Despite Newer Agents, Clopidogrel Still Holds Strong in Acute Coronary Syndrome Care: IHJ 2025

A recent opinion paper concluded that timely revascularization and dual antiplatelet therapy (DAPT) are crucial in the management of acute coronary syndrome (ACS). Guidelines clearly endorse the use of newer P2Y12 inhibitors, such as ticagrelor and prasugrel, over clopidogrel. However, it is imperative that research addresses several critical issues, including the efficacy and safety of these newer agents in Asian populations, particularly among the elderly.

These findings were published in Indian Heart Journal in August 2025.

The authors highlight that in specific situations, clopidogrel should be considered a viable alternative to the newer agents.

Foundational Principles of Acute Coronary Syndrome (ACS) Management

Cardiovascular diseases are responsible for approximately one-third of global deaths, with ischemic heart disease (IHD) being a major contributor. Managing ACS, which includes STEMI, non-STEMI, and unstable angina, hinges on timely revascularization and Dual Antiplatelet Therapy (DAPT), combining aspirin with a P2Y12 inhibitor. Historically, aspirin reduced composite cardiovascular outcomes by 25%. The introduction of clopidogrel offered an additional 8.7% relative risk reduction and carried a lower incidence of clinical bleeding compared to 325 mg of aspirin. Modern European and American guidelines now favor ticagrelor and prasugrel for ACS patients undergoing percutaneous coronary intervention (PCI), a preference largely established by major randomized controlled trials (RCTs).

Interpreting RCT Data Versus Real-World Clinical Practice Scenarios

While key RCTs drove guideline changes—specifically the PLATO study for ticagrelor and TRITON TIMI 38 for prasugrel—physicians must recognize that real-life patients are significantly more complex than the highly selected populations in these trials. RCTs demonstrated that newer agents reduced ischemic events: ticagrelor significantly reduced vascular death, MI, or stroke compared to clopidogrel. Prasugrel also significantly reduced ischemic events but did not show a difference in mortality compared to clopidogrel. Critically, both newer agents showed an increased risk of major bleeding compared to clopidogrel (including non-CABG major bleeding with ticagrelor and major/life-threatening bleeding with prasugrel). Because real-life patients often have more comorbidities and higher rates of major adverse cardiovascular events (MACE) and bleeding, incorporating real-world registries and observational data is essential for accurate clinical decision-making.

Safety and Efficacy of Clopidogrel in Vulnerable Patient Cohorts

Clinical evidence suggests critical differences in how patient sub-groups respond to potent P2Y12 inhibitors:

• Elderly Patients (≥70 Years): Guidelines recommend strong antiplatelet therapies across all age groups, but the risk of bleeding complications is significantly higher in older patients. Prasugrel is contraindicated in those over 75. A large, randomized study in non-ST-elevation ACS patients aged over 70 found that clopidogrel was associated with fewer major and fatal bleeding episodes compared to ticagrelor, without increasing ischemic complications.

• Asian Populations (East Asian Paradox): Patients from the Asian subcontinent, often characterized by lower body mass index (BMI), show a higher incidence of overall bleeding with ticagrelor compared to clopidogrel. This is partly explained by the "East Asian paradox," linked to higher carriage rates of the CYP2C19 loss-of-function allele. Studies conducted across Japan, Korea, and Taiwan indicated that ticagrelor use was associated with higher major bleeding episodes or no significant reduction in ischemic events compared to clopidogrel.

• Need for Triple Therapy: For patients requiring oral anticoagulation (due to conditions like atrial fibrillation or mechanical heart valves) who undergo PCI, triple therapy is mandated by guidelines. In all major randomized trials involving both Vitamin K antagonists and direct oral anticoagulants (DOACs), clopidogrel has been exclusively used as the P2Y12 antagonist component. Expert clinical consensus advocates for clopidogrel over newer, more potent inhibitors in this high-risk setting.

Clinical Imperatives: Adherence, Advanced Stents, and Broad Cost-Effectiveness

Physicians must account for challenges in long-term adherence, which is crucial for reducing thrombotic events. Real-world data shows that approximately one-quarter of patients discontinue ticagrelor therapy early due to side effects such as bleeding manifestations and dyspnea, with dyspnea discontinuation rates surpassing 10% in some registries. This premature discontinuation is strongly correlated with increased thrombotic risks.

Furthermore, advancements in the latest generation of stents have reduced the necessity for highly potent antiplatelet agents, as studies show no significant benefit of ticagrelor over clopidogrel when contemporary drug-eluting stents are used. Finally, cost remains a consideration; in the East Asian context, ticagrelor administration for 12 months is not considered a cost-effective treatment option.

However, the absence of head-to-head trials in South and East Asian patients leaves important gaps, emphasizing the need for region-specific evidence. As the authors conclude, clopidogrel remains a viable and sometimes preferable choice in everyday ACS management, especially in resource-constrained settings and high-bleeding-risk groups.

Clinical Inference: A Practical, Patient-Centered Approach to Antiplatelet Selection

For practicing cardiologists, this review reinforces that antiplatelet choice in ACS must be individualized rather than guideline-driven alone. While newer P2Y12 inhibitors remain powerful options, their benefits are not uniform across populations. Asian patients, elderly individuals, those requiring triple therapy, and patients at high bleeding risk may be better served by clopidogrel—an agent with decades of safety data, lower bleeding rates, better tolerance, and significantly better adherence.

Reference: Yadav S, Yadav R. Clopidogrel therapy in Acute Coronary Syndrome: Contemporary issues. Indian Heart Journal. 2025 Feb 5.