Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - Canadian Cardiovascular Congress 2009

Edmonton, Alberta / October 24-28, 2009

There have been two recent multicentre, randomized trials demonstrating that agents which offer more effective platelet inhibition than clopidogrel provide significantly greater protection against thrombotic events. In the first of these, TRITON-TIMI 38 (TRial to assess improvement In Therapeutic Outcomes by optimizing platelet iNhibition with prasugrel - Thrombolysis In Myocardial Infarction 38), the thienopyridine prasugrel produced a 19% reduction (HR 0.81; 95% CI, 0.73-0.90; P<0.001) in the primary composite end point of death from cardiovascular (CV) causes, nonfatal myocardial infarction (MI) or nonfatal stroke. In the second, PLATO (PLatelet inhibition And paTient Outcomes), the reversible ADP P2Y12 receptor antagonist ticagrelor produced a 16% reduction (HR 0.84; 95% CI, 0.77-0.92; P<0.001) in the same end point.

Benefit of Potency

“The data suggest that more potent antiplatelet agents can calm the storms of acute coronary syndrome [ACS],” reported Dr. Stephen D. Wiviott, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, here at the CCC. Senior author of the TRITON-TIMI 38 trial, Dr. Wiviott reported that the results of this study and of the more recently completed PLATO were predicted by relative potency in experimental and clinical studies. In a direct comparison of a prasugrel 60-mg loading dose to the 600-mg loading dose of clopidogrel in patients undergoing a percutaneous intervention (PCI), platelet aggregation inhibition was 33% higher on prasugrel relative to the double-the-standard dose clopidogrel, and the difference was already significant at 30 minutes (Wiviott et al. Circulation 2007;116:2923-32).

This greater potency of prasugrel, along with a more rapid onset of action and freedom from resistance, is credited for producing the results of TRITON-TIMI 38. Over the six to 15 months of follow-up, the relative protection included a 24% relative reduction in MI (P<0.001), a 32% reduction in urgent revascularization (P<0.001) and a 54% reduction in stent thrombosis (P<0.001). Perhaps demonstrating the importance of a rapid onset of action, the reduction in stent thrombosis at 30 days was 71% (P=0.0001).

While TRITON-TIMI 38 enrolled patients with scheduled PCI and PLATO enrolled all patients admitted to a hospital with ACS, they were both testing relative antiplatelet efficacy in a high-risk group using the same end point. In PLATO, ticagrelor has been shown to be more potent for platelet inhibition than clopidogrel in both the experimental and the clinical setting. In both studies, each agent was more effective at reducing both the primary end point and secondary outcomes, such as MI and death from vascular causes than clopidogrel.

Weighing Bleeding Risks to Benefits

Despite the fact that both prasugrel and ticagrelor were more effective than clopidogrel in studies, experts believe that individualized therapy will be essential for optimal benefit. There is a direct correlation with a reduced risk of thrombotic events from greater antiplatelet effect and increased bleeding. As the studies demonstrate, this relative risk differs among patients based on their relative risk for events and their relative vulnerability for bleeds.

“The price to pay with more potent antiplatelet therapies is an increased bleeding risk. This has been seen with prasugrel, high-dose clopidogrel and ticagrelor in the case of spontaneous bleeds,” Dr. Wiviott confirmed. He noted that major bleeding (2.4% vs. 1.8%; P=0.03) and life-threatening bleeding (1.4% vs. 0.9%; P=0.01) were both increased on prasugrel vs. clopidogrel in TRITON-TIMI 38, but the increased bleeding risk was greatly diminished when eliminating patients who weighed less than 60 kg, those with a previous cerebrovascular event and those over the age of 75 years.

Yet relative benefits were even greater in many of the TRITION-TIMI 38 subgroups, such as those with diabetes, in whom the relative risk reduction for reaching the primary end point was 30% (HR 0.70; P<0.001). In patients who entered the study with ST-elevation MI (STEMI), the reduction in the primary end point was 21% (HR 0.79; P<0.01) and there was no increase in major bleeds in this patient population. The increased risk reduction without an increased risk of bleeding was attributed by Dr. Wiviott to the fact that this population was younger than the study population overall, which reduced the likelihood of a previous cerebrovascular event or other bleeding risks.

Individual differences in response to antiplatelet therapy have been a driving force for developing new options. Up to 15% of patients have no response to clopidogrel and almost the same proportion have a subtherapeutic response, according to interventional cardiologist Dr. Robert Welsh, University of Alberta, Edmonton, here at the CCC. Although resistance, which appears to be at least partially genetic, can sometimes be overcome by increasing the dose of clopidogrel, patients who are not responding or not responding adequately must first be identified. Although platelet function tests have been proposed, these may not be practical in the acute setting when rapid introduction of an effective antiplatelet therapy is critical.

Building a Benefit:Risk Algorithm

The evidence that newer antiplatelet agents can significantly reduce thrombotic events in ACS patients predicts treatment algorithms to match benefit:risk advantages with specific patient profiles. For example, prasugrel at the dose studied in TRITON-TIMI 38 does not appear to be appropriate in patients with a low body weight (<60 kg) or the elderly (age >75 years), suggesting that clopidogrel may remain the first-line therapy in these individuals. Conversely, clopidogrel may not be the appropriate choice in high-risk patients undergoing PCI with stent placement even in the absence of clopidogrel resistance.

“Stent thrombosis continues to be a major clinical problem, providing the best evidence that we do not yet have adequate antiplatelet regimens for these patients,” Dr. Welsh told delegates.

It is illogical to expect all patients to derive the same relative benefit:risk ratio from any given antiplatelet effect. There is now substantial evidence that benefits and risks differ for a variety of patient characteristics. Although it is unclear when the newer agents will be made available in Canada, there was a general consensus among interventionalists here at the CCC that these therapies are urgently needed to improve risk management.

As these therapies become available, it may be necessary to adjust antiplatelet effect not only for individual patient characteristics but also for relative risk over the course of treatment, with adjustments to ensure early onset of antiplatelet effect in patients hospitalized with ACS and then to maintain long-term protection. However, it is important to recognize that the overall benefit greatly favoured the newer agents even when including bleeding risk. Based on all patients randomized in TRITON-TIMI 38, for example, it was calculated that 23 MIs would be avoided but only six non-CABG major hemorrhages would be incurred for every 1000 patients treated. These data support an important opportunity to improve outcomes in the ACS population by offering therapies that provide better antiplatelet effects than current options.

Summary

The publication of the TRITON-TIMI 38 and PLATO study findings have confirmed that ACS patients can achieve significantly greater protection against major CV events with more potent antiplatelet therapies than the combination of ASA/clopidogrel. Although greater antiplatelet activity generally correlated with a greater risk of bleeding, the absolute increases in major and life-threatening bleeding has been acceptably low and easily outweighed by the reduction in MIs and death from vascular causes. Yet this benefit:risk ratio will be even more refined with individualized therapy that directs the most potent antiplatelet agents to those at greater risk of thrombotic events. The large benefits achieved with prasugrel in the highest-risk patients, such as those with diabetes or STEMI patients receiving stents, suggest that newer therapies will have an important role in improving outcomes.

Note: At press time, prasugrel and ticagrelor were not available in Canada.