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The Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation–Thrombolysis in Myocardial Infarction 44 Trial - PRINCIPLE-TIMI 44
Description:
The goal of this trial was to evaluate the relative antiplatelet effects of prasugrel versus high-dose clopidogrel in patients undergoing planned percutaneous coronary intervention (PCI) for angina.
Hypothesis:
Use of prasugrel in PCI patients would result in greater inhibition of platelet aggregation (IPA) than high-dose clopidogrel, both during the loading and maintenance phases.
Study Design
Study Design:
Patients Screened: 201
Patients Enrolled: 201
Mean Follow Up: 29 days if PCI, 15 days if no PCI
Mean Patient Age: 63.9 years
Female: 25
Patient Populations:
Adults >18 years of age scheduled to undergo cardiac catheterization with planned PCI for angina, along with either recent (<14 days) coronary angiography with at least one lesion amenable to PCI, a functional study within 8 weeks with objective findings of ischemia, or prior PCI or coronary artery bypass graft surgery.
Exclusions:
Planned PCI for immediate treatment of MI, any thienopyridine within 5 days, glycoprotein IIb/IIIa inhibitor within 7 days or planned use, high risk of bleeding, thrombocytopenia, or anemia.
Primary Endpoints:
The primary endpoint of the loading phase was IPA with 20 µmol/L ADP at 6 hours in patients who received a LD and did not receive a glycoprotein IIb/IIIa inhibitor, regardless of PCI status. The primary endpoint of the MD phase was IPA with 20 µmol/L ADP after 14 ± 2 days of high-dose clopidogrel, including both pre-crossover and post-crossover periods during the MD phase. In addition, thienopyridine hyporesponsiveness was compared between the two groups, which was defined as IPA with 20 µmol/L ADP <20%.
Secondary Endpoints:
The main secondary endpoints for the LD and MD phases were mean MPA with 20 µmol/L ADP, VASP platelet reactivity index, and mean VerifyNow P2Y12 assay percent inhibition. An MPA >50% on therapy was considered as another marker for thienopyridine hyporesponsiveness. Additional efficacy measures included primary and secondary measures at 30 minutes, 2 hours, and 18-24 hours; IPA and MPA with 5 µmol/L ADP; and IPA (final).
Drug/Procedures Used:
Patients were randomized to treatment with clopidogrel 600 mg or prasugrel 60 mg loading dose (LD), given at least 30 minutes prior to cardiac catheterization. Patients were then to undergo PCI if coronary anatomy was suitable. After PCI, they received once-daily maintenance dose (MD) for 14 ± 2 days of either prasugrel 10 mg or clopidogrel 150 mg, corresponding to the LD assignment, after which they crossed over to the alternate maintenance therapy for an additional 14 ± 2 days, without an intervening washout period.
Glycoprotein IIb/IIIa inhibitor agents were to be used only if deemed necessary at the time of PCI.
Principal Findings:
A total of 201 patients were randomized in this multicenter trial, 102 to the prasugrel arm, and 99 to the clopidogrel arm. Approximately 88% of patients had been on aspirin prior to randomization. Glycoprotein IIb/IIIa inhibitors were used in four (2%) patients during PCI. Pretreatment platelet aggregation was similar between the two groups.
Pharmacodynamic endpoints: The primary efficacy endpoint of IPA with 20 µmol/L adenosine diphosphate (ADP) at 6 hours after LD was significantly greater after prasugrel 60 mg, compared with clopidogrel 600 mg (74.8 vs. 31.8%, p < 0.0001). Patients treated with prasugrel also had more consistent levels of inhibition, with lower intersubject variability. The greater antiplatelet effect of the prasugrel LD measured by IPA with 20 µmol/L ADP was maintained at all time points studied.
In addition, prasugrel demonstrated significantly greater antiplatelet effects compared with clopidogrel, as assessed by various secondary endpoints over the same time points such as: 1) significantly higher levels of IPA with 5 µmol/L ADP, 2) lower levels of maximal platelet aggregation (MPA) with 5 and 20 µmol/L ADP, 3) higher vasodilator-stimulated phosphoprotein (VASP) platelet reactivity index, and 4) greater percent inhibition with the VerifyNow P2Y12 assay.
