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PRIORITY PRESS - Canadian Cardiovascular Congress 2010

Montreal, Quebec / October 23-27, 2010

According to new Canadian Cardiovascular Society (CCS) guidelines released here at the CCC, antiplatelet therapy in patients with an acute coronary syndrome (ACS) can now be individualized. While the dual antiplatelet strategy of ASA/clopidogrel has been a standard of treatment in both initial and extended management of ACS, a newer agent, prasugrel, has been added. Its recent approval in Canada provided the basis for the change in the CCS guidelines. The addition represents a significant reorientation in risk management with antiplatelet agents.

Tailoring Therapy Now Mandatory

In secondary risk prevention in ACS patients, “tailored therapy is now mandatory,” stated Dr. Jean-Philippe Collet, Professor of Cardiology, Hôpital Pitié-Salpêtrière, Paris, France. An expert with substantial experience in applying similar strategies to the ones now outlined in the new CCS antiplatelet guidelines, Dr. Collet was invited to the CCC to provide guidance about how to match antiplatelet potency to risk. Although more potent antiplatelet effects have been associated with an increased risk of bleeding, the substitution of prasugrel for clopidogrel in a dual antiplatelet regimen with ASA can provide the opportunity for substantial reductions in major adverse cardiac events when used appropriately.

The decision to approve prasugrel, which is now indicated in combination with ASA for secondary risk prevention in ACS patients undergoing a percutaneous coronary intervention (PCI), was based on a multinational comparative trial. In that study, the novel agent was associated with a 19% (OR 0.81; 95% CI, 0.73-0.90; P<0.001) reduction relative to clopidogrel for the composite end point of death from cardiovascular (CV) causes, nonfatal myocardial infarction (MI) or nonfatal stroke (Wiviott et al. N Engl J Med 2007;357:2001-15). The rate of major bleeding in this 13,608-patient PCI trial, called TRITON-TIMI 38 (Trial to assess improvement In Therapeutic Outcomes by optimizing platelet iNhibition with prasugrel - Thrombolysis In Myocardial Infarction 38), was increased by a relative 32% (P=0.03) in the prasugrel arm, but the overall benefit:risk ratio favouring prasugrel further improved by eliminating readily identifiable high-risk patients, such as those of low weight or advanced age.

“If you take away the vulnerable patients, the HR for the primary composite outcome was 0.75,” reported Dr. Dominick Angiolillo, Director, Cardiovascular Research, University of Florida, Jacksonville. Speaking at the same CCC session as Dr. Collet, Dr. Angiolillo agreed that the 19% to 25% risk reduction warrants a reorientation toward individualization of antiplatelet therapy in ACS patients.

The principles of employing prasugrel to reduce the immediate and extended thrombotic risk in ACS patients are straightforward. The guidelines reiterate their Canadian indication in patients scheduled for PCI and specifically identify it as an option for PCI patients receiving a stent who are at increased risk for thrombosis. There are several potential reasons for increased risk of thrombosis, particularly clopidogrel resistance, but other examples include ST-segment elevation MI (STEMI), the presence of diabetes and a history of stent thrombosis.

Potential for an Alternative Dosing Strategy

The guidelines recommend avoiding prasugrel in patients likely to undergo coronary artery bypass grafting (CABG) within 7 days, who have a history of stroke or transient ischemic attack (TIA), who are aged 75 years or older or who weigh <60 kg.

The latter 2 exclusions stem from a post-hoc analysis of TRITON-TIMI 38 that suggested that the benefit:risk advantage of prasugrel relative to clopidogrel was lost in older patients and those with a low body weight. Dr. Angiolillo indicated that the CCS guidelines are a reasonable interpretation of the TRITON-TIMI 38 data but noted that lowering the dose of prasugrel in low-weight patients is another option that deserves further study. One reason to pursue an alternative dosing strategy is that prasugrel not only provides a greater peak inhibition of platelet reactivity than clopidogrel but is also associated with more rapid onset and greater consistency of effect.

