, there is an imminent need for an antiplatelet agent that is not only good in reducing ischemic events but also in mitigating bleeding events.

Clopidogrel has been the major P2Y12 inhibitor available worldwide for quite sometime. It has got the maximum patient data and safety record over the years with vast experience of more than 2 decades. The journey of clopidogrel started with Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE), Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE), Clopidogrel for the Reduction of Events During Observation (CREDO), and Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT) trials and they established its use in non-ST segment myocardial infarction (NSTEMI) ACS and post-PCI patients. The CAPRIE trial first reported the superiority of clopidogrel over aspirin in reducing ischemic events following high-risk unstable angina. The Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY) AND PCI-CLARITY established the role of clopidogrel in ST segment myocardial infarction (STEMI) patients (8,9). However, almost all of these studies utilized the drug in the 6 month–1 year period following PCI/ACS as a part of DAPT and the long-term single antiplatelet had been aspirin by convention.

In the recent past, two studies Harmonizing Optimal Strategy for Treatment of Coronary Artery Diseases-Extended Antiplatelet Monotherapy (HOST-EXAM) trial and the HOST-EXAM Extended studies have established the superiority of clopidogrel in reducing the composite thrombotic and bleeding risk vis-à-vis aspirin beyond 1 year of ACS/PCI (5,6). In addition, a recent meta-analysis involving all the studies which compared aspirin with P2Y12 inhibitors validated that P2Y12 inhibitors reduce ischemic risk without increasing bleeding risk compared with aspirin (7).

The current post-hoc analysis of the HOST-EXAM Extended study evaluated the comparative efficacy and safety of clopidogrel vs. aspirin for chronic maintenance in patients characterized by high bleeding risk (HBR) and/or PCI complexity (10). The HOST-EXAM was a randomized, open-label trial in which enrolled patients underwent PCI with drug-eluting stent and remained on DAPT for 6 to 18 months without any ischemic or major bleeding events after PCI (5). After cessation of DAPT, they received either clopidogrel (75 mg once daily) or aspirin (100 mg once daily) in a 1:1 ratio. The composite of all cause death, non-fatal myocardial infarction, stroke, readmission due to ACS and Bleeding Academic Research Consortium (BARC) bleeding type 3 or greater was the primary endpoint. The antiplatelet prescription was at the discretion of the treating physician during the post-trial period. The primary outcome occurred in 152 (5.7%) patients in the clopidogrel group and 207 (7.7%) in the aspirin group {hazard ratio (HR) 0.73 [95% confidence interval (CI): 0.59–0.90]; P=0.0035} during 24-month follow-up. These findings were reaffirmed in a long-term follow-up study (>5 years) where clopidogrel maintained its benefits (6).

In the present post-hoc analysis, the patient in both groups were divided according to the presence or absence of HBR and PCI complexity. Patients were referred to as HBR if they had at least 1 major or 2 minor criteria from the Academic Research Consortium for HBR (ARC-HBR) definition. Complex PCI was considered if patient had 3 or more stents implanted or 3 or more lesions treated or dedicated bifurcation stenting or total stent length more than 60 mm, or chronic total occlusion treatment (Figure 1). The co-primary end points were composite of thrombotic end point (cardiac death, nonfatal myocardial infarction, ischemic stroke, readmission due to ACS, and definite or probable stent thrombosis) and any bleeding (defined as BARC bleeding type 2 or higher). The secondary end points were included individual components of the coprimary end points and revascularization.

Figure 1 The high bleeding risk and high ischemic risk criteria used in the post-hoc analysis of HOST-EXAM 1 study. AVM, arteriovenous malformation; CTO, chronic total occlusion; DAPT, dual antiplatelet therapy; HTN, hypertension; ICH, intracranial hemorrhage; OAC, oral anticoagulation.

