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MEDICAL FRONTIERS - 82nd Scientific Sessions of the American Heart Association

Orlando, Florida / November 14-18, 2009

New data suggest that the interpatient variability in response to antiplatelet therapy can be circumvented with new agents that have a more predictable antiplatelet effect or by platelet function testing. Multicentre studies evaluating two reversible P2Y₁₂ inhibitors and platelet function testing illustrate new directions in treatment.

The most significant of the results so far has been with ticagrelor, a reversible P2Y₁₂ inhibitor. Initial results of the PLATO (PLATelet Inhibition and Patient Outcomes) trial involving ticagrelor and clopidogrel were published several months ago, but a latebreaking presentation here at the AHA provided data on the subset of ACS patients presenting with an ST-elevation myocardial infarction (STEMI).

“Once again, we see a reduction in total mortality among those randomized to ticagrelor. This is not something that is very common when comparing two active agents in cardiovascular (CV) disease,” stated Dr. Gabriel Steg, Director, Coronary Care Unit, Hôpital Bichat-Claude Bernard, Paris, France. “We are seeing this mortality reduction on top of modern care, so this is providing very clear evidence of a clinical advantage that speaks to both efficacy and safety.”

Study Findings from STEMI Population

In the PLATO study, 18,624 patients who were admitted to a hospital with ACS were randomized to ticagrelor (loading dose of 180 mg followed by 90 mg b.i.d.) or clopidogrel (loading dose of 300 or 600 mg followed by 75 mg q.d.) (Wallentin et al. N Engl J Med 2009; 361:1045-57). At 12 months, ticagrelor was associated with a 16% reduction (HR 0.84; 95% CI, 0.77-0.92; P<0.001) in the relative risk of the primary composite end point of death from vascular causes, MI or stroke compared to clopidogrel. There was no significant difference in the rate of major bleeding.

In newly reported outcomes in the 8430 PLATO STEMI patients, the results favouring the novel agent were almost exactly the same. The primary end point was reduced by 15% (HR 0.85; 95% CI, 0.74-0.97; P=0.02) in those receiving ticagrelor relative to those receiving clopidogrel, while the rate of major bleeding was lower but not significantly different among those receiving ticagrelor compared to those receiving clopidogrel (HR 0.96; 95% CI, 0.83-1.12; P=0.63).

Figure 1.

Importantly in a population in which almost all patients underwent percutaneous intervention (PCI) and the majority received a stent, ticagrelor also provided substantial relative reductions in stent thrombosis. Whether defined as definite thrombosis (39% reduction; P=0.01), probable or definite thrombosis (31% reduction, P=0.01) or possible, probable or definite (27% reduction; P=0.02), the advantage of ticagrelor was observed early and persisted throughout the course of the study.

Like the 22% (P<0.001) relative reduction in all-cause mortality observed in the complete PLATO dataset, STEMI patients randomized to the novel agent had an 18% reduction (HR 0.82; 95% CI, 0.68-0.99; P=0.04) in mortality relative to clopidogrel at the end of 12 months. Several experts, including the discussant invited by the AHA to evaluate the PLATO STEMI results, Dr. Lisa K. Jennings, Vascular Biology Center, University of Tennessee Health Science Center, Memphis, placed particular emphasis on this outcome. More specifically, the substantial mortality advantage validated that the large reduction in CV events was not modified by a relative disadvantage in the risk of bleeding, which has been the key obstacle to employing more potent antipl
ast.

Figure 2.

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Mechanism of Action

Dr. Jennings indicated that these results confirm several pharmacological advantages of a reversible P2Y₁₂ inhibitor. “The potential explanations for the greater efficacy of ticagrelor include the fact that it does not require metabolic activation, which is required for both clopidogrel and prasugrel,” Dr. Jennings told delegates. “A more reversible characteristic may make this agent better suited for the immediate goal of rapid inhibition of platelet function while reducing the risk of bleeding complications.”