The difference between the 2 antiplatelet therapies, which are both inhibitors of the P2Y₁₂ subtype of the ADP receptor on the platelet surface, is that the metabolism of prasugrel is more rapid. Although both are prodrugs that must be converted to their active metabolites, the greater dependence of clopidogrel on the hepatic CYP450 isoenzyme system explains its slower onset of action. The active metabolite of prasugrel is produced partially during the absorption process. As a result, its antiplatelet activity at 1 hour is similar to that of clopidogrel at 6 hours. In addition, the clinical efficacy of prasugrel, unlike clopidogrel, has not been shown to be adversely affected by CYP2C19 polymorphisms. In clopidogrel patients, it has been estimated that up to 30% of individuals obtain a suboptimal antiplatelet effect.

At least some association is observed between greater protection from CV events and greater risk of bleeding for all drugs that provide an antithrombotic effect, including agents that act on other systems that affect thrombotic risk, such as the coagulation cascade. The results of TRITON-TIMI 38 demonstrate that the antiplatelet effect can be improved with an acceptable risk of bleeding in high-risk patients.

Expanding Array of Antithrombotics: Weighing Efficacy with Bleeding Risk

Other antiplatelet agents are in development that will attempt to provide the same advantage. This includes reversible P2Y12 inhibitors, such as ticagrelor, which has also been evaluated in a large multinational trial. The theoretical benefit of a reversible antiplatelet agent is that it could be halted to permit CABG or other surgery, but this potential advantage has yet to be demonstrated, and irreversible and reversible agents have not been compared for relative efficacy.

“The situation is that the offset of ticagrelor and the other reversible agents we have seen so far is still very slow, so it is not clear that reversibility offers a practical difference,” Dr. Collet told delegates. It is also not yet clear where the role of reversible agents will be defined in treatment guidelines once they receive regulatory approval. However, Dr. Collet did indicate that such agents might further advance the reorientation toward individualized care.

“The risk of thrombotic events varies substantially between ACS patients and we are now obtaining some options to modify therapy according to this risk,” Dr. Collet noted. However, he also indicated that the increase in antiplatelet options might further complicate ongoing questions of how intensively and how long to treat patients with different risk profiles who are recovering from a PCI. Again, the antithrombotic efficacy must be weighed against the bleeding risk for any of the expanding array of therapies.

In the new CCS guidelines, indefinite ASA therapy in a dose of 75 mg to 162 mg is recommended for all ACS patients, while the addition of a P2Y₁₂ receptor inhibitor is recommended for up to 12 months in the absence of excessive bleeding risk. When combined with ASA, prasugrel is specifically identified as an option in the CCS guidelines for up to 12 months in high-risk patients, such as those with a stent after STEMI when considered in the context of the relative bleeding risk.

Summary

New antiplatelet guidelines for ACS patients issued by the CCS reflect the current evidence that secondary prevention of CV events may be improved with individualization of therapy. The guidelines include specific suggestions for the application of prasugrel, the most recently approved antiplatelet agent in Canada for ACS patients undergoing PCI, in risk management. Treatment with ASA/prasugrel, like ASA/clopidogrel, may continue for up to 12 months in suitable patients. Although this combination is not recommended in elderly (=75 years) or low-weight (<60 kg) individuals, or in patients with a history of cerebrovascular disease, the phase III data suggest an opportunity for substantial risk reduction when therapy is individualized to specific risk characteristics.

Based on CCC session: “The Evolution of ACS: A Town Hall Discussion Focusing on Practical Considerations in Antiplatelet Therapy,” Tuesday, October 26, 2010.

This event is an accredited group learning activity under Section 1 as defined by the Royal College of Physicians & Surgeons of Canada for the Maintenance of Certification program. It is approved by the Canadian Cardiovascular Society for a maximum of 1 credit. This conference report was co-developed with the Canadian Cardiovascular Society and Mednet and was planned to ensure the evidence presented is valid, objective and balanced.