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 - Canadian Cardiovascular Congress 2009

Edmonton, Alberta / October 24-28, 2009

The standard for antiplatelet therapy to prevent thrombotic events in patients with acute coronary syndrome (ACS) will almost certainly evolve with the expected approval of two new agents that were found to be more effective in large multinational trials. In the first of the two studies, prasugrel, which like clopidogrel, blocks platelet activation by inhibiting the P2Y₁₂ receptor, was associated with a highly significant reduction in the primary composite end point of vascular events among ACS patients scheduled for a percutaneous coronary intervention (PCI). In the second, ticagrelor, a reversible P2Y₁₂ inhibitor, provided a similar reduction in events among any patient admitted to hospital for ACS and it also reduced overall mortality.

Reduction in CV Death

“A reduction in cardiovascular (CV) death is something that we have never seen in this type of trial before,” commented Dr. Robert C. Welsh, Director, Adult Cardiac Catheterization, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, here at the CCC. He noted that the 22% reduction (4.0% vs. 5.1%; P<0.001) in CV mortality was highly statistically significant and compelling evidence that more effective antiplatelet activity than offered by clopidogrel translates into important clinical benefits in these high-risk patients.

The large multinational studies were conducted on the basis of a series of experimental and clinical trials that predicted major advantages. Mechanistic studies have shown that ticagrelor achieved a more rapid onset of antiplatelet effect (41% inhibition of platelet aggregation [IPA] at 30 minutes vs. 8% for clopidogrel; P<0.0001) and greater IPA that was sustained during the maintenance phase of treatment. In addition, ticagrelor, unlike either clopidogrel and prasugrel, is reversible so that the inhibitory activity, although still greater than clopidogrel 24 hours after the last dose, falls more rapidly over the next 72 hours. This provides more versatility relative to the irreversible and much more prolonged effect of the other two agents. Both of the newer agents have been shown to provide greater protection against events than clopidogrel.

The multinational trial establishing efficacy for prasugrel was TRITON-TIMI 38 (Trial to assess improvement In Therapeutic Outcomes by optimizing platelet iNhibition with prasugrel-Thrombolysis In Myocardial Infarction 38) and was published two years ago (Wiviott et al. N Engl J Med 2007;357:2001-15). The ticagrelor trial, PLATO (PLatelet inhibition And PaTient Outcomes), was published earlier this year (Wallentin et al. N Engl J Med 2009;361:1045-57). There were important differences between the studies, but both demonstrated that more effective platelet inhibition reduces vascular events in an ACS population.

Study Findings

According to the most recent findings from TRITON-TIMI 38, prasugrel was associated with a 19% reduction (HR 0.81; 95% CI, 0.73-0.93; P<0.001) in death from CV causes, myocardial infarction (MI) and stroke relative to clopidogrel in patients with unstable angina or ST-segment elevation MI with a scheduled PCI. Follow-up ranged from six to 15 months in the 13,608 ACS patients, all of whom were scheduled for PCI. Relative to clopidogrel, which was administered in a 300-mg loading dose followed by a 75-mg daily maintenance dose, prasugrel (60-mg loading dose followed by a 10-mg daily maintenance dose) was also associated with a significant reduction in MI (P<0.001) when this end point was evaluated separately, and it provided significant relative reductions in urgent target revascularization (P<0.001) and stent thrombosis (P<0.001). Although prasugrel was associated with a 32% increase in major bleeding (HR 1.32; 95% CI, 1.03-1.68; P=0.03), including significant increases in life-threatening bleeding (P=0.01) and fatal bleeding (P=0.002), a net benefit for prasugrel was preserved. For every 1000 ACS patients treated, TRITON-TIMI 38 predicted 23 fewer MIs with only six excess major hemorrhages in patients receiving prasugrel instead of clopidogrel.

