Reports

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European Society of Cardiology Congress 2008

Munich, Germany / August 30-September 3, 2008

Dual antiplatelet therapy is critical for the prevention of thrombosis in both ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) patients with acute coronary syndrome (ACS) and is widely recommended by many expert societies. Nevertheless, rates of recurrent thrombotic events remain high despite treatment. Patients are also at increased risk for bleeding should they need urgent surgery before platelets fully recover. As several investigators here at the ESC noted, the consequences of a major bleed in the setting of ACS should not be underestimated.

Assessing Bleeding Complications: Results from the Euro Heart Survey

On behalf of the Euro Heart Survey investigators, Gitt et al. examined the impact of major bleeding complications on hospital outcomes of ACS patients enrolled in the ongoing ACS-Registry of the Euro Heart Survey Programme. Out of 6498 patients, the prevalence of major bleeding complications was 3.9% and major bleeds were more likely to occur in older patients, female patients and those who received either a glycoprotein IIb/IIIa blocker or a heparin. But even after correction for differences in potential confounders, major bleeds were associated with an 11.1% in-hospital mortality, compared to a 4.9% in-hospital mortality rate for ACS patients who did not experience a major bleed.

Based on the Euro Heart Survey percutaneous coronary intervention (PCI) registry data between 2005 and 2007, Klein et al. also separated out ACS patients undergoing non-elective vs. elective PCI. In the non-elective group, there was a 1.4% bleeding rate vs. 0.5% in the elective group, but rates of in-hospital death were again high in both groups if they experienced a major bleed at 25.7% for the non-elective PCI group and 5.4% for the elective group. In the absence of major bleeds, rates of in-hospital death were low in both groups at 3.8% for the non-elective PCI group and 0.2% for the elective group. The incidence of major bleeding was lower at 1.6% in 4717 patients undergoing PCI for STEMI in another prospective observation study carried out in one teaching hospital in the Netherlands. But at one year, the mortality rate was 40% among those who experienced a major bleed and the risk of death at a hazard ratio of 2.0 was still elevated even when there were only minor bleeds.

As discussed by Dr. Sunil Rao, Assistant Professor of Medicine, Duke University Medical Center, Durham, North Carolina, bleeding is a significant complication of ACS therapy and registries around the world indicate that major bleeding does increase the risk of death as well as MI, stroke and stent thrombosis in these vulnerable patients. Nevertheless, as he also stressed, defining the incidence of bleeding is difficult as it depends on the elements investigators use to define bleeding in individual clinical trials.

For example, clinically based bleeding-related data elements may well determine prognosis far more accurately than laboratory-based data elements such as hemoglobin levels.

Thus, without consistent across-trial definitions of bleeding, it is both impossible—and inappropriate—to compare safety results across studies, as Dr. Rao emphasized.

Antiplatelet Therapy Mechanism of Action

Speakers here agreed that there remains a significant unmet need in current antiplatelet therapy for ACS patients. As explained by Dr. Robert Storey, Senior Clinical Lecturer in Cardiology, University of Sheffield, UK, the P2Y12 receptor amplifies the platelet activation process, not only aggregation but all other factors that contribute to thrombosis. The oral antiplatelet clopidogrel inhibits this receptor but it requires several steps of conversion before it becomes metabolically active: hence, onset of action is relatively slow.

Perhaps more importantly, even when therapy is optimized, “you are left with an unblocked receptor that can still mediate platelet activation,” Dr. Storey told delegates. Moreover, both clopidogrel and prasugrel are irreversible inhibitors of the P2Y12 receptor, meaning that they induce an irreversible change in the platelet once they occupy the receptor. Platelet function is only restored when new platelets are produced five to seven days after administration.

