kaytharalotus

Review of Paper title “Parasugrel versus Clopidogrel in Patients with Acute Coronory Syndrome” Phase 3 Clinical Trials in 2019

Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes Phase 3 Clinical Trials

Kay Thwe Kyaw, DrPH,M.B.,B.S,MPH

Background:

Prasugrel (a novel thienopyridine anti-platelet, a pro-drug), similar to clopidogrel, requires conversion to an active metabolite before binding to platelet P2Y12 receptor to have anti-platelet activity. Patients with acute coronary syndrome (ACS) underwent percutaneous coronary intervention (PCI) are having recurrent atherothrombotic events while taking dual anti-platelet therapy (aspirin-clopidogrel) although proven clinical benefits of short term and long-term anti-platelet therapy.^[1] Dual antiplatelet therapy (aspirin-thienopyridine) have proven benefits in preventing complication of ACS and PCI.^[1]

Earlier studies showed that loading dose of a 60 mg prasugrel had more rapid, potent, consistent inhabitation of platelet aggregation (IPA) in healthy patients, patients with coronary artery diseases, patients undergo PCI compared with clopidogrel.^[1] According to previous phase 2 clinical trials, there was no significant differences in the rate of significant bleeding (Hazard ratio (HR):1.42; 95%CI: 0.40, 5.08) and lower incidence of primary composite end points and rate of ischemic events in prasugrel group (a 60 mg loading dose) compared with clopidogrel among patients with ACS who undergo PCI.^[2]

Table 1. Comparison of Three anti-platelet drug

The objective of this study was assessing improvement in therapeutic outcomes by optimizing platelet inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TIMI) with phase 3 clinical trials in patients having a cute coronary syndromes with scheduled PCI comparing a regime of prasugrel with the standard dose regimen of clopidogrel.^[1] This study also aimed to identify higher level of adenosine diphosphate (ADP)-induced platelet aggregation and a less-variable response in prasugrel compared with standard dose of clopidogrel to reduce ischemic events.^[1]

Methods:

This study was a phase 3, double blind randomized clinical trails and included 13,608 patients with moderate to high risk ACS with scheduled PCI from 707 sites (30 countries) between Nov 2004 and Jan. 2007 with minimum 6 months and maximum 15 months follow up periods.^[1]Patients were randomly assigned to prasugeal and clopidrogel into two strata: unstable angina or non-ST elevation MI (NSTEMI) (10,074) and ST-elevation MI (STEMI) (3,534). Inclusion criteria for patients with unstable angina or NSTMI were ischemic symptoms lasting 10 mins or more and within 72 hours before randomization, a STEMI risk score of 3 or more, either ST segment elevation of 1 mm or more or elevation of cardoac biomarker of necrosis.^[1]In addition, STEMI could be enrolled within 12 hours after the onset of  symptoms if primary PCI was planned or within 14 days after receiving medical treatment.^[1]Exclusion criteria were increased risk of bleeding, anemia, thrombocytopenia, history of pathologic intracranial findings, or the use of any thienopyridine within 5 days before enrollment.^[1]Institutional review boards (all participating centers) approved the study and written informed consent was obtained from study participants.^[1]Intervention group received prasugrel (loading dose of 60 mg  and a 10 mg daily maintinance dose) while control group received standard dose of clopidogrel (loading dose 300 mg and 75 mg maintainance dose) to patients with ACS undergo PCI.^[1]Loading dose of prasugrel or prasugrel adminstered in double blind manner to participants at anytime beween randomization, 1 hour after leaving cardiac cartherization laboratory.^[1]Followed up periods for the study participants were hospital discharge, day 3, 30 days, 90 days, and 3 monthly for 6 to 15 months.^[1]Primary efficacy end points for the study was a composite of the rate of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke during follow up period.^[1]Key secondary end points at 30 days and 90 days were the primary composite end points and composite of death from cardiovascular cause, nonfatal myocardial infarction, or urgent target-vessel revascularization.^[1]Key secondary end points for the entire follow up periods were stent thrombosis and a composite of death from cardiovascular cause, nonfatal myocardial infarction, nonfatal stroke, or rehospitalization due to cardiac ischemic event.^[1]Key safety end points were TIMI major bleeding not related to coronary artery bypass grafting (CABG), non-CABG related TIMI life-threatening bleeding, and TIMI major or minor bleeding.^[1] Independent data monitoring committee monitored the safety and efficacy of the drugs.^[1]

Efficacy comparisons were carried out with intention to treat principle, based on time to first event. Safety analyses were carried out from patients who received at lease one dose of the study drug.^[1]Gehan-Wilcoxon test was carried out to compare primary efficacy end points between intervention and control group.^[1]Pre-specified sensitivity analysis for primary end points and key secondary and safety end pointes were carried by using Log-Rank test.^[1]A closed testing procedure was used to preserve a statistical power to detect difference between two treatment groups.^[1]

