Recently presented at AHA and published in the
New England Journal of Medicine and
Circulation, the results of three landmark papers emphasize the increasing difficulties to develop new anti-platelet agents which are truly able to offer greater clinical advantages over currently established treatment options.
Two new reversible fast-acting and quick offsetting nonthienopyridine P2Y12 blockers, namely ticagrelor and cangrelor have shown conflicting results in terms of efficacy over clopidogrel. While ticagrelor has shown remarkable superiority over clopidogrel, more recently, two big phase III programs, the CHAMPION PCI and CHAMPION PLATFORM trials, have consistently failed to show superiority of the new agent over the control group consisting of either placebo on top of aspirin or 600 mg clopidogrel given 30 minutes before intervention.
Are these unexpected results justified by the definition of periprocedural myocardial infarction employed in the studies when short times from admission to PCI prevent clear delineation between myocardial infarction occurring before and that occurring after randomization, as leads Authors state? Are these results explained by the two quick offset of action (drug plasma half life of 3 to 6 minutes) when infusion line is stopped, thus allowing some rebound events? Is the bolus and infusion dose appropriate to prevent ischemic complications? Are there some off target effects of the drugs which have to be considered as possible explanation for these and previous results with P2Y12 blockers?
At this stage many questions need to be addressed. Yet, as clinician the hope is that the Company (the Medicine Company) will not step back from investing in this drug as a failure is always a new opportunity to understand more and treat our patients better.
CHAMPION PCI: N Engl J Med 2009;361.
CHAMPION PCI was a randomized, double-blind, double-dummy, active-control trial comparing cangrelor with 600 mg of clopidogrel in patients undergoing PCI. Patients were eligible for enrolment in the study if they had stable angina, unstable angina, or non–ST-segment–elevation myocardial infarction with obstructive coronary artery disease and were scheduled to undergo PCI.
An additional 1000 patients with ST-segment–elevation myocardial infarction for whom primary PCI was planned were also eligible. All patients received cangrelor (in an intravenous bolus of 30 μg per kilogram of body weight and an intravenous infusion of 4 μg per kilogram per minute) or a placebo bolus and infusion. The infusion began within 30 minutes before PCI and continued for at least 2 hours or until the conclusion of the index procedure, whichever was longer. At the treating physician’s discretion, the infusion could be continued for 4 hours. Patients received 600 mg of clopidogrel (in four 150-mg capsules) or placebo at the time of infusion. To allow the transition from intravenous cangrelor to oral clopidogrel, patients received another four capsules (either clopidogrel in patients receiving cangrelor or placebo in patients receiving clopidogrel) at the discontinuation of the study-drug infusion.
8877 patients were enrolled, and 8716 underwent PCI. At 48 hours, cangrelor was not superior to clopidogrel with respect to the primary composite end point (a composite of death from any cause, myocardial infarction, or ischemia-driven revascularization at 48 hours.), which occurred in 7.5% of patients in the cangrelor group and 7.1% of patients in the clopidogrel group (odds ratio, 1.05; 95% confidence interval [CI], 0.88 to 1.24; P = 0.59). Likewise, cangrelor was not superior at 30 days. The rate of major bleeding (according to Acute Catheterization and Urgent Intervention Triage Strategy criteria) was higher with cangrelor, a difference that approached statistical significance (3.6% vs. 2.9%; odds ratio, 1.26; 95% CI, 0.99 to 1.60; P = 0.06), but this was not the case with major bleeding (according to the Thrombolysis in Myocardial Infarction criteria) or severe or life-threatening bleeding (according to Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries criteria). A secondary exploratory end point of death from any cause, Q-wave myocardial infarction, or ischemia-driven revascularization showed a trend toward a reduction with cangrelor, but it was not significant (0.6% vs. 0.9%; odds ratio, 0.67; 95% CI, 0.39 to 1.14; P = 0.14).
Odds
Ratios for the Primary End Point, According to Diagnosis at Enrolment, in the Modified Intention-to-Treat Population. Data for the primary end point — a composite of death from any cause, myocardial infarction, or ischemia-driven revascularization at 48 hours — are shown. For each subgroup, the circle represents the estimated odds ratio for the treatment effect. The horizontal lines indicate 95% confidence intervals. STEMI denotes ST-segment–elevation myocardial infarction.
CHAMPION PLATFORM - N Engl J Med 2009;361.
In this double-blind, placebo-controlled study, investigators randomly assigned 5362 patients who had not been treated with clopidogrel to receive either cangrelor or placebo at the time of PCI, followed by 600 mg of clopidogrel. The primary end point was a composite of death, myocardial infarction, or ischemia-driven revascularization at 48 hours. Enrolment was stopped when an interim analysis concluded that the trial would be unlikely to show superiority for the primary end point.
The primary end point occurred in 185 of 2654 patients receiving cangrelor (7.0%) and in 210 of 2641 patients receiving placebo (8.0%) (odds ratio in the cangrelor group, 0.87; 95% confidence interval [CI], 0.71 to 1.07; P = 0.17) (modified intention to-treat population adjusted for missing data). In the cangrelor group, as compared with the placebo group, two pre-specified secondary end points were significantly reduced at 48 hours: the rate of stent thrombosis, from 0.6% to 0.2% (odds ratio, 0.31; 95% CI, 0.11 to 0.85; P = 0.02), and the rate of death from any cause, from 0.7% to 0.2% (odds ratio, 0.33; 95% CI, 0.13 to 0.83; P = 0.02). There was no significant difference in the rate of blood transfusion (1.0% in the cangrelor group and 0.6% in the placebo group, P = 0.13), though major bleeding on one scale was increased in the cangrelor group, from 3.5% to 5.5% (P<0.001), because of more groin hematomas.
Kaplan-Meier Curves 
The ONSET/OFFSET Study: Circ 2009, doi: 10.1161/CIRCULATIONAHA.109.912550
In a multicenter, randomized, double-blind study, 123 patients with stable coronary artery disease who were taking aspirin therapy (75 to 100 mg/d) received ticagrelor (180-mg load, 90-mg BID maintenance dose [n=57]), clopidogrel (600-mg load, 75-mg/d maintenance dose [n=54]), or placebo (n=12) for 6 weeks. Greater IPA (20 µmol/L ADP, final extent) occurred with ticagrelor than with clopidogrel at 0.5, 1, 2, 4, 8, and 24 hours after loading and at 6 weeks (P<0.0001 for all); by 2 hours after loading, a greater proportion of patients achieved >50% IPA (98% versus 31%, P<0.0001) and >70% IPA (90% versus 16%, P<0.0001) in the ticagrelor group than in the clopidogrel group, respectively. A faster offset occurred with ticagrelor than with clopidogrel (-4-to-72– hour slope [% IPA/h] -1.04 versus -0.48, P<0.0001). At 24 hours after the last dose, mean IPA was 58% for ticagrelor versus 52% for clopidogrel (P=NS). IPA for ticagrelor on day 3 after the last dose was comparable to clopidogrel at day 5; IPA on day 5 for ticagrelor was similar to clopidogrel on day 7 and did not differ from placebo (P=NS).
IPA (%; 20 µmol/L ADP, final extent) by protocol time and treatment. Data are expressed as mean±SEM. *P<0.0001, †P<0.005, ‡P<0.05, ticagrelor vs clopidogrel.