World-First Launch of New Heart Drug

LONDON - Britons First to Benefit From Latest Heart Tablet Prasugrel (Efient(R) Black Triangle Drug)

UK patients are the first to benefit from the launch of a new heart drug prasugrel (Efient), following authorisation by the European Medicines Agency (EMEA). The availability of prasugrel offers fresh hope to patients who have unstable angina or have had a heart attack - known as Acute Coronary Syndromes (ACS)(1) - who undergo a PCI* procedure (angioplasty) to re-open a narrowed or blocked artery. When taken with aspirin, data shows that prasugrel may help prevent further cardiovascular events (such as a heart attacks and stroke) in these patients.(2)

The approval of prasugrel is based upon data from several trials including TRITON-TIMI 38**, a global head-to-head superiority trial involving 13,608 patients worldwide. It found that, compared to clopidogrel (PLAVIX(R)), prasugrel reduces the risk of cardiovascular death, heart attack or stroke in ACS PCI patients by 19% (9.9% versus 12.1%; HR=0.81; [95% CI 0.73-0.90]; p<0.001; ARR=2.2%).(2) The drug also cut the risk of recurrent cardiovascular events in ACS patients who undergo PCI by 35% (10.8% versus 15.4%; HR=0.65; [95% CI 0.46-0.92]; p<0.016; ARR=4.6%).(3)

There are potential benefits to the NHS of prasugrel. Cardiovascular disease imposes a huge annual burden on the UK economy, costing GBP14.4 billion each year,(4) though this figure fails to capture production losses. Overall costs including informal care are estimated at GBP30.7 billion annually.(5)

Prasugrel is the first new oral drug of its type - known as an antiplatelet - to be licensed in the UK for more than a decade(6) and is welcomed by experts. Dr Marcus Flather, Consultant Cardiologist at Royal Brompton Hospital, London, said: “Prasugrel is a welcome breakthrough as it builds on existing treatments by further reducing the risk of heart attacks and death in patients who have had a heart attack and an angioplasty procedure. Unstable angina and heart attack are the major cause of death and disability worldwide. The UK still has one of the highest rates of these conditions in the world and new drugs like prasugrel, in addition to aspirin, are vital to decreasing the risk for patients with these life threatening conditions.”

ACS is the most dangerous, often fatal sign of coronary heart disease (CHD),(1) a global health problem.(7) CHD is the main form of cardiovascular disease - the number one killer in each of the UK,(4) the EU,(5) Europe(5) and globally(7),(8) and responsible for 35% of all deaths in the UK each year.(5)

An estimated 2.6 million Britons have had a heart attack or angina, and every six minutes someone dies from a heart attack (90,000 people annually).(4) More than 90% of heart attacks are caused by blood clots.(9)

As many as 14% of Britons with unstable angina (heart-related chest pain) or who suffer a heart attack due to a partially blocked artery die within 12 months of diagnosis.(10)

Despite current guidelines, heart medications for ACS PCI patients are underused.(11) When antiplatelet drugs are used, the risk of heart attack, stroke or death is reduced significantly(2),(3). The National Institute of Health and Clinical Excellence (NICE) recommends aspirin with clopidogrel in ACS treatment.(12) However, research has also shown that up to 25% of patients do not respond adequately to clopidogrel.(13),(14)

METHOD OF ACTION

Antiplatelet drugs work by stopping platelets (tiny blood cells vital for the normal clotting process) from clumping or sticking together and forming life-threatening clots in arteries.(15)

Prasugrel and clopidogrel are ‘prodrugs’ which means that they are pharmacologically inactive until modified by enzymes in the human body to become an active metabolite.(16) The more rapidly the body can make this transformation, the sooner the active drug can get to work - and, compared to clopidogrel, prasugrel is thought to do this more directly in fewer steps than clopidogrel.(17),(18)

