Clopidogrel in Patients with Cerebrovascular Disease Part 1: Long-term Risks Facing Cerebrovascular Patients

1. Clopidogrel in Patients with Cerebrovascular Disease Part 1: Long-term Risks Facing Cerebrovascular Patients This slide kit provides an overview of clopidogrel, and includes: pharmacology of clopidogrel � a unique antiplatelet agent clinical efficacy of clopidogrel � from CAPRIE to CURE and CREDO clopidogrel in patients with a cerebrovascular ischemic accident favorable safety and tolerability profile with clopidogrel the ongoing clinical trials with clopidogrel summaryThis slide kit provides an overview of clopidogrel, and includes: pharmacology of clopidogrel � a unique antiplatelet agent clinical efficacy of clopidogrel � from CAPRIE to CURE and CREDO clopidogrel in patients with a cerebrovascular ischemic accident favorable safety and tolerability profile with clopidogrel the ongoing clinical trials with clopidogrel summary

2. Cerebrovascular Patients Face a Long-Term Risk of Atherothrombotic Events in all Vascular Beds Atherothrombosis is a potentially life-threatening disease that can effect the entire vascular system. Its progressive nature means that the long-term outcome in patients at risk (like patients after an ischemic cerebral event) is unpredictable. Atherothrombosis is a potentially life-threatening disease that can effect the entire vascular system. Its progressive nature means that the long-term outcome in patients at risk (like patients after an ischemic cerebral event) is unpredictable.

3. Ischemic Stroke is a Major Health Burden A major health burden in Western countries: Stroke is the third most common cause of death1 Stroke is the leading cause of disability in adults1 Stroke is the second most important cause of dementia1 Key facts: In the USA: every 53 seconds, someone suffers a stroke2 In the UK: more than 47,000 working lives are lost (deaths before age of 65) each year and 8 million working days are lost3 Epidemiology: Worldwide stroke prevalence of 7.1 million in 2000 and rising4 � Stroke is the third most common cause of death in adults and the leading cause of disability and dementia.1 � Stroke is a major cause of lost productivity; for example, in the UK alone, eight million working days are lost due to stroke each year.2 References 1. Leys D. Cerebrovascular Disease 2001: 11(suppl 2):1�4. 2. NHS Executive. Burdens of Disease: a discussion document. London: Department of Health, 1996 � Stroke is the third most common cause of death in adults and the leading cause of disability and dementia.1 � Stroke is a major cause of lost productivity; for example, in the UK alone, eight million working days are lost due to stroke each year.2 References 1. Leys D. Cerebrovascular Disease 2001: 11(suppl 2):1�4. 2. NHS Executive. Burdens of Disease: a discussion document. London: Department of Health, 1996

4. Stroke Has a Major Impact on Quality of Life � Estimates of quality of life scores after stroke have been made for various categories of disability � a mild event was scored at 0.75; a moderate to severe event was scored at 0.39; and a recurrent event was scored at 0.12 (0=dead and 1=perfect health).1 � Stroke has a considerable impact on patients� quality of life: even a mild stroke has a similar impact on quality of life as does asthma and a much greater detrimental effect than chronic low back pain. In a study which compared the quality of life impact of various diseases in Sweden, asthma scored 0.79 and low back pain 0.66.2 References 1. Gage BF, Cardinalli AB, Albers GW, Owens DK. JAMA 1995; 274: 1839�1845. 2. Burstrom K, Johannesson M, Diderichsen F. Qual Life Res 2001; 10(7): 621�635. � Estimates of quality of life scores after stroke have been made for various categories of disability � a mild event was scored at 0.75; a moderate to severe event was scored at 0.39; and a recurrent event was scored at 0.12 (0=dead and 1=perfect health).1 � Stroke has a considerable impact on patients� quality of life: even a mild stroke has a similar impact on quality of life as does asthma and a much greater detrimental effect than chronic low back pain. In a study which compared the quality of life impact of various diseases in Sweden, asthma scored 0.79 and low back pain 0.66.2 References 1. Gage BF, Cardinalli AB, Albers GW, Owens DK. JAMA 1995; 274: 1839�1845. 2. Burstrom K, Johannesson M, Diderichsen F. Qual Life Res 2001; 10(7): 621�635.

