Strategies for Tailored Antiplatelet Therapy after Percutaneous Coronary Intervention: Unraveling Complexities, Embracing Nuances

Guided Anti-P2Y12 Therapy in Patients Undergoing PCI: Three Systematic Reviews with Meta-analyses of Randomized Controlled Trials with Homogeneous Design

The discovery that approximately 20 to 40% of patients who receive the anti-P2Y₁₂ drug clopidogrel exhibit high on-treatment platelet reactivity (HTPR), indicating inadequate inhibition of platelet function, has been a central topic in discussions concerning antithrombotic therapy following percutaneous coronary intervention (PCI) for years.[1]

This finding also paved the way for numerous studies exploring distinct yet interconnected hypotheses. First, it prompted exploration of whether patients with high platelet reactivity while on standard-dose clopidogrel might derive greater benefits (i.e., a reduction in major adverse cardiac events [MACE]) from more potent antithrombotic treatments, such as doubling the clopidogrel dose or utilizing more potent P2Y₁₂ inhibitors like prasugrel or ticagrelor. Second, the concept of using a platelet function test (PFT) to identify individuals with HTPR or predicting those likely to have HTPR via genotyping gained momentum. Studies exploring these approaches diverge in their methodologies: the first type involves randomizing HTPR or non-HTPR patients into groups receiving investigational therapies or controls, while the second type randomizes an entire cohort into groups receiving antiplatelet therapy based on a guided or unguided strategy.[2] The effect of these study designs on the actual number of PCI patients who finally receive clopidogrel or a more potent antiplatelet regimen is noteworthy and may impact the overall incidence of ischemic and hemorrhagic complications ([Fig. 1]). While pooling these studies in meta-analyses proves valuable for amplifying their capacity to discern meaningful differences in infrequent outcomes, it fails to capture the intricate subtleties linked to their variations in study design, populations, outcomes, and definitions.

Fig. 1 Impact of design on antiplatelet regimens in trials of patients with and without high on-treatment platelet reactivity. The figure illustrates four case scenarios in trials of antiplatelet therapy or guided therapy. The top-left panel shows a hypothetical trial of 500 patients with a chronic coronary syndrome (CCS) undergoing PCI, of which 150 (i.e., 30%) present with high on-treatment platelet reactivity (HTPR). These patients are randomized to escalation to more potent antiplatelet regimens (i.e., ticagrelor or prasugrel) or standard of care (i.e., clopidogrel). As a result, 15% of the original cohort receives the more potent regimen and 85% receives clopidogrel. The top-right panel shows the same situation but in a trial of 500 patients with an acute coronary syndrome (ACS), of which 350 (i.e., 70%) present without HTPR and are randomized to de-escalation to clopidogrel or standard of care. As a result, 35% of the original cohort receives clopidogrel and 65% receives the more potent regimen. The bottom-left panel shows a trial of 500 CCS patients randomized to guided therapy or standard of care, where 15% of the original cohort receives the more potent antiplatelet regimen. Finally, the bottom-right panel shows a trial of 500 ACS patients randomized to guided therapy or standard of care, where 35% of the original cohort receives clopidogrel. These numbers vividly demonstrate how the study design significantly influences the distribution of patients receiving each drug, resulting in considerable heterogeneity and often divergent outcomes concerning both ischemic events and bleeding complications.

In this issue of Thrombosis & Haemostasis, Birocchi and colleagues present the results of three new meta-analyses cumulatively including 21 trials of PCI.[3] Out of these, eight trials looked at treatments for patients with HTPR, six trials explored therapy guided by PFT, and seven trials focused on genotype-guided therapy. Guided therapy primarily aimed to switch patients from clopidogrel to more potent antithrombotic regimens, but some trials also considered de-escalation approaches, and a few examined both escalation and de-escalation. The study found no significant differences in bleeding for genotype-guided therapy trials (risk ratio [RR]: 1.06; 95% confidence interval [CI]: 0.73–1.54; p = 0.76); however, there was a notable 35% reduction in the risk of MACE (RR: 0.65; 95% CI, 0.47–0.91; p = 0.01), driven by a significant reduction in myocardial infarction and stent thrombosis. Conversely, for PFT-guided therapy trials, there were no significant differences in major bleeding (RR: 0.91; 95% CI: 0.64–1.28; p = 0.58) or MACE (RR: 0.82; 95% CI: 0.56–1.19; p = 0.30). Lastly, in trials involving antiplatelet treatments for HTPR patients, the major bleeding risk remained similar (RR: 0.71; 95% CI: 0.41–1.23; p = 0.22), while the risk of MACE was 43% lower for patients given alternative treatments compared to clopidogrel recipients (RR: 0.57; 95% CI: 0.44–0.75; p < 0.0001).

