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

2. Objectives
Review the critical role of platelets in the development of atherothrombosis.
Outline the rationale for ASA in primary prevention.
Review the variability in current recommendations
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
Speaker’s Notes
Please disclose any relevant financial relationships
Speakers should be very clear in identifying any current or previous forms of support that they have received from granting agencies, health organizations and/or industry, etc.

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
Atherothrombosis is the most frequent underlying cause of ischemic heart disease and cardiovascular (CV) disease and is the leading cause of death in Western societies.1
Acute coronary syndrome (ACS) and ischemic stroke are usually caused by acute thrombosis superimposed on a chronic atherosclerotic plaque that has erupted, a condition commonly called atherothrombosis.2
Atherothrombosis is a slowly progressive, degenerative disease of the large- and middle-sized elastic and muscular arteries, beginning with fatty streak formation in adolescence. When it progresses unabated, the streaks develop into plaques, culminating in thrombotic occlusions and CV events later in life.1
MI, myocardial infarction; PAD, peripheral artery disease. Fuster V, et al. Vasc Med. 1998;3:
Rauch U, et al. Ann Intern Med. 2001;134:
References
1 Fuster V, Badimon JH, Chesebro JJ. Atherothrombosis and clinical therapeutic approaches. Vasc Med. 1998;3:
2 Rauch U, Osende JI, Fuster V, Badimon JJ, Fayad Z, Chesebro JH. Thrombus formation on atherosclerotic plaques: pathogenesis and clinical consequences. Ann Intern Med. 2001;134:

5. Atherothrombosis: A Generalized and Progressive Process
Unstable angina MI
Ischemic stroke/TIA
Critical leg ischemia
Intermitent claudication
CV death
ACS
Atherosclerosis
Atherosclerosis is an ongoing process affecting mainly large- and medium-sized arteries; it can begin in childhood and progress throughout a person’s lifetime.1
Stable atherosclerotic plaques may encroach on the lumen of the artery and cause chronic ischemia, resulting in (stable) angina pectoris or intermittent claudication, depending on the vascular bed affected.2
Unstable atherosclerotic plaques may rupture, leading to the formation of a platelet-rich thrombus that partially or completely occludes the artery and causes acute ischemic symptoms.2,3
References
1 Libby P. Current concepts of the pathogenesis of the acute coronary syndromes. Circulation. 2001;104:
2 Rauch U, Osende JI, Fuster V, et al. Thrombus formation on atherosclerotic plaques: pathogenesis and critical consequences. Ann Intern Med. 2001;134:
3 Yeghiazarians Y, Braunstein JB, Askari A, et al. Unstable angina pectoris. N Eng J Med. 2000;342:
Stable angina/ Intermittent claudication
Adapted from Libby P. Circulation. 2001;104:

6. Clopidogrel/Ticlopidine GP IIb/IIIa Inhibitors
Platelets Role in Thrombosis
1. Platelet Adhesion
Platelet
GP Ib
2. Platelet Activation
Activated Platelet
GP IIb/IIIa
Plaque rupture
3. Platelet Aggregation
ASA,
Clopidogrel/Ticlopidine
TxA2
Fibrinogen
Primary hemostasis: process of platelet adhesion (a), activation (b), and aggregation (c).
Platelets initiate thrombosis at the site of a ruptured plaque: the first step is platelet adhesion (a) via the glycoprotein Ib receptor in conjunction with von Willebrand factor.
This is followed by platelet activation (b), which leads to a shape change in the platelet, degranulation of the alpha and dense granules, and expression of GP IIb/IIIa receptors on the platelet surface with activation of the receptor, such that it can bind fibrinogen.2
The final step is platelet aggregation (c), in which fibrinogen (or von Willebrand factor) binds to the activated GP IIb/IIIa receptors of two platelets.2
Aspirin and clopidogrel act to decrease platelet activation3 whereas the glycoprotein IIb/IIIa inhibitors inhibit the final step of platelet aggregation.2
References
1 Cannon CP and Braunwald E. Heart Disease
2 Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guidelines for the management of patients with unstable angina and nonST-segment elevation myocardial infarction: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). J Am Coll Cardiol. 2000;36:
3 Cannon CP, on behalf of the Caprie Investigators. Effectiveness of clodipogrel versus aspirin in preventing acute myocardial infarction in patients with sympotomatic atherothrombosis (CAPRIE trial). Am J Cardiol. 2002;90:
GP IIb/IIIa Inhibitors
ASA, acetylsalicyclic acid.
Cannon and Braunwald, Heart Disease 3

7. The Role of Platelet Activation
Platelet activation and aggregation play a central role in atherothrombotic vascular disease1, 2
Platelet activation results in the release of adenosine 5’-diphosphate (ADP), amplifying activation and aggregation via P2Y1 and P2Y12 receptors3-6
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
Page 421, column 1, paragraph 1
Reference 1, full citation: Badimon et al. In Platelets in thrombotic and non thrombotic disorders, 1st ed., New York: Cambridge University Press, 2002,
1Badimon L et al. In Platelets in Thrombotic and Non Thrombotic Disorders, 1st ed, 2002,
2Goldschmidt PJ et al. In Platelets, 1st ed, 2002,
3Jin J et al. J Biol Chem 1998;273(4):
4Foster CJ et al. J Clin Invest 2001;107(12):
5Dorsam RT, Kunapuli SP. J Clin Invest 2004;113(3):
6Hollopeter G et al. Nature 2001;409(6817):
7Bertrand ME et al. Eur Heart J 2002;23(23):
Jakubowski JA et al. Br J Clin Pharmacol 2007;63(4):