The antiplatelet agents ticagrelor, clopidogrel and prasugrel all inhibit the P2Y₁₂ adenosine diphosphate receptor, which is a key factor in platelet aggregation. Relative to clopidogrel, both ticagrelor and prasugrel have a much faster onset of action. Unlike clopidogrel, which has diminished effect in up to 30% of patients due primarily to genetic polymorphisms that affect liver metabolism, neither ticagrelor nor prasugrel are burdened by substantial interpatient differences in response. However, ticagrelor, unlike prasugrel or clopidogrel, is a reversible P2Y12 inhibitor, which may partly explain why ticagrelor did not increase bleeding despite a reduction in vascular events. In the TRITON-TIMI 38 (Trial to assess improvement In Therapeutic Outcomes by optimizing platelet iNhibition with prasugrel – Thrombolysis In Myocardial Infarction 38), prasugrel was also more effective than clopidogrel but was associated with increased bleeding. ONSET-OFFSET Study

The clinical dimensions of a reversible effect, which substantially increases versatility in the management of ACS patients, was the specific focus of the ONSET-OFFSET study presented here at the AHA. In this multicentre, double-blind study, 123 patients with stable coronary artery disease (CAD) currently receiving ASA (75-100 mg) were randomized to ticagrelor (180-mg loading dose followed by 90 mg b.i.d.) or clopidogrel (600-mg loading dose followed by 75 mg daily). The times to onset and offset at six weeks were compared. There were highly significant differences in both.

“By one hour [after administration], the antiplatelet effect on ticagrelor was two times greater than the maximum effect of clopidogrel at six hours,” reported Dr. Paul Gurbel, Sinai Center for Thrombosis Research, Johns Hopkins University, Baltimore, Maryland. At two hours, 70% or greater inhibition of platelet activity (IPA) was achieved in 90% of patients receiving ticagrelor vs. 16% of patients (P<0.0001) receiving clopidogrel.

Conversely, although the IPA was similar in the two groups 24 hours after therapy had been discontinued, the subsequent offset was far more rapid on ticagrelor despite a much greater peak platelet inhibition, reflecting its reversibility. At three days, the IPA on ticagrelor was comparable to the IPA on clopidogrel at five days. At five days, the ticagrelor IPA was comparable to the IPA on clopidogrel at seven days. As Dr. Gurbel explained, these have very important implications for ACS patients in the acute setting requiring coronary artery bypass grafting (CABG) when PCI is found unsuitable, but it would be an advantage at any time when prompt offset of effect would be clinically valuable.

Results from the CHAMPION Trials

In reducing vascular events without increasing risk of bleeding, the dynamics of onset and offset appear to be important, given the negative results from two separate but related studies of cangrelor, another reversible P2Y12 inhibitor. The studies were called the CHAMPION PCI and the CHAMPION PLATFORM trials. Both compared cangrelor (30-µg/kg loading dose followed by 4 µg/kg/min) to clopidogrel 600 mg in ACS patients undergoing a planned PCI. The difference in the studies was that patients in the CHAMPION PCI study received either cangrelor or clopidogrel 600 mg at the time of the procedure (followed by clopidogrel 75 mg in both groups), whereas patients in the CHAMPION PLATFORM study were randomized to cangrelor or placebo. After the procedure, both groups in the CHAMPION PLATFORM study received clopidogrel 600 mg. Outcomes at 48 hours were compared.

In the CHAMPION PCI study, 8716 patients were randomized to study drugs. At 48 hours, there was no significant difference in the composite end point of all-cause mortality, MI or ischemia-driven revascularization for cangrelor relative to clopidogrel (HR 1.05; 95% CI, 0.88-1.24; P=0.59) although the higher rate of major bleeding on cangrelor did approach statistical significance (HR 1.26; 95% CI, 0.99-1.60; P=0.06).

