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 2010

Montreal, Quebec / October 23-27, 2010

Two large multinational trials discussed here at the CCC have demonstrated that when clopidogrel is substituted for either prasugrel or ticagrelor in a dual antiplatelet regimen in patients being treated for an acute coronary syndrome (ACS), major cardiovascular (CV) event rates are reduced. The trial designs were different, but both indicated that clopidogrel is inferior for secondary prevention in the ACS setting. The features of prasugrel and ticagrelor also differ. The new era of antiplatelet therapy in ACS patients requires an understanding of these differences and how they can be best applied to achieve optimal protection from recurrent thrombotic events.

“The next generation of oral antiplatelets features quicker, more efficient and simpler metabolism,” stated Dr. Philippe-Gabriel Steg, Director, Coronary Care Unit, Centre Hospitalier Bichat-Claude Bernard, Paris, France. Citing the randomized, double-blind multinational trials, Dr. Steg emphasized that both of the newer agents provided highly statistically significant reductions in a composite end point of death from vascular causes, myocardial infarction (MI) or stroke relative to clopidogrel. However, he indicated that it might not be possible to substitute the old standard of clopidogrel/ASA with a single new standard. Rather, it may be necessary to customize antiplatelet therapy to achieve optimal antithrombotic effect with minimal bleeding risk.

TRITON-TIMI 38, PLATO Findings

Clopidogrel, prasugrel and ticagrelor are all inhibitors of the P2Y₁₂ receptor on the platelet surface, preventing formation of platelet thrombus. Clopidogrel and prasugrel are irreversible inhibitors, and both are prodrugs. Their active metabolites are equipotent in terms of platelet inhibition but prasugrel is more effectively converted to its active metabolite, through a process involving a single hepatic CYP-dependent step. It has a faster onset of action and less interindividual response variability than clopidogrel.

On the basis of the TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38) (Wiviott et al. N Engl J Med 2007;357:2001-15), prasugrel was recently approved for use in ACS patients scheduled for a percutaneous coronary intervention (PCI). Ticagrelor, which is in late stages of regulatory review, is the first oral reversible P2Y₁₂ inhibitor. In an all-comer ACS population enrolled in the PLATO (Platelet Inhibition and Patient Outcomes) study, ticagrelor was significantly superior to clopidogrel for the primary composite end point but also provided a 16% (P<0.001) relative reduction in death from any cause (Wallentin et al. N Engl J Med 2009;361:1045-57).

Further commenting on PLATO, “I think it was the reversibility. The lower risk of bleeding [from this reversibility] preserved the advantage from the protection against events,” suggested Dr. Deepak L. Bhatt, Chief of Cardiology, VA Boston Healthcare System, Massachusetts. Calling the reduction in mortality “real, believable and important,” Dr. Bhatt indicated that understanding the differences between the antiplatelet drugs will be critical to employing them correctly for different degrees of risk relative both to thrombotic events and to bleeding.

In past studies, there has been a close correlation between increased antithrombotic effect and increased risk of bleeding events. This was again seen in the TRITON-TIMI 38 trial in which patients were randomized to clopidogrel or prasugrel after angiography when patients were scheduled for a PCI. The 19% (P<0.0001) relative reduction in the primary composite end point of vascular events was accompanied with a 32% (P=0.03) relative increase in the risk of bleeding. However, the benefit:risk ratio for every 1000 patients treated remained favourable with an estimated 23 MIs avoided for every 6 major hemorrhages caused.

As a result of this study, prasugrel is indicated in ACS patients undergoing PCI, but patient selection remains potentially important. On the basis of subsequent TRITON-TIMI 38 data analysis, Dr. Steg told delegates that no net clinical benefit was found in patients =75 years old or weighing <60 kg. There was an adverse effect in patients with a previous stroke or transient ischemic attack. This underlines the need for tailoring antiplatelet therapy in ACS so that the advantage of greater platelet inhibition with prasugrel is not outweighed by the increased risk of bleeding.