5. Major Clinical Manifestations of Atherothrombosis Atherothrombosis can be an extensive vascular disease affecting the coronary, cerebral and peripheral circulation. It is a progressive, generalized disorder with many clinical manifestations � either acute or chronic and often multiple in any single patient. Stenosis in an atherosclerotic artery may give rise to angina, a transient ischemic attack (TIA) or intermittent claudication. Atherothrombosis in the coronary arteries is the major cause of acute coronary syndrome (ACS), defined as unstable angina and non Q�wave myocardial infarction. Atherothrombosis of the cerebral arteries may also result in TIA or ischemic stroke. In the peripheral arteries, thrombosis superimposed on atherosclerosis can contribute to the progression of peripheral arterial disease, producing intermittent claudication (leg pain on walking that is relieved by rest) as well as ischemic necrosis and, potentially, loss of the limb.Atherothrombosis can be an extensive vascular disease affecting the coronary, cerebral and peripheral circulation. It is a progressive, generalized disorder with many clinical manifestations � either acute or chronic and often multiple in any single patient. Stenosis in an atherosclerotic artery may give rise to angina, a transient ischemic attack (TIA) or intermittent claudication. Atherothrombosis in the coronary arteries is the major cause of acute coronary syndrome (ACS), defined as unstable angina and non Q�wave myocardial infarction. Atherothrombosis of the cerebral arteries may also result in TIA or ischemic stroke. In the peripheral arteries, thrombosis superimposed on atherosclerosis can contribute to the progression of peripheral arterial disease, producing intermittent claudication (leg pain on walking that is relieved by rest) as well as ischemic necrosis and, potentially, loss of the limb.

6. Atherothrombosis is a Systemic Disease: Long-Term Risk Increase for Stroke As a Function of Coronary Calcification1 Coronary atherosclerosis is the most common predisposing factor for atherothrombosis. Coronary calcification is indicative of advanced atherosclerosis not only in the coronary arteries but, in addition, ultimately of cerebrovascular disease. There is a strong relationship between increased calcium score in the coronary artery and long-term risk of stroke, further elucidating the principle of atherothrombosis as a generalized and progressive disease. Coronary atherosclerosis is the most common predisposing factor for atherothrombosis. Coronary calcification is indicative of advanced atherosclerosis not only in the coronary arteries but, in addition, ultimately of cerebrovascular disease. There is a strong relationship between increased calcium score in the coronary artery and long-term risk of stroke, further elucidating the principle of atherothrombosis as a generalized and progressive disease.

7. Atherothrombosis is a Systemic Disease: Long-term Risk Increase for Myocardial Infarction as a Function of Carotid Intima Media Thickness1 Atherosclerosis of the carotid arteries has a strong correlation with stroke � which is to be expected as the brain is the arterial bed it serves. However, carotid artery atherosclerosis is associated with a similar significant risk of atherothrombotic events in the coronary arteries, demonstrating the generalized nature of atherosclerosis and consequently atherothrombosis. Atherosclerosis of the carotid arteries has a strong correlation with stroke � which is to be expected as the brain is the arterial bed it serves. However, carotid artery atherosclerosis is associated with a similar significant risk of atherothrombotic events in the coronary arteries, demonstrating the generalized nature of atherosclerosis and consequently atherothrombosis.

8. Long-term risks of stroke, MI and vascular death in ��low risk�� TIA patients This study investigated the long term risks of stroke and other vascular events in patients with TIA who survived the initial high risk period. 290 patients were studied who had initially been followed after a TIA in the Oxford community stroke project. Median time since last TIA was 3,8 years. The risk of major vascular events was constant through time. The 10 year risk of first stroke was 18,8% (95% CI 13,6 to 23,7%) and 27,8% for the 10 year risk of MI (myocardial infarction or death from coronary heard disease) (95% CI 21,8% to 33,3%) A total of 114 patients had at least one major vascular event with a 10 year risk of any first stroke, MI or vacular death of 42,8%.This study investigated the long term risks of stroke and other vascular events in patients with TIA who survived the initial high risk period. 290 patients were studied who had initially been followed after a TIA in the Oxford community stroke project. Median time since last TIA was 3,8 years. The risk of major vascular events was constant through time. The 10 year risk of first stroke was 18,8% (95% CI 13,6 to 23,7%) and 27,8% for the 10 year risk of MI (myocardial infarction or death from coronary heard disease) (95% CI 21,8% to 33,3%) A total of 114 patients had at least one major vascular event with a 10 year risk of any first stroke, MI or vacular death of 42,8%.

