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PRIORITY PRESS - A Canadian Debate on Antiplatelet Therapy - Post 83rd Scientific Sessions of the American Heart Association

Hamilton, Ontario / November 17, 2010

In the first presentation of the GRAVITAS (Gauging Responsiveness with A VerifyNow Assay-Impact on Thrombosis And Safety) data made here in Canada, Dr. Tanguay, reminded attendees that there is a wide interpatient variability in platelet inhibition following a single bolus of clopidogrel. Using different assays, results show there are “hyper-” as well as “hypo-” responders to clopidogrel. Studies involving more than 3000 patients have consistently shown that high residual platelet reactivity as measured by the VerifyNow P2Y12 assay is associated with poor clinical outcomes after percutaneous coronary intervention (PCI).

GRAVITAS, which was first presented at the American Heart Association 2010 Scientific Sessions by Dr. Matthew Price, Scripps Clinic, La Jolla, California, was the first large randomized trial designed specifically to determine if doubling the dose of clopidogrel improves clinical outcomes in a population of PCI patients with high residual platelet reactivity (PRU =230). Patients scheduled for either elective or urgent PCI with a drug-eluting stent were assessed for their reactivity profile using the VerifyNow assay 12 to 24 hours after angiography; those with a PRU above the threshold of 230 were randomized to high- or standard-dose clopidogrel for 6 months.

One month after undergoing angioplasty, 62% of those randomized to standard-dose clopidogrel still had persistently high reactivity levels compared with 40% of those randomized to the high-dose clopidogrel (P<0.001). Nevertheless, at 6 months, 2.3% of patients in both arms had reached the primary end point of cardiovascular (CV) death, myocardial infarction (MI) or stent thrombosis (HR 1.01; P=0.98)—“a surprising finding,” Dr. Tanguay stated, “but which means that the way we screen patients after angioplasty, identifying them via PRU testing and doubling the dose of clopidogrel [for those with high reactivity] had no impact on clinical outcomes. So GRAVITAS does not support a treatment strategy of high-dose clopidogrel in low-risk patients with high residual reactivity identified by a single platelet function test after PCI.”

Alternative Antiplatelet Strategies

On the other hand, several important clinical trials, including the TRITON-TIMI 38 trial, do support alternative antiplatelet strategies in acute coronary care (ACS)/PCI patients. In TRITON-TIMI 38, 13,608 ACS STEMI or unstable angina/non-STEMI patients scheduled for planned PCI were randomized to either clopidogrel 300 mg loading dose (LD) followed by a 75-mg maintenance dose (MD) or to prasugrel 60 mg LD followed by a 10-mg MD for a median duration of 14.5 months. Clopidogrel and prasugrel both inhibit the P2Y₁₂ receptor on the platelet surface, preventing formation of platelet thrombus; both are irreversible inhibitors as well. However, prasugrel is converted to its active metabolite more effectively than clopidogrel and has a more rapid onset of action and less interpatient response variability than clopidogrel. The primary end point of TRITON-TIMI 38 was CV death, MI and stroke, while stent thrombosis was a secondary end point. Safety end points included TIMI major and life-threatening bleeds.

At study end point, 12.4% patients who underwent PCI for STEMI on clopidogrel vs. 10% of patients randomized to prasugrel had reached the primary ischemic end point for a relative risk reduction of 21% in favour of prasugrel (P=0.02). There was also no safety difference, with 2.4% of the clopidogrel arm and 2.1% of the prasugrel arm having a TIMI major bleed (P=0.65). “You do not have a reason not to use prasugrel in STEMI patients undergoing PCI,” Prof. Montalescot noted.

In a subset of patients with diabetes in the TRITON-TIMI 38 trial, treatment with prasugrel was again associated with a significant 31% relative risk reduction in the primary end point compared with clopidogrel (12.2% vs. 17%; P<0.001). This is the first antiplatelet shown to have a good effect in ACS patients with diabetes, as Prof. Montalescot observed, so it was a very important finding. As importantly, the following groups in TRITON-TIMI 38 did not enjoy a net clinical benefit from treatment with prasugrel, i.e. those =75 years of age among whom TIMI major bleeds occurred in 4.2% compared with 3.6% and in those <60 kg, 6% of whom had a TIMI major bleed compared to 3.5% in the prasugrel and clopidogrel cohorts, respectively. Patients with a prior stroke or a transient ischemic attack had a significantly greater risk for bleeding when treated with prasugrel compared with clopidogrel. Consequently, it is contraindicated in this patient population.