In PLATO, the correlation between increased antithrombotic effect and increased risk of bleeding was far less remarkable. In this study, randomization of the ACS patients was conducted immediately after hospital admission, “upstream of angiography,” and before subsequent treatment strategies were known, Dr. Steg told delegates. There was no difference in major bleeding between the clopidogrel or ticagrelor arms (P=0.43). When bleeding stratifications were performed in detail, there was an increase in bleeding not related to coronary artery bypass grafting (CABG) (4.5% vs. 3.8%; P=0.03) in the ticagrelor group, but there was no significant difference in fatal bleeding, life-threatening bleeding or bleeding requiring transfusion. All 3 of these types of bleeding were significantly increased on prasugrel relative to clopidogrel in TRITON-TIMI 38.

The absence of a significant increase in overall major bleeds, which are believed to impose a variety of risks independent of direct bleeding-related fatality (e.g. a pro-thrombotic inflammatory response to transfusions), may explain the mortality benefit in PLATO. This not only included the reduction in all-cause mortality, but also a 21% (HR 0.79; 95% CI, 0.69-0.91; P<0.001) reduction in death from vascular causes, which is consistent with the theory that bleeding is an independent risk factor for major adverse cardiac events. This is an emerging clinical issue for considering the benefit:risk ratios of the duration of maintenance antiplatelet regimens in ACS patients. While it is clear that ACS patients remain at increased lifetime risk of recurrent thrombotic events, it is unclear what degree of platelet inhibition provides the greatest protection against these events without imposing an unacceptable burden of bleeding.

Debate: Optimal Duration of Antiplatelet Therapy

“The default in Canada seems to be 12 months of dual antiplatelet therapy,” observed interventional cardiologist Dr. Michael P. Love, Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia. However, participating in a debate about the optimal duration of therapy, Dr. Love cited data from CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) (N Engl J Med 2001;395:494-502) indicating that thrombotic risk diminished about 3 months after the acute episode but bleeding risk remained constant over the 12 months of follow-up. He questioned the benefit:risk ratio for applying a standard duration of 12 months of dual antiplatelet therapy in lower-risk patients, such as those who have not undergone PCI and have not received a stent.

His opponent in the debate, Dr. Shaun G. Goodman, Associated Head, Division of Cardiology, St. Michael’s Hospital, Toronto, Ontario, interpreted the same data differently. Citing a subsequent analysis (Yusuf et al. Circulation 2003;107:966-72), Dr. Goodman agreed that the bleeding risk remains constant, but he emphasized that it did not increase over time, even though protection from events continued to accrue. He suggested that extended dual antiplatelet therapy could be considered for a much broader array of ACS patients over a longer period. Recently released CCS guidelines recommend dual antiplatelet therapy for at least a month but allow consideration of treatment for up to 12 months and even longer for high-risk patients with a low risk of bleeding.

However, the duration of dual antiplatelet therapy has been based on studies with clopidogrel. The introduction of newer agents with different benefit:risk profiles may allow maintenance therapy to be tailored in the same way that antiplatelet agents will be increasingly optimized in the acute setting. The critical issue will be better stratification of patients by both risk of thrombotic events and bleeding. The newer agents are expected to expand options substantially and produce the same type of evolution in long-term therapy as is now underway in early treatment.

Summary

In TRITON-TIMI 38 and PLATO, respectively, prasugrel and ticagrelor were both found to be superior to clopidogrel for reducing the risk of thrombotic events in acute treatment of ACS patients. Both studies demonstrating this advantage challenge clopidogrel/ASA as the standard in ACS populations. Differences between the studies demonstrating these advantages as well as between the agents themselves suggest opportunities to tailor antiplatelet therapy according to underlying risk of thrombotic events as well as risk for major bleeds. These differences are relevant to initial treatment as well as to maintenance therapy for which optimal regimens and duration remain unsettled. Such characteristics as potency and reversibility are expected to be relevant to efforts to optimize benefit:risk ratios.