Clinical Studies With Oral P2Y12 Inhibitors—STEMI Cohorts

In the Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent EveNTs/Optimal Antiplatelet Strategy for InterventionS (CURRENT-OASIS) 7 trial, double clopidogrel (600-mg loading dose [LD]/150-mg maintenance dose [MD] for 7 days, then 75 mg MD) was compared with standard (300-mg LD/75-mg MD) dose regimen ( Table 1 ). In the STEMI subgroup—mostly treated with primary PCI and 40.6% receiving a IIb/IIIa inhibitor—the reduction in the primary end point (cardiovascular death, myocardial infarction [MI], or stroke) at 30 days with high dose was nominally nonsignificant, 4.2% versus 5% (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.66 to 1.05, p = 0.117). However, the results were consistent with the overall PCI cohort (p for interaction = 0.817).

In the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis In Myocardial Infarction (TRITON-TIMI) 38 trial in patients with moderate-to-high risk acute coronary syndrome, prasugrel (60-mg LD/10-mg MD) was compared with clopidogrel (300-mg LD/75-mg MD). In the STEMI cohort, prasugrel reduced the primary end point (death from cardiovascular causes, nonfatal MI, or nonfatal stroke) at 30 days (HR 0.68, 95% CI 0.54 to 0.87, p = 0.0017), and at 15 months (HR 0.79, 95% CI 0.65 to 0.97, p = 0.0221). This was consistent with the overall trial results, with no significant interaction noted between presenting syndrome and benefits of prasugrel. Stent thrombosis was also reduced with prasugrel at 30 days (HR 0.49, 95% CI 0.28 to 0.84, p = 0.0084) and 15 months (HR 0.58, 95% CI 0.36 to 0.93, p = 0.0232). TIMI major bleeding unrelated to coronary artery bypass grafting, TIMI life-threatening bleeding, and TIMI major or minor bleeding did not differ between groups. However, TIMI major bleeding after coronary artery bypass grafting was increased with prasugrel (p = 0.0033).

Interestingly, the STEMI cohort included 2 subgroups, primary or secondary PCI. The latter consisted of patients enrolled from 12 hours to 14 days after symptom onset. At 30 days, in the primary PCI group, HR for prasugrel was 0.80 (95% CI 0.60 to 1.08), p = 0.1440, whereas in the secondary PCI group, 0.50 (95% CI 0.34 to 0.76), p = 0.0008. At 15 months, the respective results were 0.87 (95% CI 0.68 to 1.11), p = 0.2662 and 0.65 (95% CI 0.46 to 0.92), p = 0.0154. Although the test for heterogeneity showed that the effect was not significant, it is apparent that most of the benefit seen with prasugrel in the whole STEMI group was driven by its anti-ischemic superiority over clopidogrel in the secondary PCI group. Possible explanations for the observed differences between primary and secondary PCI outcomes could be the higher risk profile in the secondary PCI group (more diabetes, history of revascularization, and multivessel PCI) along with a delayed onset of prasugrel antiplatelet action in STEMI (described in detail in the following).

In the study of Platelet Inhibition and Patient Outcomes (PLATO) trial, ticagrelor (180-mg LD/90-mg twice daily MD) was compared with clopidogrel (300- to 600-mg LD/75-mg MD). In the STEMI cohort of patients with ST elevation or left bundle branch block, the primary end point (a composite of death from vascular causes, MI, or stroke) occurred in 9.4% and 10.8% of patients receiving ticagrelor and clopidogrel, respectively, with an HR of 0.87 (95%CI 0.75 to 1.01), p = 0.07. There was no interaction between presentation with ST elevation or left bundle branch block and randomized treatment, and these results were consistent with the overall PLATO findings. Several secondary end points were reduced by ticagrelor, such as total mortality (HR 0.82, p = 0.05), the frequency of MI alone (HR 0.80, p = 0.03), and definite stent thrombosis (HR 0.66, p = 0.03). The risk of stroke was higher with ticagrelor (HR = 1.63, p = 0.02). Of note, secondary end point results are only exploratory. Rate of major bleeding appeared similar in the 2 groups; however, the effects on bleeding are consistent with the main trial (p for interaction = 0.30).

Clinical Studies With Intravenous P2Y12 Inhibitors—STEMI Cohorts

Cangrelor, a nonthienopyridine adenosine triphosphate analogue, is a direct-acting intravenous P2Y12 adenosine diphosphate blocker that provides rapid, predictable, and profound but reversible platelet inhibition. In the Comparison of Intravenous Cangrelor to Clopidogrel in coronary stenting (CHAMPION)–PCI study, cangrelor administered 30 minutes before PCI was compared with 600 mg of clopidogrel. In the STEMI cohort, the odds ratio (OR; 95% CI) with cangrelor for the primary end point (composite of death from any cause, MI, or ischemia-driven revascularization at 48 hours) was 1.06 (95% CI 0.54 to 2.09). In the Clinical Trial Comparing Cangrelor to Clopidogrel Standard of Care Therapy in Subjects Who Require Percutaneous Coronary Intervention CHAMPION PHOENIX study, patients who were undergoing either urgent or elective PCI were randomized to receive a bolus and infusion of cangrelor or to receive 600-mg or 300-mg LD of clopidogrel. In the STEMI cohort, the OR (95% CI) of the primary end point (a composite of death, MI, ischemia-driven revascularization, or stent thrombosis) at 48 hours for cangrelor was 0.75 (95% CI 0.46 to 1.25), with p for interaction = 0.98. In a pooled analysis of data (n = 24,910) from the CHAMPION trials (CHAMPION PLATFORM included) the benefits of cangrelor over clopidogrel were consistent irrespective of the clinical presentation as STEMI (p for interaction = 0.8663).