PLATO Trial

PLATO (Platelet Inhibition and Patient Outcomes) was another large-scale trial (n=18,624) in moderate to high-risk NSTE-ACS (or STEMI patients if undergoing primary PCI) randomized to either clopidogrel or ticagrelor. Unlike clopidogrel and prasugrel, ticagrelor is not a thienopyridine and its mechanism of action is reversible, a potential advantage over the thienopyridines. Patients randomized to either arm in PLATO could have been pretreated with clopidogrel; those who received no additional clopidogrel as a LD or, if clopidogrel-naive, they received the standard 300 mg LD followed by a 75 mg MD if assigned to clopidogrel. If assigned to ticagrelor, they received a 180 mg LD, followed by a 90 mg b.i.d. MD (both arms could receive additional clopidogrel or ticagrelor pre-PCI).

Patients were exposed to either regimen for 6 to 12 months, at the end of which ticagrelor proved to be significantly superior to clopidogrel for the primary composite end point of CV death, MI and stroke. There was also a 16% (P<0.001) relative reduction in death from any cause in favour of ticagrelor (Wallentin et al. N Engl J Med 2009;361:1045-57). It also proved to be significantly more effective in patients with renal insufficiency than those without, significantly reducing the composite end point compared with clopidogrel in similarly-matched patients. Unlike prasugrel, however, ticagrelor appeared to have no advantage over clopidogrel in ACS patients with diabetes.

Historical Bleeding Risk Data

Prof. Montalescot discussed the effect the new antiplatelets have on mortality rates in STEMI patients. Starting years ago with the IIb/IIIa inhibitors, abciximab reduces not only major acute coronary events (MACE) but mortality by 29% vs. placebo although it does increase bleeding risk. Early use of high-dose tirofiban also reduces the risk of MACE and mortality by 36% relative to placebo and selective use of tirofiban; but it too, increases bleeding risk.

Both prasugrel and ticagrelor reduce the incidence of MACE compared with clopidogrel and they also reduce mortality by 24% and 18%, respectively. Both are neutral in their bleeding risk relative to clopidogrel, with the exception of patients =75 years and <60 kg in whom prasugrel increases bleeding risk relative to clopidogrel. All three antiplatelets also reduce stent thrombosis.

Based on findings from the CURRENT-OASIS 7 trial, double-dose clopidogrel reduced stent thrombosis by 31% at 30 days compared with standard-dose clopidogrel (P=0.001); ticagrelor by 25% compared with clopidogrel at 12 months (P=0.02); and prasugrel by 71% (relative risk reduction) between days 0 and 30 (P=0.0001) and by 54% (relative risk reduction) between days 30 and 450 (P=0.04) for an overall risk reduction of 52% at 15 months compared with clopidogrel (P<0.0001).

In his concluding remarks, Prof. Montalescot stated that prasugrel is best used in the PCI treatment of STEMI and for preventing late stent thrombosis. It is also likely the treatment of choice in ACS diabetic patients undergoing PCI. Prasugrel or ticagrelor can both be used if ACS recurs in patients already on clopidogrel but ticagrelor is best used in the medical phase of treatment in the critical care unit while waiting for catheterization. Clopidogrel is best used in the medical management of ACS, in patients =75 years of age and in patients with a high bleeding risk. In the end, Canadian physicians will have considerably more choice when selecting an antiplatelet for ACS/PCI patients and findings from GRAVITAS as reported by Dr. Tanguay and insights from clinical trials as interpreted by Prof. Montalescot should help with the decision-making.

Note: This report was based on a Post-AHA, Canadian Cardiovascular Society-accredited session entitled “The Great Debate In Antiplatelet Therapy: The Trials, The Data, The Patients.” Hamilton, Ontario, November 17, 2010. Hamilton Health Sciences, David Braley Cardiac Vascular and Stroke Research Institute, Main floor auditorium, 237 Barton St. E. Hamilton, Ontario. Faculty included Gilles Montalescot, MD, PhD, and Jean-Francois Tanguay, MD, FRCPC, FACC, FAHA, FESC.

This event is an accredited group learning activity under Section 1 as defined by the Royal College of Physicians & Surgeons of Canada for the Maintenance of Certification program. It is approved by the Canadian Cardiovascular Society for a maximum of 1 credit. This conference report was co-developed with the Canadian Cardiovascular Society and the Mednet and was planned to ensure the evidence presented is valid, objective and balanced.