Oral P2Y12 Inhibitors
Haytham A. Wali, PharmD
Introduction
Coronary atherothrombosis is the most common cause of the development of acute coronary syndrome (ACS), and plays a central role in complications occurring around percutaneous coronary intervention (PCI) including recurrent ACS, procedure-related myocardial infarction (MI) or stent thrombosis.1 In patients who have ACS with or without ST-segment elevation (STEMI or NSTEMI, respectively), the 2016 American College of Cardiology/ American Heart Association (ACC/AHA) guidelines recommend dual antiplatelet treatment with aspirin and a P2Y12 receptor inhibitor (clopidogrel, prasugrel, or ticagrelor) for at least 12 months.2 Clopidogrel and prasugrel are both irreversible inhibitors of the P2Y12 component of Adenosine diphosphate (ADP) receptors on the platelet surface, which prevents activation of the Glycoprotein (GPIIb/IIIa) receptor complex, thereby reducing platelet aggregation. Ticagrelor, on the other hand, is a reversible inhibitor.3-5 Several studies have been conducted to compare the efficacy and safety of these agents. This review summarizes the highlights of these studies.
Literature review
TRITON-TIMI 38 (2007)
The TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction) trial randomized 13,608 moderate- to high-risk patients with ACS scheduled for PCI to receive prasugrel (60-mg loading dose and then 10-mg daily maintenance dose) or clopidogrel (300-mg/75-mg) for six to 15 months. Results showed a significant reduction in the primary efficacy end point (death from cardiovascular causes, nonfatal MI, or nonfatal stroke) in favor of prasugrel (HR 0.81; 95% CI, 0.73-0.90; P<0.001), as well as in MI (HR 0.76; 95% CI, 0.67-0.85; P<0.001), urgent target vessel revascularization (TVR) (HR 0.66; 95% CI, 0.54-0.81; P<0.001), and stent thrombosis (HR 0.48; 95% CI, 0.36-0.64; P<0.001). However, this was at the expense of a significant increase in non–CABG-related thrombolysis in myocardial infarction (TIMI) major bleeding (2.4% versus 1.8%; HR 1.32; 95% CI, 1.03-1.68; P=0.03), life-threatening bleeding (1.4% versus 0.9%; HR 1.52; 95% CI, 1.08-2.13; P=0.01), and fatal bleeding (0.4% versus 0.1%; HR 4.19; 95% CI, 1.58-11.11; P=0.002).6 One of the study limitations is the high enrollment of elderly patients and those with renal dysfunction, which may have resulted in increased bleeding rates.
PLATO (2009)
The PLATO (Study of Platelet Inhibition and Patient Outcomes) trial was a multicenter, randomized, double-blind trial which compared ticagrelor with clopidogrel in 18,624 ACS patients. In this study, patients were randomly assigned on presentation, regardless of revascularization strategy (43% had non-ST elevation MI). Unlike the protocol in the TRITON-TIMI 38 trial, treatment was started as soon as possible after hospital admission (median of five hours), but many patients received the drug after coronary angiography. The median time from the first dose of the study drug to PCI was approximately four hours (interquartile range [approximately] 0.45 to 50.8 hours). PLATO included patients who underwent PCI, were referred for coronary artery bypass grafting (CABG) or were managed medically. At 12 months, the composite primary end point (first event of death from vascular causes, MI, or stroke) occurred significantly less often in patients receiving ticagrelor (9.8% versus 11.7%; HR 0.84, 95% CI 0.77-0.92). There was no significant difference in the rates of major bleeding between the ticagrelor and clopidogrel groups (11.6% versus 11.2%; HR 1.04; 95% CI 0.95-1.13; P=0.43), nor were there differences in transfusion rates (8.9% versus 8.9%; HR 1.00; 95% CI 0.91-1.11; P=0.96), although ticagrelor was associated with a significantly higher rate of major bleeding not related to CABG (4.5% versus 3.8%; HR 1.19; 95% CI 1.02-1.38; P=0.03).7 Some of the limitations of this study include the lower rate of bolusing with the intervention medication in PCI with the clopidogrel group, which may have introduced bias to the results. Also, since almost half of the patients were on clopidogrel at baseline, this trial may have involved clopidogrel non-responders.
