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MEDICAL FRONTIERS - European Society of Cardiology (ESC) 2010 Congress

Stockholm, Sweden / August 28-September 1, 2010

The recent approval of prasugrel in Canada for acute coronary syndromes (ACS) in patients with scheduled percutaneous coronary intervention (PCI) was largely based on results of the TRITON-TIMI 38 (TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitiON). This trial associated prasugrel, a P2Y₁₂ receptor inhibitor, with greater reduction in a composite end point of thrombotic events than clopidogrel (Wiviott et al. N Engl J Med 2007;357:2001-15). The relative advantage of prasugrel over clopidogrel can be found in its pharmacokinetics. Although newer agents within the same drug class promise similar advantages of rapid onset and greater peak antiplatelet effect, these are reversible, accelerating recovery of platelet activity. The potential advantages over both clopidogrel and prasugrel are substantial.

According to Dr. Claes Held, Uppsala Clinical Research Centre, Sweden, “One drawback of clopidogrel is its slow and inefficient transformation to an active metabolite. In addition, clopidogrel provides irreversible platelet inhibition so that recovery of platelet function does not occur for 5 to 7 days. Guidelines therefore recommend stopping clopidogrel 5 days prior to CABG [coronary artery bypass grafting], but this is often a problem in the ACS patient who has already received full doses of clopidogrel and ASA on an urgent basis.”

The P2Y₁₂ Receptor Inhibitor Class: Study Findings

There are three reversible P2Y₁₂ receptor inhibitors that have reached clinical testing. Although one, cangrelor, which is administered intravenously, did not show non-inferiority to clopidogrel for ACS in randomized trials (Harrington et al. N Engl J Med 2009;361:2318-29, Bhatt et al. N Engl J Med 2009;361:2330-41), it may still have a role in patients who cannot take an oral medicine. The other two, ticagrelor and elinogrel, have demonstrated encouraging efficacy and safety, and their reversibility may be among their most important advantages. Compelling results were generated by the PLATO (PLATelet inhibition and patient Outcomes) trial which associated ticagrelor with a significant reduction in a composite end point of thrombotic events relative to clopidogrel (Wallentin et al. N Engl J Med 2009;361:1045-57). Unlike TRITON-TIMI 38, the relative advantage extended to ACS patients who were medically managed or who underwent CABG.

“In TRITON, the rate of major bleeding among patients undergoing CABG was significantly higher in prasugrel compared to clopidogrel patients,” Dr. Held told delegates. “In PLATO, 1261 patients among the 18,624 randomized underwent CABG and received the study drug within 7 days of surgery. On ticagrelor, relative to clopidogrel, CABG patients had a substantial reduction in total mortality (4.7% vs. 9.7%) and cardiovascular mortality (4.1% vs. 7.9%) but without any change in the risk of CABG-related bleeding.”

There is a broad array of targets to prevent activation of platelets, but the binding to the P2Y₁₂ receptor activates platelets regardless of stimulus, making it perhaps the best single target of antithrombotic agents. As the first P2Y₁₂ inhibitor, clopidogrel is highly effective but requires hepatic metabolism to generate its active metabolite. Due to common genetic polymorphisms, up to 30% of patients on clopidogrel have a suboptimal response. The advantage of prasugrel in TRITON-TIMI 38 is attributed to faster onset of action, less inter-individual differences in response and a greater peak antiplatelet effect. Although this greater activity was accompanied by a higher risk of major bleeds, it was associated with a favourable benefit:risk ratio in most patients. Exceptions (who are now considered to have a relative contraindication for prasugrel) included patients older than 75 years, those with a previous cerebrovascular event and those with a body weight of less than 60 kg.

Although TRITON-TIMI 38 limited entry to ACS patients with a scheduled PCI, PLATO included all ACS patients, including those who had been given clopidogrel prior to randomization. Like TRITON-TIMI 38, PLATO also associated the experimental drug ticagrelor with a significant reduction in major thrombotic events relative to clopidogrel. However, unlike TRITON-TIMI 38, PLATO did not show a difference between ticagrelor and clopidogrel for total major bleeding. This is the first important study in which greater protection from thrombotic events from an antiplatelet agent was not counterbalanced by bleeding. This may explain why PLATO was also the first study to associate one antiplatelet strategy with a significant mortality benefit over another in ACS patients.

While a rapid onset and greater peak antiplatelet effect may explain the efficacy advantage of ticagrelor over clopidogrel, the reversibility of ticagrelor may explain why greater antithrombotic effect is not accompanied by greater bleeding. The differences between ticagrelor and clopidogrel in onset—which measures the time to antiplatelet effect— and offset—which measures the time to restoration of platelet activity were first documented in the ONSET/OFFSET trial, which was published last year (Gurbel et al. Circulation 2009;120:2577-85). Among the findings was that 98% of ticagrelor patients vs. 31% of clopidogrel patients (P<0.0001) had more than 50% inhibition of platelet activity by 2 hours after the loading dose, but that the offset was also faster. Indeed, the slope of offset over 72 hours after the last dose was twice as greater on ticagrelor relative to clopidogrel (P<0.0001). In a new subanalysis of the same study, the advantage was retained even in optimal clopidogrel responders.

“Patients were only included in this subanalysis if they had a high response to their assigned therapy,” explained the lead author of this study, Dr. Robert Storey, Department of Cardiovascular Science, University of Sheffield, UK. Of the criteria for the strictly-defined “high response,” patients had to have more than 75% inhibition of platelet aggregation within 4 hours of their loading dose. This included 83% of those randomized to ticagrelor and 39% of those randomized to clopidogrel. Several assays were used to measure offset, and the advantage of ticagrelor was significant across all of them. Specifically, recovery of platelet function was much faster between 4 and 48 hours leading to significantly greater platelet reactivity at all timepoints measured between 48 and 168 hours (Figure 1).

