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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.

MEDICAL FRONTIERS - 83rd Scientific Sessions of the American Heart Association

Chicago, Illinois / November 13-17, 2010

A substantial minority of patients who receive clopidogrel experience suboptimal effects, due largely to a common genetic polymorphism that impairs drug metabolism; the rate of “low responders” or “resistant patients” ranges from 5% to 40%, depending on population characteristics as well as the platelet function assay and cut-off values used. In major multinational studies conducted in patients with an acute coronary syndrome (ACS), substituting ticagrelor or prasugrel for clopidogrel in a dual antiplatelet combination with ASA has produced highly significant reductions in event rates. It had been hypothesized previously that platelet function tests might be used to identify poor response to clopidogrel in order to intensify therapy, but a trial designed specifically to test this strategy produced disappointing results.

“In patients with high residual platelet reactivity measured after PCI, 6 months of high-dose clopidogrel did not reduce the primary end point of cardiovascular (CV) death, non-fatal myocardial infarction (MI), or stent thrombosis,” reported Dr. Matthew Price, Director, Cardiac Catheterization Laboratory, Scripps Clinic, La Jolla, California. He cautioned that the results of this trial do not completely close the door on platelet function assay as a tool for identifying patients with high on-treatment platelet reactivity (HPR). Rather, he added that “a treatment strategy of switching to high-dose clopidogrel in patients who demonstrate HPR based on a single platelet function test while on a conventional dose of clopidogrel is not supported by our results.”

GRAVITAS Results: Platelet Testing Fails

The study of high-dose clopidogrel was called GRAVITAS (Gauging Responsiveness with A VerifyNow assay —Impact on Thrombosis and Safety trial). One of the most awaited studies presented at the AHA this year, GRAVITAS tested the hypothesis that individualizing clopidogrel doses on the basis of platelet function testing could reduce the risk of CV events in patients with suboptimal responses. In the study, 5429 patients were screened with a proprietary platelet function test called VerifyNow 12 to 24 hours after undergoing successful PCI while being maintained on a 75 mg daily dose of clopidogrel. Some 2214 (41%) patients who had HPR, defined as PRU (P2Y₁₂ reactivity units) =230 were entered into a randomized trial of dose intensification. The 3215 (59%) patients with a PRU <230 served as non-randomized controls. Of the 2214 who entered the randomized arm, 1105 remained on the standard dose of clopidogrel 75 q.d. and 1109 received an additional loading dose of 600 mg followed by a dose of 150 mg/day for 6 months. All patients received ASA 81-162 mg/day and an intracoronary drug-eluting stent (Figure 1).

Figure 1.

The baseline characteristics of the study population, which were well matched in all study arms, were typical of a population undergoing PCI. The average age was 64 years, approximately 45% had diabetes, and about 30% had a previous MI. The indication for elective or urgent PCI was stable angina or ischemia in 60% and unstable angina without ST-segment depression in 24%. The remaining 16% had non-ST-segment elevation ACS. The average number of stents placed was approximately 1.7, and the average cumulative length of the stents was approximately 30 mm. About one-third of the patients treated were women.

Bleeding Event Rates Not Increased Significantly

On the primary end point of CV death, non-fatal MI or stent thrombosis, high-dose clopidogrel provided almost no detectable advantage over standard-dose clopidogrel. The event rates were 2.3% in both arms and the HR for events on dose intensification was 1.01 (P=0.98). Total bleeding events by the GUSTO definition were slightly higher on high-dose clopidogrel (12.1% vs. 10.3%; P=0.18), but the difference was not statistically significant; the rate of severe bleeding events was slightly lower on the higher dose (1.4% vs. 2.3%; P=0.1), although again, not statistically different (Figure 2).

When patients with HPR randomized to standard-dose clopidogrel were compared to the control group (who did not have elevated platelet reactivity and received standard-dose clopidogrel), one of the primary end points occurred more frequently in the presence of persistently high platelet reactivity, but the difference in this non-randomized comparison was not significant (2.1% vs. 1.4%; P=0.2). Overall, rejecting alternative explanations for the failure of dose intensification to reduce risk of thrombotic events, such as insufficient power, Dr. Price concluded that the results indicate stronger antiplatelet therapy rather than a strategy of testing platelet function in order to intensify clo
eded.

Figure 2.