The investigational agent AZD6140, a cyclo-pentyl-triazolo-pyrimidine and not a thienopyridine or an ATP analogue, is a direct inhibitor of the P2Y12 receptor; as such, onset of action occurs within two hours of administration and peak plasma levels are achieved within two to three hours. As a reversible inhibitor of the P2Y12 receptor, functional recovery of all circulating platelets occurs as soon as plasma drug levels drop, typically 36 to 48 hours after administration.Theoretically, this difference between the irreversible and reversible inhibitors of the P2Y12 receptor suggests that patients who require surgery, once treated with the novel agent, may no longer be at increased bleeding risk once plasma levels fall.

DISPERSE Findings

Clinical experience to date with AZD6140 is relatively limited but a few clinical trials have been conducted so far, including the Dose Confirmation Study Assessing Anti-Platelet Effects of AZD6140 vs. Clopidogrel in Non-ST-Segment Elevation Myocardial Infarction (DISPERSE-1). In DISPERSE-1, 201 patients were randomized to several different regimens of AZD6140 (50 mg b.i.d.; 100 mg b.i.d.; 200 mg b.i.d.; 400 mg/day) or to clopidogrel 75 mg/day. Patients all received ASA at a dose of 75 to 100 mg/day. Greater and more consistent inhibition of platelet aggregation was observed with AZD6140 100 mg b.i.d. than clopidogrel at 75 mg q.d.

In DISPERSE-2, a total of 990 patients with NSTEMI-ACS treated with ASA and standard therapy for ACS were randomized in a 1:1:1 double-blind fashion to receive either AZD6140 90 mg b.i.d., ADZ6140 180 mg b.i.d. or to the standard 300-mg loading dose of clopidogrel, followed by the standard maintenance dose of 75 mg/day, for 12 weeks.

Regarding the primary end point of major or minor bleeding through four weeks, there were no significant differences in major bleed in the three patient groups.

Although not statistically significant, favourable trends were seen in rates of MI over the entire study period for AZD6140 vs. clopidogrel as well.

Platelet Inhibition

Remarked Dr. Lars Wallentin, Director and Professor, Uppsala Clinical Research Center, Sweden, the Platelet Inhibition and Patient Outcomes (PLATO) study will involve some 18,000 patients and will include individuals with unstable angina, non-STEMI of both moderate and high risk, as well as STEMI patients if they are eligible for primary PCI.

All patients will receive ASA and will be randomized to receive either clopidogrel or AZD6140 within 24 hours of the index event. If they are clopidogrel-pretreated, they will receive no additional loading dose; if not, they will receive a loading dose of clopidogrel 300 mg followed by a 75-mg maintenance dose. An additional 300 mg will be allowed prior to PCI. Those randomized to the AZD6140 arm will receive a 180-mg loading dose followed by a maintenance dose of 90 mg but again, an additional 90 mg will be allowed pre-PCI.“So PLATO is very close to a real-life situation, and we are also comparing the high loading dose of clopidogrel so we are allowing the 600-mg loading dose as well as the 300-mg dose. Then we will have late follow-up to learn what happens when we discontinue treatment,” Dr. Wallentin explained.

“This is the first time that we will be evaluating an orally available, reversible inhibitor of the P2Y12 receptor and it is clearly different from the prodrugs that require metabolic activation to produce an effect,” he remarked.

There will be no waiting for an angiogram in PLATO, he added: the decision to treat will be made as early as possible because waiting for an angiogram deprives patients of the benefits of early platelet inhibition. “Patients in PLATO will be randomized to treatment as we do in Europe and in Canada, already on admission, as early as possible, the decision being made before any angiogram is done,” Dr. Wallentin confirmed.

Summary

Progress has been made in the management of STEMI and NSTEMI-ACS patients but there is room for improvement and more rapid, more consistent and more effective platelet inhibition would be welcome. The new oral direct inhibitor of the P2Y12 receptor, AZD6140, has several key features that may overcome some of the limitations of currently available antiplatelet agents, including more rapid onset and offset of activity. Further insight into the pharmacological profile of AZD6140 is currently being explored in PLATO, a phase III, head-to-head comparison of the new agent to clopidogrel, with results eagerly awaited.