Speaking of prasugrel: TRITON-TIMI 38 STEMI substudy published in Lancet

Just in case you haven’t heard anything about prasugrel in the last 10 minutes, the STEMI substudy from TRITON-TIMI 38 has been published in the Lancet, along with an accompanying editorial by Gregg Stone. The results are consistent with the main study. The authors conclude that “prasugrel is an especially attractive alternative to clopidogrel to support PCI in the course of management of patients with STEMI.”
In his editorial, Stone agrees that the overall results of the trial are applicable to the STEMI subgroup, but notes that the trial was conducted in the era before the 600 mg clopidogrel dose became standard in primary PCI. In addition, Stone points out that patients who received secondary PCI did not benefit from clopidogrel preloading. By applying “the art of clinical decision making,” Stone concludes that “balancing ischaemic and haemorrhagic risk through careful selection of patients and personalised pharmacotherapy should result in improved outcomes.”

Harlan Krumholz told CardioBrief that he “was unclear about the rationale for the substudy, since the primary study showed no interaction between the STEMI and non-STEMI groups. In evaluating subgroups it is an important and key epidemiological principle that you should be using all the data, rather than just focusing on a single subgroup. Without all the data it is not possible to determine if the experience in the STEMI group is different from what is reported in the entire group.”

You can click here to download the slideset at www.clinicaltrialresults.org.

Lilly press release:

02/27/09 14:58
Prasugrel Showed Significant Reduction in Cardiovascular Events in High-Risk Heart Attack Patients Undergoing Stenting Compared with Clopidogrel

TOKYO and INDIANAPOLIS, Feb. 27 (ANTARA/PRNewswire-AsiaNet) —

Results from a pre-specified analysis of the landmark Phase III TRITON-TIMI 38 study showed that patients with the most severe form of acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI) achieved a significant reduction in relative risk of the combined endpoint of cardiovascular death, non-fatal heart attack or non-fatal stroke at both 30 days and 15 months when treated with prasugrel compared with clopidogrel (Plavix(R)/Iscover(R)). These data appear in the February 28 issue of the medical journal The Lancet.

This analysis of the TRITON-TIMI 38 study showed a significant reduction in cardiovascular events in patients with acute ST elevation myocardial infarction (STEMI, or high-risk heart attack) treated with prasugrel compared with clopidogrel as early as 30 days (32 percent reduction, p=0.0017) and continued for up to 15 months (21 percent reduction, p=0.0221). In addition, a similar safety profile was seen in both the prasugrel and clopidogrel groups. Although the overall study population, which included patients with unstable angina, NSTEMI (non-STEMI) and STEMI, showed a significant increase in TIMI major bleeding for patients on prasugrel, in the STEMI subpopulation, there was no significant increase of non-CABG (coronary artery bypass grafting) related TIMI major or minor bleeding during the trial period. This analysis of 3,534 STEMI patients, who were enrolled in the TRITON-TIMI 38 trial, represented the first large analysis evaluating prasugrel as well as clopidogrel in this patient population undergoing PCI.

“Patients with ST elevation myocardial infarction are at higher risk of early cardiovascular events and death than patients with unstable angina,” said Professor Gilles Montalescot, key study investigator and professor of cardiology at Pitie-Salpetriere Hospital, Paris. “Our analysis showed that treatment with prasugrel significantly reduced the risk of cardiovascular events compared with clopidogrel — without an increase in major bleeding — which is certainly good news for this group of high-risk patients.”

About the Analysis
This pre-specified analysis of the landmark Phase III TRITON-TIMI 38 trial assessed the effect of prasugrel versus clopidogrel in the STEMI population undergoing PCI, an interventional procedure to re-open clogged arteries. Patients were recruited when they presented within 12 hours of symptom onset (primary PCI) or when they presented from 12 hours to 14 days after the onset of symptoms (secondary PCI).

In the sub-analysis, prasugrel reduced the key secondary combined endpoint of cardiovascular death, non-fatal heart attack or urgent target vessel revascularization (UTVR) — an emergency procedure used to open blockages in arteries when a heart attack is occurring or imminent — by 21 percent compared with clopidogrel (9.6 percent prasugrel vs. 12 percent clopidogrel, p=0.0250) through 15 months. Treatment with prasugrel also reduced the risk of stent thrombosis in the STEMI sub-population by 42 percent compared with clopidogrel (1.6 percent vs. 2.8 percent, p=0.0232) through 15 months. In both primary and secondary PCI patients, a greater reduction of cardiovascular events was seen with prasugrel versus clopidogrel.

In this sub-analysis of the STEMI population, there was no significant difference between prasugrel and clopidogrel in non-CABG, TIMI major and life-threatening bleeding through 15 months. For the combined endpoint of non-CABG, TIMI major and minor bleeding, there was no difference between the two groups both at 30 days (3 percent prasugrel vs. 3.3 percent clopidogrel, p=0.6170) and 15 months (5.1 percent prasugrel vs. 4.7 percent clopidogrel, p=0.6494). In addition, there was no significant difference between life-threatening bleeding between prasugrel versus clopidogrel at 15 months (1.3 percent vs. 1.1 percent, respectively, p=0.75).