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The same conclusion was reached by Dr. Jessica L. Mega, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, official discussant of the study during the latebreaker session in which GRAVITAS results were presented. She suggested that one possible explanation of these results is that HPR reactivity in patients on clopidogrel is simply not a modifiable marker of an increased risk of events. Had GRAVITAS demonstrated an advantage for platelet function testing, the feasibility and expense of performing this test prior to PCI might have remained a practical issue for routine patient care. However, she told delegates, the negative results facilitate the conclusion that the newer, more potent antiplatelet drugs should become a dominant strategy for improving outcome.

Corroborative Guidance from PLATO, TRITON-TIMI 38

The two antiplatelet agents found more effective than clopidogrel in large clinical trials, ticagrelor and prasugrel, are, like clopidogrel, inhibitors of the P2Y₁₂ receptor, which is an important pathway of platelet activation. Ticagrelor, a reversible P2Y₁₂ inhibitor, demonstrated a 16% reduction (P<0.001) in the primary composite outcome of death from vascular causes, MI or stroke relative to clopidogrel in PLATO (PLATelet inhibition and patient Outcomes), a study that randomized all ACS patients admitted for medical or invasive management (Wallentin et al. N Engl J Med 2009;361:1045-57). Prasugrel demonstrated a 19% reduction in the same primary composite outcome (P<0.0001) relative to clopidogrel in TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis In Myocardial Infarction), which was limited to ACS patients scheduled for a PCI (Wiviott et al. N Engl J Med 2007;357:2001-15).

While prasugrel was evaluated in a narrower patient population than ticagrelor, the greater efficacy of both agents relative to clopidogrel in randomized trials is attributed to faster and greater antiplatelet effect. In experimental studies, both agents have demonstrated greater suppression of platelet activity than clopidogrel even in the absence of the genetic polymorphisms that inhibit the clopidogrel metabolism. As might be expected with greater antiplatelet effect, the greater protection against thrombotic events on prasugrel was associated with a significantly (32%, P=0.03) increased risk of major bleeding. Ticagrelor, however, did not significantly increase the risk of total major bleeding, perhaps as a result of its reversibility.

Ticagrelor Produces 22% Mortality Reduction

Unlike prasugrel, “ticagrelor was associated with a 22% reduction [P<0.001] in all-cause mortality, which is, of course, the goal we are trying to achieve,” noted Dr. Christopher Cannon, Brigham and Women’s Hospital. Although mortality was a secondary end point in the PLATO study, Dr. Cannon told delegates that the ability of ticagrelor to lower risk of thrombotic events without significantly increasing major bleeding produced an unprecedented opportunity for a very favourable benefit:risk ratio.

In TRITON-TIMI 38, prasugrel did not reduce overall mortality or CV mortality, but the relative benefit:risk ratio still favoured prasugrel despite the increased risk of bleeding. Based on the data, it was estimated that a strategy of prasugrel plus ASA in PCI patients would prevent 23 MIs while producing only 6 excess major hemorrhages. Expressed differently, the results predicted that 47 patients would have to be treated with prasugrel rather than clopidogrel to prevent one primary end point but 167 patients would have to be treated to produce an extra major hemorrhage. However, the favourable benefit:risk ratio was lost in patients 75 years of age or older, patients weighing less than 60 kg, and in patients with a previous stroke or transient ischemic event. The results suggest these patients have a relative contraindication for prasugrel.

In PLATO, there was little variability across subgroups, according to Dr. Cannon. This included those without the CYP2C19 loss-of-function genetic polymorphism that impairs clopidogrel efficacy. It also included the 3634 patients who had already received a pre-admission 600-mg loading dose of clopidogrel. When these patients were compared to the 9771 patients who received a conventional 300-mg clopidogrel loading dose prior to randomization, the relative advantage of ticagrelor was only modestly reduced (13% relative reduction rather than the 17% relative reduction observed in those on a lower loading dose of clopidogrel).

Reversibility Evaluated as Relative Advantage

The ability of prasugrel and ticagrelor to reduce vascular events relative to clopidogrel is consistent with a greater peak inhibition of platelet reactivity, but the mortality benefit of ticagrelor is likely to stem from its ability to achieve this effect without increasing the risk of bleeding. Most experts believe that this uncommon uncoupling of antiplatelet and bleeding effects is due to the reversibility of ticagrelor. Unlike clopidogrel or prasugrel, ticagrelor comes off the P2Y₁₂ receptor at the end of its duration of action so that platelet function is restored if no further treatment is given. This may explain the mortality benefit in PLATO, because the relative risk of thrombotic and bleeding events are both relevant to outcome.

