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PRIORITY PRESS - 59th Annual Scientific Session of the American College of Cardiology

Atlanta, Georgia / March 14-16, 2010

The data generated by recent phase III, multinational trials directly comparing the newer antiplatelet agents ticagrelor and prasugrel with clopidogrel, the long-time standard, demonstrate that greater protection against vascular events can be achieved with greater antiplatelet effect. The large reductions in the primary composite end point of death from cardiovascular causes, nonfatal myocardial infarction and nonfatal stroke for both agents relative to clopidogrel indicate that the potency of antiplatelet therapies can be increased. However, important considerations should be made for the potential increased risk of bleeding events in certain patients.

In PLATO (Study of Platelet Inhibition and Patient Outcomes), the reduction in the composite end point for ticagrelor relative to clopidogrel was 16% (HR 0.84; 95% CI, 0.77-0.92; P<0.001) in patients admitted to hospital with acute coronary syndrome (ACS) whether or not they had an ST-segment elevation. In TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction 38), this composite end point was reduced 19% (HR 0.81; 95% CI, 0.73-0.90; P<0.001) on prasugrel treatment relative to clopidogrel in patients hospitalized with ACS and scheduled for a percutaneous intervention. The greater efficacy in both cases is consistent with a large body of experimental evidence demonstrating that these newer agents work more quickly and more effectively.

According to Dr. Jeffrey Anderson, University of Utah School of Medicine, Salt Lake City, “There is likely to still be a role for clopidogrel in selected patients so I do not think that this agent will be abandoned, but these large studies demonstrate that it is not the most effective antiplatelet agent for reducing vascular events in an ACS population even when used in higher doses.”

A similar assessment was made by Dr. Deepak Bhatt, Director, Integrated Interventional Cardiovascular Program, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. He noted that in TRITON-TIMI 38, the 2.2% absolute risk reduction (P<0.001) with prasugrel relative to clopidogrel in the primary composite end point of major vascular events exceeded the 0.3% absolute increase (P=0.002) in fatal bleeding. In PLATO, there was no significant difference between ticagrelor and clopidogrel for rates of major bleeding.

As published last year in PLATO (Wallentin et al. N Engl J Med 2009;361:1045-57), there was also a significant 22% relative reduction in all-cause mortality (HR 0.78; 95% CI, 0.69-0.89; P<0.001). In a recent subgroup analysis conducted in the 1899 PLATO patients who underwent coronary artery bypass grafting (CABG) post-randomization, the relative reduction with ticagrelor in death from any causes was even greater, reaching 51% (HR 0.49; 95% CI, 0.32-0.77; P<0.01). These results, from an analysis led by Dr. Claes Held, Uppsala Clinical Research Centre, Uppsala University, Sweden, not only validate an efficacy advantage, but they also help validate one of the features of ticagrelor which—unlike both clopidogrel and prasugrel—is a reversible agent. While all three of these agents exert an antiplatelet effect by inhibiting the P2Y12 receptor, both ticagrelor and prasugrel act more quickly and with greater potency, so that peak effects are achieved more rapidly. However, unlike clopidogrel or prasugrel, which are irreversibly bound, ticagrelor comes off the receptor at the end of its pharmacologic activity, restoring platelet function. ACS patients who are likely to require CABG are among those for whom reversibility is an advantage because of the opportunity to more favourably time the return of platelet activity. Under the PLATO protocol, which called for discontinuation of clopidogrel five days before and ticagrelor 24 to 72 hours prior to CABG, there were no significant differences in CABG-related major bleeding between the two treatment arms.

In the TRITON-TIMI 38 study published more than two years ago (Wiviott et al. N Engl J Med 2007;357:2001-15), there were some patient groups for whom there was no relative advantage and a potential for harm with prasugrel over clopidogrel. These included patients older than 75, patients who weighed less than 60 kg and patients with a history of stroke or transient ischemic attack. It is the range of benefit-to-risk among patients in the TRITON-TIMI 38 trial that has led to calls for individualization of therapy once these newer, more potent antiplatelet agents become available.

“There are clearly patients who can benefit from greater antiplatelet effect, and in these patients we have a potential to substantially reduce the risk of vascular events with these newer agents,” reported Dr. Marc Sabatine, Brigham and Women’s Hospital.

Dyspnea and Ventricular Pauses

While ticagrelor was well tolerated in PLATO, the two safety concerns that emerged from the data were dyspnea (13.8% vs. 7.8%; P<0.001) and ventricular pauses of at least 3 seconds on Holter monitoring (5.8% vs. 3.6%; P=0.01). Both have been the focus of new analyses to gauge their clinical significance. In one, a substudy of pulmonary function was conducted in 199 PLATO patients. The patients were evaluated with pulse oximetry, spirometry, lung volumes and diffusion capacity. Tests were performed on study medication and then 20 to 30 days after the antiplatelet agents were discontinued. The study was unable to find any difference in pulmonary function between the two groups at any timepoint.

“These data suggest that the dyspnea is not the result of a change in lung function on ticagrelor but some transient effect,” reported Dr. Robert F. Storey, University of Sheffield, UK. He noted that in the overall results of PLATO, less than 1% (0.9%) discontinued ticagrelor for dyspnea even though more than 10% (13.8%) had at least one episode. Asked to speculate on the cause, Dr. Storey suggested, “We think that it relates to the activity on adenosine. Ticagrelor inhibits uptake of adenosine which is involved in lung reactivity, although this has not yet been proven as a cause of the dyspnea observed.” The same mechanism of action is suspected in the greater rate of ventricular pauses in PLATO. In another PLATO substudy that evaluated 2908 patients with continuous electrocardiogram monitoring over 7 days, there was a higher number of ventricular pauses lasting at least 3 seconds in the ticagrelor group, but the difference between the two groups was most pronounced and only statistically significant at randomization. By day 30, the slightly higher rate in the ticagrelor group was no longer significant, although these ventricular pauses were significantly more common in patients with more than four pauses over any eight-hour period during night-time hours (but not during day or evening hours).

“Most pauses [66%] were sinoatrial nodal and most were asymptomatic,” reported Dr. Benjamin M. Scirica, Brigham and Women’s Hospital. Reiterating that the most likely explanation is transient blockade of adenosine uptake, Dr. Scirica added, “We did not observe any clinical consequences related to the excess of these pauses, so the importance even among patients with a known arrhythmia is uncertain.”

Summary

Two new antiplatelet agents have demonstrated greater protection against major vascular events in patients with ACS. The greater efficacy in the blinded and controlled multinational trials is attributed to faster onset of action and greater antiplatelet effect. Moreover, neither agent is burdened by the variability of effect and resistance that has been an obstacle to optimal antiplatelet effects with clopidogrel. Although the greater antithrombotic effect of prasugrel is accompanied with a greater risk of bleeding, ticagrelor, which has reversible activity, has not been associated with an increase in major bleeding relative to clopidogrel. In addition, the reduction in all-cause mortality has provided greater benefit from employing ticagrelor in ACS patients. The data predict an important evolution in first-line antiplatelet therapy.