Presentation on theme: "ASA - Is there a Primary Prevent Indication in Diabetes?"— Presentation transcript:
1ASA - Is there a Primary Prevent Indication in Diabetes? Contemporary Therapeutic Issues in Cardiovascular DiseaseSaturday, May 8th, 2010Patrick Robertson, BSP, PharmDManager, Clinical Pharmacy ServicesSaskatoon Health Region, SK
2ObjectivesReview the critical role of platelets in the development of atherothrombosis.Outline the rationale for ASA in primary prevention.Review the variability in current recommendationsReview recent evidence questioning the role of ASA in the primary prevention of diabetes patients.
3Disclosure I have received research grants from: Gambro, Merck I have sat on Advisory boards for Pfizer, Sanofi-Aventis, Eli-LillyI have received speaking honoraria from: Pfizer, Astra-Zeneca, Merck, BMS, Sanofi-Aventis, Novartis, Solvay, AltanaSpeaker’s NotesPlease disclose any relevant financial relationshipsSpeakers 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.
4What Is Atherothrombosis? The formation of a thrombus on an existing atherosclerotic plaqueAtherothrombosis is a new term recognizing that atherosclerosis (plaque development) and acute thrombosis are integrally related to the presentation of vascular eventsA generalized progressive disease of large- and mid-size arteries that affects multiple vascular beds, including cerebral, coronary, and peripheral arteriesThe underlying disease leading to myocardial infarction (MI), peripheral arterial disease (PAD), ischemia and many forms of strokeAtherothrombosis is the most frequent underlying cause of ischemic heart disease and cardiovascular (CV) disease and is the leading cause of death in Western societies.1Acute 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.2Atherothrombosis 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.1MI, myocardial infarction; PAD, peripheral artery disease. Fuster V, et al. Vasc Med. 1998;3:Rauch U, et al. Ann Intern Med. 2001;134:References1 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:
5Atherothrombosis: A Generalized and Progressive Process Unstable angina MIIschemic stroke/TIACritical leg ischemiaIntermitent claudicationCV deathACSAtherosclerosisAtherosclerosis is an ongoing process affecting mainly large- and medium-sized arteries; it can begin in childhood and progress throughout a person’s lifetime.1Stable 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.2Unstable 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.2,3References1 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 claudicationAdapted from Libby P. Circulation. 2001;104:
6Clopidogrel/Ticlopidine GP IIb/IIIa Inhibitors Platelets Role in Thrombosis1. Platelet AdhesionPlateletGP Ib2. Platelet ActivationActivated PlateletGP IIb/IIIaPlaque rupture3. Platelet AggregationASA,Clopidogrel/TiclopidineTxA2FibrinogenPrimary 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.2The final step is platelet aggregation (c), in which fibrinogen (or von Willebrand factor) binds to the activated GP IIb/IIIa receptors of two platelets.2Aspirin and clopidogrel act to decrease platelet activation3 whereas the glycoprotein IIb/IIIa inhibitors inhibit the final step of platelet aggregation.2References1 Cannon CP and Braunwald E. Heart Disease2 Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guidelines for the management of patients with unstable angina and nonST-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 InhibitorsASA, acetylsalicyclic acid.Cannon and Braunwald, Heart Disease3
7The Role of Platelet Activation Platelet activation and aggregation play a central role in atherothrombotic vascular disease1, 2Platelet activation results in the release of adenosine 5’-diphosphate (ADP), amplifying activation and aggregation via P2Y1 and P2Y12 receptors3-6Activated 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)7Page 421, column 1, paragraph 1Reference 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):
8What are the recommendations for the use of anti-platelet agents for primary and secondary prevention?
9XIV. Vascular Protection for Hypertensive Patients: ASA Consider low dose ASAStrong 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
10Aspirin 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 conditionThese recommendations apply to adult men and women without a history of CHD or strokeUS Preventive Services Task Force Ann Intern Med 2009;150:
1110-year CHD risk levels at which the number of CVD events prevented is balanced with the number of serious bleedsMen(AMI)Women(Stroke)Age10-Year CHD Risk, %45-49 y≥455-59 y≥360-69 y≥9≥870-79 y≥12≥11How 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:
12Recent questionShould 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:
13Aspirin for the Primary Prevention of Cardiovascular Disease in DM – Current Guidelines
14Aspirin 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-analysisPersistent 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.
17No 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:b4531Comparative risk of developing drug related side effects with aspirin compared with placebo or no treatmentSide effectNo of trials reporting outcomeNo of patientsRelative risk (95% CI)Any bleeding372812.50(0.76 to 8.21)Gastrointestinal bleeding48462.11(0.64 to 6.95)Gastrointestinal symptoms*238155.09(0.08 to )Cancer23070.84(0.62 to 1.14)*As generically reported by authors
18Conclusions 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 MenRR=0.57 (95%CI;0.34 to 0.94)ASA was not associated with a significant incidence of bleedingLacked powerExpect 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:
19Vascular 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].
20What are the recommendations for the use of anti-platelet agents for primary and secondary prevention?
21Strong Evidence Base: Antithrombotic Trialists’ Collaboration Objective:to determine the effects of antiplatelet therapy among patients at high risk of occlusive vascular eventsData reviewed:287 studies involving:135,000 patients in comparisons of antiplatelet therapy vs. control77,000 patients in comparisons of different antiplatelet regimensMain outcome measure:‘serious vascular event’: non-fatal myocardial infarction, non-fatal stroke, or vascular deathIn 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.1This 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 2Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86.Reference:1. Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86.
22Antithrombotic Trialists’ Collaboration: Efficacy of Antiplatelet Therapy on Vascular Events*1 Category % odds reductionAcute myocardial infarctionAcute strokePrior myocardial infarctionPrior stroke/transient ischemic attackOther high riskCoronary 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% ±21.00.50.01.52.0This 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%.1Stratified 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 betterControl better*Vascular events = myocardial infarction, stroke or vascular death1. Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86.Reference:1. Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86.
23Indirect Comparisons of ASA Doses on Vascular Events in High-Risk Patients OR*Aspirin Dose No. of Trials (%)Odds Ratiomgmgmg<75 mgAny aspirinThe 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.0.51.01.52.0* 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 BetterAntiplatelet WorseReferences1 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.
24Low-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 strokeTreatment of 1000 patients (average 33 months) prevent:33 CV events; 12 nonfatal MIs; 25 nonfatal strokes; and 14 deathsHarm – 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
25Risk of a Second Atherothrombotic Event Increased Risk vs General Population (%)Original EventMIStroke5-7 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 riskPAD4 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.1This 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.1The 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.1-3References1 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:
26ConclusionsDiabetes 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 patientASA continues to have a significant role in secondary prevention.