Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - Transcatheter Cardiovascular Therapeutics 2008 Conference

Washington, DC / October 12-17, 2008

Platelets play a pivotal role in atherothrombosis, the major cause of acute coronary syndromes (ACS). Patients who undergo stenting procedures are at risk for stent thrombosis, and apparently for late stent thrombosis if they receive a drug-eluting stent. A proportion of patients with ACS or at risk for ACS are hyporesponders to current antiplatelet regimens (i.e. ASA, clopidogrel). Hyporesponsiveness to antiplatelet therapy has been considered a risk factor for ischemic events after coronary stenting, especially in patients with acute myocardial infarction (AMI). Among possible strategies suggested to circumvent hyporesponsiveness with the goal to improving ischemic outcomes, adding a third antiplatelet agent or using newer more potent agents should be considered.

Exploring Triple Therapy

Dr. Young-Hoon Jeong, Gyeongsang National University Hospital, Jinju, South Korea, and colleagues explored triple antiplatelet therapy by adding to ASA and clopidogrel the selective cyclic AMP phosphodiesterase inhibitor cilostazol.

In the ACCEL-AMI (Adjunctive Cilostazol Vs. High Maintenance Dose Clopidogrel in Patients with AMI) study of 90 patients with AMI undergoing stent implantation, maximal platelet aggregation in response to ADP was significantly greater (P<0.001) at 30 days among patients randomized to triple antiplatelet therapy that included cilostazol compared with dual antiplatelet therapy. Triple therapy was also associated with the lowest rate of clopidogrel hyporesponsiveness.

According to data from the DECREASE registry, the enhanced antiplatelet effect of cilostazol when added to ASA and clopidogrel resulted in a lower rate of stent thrombosis at one year compared with dual antiplatelet therapy, reported ACCEL-AMI co-investigator Dr. Seong-Wook Park, Asan Medical Center, Seoul, South Korea. Data derived from the single-centre registry included 1443 patients assigned to triple therapy and 1656 assigned to standard dual antiplatelet therapy following implantation of a drug-eluting stent.

In a propensity-matched analysis, the risk of stent thrombosis at one year was reduced by 88% and the risk of MI was reduced by 70% with triple therapy compared with dual antiplatelet therapy, without an increased risk of major or minor bleeding, according to investigators.

While triple therapy with cilostazol may be useful when clopidogrel hyporesponsiveness is demonstrated, researchers concluded that further large-scale, long-term studies are needed to determine whether adjunctive cilostazol provides better efficacy in prevention of thrombotic events in AMI patients.

Novel Antiplatelet Phase II Results

A non-thienopyridine in phase II clinical studies, ticagrelor (AZD6140) is the first oral reversible ADP P2Y₁₂ receptor antagonist acting directly on the P2Y₁₂ receptor. In comparisons with clopidogrel, it produced more rapid, more consistent and superior platelet inhibition, and was associated with a trend toward fewer MIs, according to Dr. Dominick J. Angiolillo, University of Florida, Jacksonville.

The antiplatelet was associated with dose-dependent dyspnea and ventricular pauses <u>></u>2.5 seconds, but the percentage of patients who discontinued ticagrelor was similar to the percentage discontinuing clopidogrel. The rates of bleeding were similar between agents, investigators reported.

TRITON-TIMI 38 Results

Another agent is the novel P2Y₁₂ receptor antagonist prasugrel. Results from the phase III TRITON (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel)-TIMI 38 appear to corroborate its rapid onset of action and the reduction in ischemic events.

In TRITON-TIMI 38, 13,608 patients with ACS in whom coronary stenting was planned were randomized to clopidogrel (given as a 300-mg loading dose followed by a 75-mg/day maintenance dose) or prasugrel (60-mg loading dose followed by a maintenance dose of 10 mg/day). The duration of therapy was six to 15 months (median: 12 months). All patients were also treated with ASA.