Firstly, primary end points are analyzed in cohort with unstable angina or NSTEMI, when it showed statistical significant between two treatment groups at this end point, then analyzed overall cohort. Kaplan-Meier estimates was used to identify rates of end points at 15 months (HR, 95%CI).^[1]Statistical Significance was set at p-value <0.05. Among patients with unstable angina or NSTEMI, a total of 875 of primary end points was calculated to have a statistical power 90% to reduce 20 % relative risk of primary end points in prasugrel compared with clopridrogel.^[1] In order to obtain this number of end points, 9,500 patients with unstable angina or NSTEMI were estimated to enroll in the study.^[1]There was increased in the number of patients in the cohort with unstable or NSTEMI to approximate 10,000 as 650 patients had a primary end point soight ower than expected aggregate rate of the end point from the prespecified analysis.^[1]  

Results:

In this phase 3 double blinded randomized clinical trials included13,608 patients (10,074 with unstable angina or NSTEMI and 3,534 with STEMI) were randomly assigned to intervention or control group.^[1] The median duration of therapy was 14.5 months and 14 patients were loss to follow up (0.1%).^[1]

Characteristic of patients such as unstable angina or NSTEMI, STEMI, age, female, BMI, white race, region of enrollment, medical history (Hypertension, hypercholesterolemia, diabetes, tobacco use, previous MI, Previous CABG), PCI, CABG, type of stent, multivessel PCI, use of anti-thrombin to support PCI, glycoproten IIb/IIIa-receptor antagoniset use, timing of dtudy of drug adminstration were blanced between two treatment groups and comparable characteristics.^[1]

In view of reduction in the rate of primary efficacy end points in prasugrel group compared with clopidogrel group among unstable angina or NSTEMI (HR:0.82, 95% CI:0.73,0.93, p-0.002), the analysis was carried out in overall cohort.^[1]Similarly, the rate of primary efficacy end points was significantly reduced in prasugrel compared clopidogrel among STEMI (HR:0.79, 95 % CI: 0.65,0.97).^[1]The rate of primary efficacy end points was reduced in prasugrel compared with clopidogrel in overall cohort (HR:0.81, 95% CI: 0.73,0.90).^[1]Significant reduction in the rate of myocardial infarction in prasugrel group compared with clopidogrel group (HR:0.76, 95 % CI:0.67,0.85) leading to the differences in the reduction of primary end points between two treatment groups.^[1]

Patients in prasugrel group were less likely to had stent thrombosis compared with clopidrogel group (HR:0.48, 95% CI: 0.36-0.64).^[1]The rate of myocardial infarction with subsequent death from cardiovascular cause was reduced in prasugrel compared group with clopidogrel group (HR: 0.58, 95 % CI: 0.36,0.93).^[1] Diabetes patients has in prasgruel group vs clopidrogel group (HR: 0.70, 95% CI:0.58,0.85) while non-diabetes patients in prasgruel group vs clopidrogel group (HR:0.86, 95% CI:0.76,0.98) reduced rate of primary end points.^[1] Similarly, patients who used  glycoprotein IIb/IIIa receptor antagonist in prasgruel group vs clopidrogel group (HR: 0.79, 95% CI: 0.69, 0.91) wheras glycoprotein IIb/IIIa receptor antagonist non-user in prasgruel group vs clopidrogel group (HR: 0.84, 95%CI: 0.72,0.99) reduced rate of primary end points.^[1]

The primary efficacy end point was significantly reduced in prasugrel group (4.7 %) compared with clopidogrel (5.6%) at the first specified period, 3 days (HR:0.82, 95% CI: 0.71,0.96).^[1] The reduction of primary efficacy end points in prasugrel group (5.6%) was persistent from 3 days to 90 days compared with clopidogrel (6.9%), HR: 0.80, 95 % CI: 0.70-0.93, p-0.003).^[1] The higher number of patients (146) had at least one TIMI major hemorrhage not related to CABG in prasugrel group compared with clopidogrel (111), HR:1.32, 95 % CI:1.03,1.68.^[1] Eighty-five patients in prasugrel group compared with fifty-six patients in clopidogrel group had life threatening bleeding (HR:1.52, 95 % CI: 1.08-2.13).^[1]Fatal TIMI major bleeding were more likely to occurred in prasugrel (21) compared with clopidogrel (5), HR:4.19, 95 % CI:1.58,11.11. Risk of CABG related TIMI Major bleeding is highest (HR:4.73, 95 % CI:1.90,11.82) among safety end points in prasugrel groups (24) compared with clopidrogel (6). There were 244 patients in prasugrel and 142 in clopidogrel had bleeding requiring blood transfusion (HR:1.34, 95% CI:1.11,1.63); prasugrel (303) vs clopidogrel (231) in major or minor TIMI bleeding (HR:1.31, 95% CI:1.11,1.56); and prasugrel (24) vs clopidogrel (6).^[1]