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

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). 9

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, %
45-49 y ≥4
55-59 y ≥3
60-69 y ≥9 ≥8
70-79 y
≥12
≥11
How is 10-Year CHD Risk calculated?
The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of aspirin for CVD prevention in men and women 80 years or older.
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.
Add data on DM from:
US Preventive Services Task Force Ann Intern Med 2009;150:
How was DM handled in ATC?
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. 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.
De Berardis, G. et al. BMJ 2009;339:b4531
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
Copyright ©2009 BMJ Publishing Group Ltd.

16. 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
De Berardis, G. et al. BMJ 2009;339:b4531
Copyright ©2009 BMJ Publishing Group Ltd.

17. No of trials reporting outcome
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
Side effect
No of trials reporting outcome
No of patients
Relative risk (95% CI)
Any bleeding 3
7281
2.50
(0.76 to 8.21)
Gastrointestinal bleeding
4846
2.11
(0.64 to 6.95)
Gastrointestinal symptoms* 2
3815
5.09
(0.08 to )
Cancer
2307
0.84
(0.62 to 1.14)
*As generically reported by authors

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.
Watch for further trials – ASCEND and ACCEPT-D – ongoing trials that enrol > 15,000 DM patients that will help clarify the role of aspirin in the primary prevent of CVD.
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
In order to evaluate the full body of evidence on the effectiveness of antiplatelet therapy, an updated collaborative overview of randomized trials of antiplatelet therapy among high-risk patients has been undertaken.1
This meta-analysis included all antiplatelet agent trials up until 1997, particularly new trials with ASA, clopidogrel and dipyridamole (notably the CAPRIE* trial and ESPS2†), that were not available for the previous antiplatelet trialists’ collaboration, published in 1994 (287 vs 145 trials respectively).
*Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events
†European Stroke Prevention Study 2
Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86.
Reference:
1. Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86.

22. Antithrombotic Trialists’ Collaboration: Efficacy of Antiplatelet Therapy on Vascular Events*1
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% ±2
1.0
0.5
0.0
1.5
2.0
This slide compares risk reduction in a number of high-risk subgroups to the overall result, which demonstrated a consistent benefit across all patient groups with a mean of 22%.1
Stratified odds ratio of an event in treatment groups to that in control groups were plotted for each group of trials (white diamond) – along with a 99% confidence interval (horizontal line).
‘Other’ high risk groups (total reduction 13% ±7) include hemodialysis (reduction 41% ±16), diabetes mellitus (reduction 7% ±8), carotid disease (reduction 19% ±22).
Antiplatelet better
Control better
*Vascular events = myocardial infarction, stroke or vascular death
1. Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86.
Reference:
1. Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86.

23. Indirect Comparisons of ASA Doses on Vascular Events in High-Risk Patients
OR*
Aspirin Dose No. of Trials (%)
Odds Ratio mg mg mg
<75 mg
Any aspirin
The Antithrombotic Trialists’ Collaboration compared data from 65 aspirin trials to examine the effects of aspirin dose on vascular events in high-risk patients (in some trials, the aspirin dose was used in more than one of the comparisons).1 Serious vascular events (the primary measure of outcome) included nonfatal myocardial infarction, nonfatal stroke, death from vascular causes, and death from unknown causes. They found that all doses of aspirin studied reduced the risk of vascular events. The greatest number of trials (34) examined high aspirin doses ( mg) and revealed a proportional reduction in vascular events of 19%. Aspirin doses of 160 to 325 mg were associated with a 26% proportional reduction in vascular events, whereas 75 to 150 mg and <75 mg were associated with reductions of 32% and 13%, respectively.
0.5
1.0
1.5
2.0
* Odds reduction.
Treatment effect P<.0001.
ASA, acetylsalicylic acid.
Adapted with permission from BMJ Publishing Group. Antithrombotic Trialists’ Collaboration.
BMJ. 2002;324:71-86.
Antiplatelet Better
Antiplatelet Worse
References
1 Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324:71-86.

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 Event MI
Stroke
5-7 times greater risk (includes death)*
3-4 times greater risk (includes TIA)
2-3 times greater risk (includes angina and sudden death)*
9 times greater risk
PAD
4 times greater risk*
2-3 times greater risk (includes TIA)
Patients presenting with one type of atherothrombotic event are at increased risk for a second event, frequently in a different vascular territory.1
This demonstrates that once a patient manifests atherothrombotic disease, the patient is at high risk for future events.
Data for the associated risk increase in events were taken from different sources, but show that the risk of a second vascular event can increase 2 to 9-fold.1
The increase in risk of events was based on a 10-year follow-up, except for the risk of stroke following stroke, which measures subsequent risk per year.1-3
References
1 Kannel WB. Risk factors for atherosclerotic cardiovascular outcomes in different arterial territories. J Cardiovasc Risk. 1994;1:
2 Wilterdink JI, Easton JD. Vascular event rates in patients with atherosclerotic cerebrovascular disease. Arch Neurol. 1992;49:
3 Criqui MH, Langer RD, Fronek A, et al. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med. 1992;326:
* 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.