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 - 31st Annual Congress of the European Society of Cardiology

Barcelona, Spain / August 29-September 2, 2009

More effective prevention of thrombotic events with no increased risk of bleeding has remained an elusive goal in patients with acute coronary syndromes (ACS). Now, however, the investigational agent ticagrelor that leads to faster, greater and more consistent inhibition of the P2Y12 receptor than clopidogrel, appears to have achieved this end. These findings are based on results from PLATO (Platelet inhibition And Treatment Outcomes), a recently completed phase III trial reported here for the first time and published simultaneously (Wallentin et al. N Engl J Med 2009;361(11):1045-57).

Reduced Total Mortality

In PLATO, 18,624 patients hospitalized with ACS with or without ST-segment elevation were randomized to ticagrelor 180 mg loading dose (LD), followed by a maintenance dose of 90 mg b.i.d., or to clopidogrel at a LD of either 300 or 600 mg followed by a maintenance regimen of 75 mg/day. Both compounds were given on top of ASA. The primary composite end point was death from vascular causes, myocardial infarction (MI) or stroke and the primary safety end point was major bleeding.

At the end of 12 months of follow-up, ticagrelor was associated with a 16% reduction in the primary composite end point relative to clopidogrel (HR 0.84; 95% CI, 0.77-0.92; P<0.001). Unlike previous studies comparing a more effective antiplatelet drug to another, this relative advantage was not associated with any significant differences in the rate of major bleeding (11.6% vs. 11.2%, respectively; P=0.43). When each of the components of the primary outcome, which were predefined as secondary end points, were evaluated separately, there was a significant advantage for the novel antiplatelet agent relative to clopidogrel for all except stroke (1.5% vs. 1.3%; P=0.22).

Almost two-thirds of the cohort (11,289) received a stent. Whether stratified as definite thrombosis (1.3% vs. 1.9%; P=0.009), definite or probable thrombosis (2.2% vs. 2.9%; P=0.02) or definite, probable or possible thrombosis (2.9 vs. 3.8%; P=0.01), there was a significant advantage for the novel agent as well. As noted by lead investigator Dr. Lars Wallentin, Uppsala Clinical Research Center, Sweden, the relative mortality benefit is perhaps the most compelling finding in PLATO because the benefit was achieved against the current standard-of-care.

Relative to clopidogrel, the 1.1% absolute advantage for mortality for vascular causes (4.0% vs. 5.1%) at 12 months translated into a relative protection of 21% (HR 0.79; 95% CI, 0.69-0.91; P<0.001). The absolute difference for death from any cause was of the same magnitude (4.5% vs. 5.9%), producing a 22% relative risk reduction (HR 0.78; 95% CI, 0.69-0.89; P<0.001).

The antiplatelet agent prasugrel works along the same pathway as ticagrelor and it has also been shown to have greater antiplatelet activity than clopidogrel. However, the reduction in clinical events seen with prasugrel relative to clopidogrel in the TRITON-TIMI 38 (TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet iNhibition with prasugrel — Thrombolysis In Myocardial Infarction) was associated with a 32% relative increase in major bleeding (HR 1.32; 95% CI, 1.03-1.68; P=0.03) that included an increase in fatal bleeding (0.4% vs. 0.1%; P=0.002) (Wiviott et al. N Engl J Med 2007;357:2001-15).

“Before this trial, we did not think that it was possible to get more antiplatelet effect without also producing unacceptable rates of bleeding,” Dr. Wallentin told delegates here at the ESC. “This study has changed that concept and over the last 10 to 15 years, we have not seen any other trial with an antithrombotic compound that lowered total mortality as well.”

Improving Outcomes for PCI Patients

The CURRENT OASIS 7 (Clopidogrel optimal loading dose Usage to Reduce RecurrENT events/Optimal Antiplatelet Strategy for InterventionS) also indicated that antiplatelet potency is not necessarily inseparable from bleeding risk. In this trial, 25,087 ACS patients scheduled for early PCI were randomized by two factors. The first was the dose of clopidogrel (600-mg LD followed by 150-mg maintenance dose vs. 300-mg LD followed by 75-mg maintenance dose) and the second was the dose of ASA (300 to 325 mg vs. 75 to 100 mg). The primary end point was the same composite of events used in PLATO: cardiovascular death, MI or stroke. Major bleeding was the primary safety measure.

For the primary end point, the 0.2% absolute reduction in events on the high dose vs. the standard dose of clopidogrel translated into a non-significant 5% relative risk reduction in the composite end point (HR 0.95; 95% CI, 0.84-1.07; P=NS). However, some 7855 patients never proceeded to a PCI in this study—a far higher percentage at 31% of the cohort overall than expected. When these patients were removed from the analysis, there was a 15% relative risk reduction (HR 0.85; 95% CI, 0.74-0.99; P<0.01) in the primary end point, largely driven by a 22% reduction in MI (HR 0.78; 95% CI, 0.64-0.95; P<0.01). In addition, PCI patients on the higher dose of clopidogrel achieved a 42% relative reduction in the risk of definite stent thrombosis (HR 0.58; 95% CI, 0.42-0.79; P=0.001). As in PLATO, there was no significant difference in major bleeding (0.5% in both groups).

In contrast, the higher dose of ASA was not associated with any greater benefit in the study population overall, in those who never underwent PCI or in those who did undergo PCI. Senior author Dr. Shamir Mehta, Associate Professor of Medicine, McMaster University, Hamilton, Ontario, suggested that CURRENT OASIS 7 findings would change practice, as the higher dose of clopidogrel reduced clinical risks with no cost in major bleeds.

“It’s going from one pill to two pills a day [of clopidogrel]; the cost implications are virtually negligible, and the benefits are large,” he noted, “and this simple manoeuvre could improve patient outcomes in PCI patients.”

No PPIs Interaction

As reported here at the ESC, a detailed retrospective analysis of patients receiving P2Y12 inhibitors in large clinical trials failed to find any significant interaction with concomitant proton pump inhibitor (PPI) therapy. This analysis addressed an important controversy raised in an observational analysis almost two years ago. The analysis combined data from the 13,608 patients in TRITON-TIMI 38 and the smaller 201-patient PRINCIPLE-TIMI 44 (Prasugrel compared with high-loading and maintenance-dose clopidogrel in patients with planned PCI: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction). The new analysis did not find any significant differences in outcome when those on a PPI, representing about one-third of patients evaluated, were compared to those who were not. This was true for both clopidogrel and prasugrel.

“These data can provide some early reassurance to clinicians that these two classes of drugs may in fact be safe to use in combination for patients who have a strong indication to be on both drugs,” reported senior author Dr. Michelle L. O’Donoghue, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts.

Summary

The evidence that greater antithrombotic activity can be achieved with more potent antiplatelet agents without significantly increasing risk of major bleeding confirms progress in reducing the risk of vascular events in patients with ACS. The results of the PLATO study are considered to be particularly important because they associate the study drug with an all-cause mortality benefit, an outcome difficult to achieve in trials comparing two different active therapies. The evidence that greater risk reductions can be achieved in PCI patients by doubling the loading and maintenance dose of clopidogrel has provided an immediate potential step in improved patient management, while the absence of an effect of PPI therapy on antiplatelet effect is reassuring in a population for which PPI use is common.

Note: At press time, ticagrelor is not available in Canada.