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PRIORITY PRESS - 31st Annual Congress of the European Society of Cardiology

Barcelona, Spain / August 29-September 2, 2009

Beginning with ASA monotherapy, antiplatelet therapy strategies have progressed to the thienopyridine clopidogrel, dual antiplatelet therapies and even triple antiplatelet therapies for greater inhibitory effect in patients at greatest risk. The cumulative data suggest that the relative risk of increased bleeding rises much more slowly than this relative protection from thrombotic events when patients are at a high baseline risk. New and detailed analyses suggest that clinicians need to be aware of the risks of inadequate antiplatelet therapy.

According to Dr. Francisco-Fernández Avilés, Chief of Cardiology, Hospital Universitario Gregorio Marañón, Madrid, Spain, “Antiplatelet regimens must be adjusted to the underlying risk of thrombotic events. We have good data from the clinical trials to show the risk-to-benefit ratio ranges for a variety of factors and individual characteristics.” He added, “We want to avoid excess bleeds but not miss opportunities to prevent major vascular events.”

Balancing Efficacy and Risk

The opportunities and risks have been derived from clinical data. In high-risk patients, studies comparing either prasugrel to clopidogrel or high-dose to low-dose clopidogrel have shown that the relative benefit of the greater antiplatelet effect exceeded the modest increase in risk of bleeding. This has focused attention on the task of subdividing patients to match antiplatelet therapy to specific characteristics. Although known resistance to ASA and clopidogrel is a major obstacle to optimal antiplatelet efficacy, clinical study data indicate that high-risk patients should receive more effective antiplatelet agents.

In the TRITON TIMI-38 study (N Engl J Med 2007;357(20):2001-15), 13,608 moderate to high-risk ACS patients were randomized to prasugrel (60-mg loading dose followed by 10 mg daily) or clopidogrel (300-mg loading dose followed by 75 mg daily). With a more rapid onset and less interpatient variability, prasugrel achieved a 19% reduction in the primary end point of death from cardiovascular (CV) causes, nonfatal myocardial infarction (MI) or nonfatal stroke relative to clopidogrel (RR 0.81; 95% CI, 0.73-0.90; P<0.001). Although for the primary safety end point of major bleeding it was associated with increased risk (RR 1.32; 95% CI, 1.03-1.68; P=0.03), relative benefits among specific groups were easy to differentiate. In particular, those with a previous stroke or transient ischemic attack, age over 75, or body weight <60 kg had an unfavourable balance of risk to benefit vs. almost all other patients. High-risk groups such as individuals with diabetes had a particularly large overall advantage from prasugrel.

“In our department, we now give prasugrel to all patients except those identified at being at higher risk of bleeds in the TRITON study,” Dr. Hugo Katus, Department of Cardiology, University of Heidelberg, Germany, told delegates. Referring to the missed opportunity to prevent thrombotic events by inadequate platelet inhibition, Dr. Katus observed that the data are sufficiently consistent that it is now possible to identify specific risk groups that should receive the most effective antiplatelet regimen.

Although it is clear that greater antiplatelet effect corresponds with greater risk of bleeding, this should not obscure situations when the likelihood of preventing a thrombotic event exceeds that of the risk of bleeding. Recent studies suggest that the loading dose of clopidogrel is too low for many high-risk patients such as those receiving drug-eluting stents. While high-dose clopidogrel (600-mg loading dose followed by 150 mg maintenance) reduces the risk of clopidogrel resistance over standard doses, alternative strategies may be more predictable.

Individualizing Treatment Through Screening Tools

“We need to increase the antiplatelet effect in patients at high risk of thrombotic events,” confirmed Dr. Dominick J. Angiolillo, Division of Cardiology, College of Medicine, University of Florida, Jacksonville. Although Dr. Angiolillo was referring specifically to diabetic patients, his comments are relevant to all high-risk groups. “Our choices [in these patients] are to increase the clopidogrel maintenance dose, use a triple antiplatelet combination or use prasugrel. We must tailor the therapy.”