New data published in The Lancet show that in a pre-specified sub-analysis of 3,534 patients enrolled in the TRITON-TIMI 38 trial with the most severe form of ACS (acute ST elevation myocardial infarction) undergoing PCI, prasugrel reduced the risk of stent-related clots by 32% (6.5% versus 9.5%; HR=0.68; [95% CI 0.54-0.87]; p=0.0017; ARR=3.0%) compared with clopidogrel, with a similar safety profile.(19) More than 90% of PCI procedures in the UK involve insertion of a stent, a short tube of steel mesh left in place to hold open the narrowed artery.(20)

Dr Robert Storey, Cardiologist at the Department of Cardiovascular Science, University of Sheffield, said: “The availability of prasugrel in the UK is good news for physicians and patients in view of the encouraging data from the TRITON study. UK physicians face many challenges with antiplatelet therapy including risk of bleeding and variability of patient response. Prasugrel, taken with aspirin, offers consistent platelet control which is particularly important for those at higher risk of recurrent heart attack. Used appropriately in the right patients, it has the potential to save lives.”

All antiplatelet drugs come with a risk of bleeding. Treatment with prasugrel had an increased risk of bleeding relative to treatment with clopidogrel.(2) The most common bleeding events seen with prasugrel in clinical trials were haematoma (a collection of blood under the skin or in a muscle), epistaxis (nosebleeds), gastrointestinal haemorrhage (bleeding in the stomach or gut), haematuria (blood in the urine) and bleeding from needle puncture sites. Trial data suggested that in patients at increased risk of bleeding, namely >75 years of age; with body weight <60 kg or with concomitant administration of medicinal products that may increase the risk of bleeding, precautions are advised and prescribing should only be considered when the benefits in terms of prevention of atherothrombotic events are deemed to outweigh the risk of serious bleedings (see Summary of Product Characteristics). Prasugrel is contraindicated in patients with a history of stroke and / or TIA.(2) However, the TRITON-TIMI 38 data identified a significant net clinical benefit in the majority (80%) of ACS PCI patients taking prasugrel compared to clopidogrel(2), which represents a similar portion of the 'real world' ACS PCI population.(21)

When the efficacy benefits were compared with the risk of serious bleeding events, for every 1,000 patients treated with prasugrel instead of clopidogrel, there were six more major bleeding events but 23 fewer heart attacks.(2)

PCI TREATMENT

Over 73,000 PCI treatments are carried out in the UK annually - this compares with around 10,000 in 1991 - a figure currently increasingly by 5% per year.(5) About 8.5% of ACS patients will experience a clot-related heart problem within a year following PCI treatment which contributes significantly to healthcare costs, making protective drug treatment necessary.(22),(23), (24)

UK charity The British Cardiac Patients Association is optimistic by the potential for prasugrel to not only save lives but also spare ACS PCI patients from serious future problems. Chairman Mr Keith Jackson said: “It’s a grim fact the battle against cardiovascular disease in the UK is far from won. There is everything to gain from new antiplatelet drugs such as prasugrel. Treatment that helps improve the management of ACS PCI patients, together with maintaining heart healthy lifestyles, is critical so that fewer people face the devastating consequences of heart attack, stroke and death.”

*A PCI (percutaneous coronary intervention) is the treatment of choice in ACI patients to re-open a narrow or blocked artery and improve blood flow to the heart

**The TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38

REFERENCES

1. British Heart Foundation. Heart attack including information on acute coronary syndrome. Heart Information Series Number 7. September 2006

2. 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

3. Murphy, SA et al. Reduction in recurrent cardiovascular events with prasugrel compared with clopidogrel in patients with acute coronary syndromes from the TRITON-TIMI 38 trial. Eur Heart J 2008;29(20):2473-2479

4. British Heart Foundation. BHF Statistics 2008

5. Heartstats. www.heartstats.org/homepage.asp (accessed 02.02.09)

6. Electronic Medicines Compendium. Summary of Product Characteristics, PLAVIX, Sanofi-Aventis. emc.medicines.org.uk/document.aspx?documentid=9483 (accessed 18.02.09)

7. World Health Organization. Cardiovascular diseases. Fact Sheet No. 317. February 2007

8. Allender S, Scarborough P, Peto V European cardiovascular disease statistics. 2008 edition. Pg. 11

9. Waters, M. Heart Attack Risk - The Dangers Associated With Blood Clotting. 8 Nov. 2007. ezinearticles.com/?Heart-Attack-Risk—The-Dangers-Associated-With-Blood-Clotting&id=824191

(accessed 05.02.09).