In PLATO, which randomized any patient hospitalized for ACS whether or not they were scheduled for PCI, ticagrelor was associated with a 16% reduction (HR 0.84; 95% CI, 0.77-0.92; P<0.001) relative to clopidogrel in the same composite primary end point that was employed in TRITON-TIMI 38. However, patients in PLATO were still eligible for randomization if they had received a loading dose of clopidogrel prior to reaching the hospital. In fact, 46% of the 18,624 patients had received some dose of clopidogrel prior to study entry, producing a sizeable proportion of patients in whom the 180-mg loading dose (followed by a maintenance regimen of 90 mg b.i.d.) was compared to clopidogrel loading dose of 600 mg, which is double the standard but increasingly used in common practice because of concern about its limitations. According to the lead investigator, Dr. Christopher Cannon, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, the concept was a “real-world investigation in which the decision was ticagrelor or clopidogrel as they came through the door.”

Like prasugrel in TRITON-TIMI 38, ticagrelor produced a highly significant advantage for secondary end points such as MI (P=0.005), but it was also associated with significant protection against CV mortality (P=0.001) and death from any cause (P<0.001). Unlike prasugrel, it was not associated with a significant increase in major bleeding (P=0.43). There was a greater rate of fatal intracranial bleeding on ticagrelor relative to clopidogrel (P=0.02), but the incidence was very low (11 cases vs. one case, producing an incidence of <0.01% in both groups). Non-CABG-related major bleeding was also greater (4.5% vs. 3.8%; P=0.03), but these were not typically fatal. Overall, the low rates of bleeding did not preclude the overall mortality benefit in the ticagrelor arm.

As part of the PLATO design, physicians were asked prior to randomization if they planned to perform PCI in order to compare these agents specifically in this population. In the 13,408 with a planned PCI (72% of the total randomized), the relative reduction in the primary end point favouring the reversible P2Y12 inhibitor was again 16% (HR 0.84; 95% CI, 0.74-0.94; P<0.0025). There was no relative excess in major bleeds in this population either. Dr. Cannon also reported that a post-hoc analysis comparing ticagrelor to clopidogrel among those who received a pre-hospital, pre-study clopidogrel loading dose (producing a group receiving a 600-mg loading dose) also revealed a similar 16% relative reduction in the primary end point favouring the investigational agent.

Potency and Onset of Action

The greater efficacy of the novel treatments relative to clopidogrel is largely attributed to the greater inhibition of platelet activity, but non-response to clopidogrel is a major problem, particularly because non-responders are not readily identifiable in an emergency setting when platelet activity tests are impractical. According to Dr. Shaun Goodman, Associate Head, Division of Cardiology, St. Michael’s Hospital, Toronto, Ontario, approximately 15% of patients are non-responders to clopidogrel when evaluated at 30 days. In the ACS setting, the slow onset is also a concern. Three hours after a clopidogrel loading dose, platelet activity remains unchanged in almost two-thirds of patients. This may explain why the reduction in ischemic events for prasugrel relative to clopidogrel reached statistical significance after only three days in TRITON-TIMI 38.

“It is very reassuring to see agents that produce more potent platelet inhibition through the P2Y₁₂ pathway also demonstrate greater protection against thrombotic events,” Dr. Cannon commented to delegates. He suggested that the reduction in mortality without a significant increase in major bleeds achieved with ticagrelor “is really a standout finding” and “may speak to the reversibility of the drug.” He added that both agents have now been proven to be superior to clopidogrel in well-controlled trials, providing new options for ACS therapy.

Summary

The evidence that clopidogrel, despite its efficacy in ACS patients, provides suboptimal inhibition of platelet activity has been provided by two large studies that each found a more potent agent to significantly reduce risk of thrombotic events with an acceptable rate of bleeding. The mortality benefit in one of these trials (PLATO with ticagrelor) provides particularly compelling proof that a more potent antiplatelet agent offers a major improvement in the benefit:risk ratio. When they become available, these novel agents are likely to immediately change treatment standards.

Note: At press time, ticagrelor and prasugrel were not available in Canada.