Similarly, the primary efficacy endpoint of IPA with 20 µmol/L ADP after 14 ± 2 days of MD therapy was significantly greater in patients receiving prasugrel 10 mg/day compared with clopidogrel 150 mg/day (61.3 vs. 46.1%, p < 0.0001). Likewise, significant differences were noted for IPA with 20 µmol/L ADP at days 15 (61.9 vs. 45.4%) and 29 (60.8 vs. 46.8%) between the two groups (p < 0.0001 for both). As during the LD phase, prasugrel demonstrated significantly greater antiplatelet effects compared with clopidogrel, as assessed by the same secondary endpoints at 15 and 29 days following randomization.
The incidence of thienopyridine hyporesponsiveness, as measured by an IPA with 20 µmol/L ADP <20%, was 0% with prasugrel by 6 hours following the LD, with levels around 2.4% during the MD phase. In contrast, thienopyridine hyporesponsiveness with clopidogrel was around 27% at 6 hours following the LD, with levels around 13% during the MD phase.
Clinical endpoints: No major bleeds were observed in either treatment arm, based on a priori definitions by the TIMI group. Two subjects in the prasugrel group and none in the clopidogrel group experienced minor TIMI bleeding before crossover; none were noted during the MD phase. When all investigator-reported hemorrhagic events were considered, 18.6% of patients in the prasugrel group and 14.1% in the clopidogrel group had a bleeding episode during the LD and pre-crossover MD period. After crossover, four patients in the clopidogrel followed by prasugrel group and none in the other group had any bleeding episode.
No deaths or strokes were reported in either treatment group. One patient in the clopidogrel group had acute stent thrombosis resulting in myocardial infarction (MI), and two patients in the prasugrel group had periprocedural MIs. One patient in the prasugrel followed by clopidogrel arm experienced an MI after crossover.
Interpretation:
In patients undergoing planned PCI for angina, prasugrel 60 mg LD, as well as 10 mg/day MD results in more rapid, higher, and more consistent levels of antiplatelet effects, compared with clopidogrel 600 mg LD and 150 mg/day MD. This effect was apparent as early as 30 minutes after the initial LD, and persisted throughout the duration of follow-up.
There is a growing body of literature linking poor antiplatelet response to adverse clinical outcomes, including stent thrombosis and recurrent ischemic events. Hence, there has been recent interest in the use of higher dose clopidogrel for loading and for maintenance in patients with coronary artery disease, with a view to increasing platelet inhibition. The current study suggests that prasugrel, in the doses studied, may achieve even greater platelet inhibition in vivo than high-dose clopidogrel, and thus potentially achieve a greater reduction in the incidence of major adverse cardiovascular outcomes.
The recent TRITON-TIMI 38 trial had demonstrated a significant reduction in ischemic events in patients with acute coronary syndromes undergoing PCI randomized to 60 mg LD and 10 mg/day MD of prasugrel, compared with standard approved 300 mg LD and 75 mg/day MD of clopidogrel. Further studies are needed to determine whether such a reduction in clinical outcomes will be observed in patients undergoing planned PCI who receive prasugrel compared with high-dose clopidogrel as well.
Bleeding tended to be more frequent with prasugrel, although no significant differences were noted. Findings from the current study are applicable to the patient population studied, namely patients undergoing PCI for angina, and not to patients with acute coronary syndromes and those who received glycoprotein IIb/IIIa inhibitors.
References:
1. Wiviott SD, Trenk D, Frelinger AL, et al., on behalf of the PRINCIPLE-TIMI 44 Investigators. Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: The Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial. Circulation. 2007;116:2923-32.
2. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001-15.
3. Bhatt DL. Intensifying platelet inhibition--navigating between Scylla and Charybdis. N Engl J Med 2007;357:2078-81.
Keywords: Coronary Artery Disease, Myocardial Infarction, Acute Coronary Syndrome, Stroke, Follow-Up Studies, Platelet Aggregation Inhibitors, Cardiac Catheterization, Thiophenes, Polyethylene Glycols, Ticlopidine, Blood Platelets, Piperazines, Purinergic P2Y Receptor Antagonists, Vasodilator Agents, Stents, Percutaneous Coronary Intervention, Coronary Angiography, Thrombosis, Research Personnel, Phosphoproteins, Coronary Artery Bypass
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