In view of lower rates of ischemic end points (efficacy) and higher rates of bleeding end points (safety) with prasugrel than clopidogrel in overall follow up periods, a series of post -hoc explanatory analysis was carried out to identify the subgroups of patients without net clinical benefit or net harm.^[1] Patients with previous stroke or transient ischemic attack (TIA) had net harm (HR:1.54, 95 % CI: 1.02,2.32) from prasugrel while no net benefit from prasugrel was ideitified in age ≥75 year (HR:0.99, 95 % CI: 0.81,1.21) and patients with body weight < 60 kg (HR:1.03,95 % CI: 0.69,1.53).^[1] Patients having at least one of three risk groups were increase risk of bleeding compared with patients without them in both treatment groups.^[1]

Net clinical benefit was shown in the patients age < 75-year, body weight ≥ 60 kg, no history of stroke or TIA with regard to primary efficacy end points (HR:0.74, 95% CI:0.66,0.84) and reducing the rate of death from any cause, nonfatal MI, nonfatal stroke, or non-CABG related nonfatal TIMI major bleeding (HR: 0.80, 95 % CI: 0.71,0.89).^[1] The study drug was stopped due to adverse events not related to hemorrhage (4.7 % in prasugrel and clopidogrel 5.0 %).^[1] The number of  adverse events were thrombocytopenia (17 in prasugrel and 18 in clopidogrel); neutropenia (2 in prasugrel and 10 in clopidogrel); and colonic neoplasm (in 13 prasugrel and 4 clopidogrel).^[1]

Discussion:

The findings of this study showed that prasugrel treatment was significantly associated with reducing in the rate of nonfatal myocardial infarction compared with clopidogrel (HR:0.76, 95% CI: 0.67,0.85).^[1] Among patients receiving regime prasugrel vs clopidogrel, rate of primary efficacy end points was reduced (Relative Reduction:19%) and rate of ischemic events was reduced in myocardial infarction (Relative Reduction: 24 %), urgent target-vessel revascularization (Relative Reduction: 34 %), and stent thrombosis (Relative Reduction: 52%) compared with clopidogrel.^[1] However, there was not significant reduction in the rate of death from cardiovascular case in prasugrel compared with clopidogrel (HR:0.89, 95 % CI: 0.70,1.12).^[1]

Net clinical benefits, reducing the rate of death from any cause, nonfatal MI, nonfatal stroke, or non-CABG related nonfatal TIMI major bleeding were found in age < 75-year, body weight ≥ 60 kg, no history of stroke or TIA with regard to reducing primary efficacy end points and the rate of death from any cause, nonfatal MI, nonfatal stroke, or non-CABG related nonfatal TIMI major bleeding in prasugrel groups l.^[1] The loading dose 60 mg prasugrel in this study showed higher and more consistent levels of active metabolites and higher mean inhibition of platelet aggregation than approved dose of clopidogrel.^[1]

The findings of reduction of rate of early myocardial infarction before day 3 could be explained by more rapid onset of action in Prasugrel (within 30 minutes) with respect to IPA vs clopidogrel (6 hours).^[1] The risk of non-CABG related major bleedings were 32 % increase in prasugrel group compared with clopidogrel group.^[1] The net clinical harm from prasugrel vs clopidogrel, found in age ≥ 75-year, body weight < 60 kg, could be from altered disposition of the drug or small body size.^[1]

Conclusions:

Although the regime of prasugrel in this study showed clinical benefits and lower ischemic events from the greater inhibition of platelet aggregation in patients having moderate to high risk ACS undergo PCI compared with standard dose of clopidogrel, risk for higher rate of bleeding in prasugrel group was concerned for safety.^[1]It was suggested to weigh benefits versus safety and risk of bleeding in considering treatment options of anti-platelet for patients with ACS undergo PCI.^[1]

Evaluation of the study:

Including patients with STEMI within 14 days after receiving medical treatment who were initially treated with some type of anti-platelet drug could lead to reduce efficacy end points from distortion of the estimate of effect. Majority of White patients in this study could be less generalizable to non-White. (external validity). Glycoprotein IIb/IIIa receptor antagonist and diabetes would be potential effect modifier in prasugrel group compared with clopidogrel in reducing primary end points. Genetic responses to prasugrel and irreversibility mechanism of action of prasugrel could increase risk of major bleeding in some patients. The study did not provide about the magnitude of mean inhibition of platelet between two groups although it was mentioned.

Although distribution of male and female was balanced in this study, generalizing to female should be considerable in view of biological differences between them. Study should mention the methods of assessments of safety to have general ideas of adverse events.

No conflict of interest to disclose.

This review was established in 2019.

References:

1.         Wiviott, S.D., et al., Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes. New England Journal of Medicine, 2007. 357(20): p. 2001-2015.

2.         Wiviott, S.D., et al., Randomized comparison of prasugrel (CS-747, LY640315), a novel thienopyridine P2Y12 antagonist, with clopidogrel in percutaneous coronary intervention: results of the Joint Utilization of Medications to Block Platelets Optimally (JUMBO)-TIMI 26 trial. Circulation, 2005. 111(25): p. 3366-73.