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ASA - Is there a Primary Prevent Indication in Diabetes? Contemporary Therapeutic Issues in Cardiovascular Disease Saturday, May 8 th, 2010 Patrick Robertson,

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Presentation on theme: "ASA - Is there a Primary Prevent Indication in Diabetes? Contemporary Therapeutic Issues in Cardiovascular Disease Saturday, May 8 th, 2010 Patrick Robertson,"— Presentation transcript:

1 ASA - Is there a Primary Prevent Indication in Diabetes? Contemporary Therapeutic Issues in Cardiovascular Disease Saturday, May 8 th, 2010 Patrick Robertson, BSP, PharmD Manager, Clinical Pharmacy Services Saskatoon Health Region, SK

2 Objectives 1. Review the critical role of platelets in the development of atherothrombosis. 2. Outline the rationale for ASA in primary prevention. 3. Review the variability in current recommendations 4. Review recent evidence questioning the role of ASA in the primary prevention of diabetes patients.

3 Disclosure  I have received research grants from: Gambro, Merck  I have sat on Advisory boards for Pfizer, Sanofi-Aventis, Eli-Lilly  I have received speaking honoraria from: Pfizer, Astra-Zeneca, Merck, BMS, Sanofi-Aventis, Novartis, Solvay, Altana

4 What Is Atherothrombosis?  The formation of a thrombus on an existing atherosclerotic plaque  Atherothrombosis is a new term recognizing that atherosclerosis (plaque development) and acute thrombosis are integrally related to the presentation of vascular events  A generalized progressive disease of large- and mid-size arteries that affects multiple vascular beds, including cerebral, coronary, and peripheral arteries  The underlying disease leading to myocardial infarction (MI), peripheral arterial disease (PAD), ischemia and many forms of stroke MI, myocardial infarction; PAD, peripheral artery disease. Fuster V, et al. Vasc Med. 1998;3: Rauch U, et al. Ann Intern Med. 2001;134:

5 Unstable angina MI Ischemic stroke/TIA Critical leg ischemia Intermitent claudication CV death ACS Atherosclerosis Stable angina/ Intermittent claudication Atherothrombosis: A Generalized and Progressive Process Thrombosis Adapted from Libby P. Circulation. 2001;104:

6 GP IIb/IIIa Inhibitors 1. Platelet Adhesion 2. Platelet Activation Platelet GP Ib Plaque rupture Activated Platelet GP IIb/IIIa 3. Platelet Aggregation ASA, Clopidogrel/Ticlopidine ASA, Clopidogrel/Ticlopidine ASA, acetylsalicyclic acid. Cannon and Braunwald, Heart Disease TxA2 Fibrinogen Platelets Role in Thrombosis

7 Jakubowski JA et al. Br J Clin Pharmacol 2007;63(4): The Role of Platelet Activation  Platelet activation and aggregation play a central role in atherothrombotic vascular disease 1, 2  Platelet activation results in the release of adenosine 5’-diphosphate (ADP), amplifying activation and aggregation via P2Y 1 and P2Y 12 receptors 3-6  Activated platelets are recruited to sites of coronary plaque rupture, forming aggregates that may lead to platelet-rich thrombi, vascular occlusion, tissue ischemia, and necrosis, collectively known as acute coronary syndrome (ACS) 7 1 Badimon L et al. In Platelets in Thrombotic and Non Thrombotic Disorders, 1 st ed, 2002, Goldschmidt PJ et al. In Platelets, 1 st ed, 2002, Jin J et al. J Biol Chem 1998;273(4): Foster CJ et al. J Clin Invest 2001;107(12): Dorsam RT, Kunapuli SP. J Clin Invest 2004;113(3): Hollopeter G et al. Nature 2001;409(6817): Bertrand ME et al. Eur Heart J 2002;23(23):

8 What are the recommendations for the use of anti-platelet agents for primary and secondary prevention?

9 2009 Canadian Hypertension Education Program Recommendations 9 XIV. Vascular Protection for Hypertensive Patients: ASA Consider low dose ASA Strong consideration should be given to the addition of low-dose ASA therapy in hypertensive patients (Grade A in patients older than 50 years). Caution should be exercised if blood pressure is not controlled (Grade C).

