Wednesday, 29 September 2010

Phase II study showed switching ACS-PCI patients on maintenance clopidogrel/aspirin to prasugrel/aspirin

In a Phase II study, Acute Coronary Syndrome (ACS) patients on maintenance clopidogrel/aspirin therapy who were switched to prasugrel (Efient - either 10 mg maintenance dose [MD] or 60 mg loading dose [LD] followed by 10 mg MD) plus aspirin demonstrated a statistically significant greater reduction in Maximal Platelet Aggregation (MPA) after one week when compared to patients who remained on maintenance therapy (MD) with clopidogrel.[i] <#_edn1>

The study, published today in the Journal of the American College of Cardiology, evaluated the level of platelet aggregation achieved after switching from clopidogrel 75 mg once daily MD plus aspirin, to prasugrel 10 mg once daily MD in patients with acute coronary syndrome.
The Switching Anti Platelet Study (SWAP) was sponsored by Daiichi Sankyo Co, Ltd. and Eli Lilly and Company.

Platelet aggregation is a critical step in the formation of blood clots, which pose a significant risk to patients following an ACS event, including heart attack and heart-related chest pain. The study provides further evidence to suggest that prasugrel can reduce platelet aggregation to a greater extent among ACS patients compared with clopidogrel.[ii] <#_edn2>

Of the 128 patients who completed the study, 100 patients with evaluable data were eligible to be included in the platelet function analysis. After a 10-14 day run-in phase with open label clopidogrel 75 mg once daily plus aspirin, patients were randomized to either remain on clopidogrel 75 mg plus aspirin for seven days (n=33), switch to prasugrel 10 mg plus aspirin for seven days (n=36), or switch to prasugrel 60 mg loading dose plus aspirin followed by prasugrel 10 mg plus aspirin daily for 6 days (n=31).1

At day seven, MPA (as measured using 20 mM ADP) was significantly lower in patients switched to prasugrel MD 10 mg plus aspirin when compared to the patients who remained on clopidogrel MD (41.1 percent vs. 55.0 percent, p<0.0001). It was also significantly lower in those patients switched to prasugrel 60 mg LD followed by prasugrel 10 mg MD compared to clopidogrel MD (41.0 percent vs. 55.0 percent, p<0.0001).1

“These findings are important because they provide new insights into potential differences in the levels of platelet inhibition that can be achieved with dual oral antiplatelet therapy in patients with ACS,” said Dominick J. Angiolillo, M.D., Assistant Professor, Department of Medicine, Division of Cardiology, University of Florida College of Medicine, Jacksonville, and lead author of the paper. “The data showed that prasugrel plus aspirin may be able to provide additional reduction in platelet aggregation in ACS patients over those taking standard dose clopidogrel plus aspirin. However, a larger study would be needed to assess the potential impact of switching on cardiovascular outcomes.”

The SWAP study was not designed to evaluate efficacy or safety endpoints. The clinical safety and efficacy of switching from clopidogrel to prasugrel has not been studied.

SWAP was a Phase II, multicentre, randomized, double-blind, double-dummy, active-controlled trial evaluating the effects on platelet function after switching patients on daily clopidogrel therapy following an ACS event to daily prasugrel therapy. Patients were eligible for enrollment if they were between 18 and 75 years of age, presented 30 to 330 days after an ACS event and treated with daily aspirin and clopidogrel. They were excluded if they had any of the following: a planned coronary revascularization procedure (coronary artery bypass surgery or coronary angioplasty) during the study, high risk of bleeding, history of stroke or mini stroke, or weigh less than 60 kg.

Platelet function was evaluated at 2 hours, 24 hours, 7 days and 14 days using three different tests, including light transmittance aggregometry, the standard way to measure platelet aggregation.1

In TRITON, the risk of non-coronary artery bypass graft (non-CABG) major bleeding, including fatal bleeding, was higher with prasugrel (2.2 percent incidence) compared with clopidogrel (1.7 percent incidence).[iii] <#_edn3> Compared with the overall study population, a higher risk of serious bleeding among prasugrel patients was most evident in three distinct patient populations that are readily identifiable: patients who weighed less than 60 kg (132 lbs), patients who were 75 years of age or older and patients who have had a prior transient ischemic attack (TIA) or stroke.[iv] <#_edn4> A 5 mg maintenance dose is recommended for patients who weigh less than 60 kg.3 Prasugrel is generally not recommended for use in patients 75 years or older. If treatment is deemed necessary, a 5mg dose of prasugrel may be used after careful risk-benefit evaluation.3 Patients with prior TIA or stroke should not be treated with prasugrel.3

Daiichi Sankyo Company, Limited, and Eli Lilly and Company co-developed prasugrel, an oral antiplatelet agent discovered by Daiichi Sankyo and its Japanese research partner, Ube Industries, Ltd. Prasugrel helps keep blood platelets from clumping together and developing a blockage in an artery. The European Commission granted marketing authorization for prasugrel for the prevention of atherothrombotic events in patients with ACS undergoing PCI.

Acute coronary syndrome includes heart attacks and unstable angina (chest pain). Coronary heart disease, which can result in ACS, is the single most common cause of death in the European Union, accounting for more than 741,000 deaths in the EU each year.[v] <#_edn5> In addition, ACS affects nearly 1.5 million people in the United States annually.[vi] <#_edn6> Heart attack is a major manifestation of coronary heart disease, which occurs when the arteries become narrowed or clogged by cholesterol and fat deposits. In some cases the plaque can rupture, resulting in a blood clot, which may partially or totally block the blood supply to portions of the heart, resulting in ACS.[vii] <#_edn7> Many ACS patients undergo PCI to re-open the artery, which usually includes a stent placement.

[i] <#_ednref1> Angiolillo, DJ., Saucedo, JF., DeRaad, R., et al. Increased platelet inhibition after switching from maintenance clopidogrel to prasugrel in patients with acute coronary syndromes: Results of the SWitching Anti Platelet (SWAP) Study. J Am Coll Cardiol 2010. Published online 14th September 2010.

[ii] <#_ednref2> Montalescot, G, et al. Prasugrel compared with high-dose clopidogrel in acute coronary syndrome: The randomised, double blind ACAPULCO study. Thrombosis and Haematosis 2010; 103: 213

[iii] <#_ednref3> European Medicines Agency. Summary of Product Characteristics.

[iv] <#_ednref4> Wiviott, S.D et al. Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes. New England Journal of Medicine 2007 Vol 357 (20); 2001-2015

[v] <#_ednref5> British Heart Foundation Health Promotion Research Group. European Cardiovascular Disease Statistics 2008 <> . Accessed 5 March 2010.

[vi] <#_ednref6> American Heart Association. Heart Disease and Stroke Statistics – 2008 Update <> . Accessed 5 March 2010.

[vii] <#_ednref7> WebMD Medical Reference in Collaboration with the Cleveland Clinic. Heart Disease: Coronary Artery Disease <> . Accessed 5 March 2010.

Eli Lilly and Company