ASA - Is there a Primary Prevent Indication in Diabetes?

Contemporary Therapeutic Issues in Cardiovascular DiseaseSaturday, May 8th, 2010

Patrick Robertson, BSP, PharmDManager, Clinical Pharmacy ServicesSaskatoon Health Region, SK

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.

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

What Is Atherothrombosis?What Is Atherothrombosis?

The formation of a thrombus on an existing The formation of a thrombus on an existing atherosclerotic plaqueatherosclerotic plaque

Atherothrombosis is a new term recognizing that Atherothrombosis is a new term recognizing that atherosclerosis (plaque development) and acute atherosclerosis (plaque development) and acute thrombosis are integrally related to the presentation of thrombosis are integrally related to the presentation of vascular events vascular events

A generalized progressive disease of large- and A generalized progressive disease of large- and mid-size arteries that affects multiple vascular beds, mid-size arteries that affects multiple vascular beds, including cerebral, coronary, and peripheral arteries including cerebral, coronary, and peripheral arteries

The underlying disease leading to myocardial infarction The underlying disease leading to myocardial infarction (MI), peripheral arterial disease (PAD), ischemia and (MI), peripheral arterial disease (PAD), ischemia and many forms of strokemany forms of stroke

MI, myocardial infarction; PAD, peripheral artery disease.Fuster V, et al. Vasc Med. 1998;3:231-239.Rauch U, et al. Ann Intern Med. 2001;134:122-238.

UnstableanginaMI

Ischemic stroke/TIA

Critical legischemia

Intermitentclaudication

CV death

ACS

Atherosclerosis

Stable angina/ Intermittent claudication

Atherothrombosis: A Generalized and Progressive ProcessAtherothrombosis: A Generalized and Progressive Process

Thrombosis

Adapted from Libby P. Circulation. 2001;104:365-372.

GP IIb/IIIa InhibitorsGP IIb/IIIa Inhibitors

1. Platelet Adhesion

2. Platelet Activation

Platelet

GP Ib

Plaque rupture Activated Platelet

GP IIb/IIIa 3. Platelet AggregationASA,

Clopidogrel/Ticlopidine

ASA, Clopidogrel/Ticlopidine

ASA, acetylsalicyclic acid.Cannon and Braunwald, Heart Disease. 2001.

TxA2

Fibrinogen

Platelets Role in ThrombosisPlatelets Role in Thrombosis

Jakubowski JA et al. Br J Clin Pharmacol 2007;63(4):421-430

The Role of Platelet ActivationThe 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

1Badimon L et al. In Platelets in Thrombotic and Non Thrombotic Disorders, 1st ed, 2002, 727-7372Goldschmidt PJ et al. In Platelets, 1st ed, 2002, 375-3983Jin J et al. J Biol Chem 1998;273(4):2030-20344Foster CJ et al. J Clin Invest 2001;107(12):1591-15985Dorsam RT, Kunapuli SP. J Clin Invest 2004;113(3):340-3456Hollopeter G et al. Nature 2001;409(6817):202-2077Bertrand ME et al. Eur Heart J 2002;23(23):1809-1840

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

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).

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;150:396-404

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, %

45-49 y ≥4 55-59 y ≥3

60-69 y ≥9 60-69 y ≥8

70-79 y ≥12 70-79 y ≥11

US Preventive Services Task Force Ann Intern Med 2009;150:396-404

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;150:396-404

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

Aspirin for primary prevention of cardiovascular events in people with Diabetes: Meta-Analysis of RCTsDe 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.

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

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

ConclusionsDe 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;353:2373-83

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].

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

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.

Antithrombotic Trialists’ Collaboration: Antithrombotic Trialists’ Collaboration: Efficacy of Antiplatelet Therapy on Vascular EventsEfficacy of Antiplatelet Therapy on Vascular Events*1*1

1. Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86.

*Vascular events = myocardial infarction, stroke or vascular death

CategoryCategory % odds reduction% odds reductionAcute myocardial infarctionAcute myocardial infarction

Acute stroke Acute stroke

Prior myocardial infarction Prior myocardial infarction

Prior stroke/transient ischemic attackPrior stroke/transient ischemic attack

Other high riskOther high risk

Coronary artery diseaseCoronary artery disease

(e.g. unstable angina, heart failure)(e.g. unstable angina, heart failure)

Peripheral arterial diseasePeripheral arterial disease

(e.g. intermittent claudication)(e.g. intermittent claudication)

High risk of embolism High risk of embolism (e.g. atrial fibrillation)(e.g. atrial fibrillation)

Other Other (e.g. diabetes mellitus)(e.g. diabetes mellitus)

All trialsAll trials 22%22% ±2±2

1.00.50.0 1.5 2.0

Control betterAntiplatelet better

Indirect Comparisons of ASA Doses on Vascular Indirect Comparisons of ASA Doses on Vascular Events in High-Risk PatientsEvents in High-Risk Patients

* Odds reduction. Treatment effect P<.0001.ASA, acetylsalicylic acid.Adapted with permission from BMJ Publishing Group. Antithrombotic Trialists’ Collaboration.

BMJ. 2002;324:71-86.

0.5 1.0 1.5 2.0

500-1500 mg 34 19

160-325 mg 19 26

75-150 mg 12 32

<75 mg 3 13

Any aspirin 65 23

Antiplatelet Better Antiplatelet Worse

Aspirin Dose No. of Trials (%) Odds Ratio

0

OR*

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, 1.41-3.35; p<0.01)

Berger JS, Brown DL, Becker RC, Am J Med 2008;121:43-49

Risk of a Second Atherothrombotic Event

Increased Risk vs General Population (%)Original Event MI Stroke

MI 5-7 timesgreater risk

(includes death)*

3-4 timesgreater risk

(includes TIA)

Stroke 2-3 timesgreater risk

(includes angina and sudden death)*

9 timesgreater risk

PAD 4 timesgreater risk*

2-3 timesgreater 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;89:1333-1363.Kannel, WB. J Cardiovasc Risk. 1994;1:333-339.Wilterdink, JI, et al. Arch Neurol. 1992;49:857-863. Crique, MH, et al. N Engl J Med. 1992;326:381-386.

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.