10 Aspirin for the Prevention of Cardiovascular disease: US Preventive Services Task Force  The US Preventive Services Task Force makes recommendations about preventative care services for patients without recognized signs or symptoms of the target condition  These recommendations apply to adult men and women without a history of CHD or stroke US Preventive Services Task Force Ann Intern Med 2009;150:

11 10-year CHD risk levels at which the number of CVD events prevented is balanced with the number of serious bleeds Men (AMI) Women (Stroke) Age 10-Year CHD Risk, % Age 10-Year CHD Risk, % y≥ y≥ y≥ y≥ y≥ y≥11 US Preventive Services Task Force Ann Intern Med 2009;150:

12 Recent question  Should ASA be recommended for primary prevention of cardiovascular events in DM patients?  US Preventive Services Task Force recommends that men >45 years and women >55 years of age with DM (and no other risk factor) be treated with ASA to prevent AMI or stroke, respectively. US Preventive Services Task Force Ann Intern Med 2009;150:

13 Aspirin for the Primary Prevention of Cardiovascular Disease in DM – Current Guidelines

14 Aspirin for primary prevention of cardiovascular events in people with Diabetes: Meta-Analysis of RCTs De Berardis, et al. BMJ 2009;339:b4531;1-8. Recent Meta-analysis Persistent uncertainty of the benefit and harm of aspirin in people with diabetes and no pre-existing CVD. Well conducted meta-analysis including 6 RCTs (10,117 DM patients) conducted to answer the above question.

15 Copyright ©2009 BMJ Publishing Group Ltd. De Berardis, G. et al. BMJ 2009;339:b4531 Fig 2 Effect of aspirin therapy on primary prevention of major cardiovascular events, myocardial infarction, stroke, death from cardiovascular causes, and all cause mortality in participants with diabetes. JPAD=Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes; POPADAD=Prevention Of Progression of Arterial Disease And Diabetes; WHS=Women's Health Study; PPP=Primary Prevention Project; ETDRS=Early Treatment Diabetic Retinopathy Study. Number in group have been reported as provided by trialists or estimated from any available data in the publications

16 Copyright ©2009 BMJ Publishing Group Ltd. De Berardis, G. et al. BMJ 2009;339:b4531 Fig 3 Effect of aspirin therapy on primary prevention of myocardial infarction and stroke among men and women with diabetes. PPP=Primary Prevention Project; ETDRS=Early Treatment Diabetic Retinopathy Study; PHS=Physicians' Health Study; WHS=Women's Health Study. Number in group have been reported as provided by trialists or estimated from any available data in the publications

17 Aspirin for primary prevention of cardiovascular events in people with Diabetes: Meta-Analysis of RCTs De Berardis, et al. BMJ 2009;339:b4531 Comparative risk of developing drug related side effects with aspirin compared with placebo or no treatment *As generically reported by authors Side effectNo of trials reporting outcome No of patients Relative risk (95% CI) Any bleeding (0.76 to 8.21) Gastrointestinal bleeding (0.64 to 6.95) Gastrointestinal symptoms* (0.08 to ) Cancer (0.62 to 1.14)

18 Conclusions De Berardis, et al. BMJ 2009;339:b4531  Can NOT recommend ASA in the primary prevention of CV events in all patients with DM without additional risk factors. ASA reduced AMI by 43% in Men  RR=0.57 (95%CI;0.34 to 0.94) ASA was not associated with a significant incidence of bleeding  Lacked power  Expect 1-2 major bleeding complications for every 1000 people treated with low dose ASA for 1 year. Patrono C et al. N Engl J Med 2005;353:

19 Vascular Protection in People With Diabetes Low-dose ASA therapy (81–325 mg) may be considered in people with stable CVD [Grade D, Consensus]. Clopidogrel (75 mg) may be considered in people unable to tolerate ASA [Grade D, Consensus]. The decision to prescribe antiplatelet therapy for primary prevention of CV events, however, should be based on individual clinical judgment [Grade D, Consensus].