According to Dr. C. Michael Gibson, Harvard Medical School and Beth Israel Deaconess Hospital, Boston, Massachusetts, 30-day clinical outcomes favoured the novel antiplatelet with a 19% reduction in the primary composite end point of death from cardiovascular (CV) causes, nonfatal MI, or nonfatal stroke compared with clopidogrel. Significant reductions were also found in the rates of MI (9.7% vs. 7.4%; P<0.001), urgent target-vessel revascularization (3.7% vs. 2.5%; P<0.001) and stent thrombosis (2.4% vs. 1.1%; P<0.001) for clopidogrel and prasugrel, respectively.

Regardless of the type of stent used, prasugrel was also associated with significant reductions in both early (within 30 days of stenting) and late (>30 days after stenting) stent thrombosis.

The reduction in the primary end point observed was driven primarily by a reduction in MI. A consistently lower incidence of all types of MI, except for peri-coronary artery bypass graft (CABG) MI, was observed in patients assigned to prasugrel vs. clopidogel, noted Dr. Gibson. There was a 29% relative risk reduction (P=0.0015) with prasugrel on the end point of spontaneous MI, “the kind of MI that most of us are concerned about, particularly over the long haul,” he stated.

While reduction in clinical events occurred with prasugrel, an increase in bleeding events was observed with major bleeding in 2.4% vs. 1.8% of patients (P=0.03); the rate of life-threatening bleeding (1.4% vs. 0.9%; P=0.01), including nonfatal bleeding (1.1% vs. 0.9%; hazard ratio, 1.25; P=0.23); and fatal bleeding (0.4% vs. 0.1%; P=0.002), all prasugrel vs. clopidogrel.

The net clinical outcome favoured prasugrel, with a reduction of 23 MIs and an increase in five non-CABG major bleeds per 1000 patients treated with prasugrel instead of clopidogrel.

Identifying Subgroups at Higher Bleeding Risk

“When used in appropriate-risk patients, the risk of bleeding can be narrowed,” remarked Dr. Gibson. Excess bleeding with prasugrel in TRITON-TIMI 38 occurred mostly in three subgroups: patients older than 75 years, patients weighing less than 60 kg, and those with a history of stroke or transient ischemic attack (TIA). When excluding these groups from the analysis, the difference in major bleeding rates was no longer significant.

Dr. Gibson noted that it is possible that dosing adjustments may decrease the risk of bleeding in patients older than 75 years and those less than 60 kg, but it should still be avoided in those with a history of stroke/TIA who have net clinical harm with prasugrel.

Maintaining Early and Late Benefits

In prasugrel recipients, most of the bleeding occurred late (>30 days) and 80% of the clinical benefit occurred early (<30 days). Thus, Dr. John Ambrose, University of California at San Francisco, suggested that initiating therapy with prasugrel and later switching to clopidogrel might represent a sensible strategy. The rates of life-threatening bleeding were 0.4% with prasugrel and 0.3% with clopidogrel at three days; the excess major bleeding observed with the use of prasugrel occurred predominantly during the maintenance phase.

This strategy, however, ignores that both the loading dose and maintenance dose of prasugrel were superior to clopidogrel for the reduction of ischemic events, remarked Dr. Gibson. The reduction in the primary efficacy end point in patients randomized to prasugrel compared with clopidogrel was 18% at day 3 and 20% from day 3 onward.

Further, half of the MIs in TRITON-TIMI 38 were spontaneous MIs and MIs resulting from stent thrombosis, “and these are the types of MIs we want to reduce with long-term therapy,” explained Dr. Gibson. Beyond 30 days, the relative risk reduction on spontaneous MI with prasugrel was 23% (P=0.01), again indicating benefit with the maintenance dose compared with clopidogrel.

Nearly twice as many patients in TRITON-TIMI 38 who were treated with clopidogrel had a second event compared with those treated with prasugrel, observed Dr. Steven Wiviott, Brigham and Women’s Hospital, Harvard Medical School. He also noted that prasugrel treatment was associated with a reduction in infarct size and offered a consistent reduction in the primary end point across infarcts of all sizes.

Summary

Since patients experience varied responses to currently available antiplatelet therapies, the need to optimize antiplatelet therapy is essential, whether by adding another agent, increasing dosage of the current treatment regimen or using novel compounds. Although newer agents appear to offer faster onset of action and more complete platelet inhibition, long-term follow-up will help better determine their optimal use.

Note: At the time of printing, prasugrel is not approved in Canada.