10. Robinson M, Palmer S, Sculpher M, Philips Z, Ginnelly L, Bowens A, et al. Cost-effectiveness of alternative strategies for the initial medical management of non-ST elevation acute coronary syndrome: systematic review and decision-analytical modelling. Health Technol Assess 2005;9(27

11. Stafford, R., Radley, D. The underutilization of cardiac medications of proven benefit, 1990 to 2002. J of the Am Coll of Card. 2003;41:56-61

12. National Institute for Health and Clinical Excellence. TA80. Clopidogrel Technology in the treatment of non-ST elevated acute coronary syndrome. London: NICE. 2004

13. Matetzky S, Fefer P et al. Effectiveness of Reloading to Overcome Clopidogrel Nonresponsiveness in Patients with Acute Myocardial Infarction. Am J Cardiol 2008;102(5):524-529.

14. Matetzky S, Shenkman B et al. Clopidogrel Resistance Is Associated With Increased Risk of Recurrent Atherothrombotic Events in Patients With Acute Myocardial Infarction. Circulation. 2004;109:3171-3175; published online before print June 7 2004, doi:10.1161/01.CIR.0000130846.46168.03.

15. American Heart Association. “What are Anticoagulants and Antiplatelet Agents? www.americanheart.org/downloadable/heart/110080494410839%20WhatAreAnticoagAntiplat.pdf

(accessed 30.07.07)

16. Rehmel JL, Eckstein JA, Farid NA, et al. Interactions of two major metabolites of prasugrel, a thienopyridine antiplatelet agent, with the cytochromes P450. Drug Metab Dispos. 2006;34:600-607

17. Brandt, J, Payne, C, et al. A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is relative to active metabolite formation. American Heart Journal. 2007;153:66.e9-66.e16

18. Jakubowski, JA et al. Prasugrel: A Novel Thienopyridine Antiplatelet Agent. Cardiovascular Drug Reviews 2007; Vol. 25, No. 4, 357-374

19. Montalescot, G.,Wiviott, S.,Branuwald E., Murphy,S., Gibson, M., McCabe, C., and Antman, E.. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind randomised controlled trial. Lancet 2009;373:723-731

20. Ludman PF. NCIS Audit returns. Adult interventional procedures. January 2006 to December 2006. Presented at BCIS Autumn Meeting, Dublin 2007. www.bcis.org.uk/resources/audit (accessed 10.10.07)

21. Food and Drug Administration, Cardiovascular and Renal Drugs Advisory Committee, Briefing Information, February 03, 2009. www.fda.gov/ohrms/dockets/ac/09/briefing/2009-4412b1-03-Lilly.pdf (accessed 11.02.09)

22. Chechi T et al. ST-Segment Elevation Myocardial Infarction Due to Early and Late Stent Thrombosis: A New Group of High-Risk Patients. JACC 2008;51:2396-2402

23. Applegate RJ et al. Incidence of Coronary Stent Thrombosis Based on Academic Research Consortium Definitions. Am J Cardiol 2008;102:683-688

24. Steinhubl SR et al. Early and Sustained Dual Oral Antiplatelet Therapy Following Percutaneous Coronary Intervention: A Randomized Controlled Trial. JAMA 2002;288(19):2411-2420

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Source: DAIICHI SANKYO and Eli Lilly and Company

For more information contact Just:: Health PR: Laura Chambers, +44(0)20-8877-8405/ +44(0)7793-049657, laura at justhealthpr.com; Rose Lockett, +44(0)20-8877-8428/ +44(0)7859-822654, rose at justhealthpr.com