Increasingly, tailoring therapy may not just be conducted on the basis of clinical risk but also of specific screening tools. Dr. Milika Asanin, University Institute of Cardiovascular Disease, Belgrade, Serbia, reported on a study of 1350 patients that compared antiplatelet therapy adjustment using platelet function assays after PCI. The 30-day risk of a composite end point of death, nonfatal reinfarction, ischemic stroke and target vessel revascularization was reduced by 61% (OR 0.39; 95% CI, 0.2-0.77; P=0.006) in those who had their antiplatelet therapy adjusted when compared to those who did not. In this study, platelet function assays were employed to identify those who continued to demonstrate high platelet reactivity despite standard dual antiplatelet therapy of clopidogrel in a standard dose plus ASA. In those with high reactivity, the clopidogrel dose was doubled.

“By adjusting the antiplatelet therapy after PCI, we were able to show a substantial improvement outcome relative to empirical treatment,” Dr. Asanin reported. Illustrating the principles of individualized therapy, he noted that this approach is being implemented routinely at his institution.

Two studies suggest screening of cytochrome P450 2C19 polymorphisms may also be helpful. In one, 259 patients who had their first MI at <u><</u>45 years of age treated with clopidogrel were evaluated for the presence of the CYP 2C19*2 polymorphism, which has been identified as a factor for poor clopidogrel response. The study found that major adverse CV events (MACE) occurred far more frequently in those with this polymorphism (48%) than those without (8%; P=0.0036). Moreover, when residual platelet aggregation was assessed, a correlation was found with high residual platelet aggregation and MACE.

“The findings demonstrate that the CYP2C19*2 genetic variant is a major determinant of prognosis in young post-MI patients on clopidogrel,” stated Dr. Johanne Silvain, Department of Cardiology, Pitié-Salpêtrière Hospital, Paris, France. “In these patients you either need to test for the polymorphism and adjust your therapy or use a different antiplatelet agent.”

The same conclusion was drawn by an American study which evaluated the relationship of the CYP2C19*2 polymorphism to platelet function in 227 patients on clopidogrel therapy who underwent PCI. As in the French study, those with the polymorphism were at far greater risk of ischemic events when assessed one year after PCI (HR 2.42; P=0.02). The authors of the study, led by Dr. Paul A. Gurbel, Director of Cardiovascular Research, Sinai Hospital, Baltimore, Maryland, concluded that the CYP2 C19*2 polymorphism “is strongly associated with a diminished antiplatelet effect of clopidogrel and reduced CV protection following PCI.”

Concomitant PPI Use

Despite the evidence that CYP2C19*2 polymorphisms do alter response to clopidogrel, pooled data from the TRITON TIMI-38 trial and PRINCIPLE TIMI-44 trial have produced important and highly compelling evidence that concomitant use of PPIs does not have a clinically meaningful effect on the efficacy of clopidogrel or prasugrel. In a presentation by Dr. Michelle L. O’Donoghue, Department of Cardiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, there was no association between PPI use and effect of clopidogrel (HR 0.94; 95% CI, 0.80-1.11) or prasugrel (HR 1.0; 95% CI, 0.84-1.2) on the primary end point of MACE in either study.

“Our findings do not provide any support for avoiding PPI use in patients receiving thienopyridine therapy,” confirmed Dr. O’Donoghue, whose results were simultaneously published in The Lancet (2009;epub September 1). Although she acknowledged that definitive data require a prospective, randomized trial, these pooled data were subjected to a vast array of analyses, including platelet function tests, that produced no signal of an interaction, reversing evidence of a potential association from registries and previous retrospective studies.

Summary

The introduction of newer and more effective antiplatelet therapies and combination strategies is helping to provide very specific information about the balance between anti-thrombotic efficacy and bleeding risk in ACS and STEMI patients. Such trials as TRITON TIMI-38 are generating data to permit algorithms to be created to allow high-risk patients to be directed to the most effective antiplatelet agents, where anti-thrombotic efficacy dominates the benefit:risk ratio. The recognition that therapy must be individualized to achieve the appropriate balance of antiplatelet benefit and risk is critical to optimal clinical practice.