In the CHAMPION PLATFORM study, which was stopped prematurely after an interim analysis predicted that cangrelor would not be superior, 5362 patients were randomized. At 48 hours, there was a non-significant 13% reduction (HR 0.87; 95% CI, 0.71-1.07; P=0.17) in the composite end point of death, MI or ischemia-driven revascularization for cangrelor relative to clopidogrel. Although cangrelor did produce a 69% reduction (HR 0.31; 95% CI, 0.11-0.85; P=0.02) in stent thrombosis and a 67% reduction (HR 0.33; 95% CI, 0.12-0.83; P=0.02) in death from any cause relative to clopidogrel, it did increase major bleeding by 61% (HR 1.61; 95% CI, 1.23-2.1; P<0.001).

Several experts, including the senior author of the CHAMPION PCI trial, Dr. Robert A. Harrington, Director, Duke Clinical Research Institute, Durham, North Carolina, remarked that CHAMPION PCI results did not negate a potential benefit from cangrelor. He reported that several changes, including longer infusion times, are being considered in future studies.

“Our findings, combined with those from the companion CHAMPION PLATFORM study, suggest that cangrelor reduces the risk of some clinically meaningful ischemic events in patients undergoing PCI, including stent thrombosis,” Dr. Harrington maintained. “With its fast onset and reversibility, we believe that cangrelor continues to hold promise. The results of these studies were disappointing, but there is suggestion of potential benefit to warrant further investigation.”

The results were considered particularly disappointing after the substantial advantage of ticagrelor over clopidogrel as a first-line agent in unselected ACS patients, including those, as in STEMI PLATO, who went on to receive a PCI. Further analysis of the onset-offset differences between ticagrelor and cangrelor might be useful both for understanding the differences in efficacy for these agents relative to clopidogrel and in the differences in relative risk of bleeding.

Measuring Platelet Activity

As part of current efforts to improve efficacy of clopidogrel, particularly in the 30% of patients who do not now achieve the predicted antiplatelet response, another latebreaking study presented here at the AHA tested a strategy of platelet function analysis. Although platelet reactivity testing has been long employed as a research tool, a study called POPULAR was a comparison of specific studies that might be employed in the acute setting to determine whether patients are receiving an adequate antiplatelet therapy.

Of the eight tests evaluated, three predicted the primary end point of all-cause death, MI, urgent revascularization, stent thrombosis or stroke at the end of 12 months. These commercially available tests were Light Transmittance Aggregometry (LTA), VerifyNow-P2Y₁₂ and Plateletworks. Several tests were not predictive of the clinical end point, but it is still not clear whether altering therapy based on these tests would improve outcome or which test is the most practical from a clinical standpoint.

“Some of these tests are more labour-intensive than others and may require trained personnel, but one of the tests that was predictive is fairly easy to use at the bedside,” noted senior investigator Dr. Jurriën M. ten Berg, St. Antonius Hospital, Nieuwegein, The Netherlands, referring to the VerifyNow-P2Y₁₂ test. However, he indicated that further feasibility testing is needed, particularly studies to determine whether platelet function tests can predict both efficacy and risk of bleeding.

Inhibiting platelet activity in patients with ACS has long been recognized as one of the most important steps to preventing thrombotic events. While the benefits of clopidogrel have been well demonstrated, the limitations have become better recognized with the development of alternatives that act more quickly and more consistently. However, the more important obstacle to greater reductions in clinical events may be the close correlation between greater anti-thrombotic activity and greater risk of bleeding. The recent trials are identifying strategies that improve protection against vascular events without a major increase in clinically significant bleeds.

Summary

Results of the PLATO STEMI, CHAMPION PCI, CHAMPION PLATFORM and POPULAR trials, all presented as latebreaking data here at the AHA, indicate substantial progress toward better strategies to prevent vascular events in ACS patients. Of these studies, PLATO STEMI generated the most important immediate findings by demonstrating that a reversible P2Y₁₂ inhibitor can significantly reduce events and all-cause mortality without increasing risk of major bleeding in ACS patients. The CHAMPION PCI and PLATFORM studies, although negative, provided insight about timing of platelet inhibition that is likely to be applied in future trial designs. The POPULAR study demonstrated that bedside measurements of platelet activity may be a feasible approach to modifying antiplatelet regimens, although it is now necessary to demonstrate that changes in treatment based on platelet function improve outcome.