P2Y12 Inhibitors in STEMI Patients — One Size Does Not Fit All

The use of dual anti-platelet therapy (DAPT), the combination of aspirin + a loading dose of a P2Y₁₂ inhibitor, is standard of care in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). There are currently 3 P2Y₁₂ inhibitors in widespread use with European and US guidelines favoring prasugrel and ticagrelor over clopidogrel for STEMI because of a more consistent anti-platelet effect [1,2,3]. But despite a reduction in “poor responders” with the use of prasugrel and ticagrelor, individual variability in response to P2Y₁₂ inhibitors persists with studies of STEMI patients reporting high on-treatment platelet reactivity (HTPR) in 20–60% of patients when measured 2 h after a loading dose of prasugrel or ticagrelor [4,5,6,7,8].

Various factors have been linked to variability in therapeutic response to P2Y₁₂ inhibitors including whether the tablet is crushed, concurrent use of morphine, diabetes, chronic kidney disease, age, and clinical presentation [7, 9, 10]. To this list, we can now add body mass index (BMI). In the current issue of the journal, Scudiero et al. report an observational, multicenter study of 429 STEMI patients who presented within 12 h of symptom onset and were P2Y₁₂ inhibitor naïve [11]. All patients received a loading dose of either ticagrelor (180 mg; 78% of patients) or prasugrel (60 mg; 22% of patients) along with aspirin (325 mg) prior to PPCI. Platelet reactivity was assessed by VerifyNow P2Y₁₂ assay, a point of care, citrated whole-blood optical detection system, at baseline and then 1 h, 2 h, 4–6 h, and 8–12 h after the loading dose.

The current study is a post hoc analysis of patients drawn from 4 separate pharmacodynamic studies and divided into overweight (defined as BMI ≥ 25; 70% of patients) or normal (BMI < 25; 30% of patients) groups. HTPR was defined as ≥ 208 P2Y₁₂ reaction units (PRU). In propensity score-matched cohorts (n = 127), overweight patients had higher levels of platelet reactivity and higher rates of HTPR in the crucial early phase after PPCI (at 1 and 2 h after the loading dose). There was also a difference in platelet reactivity at 4–6 h although it did not reach statistical significance (p = 0.08). In contrast, the overweight and normal groups had similar values of platelet reactivity at baseline and 8–12 h. In a multivariate analysis, BMI ≥ 25 and morphine use were independent predictors of HTPR at 2 h.

Obesity is a significant and growing public health problem with a 2011 analysis of the US-based National Cardiovascular Data Registry demonstrating that more than 50% of individuals diagnosed with STEMI have BMI ≥ 30 kg/m² [12]. This study provides evidence that being overweight results in a higher rate of HTPR in the early phase after PPCI and highlights the need for additional studies to optimize P2Y₁₂ inhibitor dosing and delivery among overweight patients.

The study also provides more data that a one-size-fits-all approach to P2Y₁₂ inhibitors does not result in optimal patient care. The most dramatic example of this is the interindividual variability in responses to clopidogrel, still one of the most commonly prescribed P2Y₁₂ inhibitors in the world. Clopidogrel is a pro-drug activated by cytochrome P450 enzyme system, and patients carrying a CYP2C19 loss-of-function allele have reduced levels of active clopidogrel metabolite resulting in reduced inhibition of platelet reactivity and increased rates of major adverse cardiovascular events (MACE) [13,14,15]. In contrast, CYP2C19 genotype does not influence the anti-platelet effects of prasugrel or ticagrelor.

Several limitations must be noted when interpreting this study. First, platelet function was only measured using a single technique — the VerifyNow P2Y₁₂ assay. Second, there is still controversy about the best definition of HTPR. In various studies, a cutoff value of > 208 PRU predicted MACE in patients treated with P2Y₁₂ inhibitors, but three large, randomized studies failed to find any benefit when VerifyNow P2Y₁₂ results were used to customize anti-platelet therapy [16,17,18]. Third, the definition of overweight was arbitrary. The authors note this limitation and report that analyzing the data using a BMI cutoff of ≥ 30 kg/m² was not feasible due to limited sample size. Since the differences in BMI between the two groups were relatively small (23 vs 28), this, in some ways, makes the results more impressive. Fourth, it is not clear how many patients received a crushed formation of ticagrelor or prasugrel; as these investigators and others have shown, crushed tablets lead to more rapid absorption and significantly lower PRU values for up to 4 h after a loading dose when compared to the drug delivered in tablet form [10, 19]. And lastly, this study assumes that earlier onset of anti-platelet effects will lead to better clinical outcomes in STEMI patients but that remains controversial. Studies of potent, intravenously administered platelet inhibitors such as glycoprotein IIb/IIIa inhibitors or cangrelor have shown minimal benefit in STEMI patients treated with aspirin and P2Y₁₂ inhibitors, despite early and profound platelet inhibition [20].

In summary, this study provides more evidence that optimal anti-platelet drug delivery and patient care require a better understanding of how individual factors, such as age, weight, comorbidities, genetic polymorphisms, other medications, and/or other factors, influence anti-platelet efficacy following an oral loading dose of a P2Y₁₂ inhibitor.