20 What are the recommendations for the use of anti-platelet agents for primary and secondary prevention?

21 Strong Evidence Base: Antithrombotic Trialists’ Collaboration  Objective: to determine the effects of antiplatelet therapy among patients at high risk of occlusive vascular events  Data reviewed: 287 studies involving:  135,000 patients in comparisons of antiplatelet therapy vs. control  77,000 patients in comparisons of different antiplatelet regimens  Main outcome measure: ‘serious vascular event’: non-fatal myocardial infarction, non-fatal stroke, or vascular death Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86.

22 Antithrombotic Trialists’ Collaboration: Efficacy of Antiplatelet Therapy on Vascular Events *1 1. Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86. *Vascular events = myocardial infarction, stroke or vascular death Category% odds reduction Acute myocardial infarction Acute stroke Prior myocardial infarction Prior stroke/transient ischemic attack Other high risk Coronary artery disease (e.g. unstable angina, heart failure) Peripheral arterial disease (e.g. intermittent claudication) High risk of embolism (e.g. atrial fibrillation) Other (e.g. diabetes mellitus) All trials 22% ± Control better Antiplatelet better

23 Indirect Comparisons of ASA Doses on Vascular Events in High-Risk Patients *Odds reduction. Treatment effect P< ASA, acetylsalicylic acid. Adapted with permission from BMJ Publishing Group. Antithrombotic Trialists’ Collaboration. BMJ. 2002;324: mg mg mg12 32 <75 mg 3 13 Any aspirin65 23 Antiplatelet BetterAntiplatelet Worse Aspirin DoseNo. of Trials (%) Odds Ratio 0 OR*

24 Low-Dose ASA in Patients with Stable Cardiovascular Disease: A Meta-analysis  Confirmed the results of ATC: Low dose ASA (50-325mg) beneficial in stable CVD patients (n=9857, 6 trials). ASA significantly reduces all-cause mortality, adverse cardiovascular events, non-fatal MI and non-fatal stroke Treatment of 1000 patients (average 33 months) prevent:  33 CV events; 12 nonfatal MIs; 25 nonfatal strokes; and 14 deaths  Harm – 9 major bleeding event (HR=2.18; 95%CI, ; p<0.01) Berger JS, Brown DL, Becker RC, Am J Med 2008;121:43-49

25 Risk of a Second Atherothrombotic Event Increased Risk vs General Population (%) Original EventMIStroke MI5-7 times greater risk (includes death)* 3-4 times greater risk (includes TIA) Stroke2-3 times greater risk (includes angina and sudden death)* 9 times greater risk PAD4 times greater risk* 2-3 times greater risk (includes TIA) *Death documented within 1 hour of an event attributed to CHD. Note:This chart is based on epidemiologic data and is not intended to provide a direct basis for comparison of risks between event categories. M myocardial infarction; TIA, transient aschemic attack, PAD, peripheral artery disease. Adult Treatment Panel II. Circulation. 1994;89: Kannel, WB. J Cardiovasc Risk. 1994;1: Wilterdink, JI, et al. Arch Neurol. 1992;49: Crique, MH, et al. N Engl J Med. 1992;326:

26 Conclusions  Diabetes patients continue to be at significant risk of developing cardiovascular disease.  Based on recent evidence, the role of ASA in primary prevent of vascular events is equivocal. ASA does not seem to be associated (non- significant trend) with a significant increase in hemorrhagic complications in the DM patient  ASA continues to have a significant role in secondary prevention.


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