“Bleeding is the major downside of increasing the potency of antiplatelet agents,” emphasized Dr. Deepak Bhatt, Chief of Cardiology, VA Boston Healthcare System, Harvard Medical School. While cautioning against cross-trial comparisons, he agreed with Dr. Cannon that ticagrelor “does seem to have a very different bleeding profile than prasugrel or high-dose clopidogrel,” and he speculated that the reversibility of ticagrelor at the receptor might explain the difference. He explained that relative advantage is not likely to be produced by the lower risk of fatal bleeding events, which are rare, but by the complications of bleeding.

“We know that bleeding is really bad. Patients who require a transfusion have worse outcomes, and there are probably several reasons for this, including the pro-inflammatory response from a transfusion that is likely to participate in an increased risk for thrombotic events,” Dr. Bhatt observed.

PPIs and Clopidogrel: No Interactions Observed

The risk of bleeding is the reason for the urgency in attempting to determine whether PPIs and clopidogrel have an important drug-drug interaction. PPIs can prevent upper gastrointestinal (GI) bleeding but like clopidogrel, they are also dependent to varying degrees on the CYP2C19 pathway for metabolism. Several observational studies have suggested that thrombotic events increase in clopidogrel patients who also receive a PPI, but others have not. A newly published prospective, randomized, double-blind study led by Dr. Bhatt called COGENT (Clopidogrel and the Optimization of Gastrointestinal Events Trial) appears to have resolved this issue. No meaningful interaction was found (Bhatt et al. N Engl J Med 2010;363:1909-17).

“Our study did not associate clopidogrel and [the PPI] omeprazole with an increased risk of CV events relative to clopidogrel alone, but it did associate this combination with a significant reduction in the risk of overt upper GI bleeding,” reported Dr. Bhatt. He suggested the risk previously observed in observational studies might have been generated by the fact that patients who receive a PPI tend to be simply at greater risk of thrombotic events.

In COGENT, 3873 patients with an indication for dual antiplatelet therapy were randomized to receive clopidogrel and ASA in combination with omeprazole or the same antiplatelet regimen with placebo. The combination produced a 66% relative reduction (HR 0.34; 95% CI, 0.18-0.63; P<0.001) in the risk of Gl events which did not alter the HR for a CV event (HR 0.99; 95% CI, 0.68-1.44; P=0.96). As a result, the data encourage use of PPIs to reduce bleeding events in high-risk patients on dual antiplatelet therapy.

The likelihood that PPI use is a marker for patients at higher thrombotic risk and not the source of an interaction that inhibits antiplatelet agents was also suggested by a re-analysis of the PLATO data. In PLATO, whether or not patients were on PPIs was documented in 18,601 of the 18,624 patients. Of these patients, 6539 (32%) were taking a PPI. There was a trend for higher event rates on PPIs whether patients were taking clopidogrel or ticagrelor even though only clopidogrel competes with PPIs for hepatic metabolism. When a multivariate analysis was conducted that included risks factors, the association between PPI use and an increased risk of the primary end point disappeared.

“Regardless of PPI use, ticagrelor was superior to clopidogrel in preventing ischemic events,” reported Dr. Shaun Goodman, St. Michael’s Hospital, Toronto, Ontario. Like Dr. Bhatt, Dr. Goodman proposed that “PPI use may be a marker for, rather than a cause of, higher risk of CV events.”

These data have convinced several experts that PPIs are not only safe to prescribe in patients on antiplatelet therapies, including clopidogrel, but may also be indicated in many of these individuals to reduce the risk of GI bleeds.

“We are offering PPIs in an increasing proportion of patients who we consider to be at risk, because the data tell us that we can prevent bleeding events,” commented Dr. Gregg Stone, Professor of Medicine, Columbia University, New York City. Overall, he believes that rather than increasing risk of CV events, PPIs reduce a major source of the major bleeds to provide an overall improvement in the benefit:risk ratio.

Summary

The best opportunity to reduce thrombotic events in patients with ACS is to replace clopidogrel with more potent antiplatelet agents, according to large studies comparing these therapies and to the recently completed study evaluating intensification of clopidogrel. Bleeding risk, however, will remain a confounding factor when comparing agents for relative antithrombotic protection. In addition to selecting an antiplatelet that provides the greatest antithrombotic effect with the least risk of bleeding, adjunctive strategies, such as PPI gastroprotection, are likely to be incorporated into risk management.