Abstract
TR ial to assess I mprovement in T herapeutic O utcomes by optimizing platelet inhibitio N with prasugrel Thrombolysis In Myocardial Infarction 38 (TRITON-TIMI 38) was a Phase 3, randomized, double blind, parallel-group, multinational head-to-head study of prasugrel vs. clopidogrel both on top of aspirin. The primary end point was the rate of cardiovascular death, nonfatal myocardial infarction (MI), or stroke, and was reached in 12.1% of patients treated with clopidogrel and in 9.9% of patients randomized to prasugrel, suggesting impressive vascular outcome benefit of prasugrel over clopidogrel. However, this overoptimistic interpretation of the trial results was challenged by the Food and Drug Administration (FDA) Secondary Review, which revealed several shortcomings with TRITON design and data interpretation including the front-loaded nature of prasugrel benefit. Recently, following approval with black box warning, the FDA posted the complete documentation set (Action Package), revealing additional information including the timing of loading in TRITON, and how it affects vascular outcomes. The detailed FDA communications revealed highly significant correlation of the loading dose delay and primary efficacy outcomes favoring prasugrel. Indeed, when patients in TRITON were loaded early, or pretreated, the benefit of prasugrel was nonexistent. However, the longer it takes during or especially after PCI to load with thienopyridine, the more prasugrel benefit occurs. Considering that pretreatment with clopidogrel was disallowed; that three quarters of patients in TRITON were loaded during or after intervention; and that prasugrel was used at the 60-mg loading dose, which is over three times more potent than 300 mg clopidogrel, the claim of superiority of prasugrel over clopidogrel is not valid due to inappropriate use of clopidogrel.
1
Introduction
The TR ial to assess Improvement in T herapeutic O utcomes by optimizing platelet inhibitio N with prasugrel Thrombolysis In Myocardial Infarction 38 (TRITON -TIMI 38) was a Phase 3, randomized clinical study that assessed the efficacy and safety of prasugrel vs. standard care with clopidogrel. Patients with moderate to high-risk acute coronary syndromes with the defined coronary anatomy and planned stent placement were randomized to prasugrel or clopidogrel for 6 to 15 months. The primary end point was cardiovascular death, MI, or stroke. The trial showed that primary end point occurred in 12.1% of patients treated with clopidogrel and in 9.9% of patients randomized to prasugrel . Analysis of the individual components of the combined efficacy end point suggests that the difference between the two treatment arms was exclusively driven by the rates of nonfatal MI (475 vs. 620 events) favoring prasugrel. Mortality rate was similar between the groups (prasugrel, 142; clopidogrel, 150), when the trend towards cardiovascular death benefit prevented by prasugrel vs. clopidogrel failed to overcome additional bleeding and cancer fatalities occurred in the prasugrel group. There was no difference in stroke prevention (prasugrel, 61; clopidogrel, 60). The increased bleeding risk after prasugrel was not surprising because the antiplatelet potency of the prasugrel loading and maintenance dose chosen for TRITON was about 2.5–3.2 times more potent than caused by chosen clopidogrel regimen. The first scrutiny of the TRITON data has been undertaken by the Food and Drug Administration (FDA) Secondary Review, which revealed several shortcomings with TRITON design and data interpretation including the front-loaded nature of prasugrel benefit . Recently, following approval with black box warning, the FDA posted the complete documentation set (Action Package), revealing additional information including the timing of loading in TRITON, and how it affects vascular outcomes . The Action Package for prasugrel is a huge >900-page document, and it will be a challenge for practicing cardiologists to retrieve valuable information from its contents. We here outlined the latest FDA outlook on thienopyridine loading and vascular outcomes in TRITON.
2
What was previously known
The use of loading/maintenance ratio in TRITON was 6:1 for prasugrel (60 mg loading, followed by 10 mg maintenance) vs. 4:1 (300 mg loading followed by 75 mg maintenance) ratio for clopidogrel obviously favoring prasugrel due to not only higher doses , but faster action as well . Importantly, loading with 40 mg prasugrel was already tested in the JUMBO study , and if the goal was to match closely the regimens, and to design TRITON fairly, 40 mg loading with prasugrel should be tested against the 300-mg loading dose of clopidogrel. Another disadvantage for clopidogrel relates to the fact that in TRITON there was a mandatory delay requirement for loading in all UA/NSTEMI and STEMI patients with the symptom onset over 12 h to PCI , and, in fact, loading occurs at the discretion of the interventionalist. Therefore, it is not surprising that 56% of TRITON patients received loading not during, but rather after, the coronary intervention (see Fig. 1 for details). This critical graph, which was shown only once at CME presentation, not only contradicts the data presented in the Table 1 of the main TRITON paper that 74% of patients in the trial received loading with thienopyridine during PCI , but rather clearly indicates that when pretreatment, or at least loading, during the intervention occurs, the outcome benefit of prasugrel is lacking.
| ACS Type | Before PCI | During or after PCI |
|---|---|---|
| STEMI | 25% | 75% |
| UA/NSTEMI | 22% | 78% |
In short, even before the detailed FDA TRITON analyses became available, there was sufficient evidence to suggest that the trial was designed with a disadvantage for patients treated with clopidogrel. Approximately half of the study population did not receive the standard of care in acute phase favoring more potent and faster antiplatelet protection with prasugrel.
2
What was previously known
The use of loading/maintenance ratio in TRITON was 6:1 for prasugrel (60 mg loading, followed by 10 mg maintenance) vs. 4:1 (300 mg loading followed by 75 mg maintenance) ratio for clopidogrel obviously favoring prasugrel due to not only higher doses , but faster action as well . Importantly, loading with 40 mg prasugrel was already tested in the JUMBO study , and if the goal was to match closely the regimens, and to design TRITON fairly, 40 mg loading with prasugrel should be tested against the 300-mg loading dose of clopidogrel. Another disadvantage for clopidogrel relates to the fact that in TRITON there was a mandatory delay requirement for loading in all UA/NSTEMI and STEMI patients with the symptom onset over 12 h to PCI , and, in fact, loading occurs at the discretion of the interventionalist. Therefore, it is not surprising that 56% of TRITON patients received loading not during, but rather after, the coronary intervention (see Fig. 1 for details). This critical graph, which was shown only once at CME presentation, not only contradicts the data presented in the Table 1 of the main TRITON paper that 74% of patients in the trial received loading with thienopyridine during PCI , but rather clearly indicates that when pretreatment, or at least loading, during the intervention occurs, the outcome benefit of prasugrel is lacking.
| ACS Type | Before PCI | During or after PCI |
|---|---|---|
| STEMI | 25% | 75% |
| UA/NSTEMI | 22% | 78% |
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