It becomes apparent that in patients receiving primary PCI, regimens which increase platelet inhibition (double clopidogrel, prasugrel, ticagrelor, cangrelor) versus standard clopidogrel result in superior anti-ischemic effects consistent with the results in the whole trial populations (p-interaction not significant). Although subgroup analyses of the primary PCI populations showed no significant benefit in primary end points for more potent antiplatelet regimens versus clopidogrel, no study was designed specifically for primary PCI patients, and even PLATO—the largest one—was underpowered for detecting differences in this subgroup. In a meta-analysis of 4 studies, a sensitivity analysis restricted to primary PCI patients (n = 11,934) revealed a reduction with the new agents compared with clopidogrel in death (OR 0.78, 95% CI 0.66 to 0.93), major adverse cardiovascular events (OR 0.84, 95% CI 0.75 to 0.95), MI (OR 0.81, 95% CI 0.69 to 0.95), and stent thrombosis (OR 0.67, 95% CI 0.53 to 0.84). Stroke was increased (OR 1.48, 95% CI 1.07 to 2.07), without an increase in major bleeding or TIMI major or minor bleeding.

Clinical Studies With Intravenous P2Y12 Inhibitors—STEMI Cohorts

Cangrelor, a nonthienopyridine adenosine triphosphate analogue, is a direct-acting intravenous P2Y12 adenosine diphosphate blocker that provides rapid, predictable, and profound but reversible platelet inhibition. In the Comparison of Intravenous Cangrelor to Clopidogrel in coronary stenting (CHAMPION)–PCI study, cangrelor administered 30 minutes before PCI was compared with 600 mg of clopidogrel. In the STEMI cohort, the odds ratio (OR; 95% CI) with cangrelor for the primary end point (composite of death from any cause, MI, or ischemia-driven revascularization at 48 hours) was 1.06 (95% CI 0.54 to 2.09). In the Clinical Trial Comparing Cangrelor to Clopidogrel Standard of Care Therapy in Subjects Who Require Percutaneous Coronary Intervention CHAMPION PHOENIX study, patients who were undergoing either urgent or elective PCI were randomized to receive a bolus and infusion of cangrelor or to receive 600-mg or 300-mg LD of clopidogrel. In the STEMI cohort, the OR (95% CI) of the primary end point (a composite of death, MI, ischemia-driven revascularization, or stent thrombosis) at 48 hours for cangrelor was 0.75 (95% CI 0.46 to 1.25), with p for interaction = 0.98. In a pooled analysis of data (n = 24,910) from the CHAMPION trials (CHAMPION PLATFORM included) the benefits of cangrelor over clopidogrel were consistent irrespective of the clinical presentation as STEMI (p for interaction = 0.8663).

It becomes apparent that in patients receiving primary PCI, regimens which increase platelet inhibition (double clopidogrel, prasugrel, ticagrelor, cangrelor) versus standard clopidogrel result in superior anti-ischemic effects consistent with the results in the whole trial populations (p-interaction not significant). Although subgroup analyses of the primary PCI populations showed no significant benefit in primary end points for more potent antiplatelet regimens versus clopidogrel, no study was designed specifically for primary PCI patients, and even PLATO—the largest one—was underpowered for detecting differences in this subgroup. In a meta-analysis of 4 studies, a sensitivity analysis restricted to primary PCI patients (n = 11,934) revealed a reduction with the new agents compared with clopidogrel in death (OR 0.78, 95% CI 0.66 to 0.93), major adverse cardiovascular events (OR 0.84, 95% CI 0.75 to 0.95), MI (OR 0.81, 95% CI 0.69 to 0.95), and stent thrombosis (OR 0.67, 95% CI 0.53 to 0.84). Stroke was increased (OR 1.48, 95% CI 1.07 to 2.07), without an increase in major bleeding or TIMI major or minor bleeding.

Clopidogrel Pharmacodynamic Studies in STEMI Patients

Despite the aforementioned clinical evidence, there is a paucity of data specifically addressing P2Y12 inhibitor pharmacokinetics and pharmacodynamics in patients with STEMI. A more thoughtful in depth consideration of P2Y12 inhibitors pharmacodynamic action may help in understanding some of the caveats with their clinical use in primary PCI patients.

The onset of action and magnitude of platelet inhibition after a 600-mg LD of clopidogrel in primary PCI patients was first described by Heestermans et al. Absolute plasma concentrations of unchanged clopidogrel (Cmax, area under the curve) were significantly lower in patients with STEMI compared with healthy volunteers, and a variably impaired intestinal absorption was implicated. At hour 4 after clopidogrel LD, only a minor decrease (6% to 7%) in platelet aggregation was seen. In a larger study, platelet reactivity assessment with the VerifyNow (Accumetrics Inc, San Diego, California) P2Y12 function assay revealed that 64.5% of patients exhibited high platelet reactivity (HPR; defined as ≥235 platelet reaction units) 2 hours after 600-mg LD of clopidogrel. In a dedicated study comparing 300 mg to 600 mg of prehospital clopidogrel, a negligible platelet inhibition was seen at the time of intervention, with no difference between the 2 doses. Hemodynamic instability seems to impact on patient response to clopidogrel because such patients on mechanical ventilation and catecholamine support exhibited a smaller decrease in the vasodilator-stimulated phosphoprotein (VASP) index than stable patients at 4 hours and 24 hours after 600 mg of clopidogrel LD.