Figure 1.

“These findings may have important clinical implications,” Dr. Storey explained. “There may be a lower risk of bleeding following treatment with ticagrelor than clopidogrel in patients undergoing surgery between 48 hours and 7 days’ post-dose due to the fast return to baseline platelet activity.”

Several experts, including Dr. Storey, have suggested that the variability in response to clopidogrel argues for baseline monitoring when this agent is used in place of newer ones that have a more predictable response. This may also be relevant to return of platelet function after stopping therapy. According to the subanalysis of the ONSET/OFFSET study, the greater antiplatelet response on clopidogrel may have an even slower offset. According to Dr. Storey, this slower offset “influences the time to recovery of platelet function, and therefore bleeding risk, if surgery is required within 7 days of clopidogrel discontinuation.”

Low HPR Rate

In another new analysis, using data from both the ONSET/OFFSET study and the RESPOND study, ticagrelor was also found to circumvent the risk of high on-treatment platelet reactivity (HPR), a common problem with clopidogrel and an established risk factor for adverse events after coronary stenting. The study evaluated HPR in a combined total of 102 patients who had received loading and maintenance doses (180 mg followed by 90 mg b.i.d.) of ticagrelor and 99 patients receiving loading and maintenance doses (600 mg followed by 75 mg o.d.) of clopidogrel. Using several assays, the prevalence of HPR ranged up to 8% on ticagrelor and up to 76% for clopidogrel (P<0.0
able 1).

Table 1.

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“There was a very consistent and marked difference between the rates of HPR on these 2 agents. We propose that the low prevalence of HPR on ticagrelor may contribute to the relative clinical benefit of ticagrelor over clopidogrel reported in PLATO trial,” suggested Dr. Kevin P. Bliden, Sinai Center for Thrombosis Research, Baltimore, Maryland, here at the ESC. He remarked that these data also contribute to the now overwhelming evidence that P2Y₁₂ receptor inhibitors differ markedly for a variety of activities relevant to ACS management.

Movement Towards Tailored ACS Treatment

It is not clear whether elinogrel, another reversible P2Y₁₂ inhibitor that was recently evaluated in a phase II study, shares all of the features of ticagrelor, but this agent also dissociates from the P2Y₁₂ receptor after initial binding, thereby providing the same potential for widening the therapeutic window between antiplatelet effect and risk of bleeding. The phase II study of elinogrel, which is being developed in both oral and intravenous formulations, was a dose-finding study that was not designed to evaluate effect on hard clinical end points such as thrombotic events. However, the results were sufficiently promising that a multicentre controlled trial is now planned, according to Dr. Sunil Rao, Duke Clinical Research Institute, Durham, North Carolina.

With elinogrel and ticagrelor, the major potential advantage is not only more consistent antiplatelet effect but also greater versatility in the ACS setting. The inter-patient differences in response to clopidogrel have increased attention to the differences between patients and the need to individualize therapy. While measuring antiplatelet activity is cumbersome in the emergency room setting, an array of agents that do not require platelet reactivity assays may also be helpful when considering the specific benefit:risk ratio of patients with different risks for major bleeding or for recurrent thrombotic events. This is not only true in the acute setting but also for managing long-term risk in patients who have survived an MI, who have received a stent or who are otherwise at high risk for vascular complications.

“The primary challenge in preventing and managing ACS, both now and in the future, will be to tailor treatments for each patient, taking into consideration patient characteristics, comorbidities, underlying short- and long-term risk factors and expected individual responses,” observed Prof. Lars Wallentin, Professor of Medicine, Uppsala University, Sweden.

For effective reversible P2Y₁₂ receptor inhibitors, there does not appear to be any disadvantage relative to prasugrel or clopidogrel. Although ticagrelor has never been directly compared to prasugrel, the degree of protection against major thrombotic events relative to clopidogrel was similar in independent trials. One of the advantages of both of these agents appears to include a reduced risk of a drug-drug interaction with concomitant use of proton pump inhibitors (PPIs). Lack of an interaction was observed in a post-hoc analysis of TRITON-TIMI 38 in the case of prasugrel and in a new PLATO substudy in the case of ticagrelor. In this latter study, platelet function was evaluated in subgroups of clopidogrel and ticagrelor patients who were or were not taking a PPI. According to the lead author of this substudy, Dr. Shankar B. Patil, University of Sheffield, there was a significant increase in platelet reactivity on clopidogrel but not on ticagrelor across several assays when patients in the PLATO trial were taking a PPI. He indicated that this finding is consistent with the fact that the metabolism of ticagrelor, like that of prasugrel, is not dependent on the hepatic CYP isoenzymes that increase the risk for a drug-drug interaction. Again, this is another variable expected to make the effect of the newer P2Y₁₂ receptor inhibitors more reliable and consistent.

Summary

After many years in which dual platelet inhibition with clopidogrel and ASA has been the recognized standard for reducing risk of recurrent thrombotic events in ACS patients, protocols will now change. Prasugrel is an irreversible P2Y₁₂ inhibitor like clopidogrel, but it has greater antiplatelet effects and despite increasing the risk of major bleeding, provides a better benefit:risk ratio in many ACS patients. Reversible P2Y₁₂ inhibitors are still in clinical development, but one such agent, ticagrelor, has completed a phase III trial and demonstrated a mortality benefit relative to clopidogrel with no increase in overall rates of major bleeding. Additional reversible P2Y₁₂ inhibitors, including intravenous formulations, are now in development and are expected to substantially increase options with the promise of better outcomes in ACS patients.