About TRITON-TIMI 38
The main TRITON-TIMI 38 clinical trial, previously published in the New England Journal of Medicine in November 2007 (Vol. 357 No.20), compared prasugrel with clopidogrel in patients with ACS undergoing PCI. In the primary analysis of the study, prasugrel reduced the relative risk of the combined endpoint of cardiovascular death, heart attack, or stroke by 19 percent (Absolute Risk Reduction 2.2 percent; p<0.001), with an increased risk of major bleeding compared with clopidogrel (2.4 percent vs. 1.8 percent, p=0.03) (1). In the overall study population, the secondary endpoint of cardiovascular death, non-fatal heart attack or UTVR was reduced by 19 percent (p<0.001) over clopidogrel through 15 months.

In the overall study population, including unstable angina, NSTEMI and STEMI patients, there were higher rates of TIMI major bleeding, including life-threatening (1.4 percent prasugrel vs. 0.9 percent clopidogrel, p=0.01) and fatal bleeding (0.4 percent prasugrel vs. 0.1 percent clopidogrel, p=0.002).

About Acute Coronary Syndromes
Acute coronary syndromes include 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 (2). In addition, ACS affects nearly 1.5 million people in the United States annually (3). 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 (4). Many ACS patients undergo PCI to re-open the artery, which usually includes a stent placement.

About Prasugrel
Daiichi Sankyo Company, Limited (TSE: 4568) and Eli Lilly and Company (NYSE: LLY) are co-developing prasugrel, an investigational oral antiplatelet agent invented by Daiichi Sankyo and its Japanese research partner Ube Industries, Ltd., as a potential treatment, initially for patients with acute coronary syndrome undergoing PCI. Prasugrel works by inhibiting platelet activation and subsequent aggregation by blocking the P2Y12 adenosine diphosphate (ADP) receptor on the platelet surface. Antiplatelet agents prevent platelets from clumping or sticking together, which can result in clogged arteries and may lead to heart attack or stroke.

About Daiichi Sankyo
A global pharma innovator, Daiichi Sankyo Co., Ltd., was established in 2005 through the merger of two leading Japanese pharmaceutical companies. This integration created a more robust organization that allows for continuous development of novel drugs that enrich the quality of life for patients around the world. A central focus of Daiichi Sankyo’s research and development are thrombotic disorders, malignant neoplasm, diabetes mellitus, and autoimmune disorders. Equally important to the company are hypertension, hyperlipidemia or atherosclerosis and bacterial infections. For more information, visit www.daiichisankyo.com .

About Eli Lilly and Company
Lilly, a leading innovation-driven corporation, is developing a growing portfolio of first-in-class and best-in-class pharmaceutical products by applying the latest research from its own worldwide laboratories and from collaborations with eminent scientific organizations. Headquartered in Indianapolis, Ind., Lilly provides answers — through medicines and information — for some of the world’s most urgent medical needs.

This press release contains certain forward-looking statements about the potential of the investigational compound prasugrel (CS-747, LY640315) and reflects Daiichi Sankyo’s and Lilly’s current beliefs. However, as with any pharmaceutical compound under development, there are substantial risks and uncertainties in the process of development and regulatory review. There is no guarantee that the compound will receive regulatory approval, that the regulatory approval will be for the indication(s) anticipated by the companies, or that later studies and patient experience will be consistent with study findings to date. There is also no guarantee that the compound will prove to be commercially successful. For further discussion of these and other risks and uncertainties, see Lilly’s filing with the United States Securities and Exchange Commission and Daiichi Sankyo’s filings with the Tokyo Stock Exchange. Daiichi Sankyo and Lilly undertake no duty to update forward-looking statements.

Plavix and Iscover are registered trademarks of Sanofi-Aventis Corp.

P-LLY

1 Wiviott, S, Braunwald, E, et al. Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes. New England Journal of Medicine. November 2007;357:2001-15.
2 British Heart Foundation Health Promotion Research Group. European Cardiovascular Disease Statistics 2008,
http://www.ehnheart.org/files/statistics%202008%20web-161229A.pdf, Accessed December 9, 2008.
3 American Heart Association. Heart Disease and Stroke Statistics – 2008
Update. http://www.americanheart.org/downloadable/heart/1200082005246HS_Stats%202008.final.pdf . Accessed December 9, 2008.
4 WebMD Medical Reference in Collaboration with the Cleveland Clinic. Heart Disease: Coronary Artery Disease.
http://www.webmd.com/heartdisease/guide/heart-disease-coronary-arterydisease . Accessed December 9, 2008.

(Logo: http://www.newscom.com/cgi-bin/prnh/20061120/DSLLOGO )

SOURCE: Eli Lilly and Company