By Nancy Rizkalla, PharmD candidate c/o 2015

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      Percutaneous coronary intervention (PCI) with subsequent stent implantation is a highly effective approach in reducing the risk of death or ischemic complications following a myocardial infarction as well as improving the quality of life in patients with stable angina. PCI is ultimately performed in 60 – 70% of patients with acute coronary syndromes who undergo diagnostic coronary angiography.¹ Its widespread use notwithstanding, there is substantial concern regarding thrombotic complications during the procedure, despite adjunctive administration of antiplatelet therapies. P2Y₁₂ receptor antagonists are most commonly the drugs of choice for this purpose, as they help reduce the risk of stent thrombosis.

However, they have their limitations. To date, the available P2Y₁₂ receptor antagonists are administered only in the oral form. Furthermore, there is a delayed onset of action, and, with most agents, the effects last for several days, which increases the risk of subsequent bleeding. Considering the circumstances in which these drugs are used, there is a need for more optimal therapy. For example, the patients who benefit most from such an intervention are the ones in the throes of an acute cardiovascular illness, such as acute coronary syndrome. Concomitant states of nausea, impaired absorption, and perfusion typically also occur in these patients. Such conditions may limit the bioavailability of oral P2Y₁₂ receptor antagonists, compromising their efficacy. Furthermore, variations in pharmacokinetic and pharmacodynamic responses among individual patients have been noted with some of these agents.² In high-risk patients, additional antiplatelet therapy, namely a GP IIb/IIIa receptor inhibitor, is given to further reduce the risk of thrombotic complications. However, the effects of these agents last for several hours and cannot be readily reversed. In addition, they have been associated with frequent episodes of major bleeding.² These issues have prompted the search for an intravenous, fast-acting, reversible, and potent antiplatelet agent, ultimately leading to the development of cangrelor.

Cangrelor certainly addresses the shortcomings of its predecessors. It is administered intravenously, eliminating the need for absorption before antiplatelet effects can be seen. The onset of action is not delayed—when a bolus of cangrelor is administered, the antiplatelet effect is immediate and can be maintained with a continuous infusion.The effects of cangrelor are reversible as the plasma half life is 3 – 5 minutes, and platelet function is restored within one hour of cessation of the infusion.² More importantly, cangrelor significantly outperformed the current gold standard P2Y₁₂ antagonist, clopidogrel, in the CHAMPION PHOENIX study, a large, phase III global trial of patients who underwent coronary stent procedures.³

CHAMPION PHOENIX, a randomized, double-blind trial, compared cangrelor with oral clopidogrel in approximately 11,000 patients at 153 centers around the world. It included a broad variety of patients with every type of acute coronary syndrome, angina, and other conditions for which people undergo PCI, as long as they had no recent exposure to a P2Y₁₂ inhibitor and could swallow a pill. Other exclusion criteria included recent use of GP IIb/IIIa inhibitors or fibrinolytics and specific factors that would predispose one to a high risk of bleeding. Cangrelor performed significantly better than clopidogrel across efficacy measures: 4.7% versus 5.9%, or a 22% reduction in the odds of the primary endpoint, which was composite incidence of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 hours after randomization (adjusted odds ratio with cangrelor, 0.78; 95% confidence interval [CI], 0.66 to 0.93; P=0.005)². Stent thrombosis developed in 0.8% of the patients in the cangrelor group and in 1.4% in the clopidogrel group. In other words, cangrelor showed a 38% reduction in the odds of the key secondary endpoint, incidence of stent thrombosis at 48 hours (odds ratio, 0.62; 95% CI, 0.43 to 0.90; P=0.01)². Both treatment arms showed a low, statistically comparable incidence for the safety endpoint of severe bleeding at 48 hours: 0.16% versus 0.11%³ (odds ratio, 1.50; 95% CI, 0.53 to 4.22; P=0.44).²

Experts agree that the endpoints measured in this study represent a real concern regarding the outcomes of PCI with stent implantation. According to Deepak L. Bhatt, MD, MPH, chief of cardiology at VA Boston Healthcare System, senior physician at Brigham and Women’s Hospital, professor of medicine at Harvard Medical School, and Robert A. Harrington, MD, chairman of medicine at Stanford University School of Medicine, co-principal investigator, “These are endpoints we worry about a lot in interventional cardiology and cardiology in general^.” As he goes on to say, “This study examined a very wide spectrum of patients, which means the results really do apply to a substantial percentage of patients undergoing stent procedures around the world.”³

The discovery of cangrelor is exciting news in the cardiology world, as it is an agent currently unmatched in its advantages and provides consistent, superior benefit to patients. The data is compelling, and we can certainly expect The Medicines Company®, the pharmaceutical company that developed cangrelor, to seek FDA approval for this new compound.

 SOURCES:

1. Kastrati A, Ndrepepa G. Cangrelor—A Cham-pion Lost in Translation? N Engl J Med. 2009; 361:2382-2384
2. Bhatt DL, Stone GW, Mahaffey KW, Gibson CM, Steg PG, Hamm CW, Price MJ, Leonardi S, Gallup D, Bramucci E, Radke PW, Widimský P, Tousek F, Tauth J, Spriggs D, McLaurin BT, Angi-olillo DJ, Généreux P, Liu T, Prats J, Todd M, Skerjanec S, White HD, Harrington RA; the CHAMPION PHOENIX Investigators. Effect of Platelet Inhibition with Cangrelor during PCI on Ischemic Events. N Engl J Med. 2013; 368:1303-1313
3. Cangrelor Solidly Outperforms Clopidogrel during Percutaneous Coronary Intervention. News Medical Web site. http://www.news-medical.net/news/20130312/Cangrelor-solidly-outperforms-clopidogrel-during-percutaneous-coronary-intervention.aspx. March 10, 2013. Accessed March 28, 2013

Published by Rho Chi Post