9. Manifestations of Atherothrombosis are Commonly Found in More than One Arterial Bed in an Individual Patient*1 A person suffering from any one manifestation of atherothrombosis is at risk of future disabling or life-threatening events caused by the same underlying disease process.1 The CAPRIE trial enrolled 19,185 patients with either established peripheral arterial disease (PAD),2,3 a recent myocardial infarction or recent ischemic stroke in approximately equal distribution. However, based on the baseline characteristics of these patients, many of them already had a prior history of ischemic events. Thus, at study entry ~26% of the patients had ischemic vascular disease in at least two vascular beds, demonstrating the generalized nature of atherothrombosis.3 For example, 11.8% of patients had both coronary disease and PAD, 7.4% had both coronary and cerebrovascular disease, 3.8% had a combination of cerebrovascular disease and PAD, and 3.3% had disease of all three arterial beds.3 Over time this overlap will most probably increase (in the CAPRIE trial more than 2,000 patients experienced a major ischemic event over the mean 1.9 year follow-up, and many others developed other ischemic events such as transient ischemic attack and angina).3A person suffering from any one manifestation of atherothrombosis is at risk of future disabling or life-threatening events caused by the same underlying disease process.1 The CAPRIE trial enrolled 19,185 patients with either established peripheral arterial disease (PAD),2,3 a recent myocardial infarction or recent ischemic stroke in approximately equal distribution. However, based on the baseline characteristics of these patients, many of them already had a prior history of ischemic events. Thus, at study entry ~26% of the patients had ischemic vascular disease in at least two vascular beds, demonstrating the generalized nature of atherothrombosis.3 For example, 11.8% of patients had both coronary disease and PAD, 7.4% had both coronary and cerebrovascular disease, 3.8% had a combination of cerebrovascular disease and PAD, and 3.3% had disease of all three arterial beds.3 Over time this overlap will most probably increase (in the CAPRIE trial more than 2,000 patients experienced a major ischemic event over the mean 1.9 year follow-up, and many others developed other ischemic events such as transient ischemic attack and angina).3

10. Summary Atherothrombosis is characterized by a sudden plaque disruption leading to platelet activation and thrombus formation1 Atherothrombosis is the common pathological link between all major clinical manifestations of vascular disease: myocardial infarction, ischemic stroke and peripheral arterial disease2 Patients with clinical manifestations of atherothrombosis in one vascular bed (like ischemic stroke) are not only at risk of a recurrent event in the same arterial distribution, but also at risk of developing ischemic events in other vascular beds3 Atherothrombosis is one of the leading causes of death worldwide4 Atherothrombosis is characterized by a sudden plaque disruption leading to platelet activation and thrombus formation.1 Atherothrombosis is a global disease and is the common pathological link between myocardial infarction, ischemic stroke and peripheral arterial disease � the main clinical manifestations of vascular ischemia.2 Patients with a clinical manifestation of atherothrombosis are at risk of subsequent events. Since atherothrombosis often reflects disseminated atherosclerosis, the subsequent events may occur not only in the same arterial distribution but also in other vascular beds.3 The health burden of atherothrombosis is considerable, and the disease is one of the leading causes of death worldwide.4Atherothrombosis is characterized by a sudden plaque disruption leading to platelet activation and thrombus formation.1 Atherothrombosis is a global disease and is the common pathological link between myocardial infarction, ischemic stroke and peripheral arterial disease � the main clinical manifestations of vascular ischemia.2 Patients with a clinical manifestation of atherothrombosis are at risk of subsequent events. Since atherothrombosis often reflects disseminated atherosclerosis, the subsequent events may occur not only in the same arterial distribution but also in other vascular beds.3 The health burden of atherothrombosis is considerable, and the disease is one of the leading causes of death worldwide.4

11. Disclaimer This slide kit presents data to support the rationale for the use of ADP-receptor antagonists in registered and non-registered indications. The slide kit has been prepared for medical and scientific purposes, and cannot be considered as an inducement to use clopidogrel in non-registered indications. Neither Sanofi-Synth�labo nor Bristol-Myers Squibb recommends the use of clopidogrel in any manner inconsistent with that described in the full prescribing information.