Out of 2,064 patients analyzed in clopidogrel group, 468 were HBR category and 441 underwent complex PCI, while in aspirin group, out of 1,910 patients, 398 were HBR category and 408 underwent complex PCI. Over this long follow-up, it was found that patient who had HBR experienced more events while there was no statistical difference in endpoints with regard to PCI complexity. The total study population was stratified into 4 groups based on the presence of HBR and PCI complexity: 2,486 (62.6%) patients in the non-HBR and non-complex PCI group, 622 (15.7%) in the non-HBR and complex PCI group, 639 (16.1%) in the HBR and non-complex PCI group, and 227(5.7%) in the HBR and complex PCI group. Clopidogrel monotherapy was associated with lower risk of the coprimary end points compared with aspirin. For the thrombotic composite end point, the greatest benefit was achieved among patient with HBR and complex PCI [HR 0.46 (95% CI: 0.23–0.91)] while the HR was 0.64 (95% CI: 0.49–0.85) among the non-HBR and non-complex PCI group, 0.53 (95% CI: 0.30–0.95) among the non-HBR and complex PCI group and 0.88 (95% CI: 0.60–1.29) among the HBR and non-complex PCI group. The reduction in bleeding by clopidogrel in comparison to aspirin was seen in all the four groups with greatest reduction in those with both HBR and complex PCI [HR 0.69 (95% CI: 0.35–1.38)].

From this post-hoc analysis of long-term follow-up HOST-EXAM study in complex PCI subset, it can be inferred that patients having HBR are at increased risk of both thrombotic and bleeding endpoints and the benefits of clopidogrel are most pronounced in highest risk patients that is those with HBR who underwent complex PCI.

Thus, the current analysis bolsters the emerging evidence pool favouring clopidogrel regimen over aspirin monotherapy in the chronic maintenance phase following ACS/PCI because it reduces not only thrombotic events but also bleeding events, which is especially important as there is a recent shift of focus in bleeding events. Bleeding events tend to cause more morbidity and mortality not only by bleeding per se but also due to additional thrombotic events as a consequence of interruption of antithrombotic agents (11). A recent meta-analysis of 7 studies comprising of >24,000 patients compared aspirin with P2Y12 inhibitors (clopidogrel & ticagrelor) for long-term secondary prevention in coronary artery disease (CAD) (7). The results are in line with the HOST-EXAM series of studies and demonstrated that P2Y12 inhibitors reduce ischemic risk without increasing bleeding risk compared with aspirin (7).

However, there are few limitations to this study and most important of them is that HBR and PCI complexity criteria were not specified in study protocol and it was a post-hoc analysis. The study was done in East Asian subjects only and the use of high-dose statins in complex PCI subset might have produced a low event rate favoring clopidogrel therapy. The issue of clopidogrel resistance was not evaluated either which is supposedly higher in Asian populations and leads to adverse cardiovascular events (12).

Need for personalized approach

There is a need for personized approach for management of various cardiac and vascular disease including CAD because practice guidelines are meant for broader patient population. Certain clinical scenarios and patient population are under-represented in these practice guidelines which need attention. Some of these patient population include elderly subjects with frailty where bleeding is a concern with antiplatelet agents and thus type of antiplatelet should be carefully selected. Elderly subjects also receive polypharmacy, which may lead to drug-drug interaction. This factor should always be kept in mind while choosing antiplatelet agent. Depression is another problem and is higher among CAD patients. Depressed patients tend to miss dosages, so its identification and proper management is necessary. Obstructive sleep apnea (OSA) is a risk factor for hypertension and stroke. It leads to inflammation and oxidative stress. OSA, stroke and CAD have common pathophysiological pathway, so identifying and properly managing it is crucial for cardiovascular health (13).

In conclusion, it can be said that clopidogrel therapy may be an acceptable alternative in the chronic maintenance phase of post-PCI and ACS patients. However, more studies on these subsets of patients can further throw light whether it will be able to dethrone aspirin therapy which has been the standard of care in this scenario for past three decades.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-25-54/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-25-54/coif). The authors have no conflicts of interest to declare.

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