TRILOGY-ACS (2012)
The TRILOGY ACS (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes) trial was a randomized, double-blind, double-dummy, active-control, event-driven trial which directly compared prasugrel with clopidogrel in 9,326 patients treated with aspirin with unstable angina or NSTEMI in whom PCI was not performed. Randomization was carried out more than four days after admission. Prasugrel was given with a loading dose of 30 mg and a maintenance dose of 10 mg/day in patients less than 75 years old or 5 mg/day for those 75 years or older or weighed less than 60 kg; clopidogrel was given with a 300 mg loading dose and a 75 mg/day maintenance dose. The primary efficacy end point was a composite of death from cardiovascular causes, nonfatal MI, or nonfatal stroke among patients under the age of 75 years. The median duration of exposure to a study drug was 14.8 months. During a median follow-up of 17.1 months, there was no statistically significant difference in the rate of the primary end point in the 7243 patients under the age of 75 years between prasugrel and clopidogrel (13.9% versus 16.0%; HR 0.91, 95% CI 0.79-1.05). The rates of life-threatening and intracranial bleeding (TIMI criteria) were not significantly different (P=0.88 and P=0.39, respectively). However, irrespective of which bleeding criteria were applied, the event rates at 30 days tended to be higher with prasugrel and the confidence intervals for the hazard ratios for bleeding often included upper boundaries that indicated as much as a doubling of the risk.8 A separate analysis of the 2083 individuals ≥75 years of age found that the risks of the primary end point and of TIMI major bleeding increased progressively with age and were two– to threefold higher in older individuals. Similar to the entire study population, there was no significant difference in these outcomes between the two interventions in these older patients.9
PRAGUE-18 (2016)
The multicenter PRAGUE-18 (Comparison of Prasugrel and Ticagrelor in the Treatment of Acute Myocardial Infarction) study was an open-label, phase IV, controlled clinical trial that was designed to compare the efficacy and safety of prasugrel and ticagrelor in MI treated with primary or immediate PCI. A total of 1,230 patients were randomly assigned, across 14 sites, to either prasugrel or ticagrelor, which was initiated before PCI. Nearly 4% were in cardiogenic shock and 5.2% were on mechanical ventilation. Primary end-point was defined as death, re-infarction, urgent target vessel revascularization, stroke, serious bleeding requiring transfusion or prolonging hospitalization at 7 days (to reflect primarily the in-hospital phase). The occurrence of the primary endpoint did not differ between groups receiving prasugrel and ticagrelor (4.0% versus 4.1%; OR 0.98; 95% CI, 0.55-1.73; P=0.939). No significant difference was found as well in any of the components of the primary endpoint. The occurrence of key secondary end-point within 30 days, composed of cardiovascular death, nonfatal MI, or stroke did not show any significant difference between prasugrel and ticagrelor (2.7% versus 2.5%; OR 1.06; 95% CI, 0.53-2.15; P=0.864).10 The study limitations include the open-label design and the relatively small sample size that made it underpowered. Furthermore, the study was terminated prematurely because of futility.
Zhang et al (2017)
This was a meta-analysis which compared newer P2Y12 inhibitors with clopidogrel from 13 clinical trials (including the aforementioned landmark trials except PRAGUE-18) and involved a total of 87,985 patients with ACS. The newer P2Y12 inhibitors included cangrelor intravenous, prasugrel, and ticagrelor. The I2, a statistic that describes the percentage of total variation across studies that is due to heterogeneity rather than chance,11 was used to assess the heterogeneity of the results, with I2 values greater than 75% indicating that the two groups had a high heterogeneity, independence, and no significance of meta-analysis. Newer P2Y12 inhibitors significantly decreased the risk of myocardial infarction (OR 0.86; 95% CI, 0.77–0.96; I2 = 54%; P<0.05) and showed a trend toward reduction of cardiovascular death (OR 0.85; 95% CI, 0.77–0.93; I2 = 42%; P<0.001). The rates of stroke events and the incidence in patients with ACS did not differ statistically between the clopidogrel group and the group with newer P2Y12 inhibitors (OR 0.95, 95% CI, 0.79–1.14, and I2 = 0%; P=0.57). However, newer P2Y12 inhibitors showed a significant increase in thrombosis in MI major or minor bleeding (OR 1.21; 95% CI, 1.03–1.42; I2 = 56%; P=0.02) compared with clopidogrel.12
PRAGUE-18 Outcomes (2018)
Since the early outcomes of patients in the PRAGUE-18 did not find any significant differences between prasugrel and ticagrelor, a one-year follow-up of the PRAGUE-18 study was conducted to provide a long-term comparison of efficacy and safety between prasugrel and ticagrelor. The primary endpoint was the composite of death from cardiovascular causes, nonfatal myocardial infarction, or stroke. At the end of the 12-month follow-up, the endpoint occurred in 6.6% of prasugrel patients and in 5.7% of ticagrelor patients (HR 1.167; 95% CI, 0.742-1.835; P=0.503). No significant differences were found in cardiovascular death (3.3% versus 3.0%; P=0.769), MI (3.0% versus 2.5%; P=0.611), stroke (1.1% versus 0.7%; P=0.423), all-cause death (4.7% versus 4.2%; P=0.654), definite stent thrombosis (1.1% versus 1.5%; P=0.535), all bleeding (10.9% versus 11.1%; P=0.999), and TIMI major bleeding (0.9% versus 0.7%; P=0.754). The percentage of patients who switched to clopidogrel for economic reasons was 34.1% (n=216) for prasugrel and 44.4% (n=265) for ticagrelor (P=0.003). Patients who were economically motivated to switch to clopidogrel had (compared with patients who continued the study medications) a lower risk of major cardiovascular events (2.5% versus 8.5%; HR 0.433; 95% CI, 0.210-0.894; P=0.024), and a significant decrease of the bleeding risk (7.3% versus 13.4%; HR 0.416; 95% CI, 0.246-0.701; P=0.001). However, this observed consequences of switching to clopidogrel were not the results of a randomized comparison.13 Since this study is based on the original PRAGUE-18 trial, it basically has the same limitations, but it has the advantage of showing the long-term outcomes.
Conclusion
For patients with ACS who have undergone PCI, prasugrel and ticagrelor have been shown to be more effective than clopidogrel but associated with more bleeding risk (TRITON-TIMI 38 and PLATO). In the absence of PCI, however, prasugrel was not different than clopidogrel in regard to the efficacy and bleeding risk (TRILOGY ACS). Finally, no difference in the efficacy has been found between prasugrel and ticagrelor (PRAGUE-18) or the bleeding risk (PRAGUE-18 Outcomes). Therefore, choosing a P2Y12 inhibitor should be based on patient factors such as the presence or absence of PCI and the level of bleeding risk.
References
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