The authors should be congratulated for an interesting meta-analysis that follows an elegant and stringent approach. While some of the results replicate the findings of other meta-analyses,[4] [5] the primary strength of this study lies in the exploration of multiple subgroups that shed light on the underlying factors contributing to the reduction in MACE. Although these subgroup analyses face unavoidable limitations in statistical power (i.e., with some chance of type I and II statistical error), their results are biologically plausible and bring up important reflections on generalizability of clinical trials. In particular, a significant reduction in MACE with genotype guidance, PFT guidance, and strategies for HTPR patients was significantly apparent in trials carried out within China's geographic boundaries. This observation encourages a reflection on the distinctive genetic and clinical landscape that characterizes patients from this region. In fact, mutations in cytochrome P450 2C19 alleles and HTPR are more frequent in East Asian populations and can therefore be more easily discovered and addressed by genotype testing compared with Western populations.[6] [7]

The results of the study from Birocchi and colleagues imply that the utility of genotype testing could be confined to certain parts of the world and be less relevant in Western countries. Yet, the utility of personalized tests must be weighed against their potential costs and limited accessibility in several health care settings. Another notable observation is that none of the investigated strategies was able to reduce the risk of major bleeding. This is likely because most of the trials of genetic or PFT guidance were aimed at identifying candidates to escalation rather than de-escalation, while trials in HTPR patients tested more potent regiments than clopidogrel, which are knowingly associated with a higher risk of bleeding.[2] [8] Current guidelines for PCI in Europe recommend only guided (or unguided) de-escalation as a class IIb, while there is no corresponding recommendation in guidelines from the United States.[9] [10] Also notably, MACE were reduced in trials of genotype guidance but not in those of PFT guidance. This is an interesting and somehow unexpected finding, as one would assume PFT to be better than genotyping in isolating the HTPR phenotype. In fact, mutations of the cytochrome P450 2C19 alleles are known to represent only one of the determinants of HTPR, together with demographic and clinical variables such as age, body mass index, chronic kidney disease, and diabetes.[11] However, PFT also carries some inherent limitations in characterizing the platelet reactivity phenotype, such as physiological variability over time, limited utility in patients on potent P2Y₁₂ inhibitors or P2Y₁₂-naïve, and modest diagnostic accuracy leading to some degree of misclassification. In contrast, the result of genotype is unique and is not dependent on preanalytical variables (e.g., circadian rhythm, time elapsed since the acute event, or last drug intake) or ongoing therapy. The finding that strategies other than clopidogrel reduced MACE in HTPR patients is somehow at odds with the results of the meta-analysis of PFT guidance trials, but can be explained by their higher proportions of misclassification (e.g., patients without HTPR who received clopidogrel actually had HTPR hence neutralizing the effect on MACE; patients with HTPR who received more potent regimens actually had no HTPR and were exposed to an unnecessarily increased risk of bleeding), and/or by the different proportion of HTPR patients who finally received clopidogrel or the alternative therapy ([Fig. 1]).

While the meta-analysis by Birocchi and colleagues enhances our understanding of personalized antiplatelet therapy, particularly for Asian regions characterized by elevated cytochrome P450 mutations,[12] [13] and underscores the potential benefit of employing more potent antiplatelet approaches than clopidogrel in appropriately selected cases of HTPR, several unresolved questions remain. Foremost, accepting indirectly that genotype-guided therapy is better than PFT-guided therapy based on their respective comparisons with standard antiplatelet therapy is fraught with challenges. The diversity of trials testing these strategies precludes facile assumptions, and addressing this issue definitively necessitates a dedicated trial with a head-to-head comparison. Furthermore, the optimal therapeutic strategy for patients with HTPR or with cytochrome P450 mutations remains unknown. A large-scale trial failed in demonstrating the superiority of ticagrelor over clopidogrel within the PCI setting.[14] Lastly, uncertainties persist on whether genotype-guided therapeutic interventions are better suited for chronic coronary syndromes, functioning as a prompt for escalation, or for acute coronary syndromes, functioning as a prompt for de-escalation.[8] The necessity of guided de-escalation itself remains controversial, with another meta-analysis suggesting that unguided de-escalation could yield less bleeding than guided de-escalation without compromising MACE.[15]

Ongoing trials will provide more definitive answers on these outstanding questions and determine whether genotype-guided antiplatelet therapy can be reliably implemented in practice (NCT05262803, NCT03783351, NCT05577988). While the three meta-analyses by Birocchi and colleagues provide important additional insights into personalized antiplatelet strategies after PCI, they also reinforce the intricate, individualized nature of optimizing antiplatelet therapy, and highlight several areas warranting further research.

Publication History

Received: 15 September 2023

Accepted: 15 September 2023

Accepted Manuscript online:
18 September 2023

Article published online:
09 October 2023

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