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Aspirin for Primary Prevention; Is it Really Worth it?

Meghan Patni, MD

Interventional Cardiology

Cox Health

Valentin Fuster. Circulation. Aspirin, Volume: 123, Issue: 7, Pages: 768-778, DOI: (10.1161/CIRCULATIONAHA.110.963843) © 2011 American Heart Association, Inc.

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Aspirin (Asa)

Pharmacology

• COX-1: found in most tissues, involved in producing prostaglandins (PG) that regulate cellular housekeeping.

• Gastric cytoprotection

• Vascular homeostasis

• Platelet aggregation

• Kidney function

• COX-2: preferentially in inflamed tissue or after exposure to growth factors, cytokines, or other mediators of inflammation.

How Does it Work?

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How Does it Work?

How Does it Work?

• Low doses (75-81 mg/day): irreversibly acetylates COX-1

• Intermediate doses (650 mg-4 g/day): inhibits COX-1 and COX-2 lead leads to inhibition of prostaglandin production.

• High doses (4g-8g/day): inhibition of COX-2 and PGE-2, leading to reduction in inflammatory effects, limited role due to toxicity.

• NSAIDS also have roles in regards to COX inhibition

Valentin Fuster. Circulation. Aspirin, Volume: 123, Issue: 7, Pages: 768-778, DOI: (10.1161/CIRCULATIONAHA.110.963843)

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Aspirin for Secondary Prevention

• Six major trials totaling 10,000 MI patients randomized between aspirin and double-blinded control placebo.

• Significant reductions in overall death, cardiovascular death and cardiovascular morbidity.

• FDA approval for MI in 1985

Aspirin for Secondary Prevention

• Four early trials demonstrated aspirin reducing risk of death or recurrent MI by > 50%. In patients who presented with unstable angina/NSTEMI.

• FDA approval for suspected MI in 1996

Aspirin for Secondary Prevention

• 1994: large meta-analysis for 70,000 high risk patients that were subdivided into acute MI, history of acute MI, past history of stroke/TIA, other vascular event.

• Statistically significant differences in all categories except for non-vascular deaths.

• No significant difference in event rate between Aspirin 75 mg as compared to higher doses.

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Proportional effects on vascular events (myocardial infarction, stroke, or vascular death) in 11 randomised trials of prolonged antiplatelet therapy (for one month or more) versus control in

patients with prior myocardial infarction.

Antiplatelet Trialists' Collaboration BMJ 1994;308: 81-106

©1994 by British Medical Journal Publishing Group

Proportional effects of antiplatelet therapy (145 t rials) on vascular events (myocardial infarction, stroke, or vascular death) in four main high risk c ategories of trial and in low risk (primary

prevention).

Antiplatelet Trialists' Collaboration BMJ 1994;308: 81-106

©1994 by British Medical Journal Publishing Group

Indirect comparisons of proportional effects on vas cular events of different antiplatelet regimens in 142 trials in high risk patients.

Antiplatelet Trialists' Collaboration BMJ 1994;308: 81-106

©1994 by British Medical Journal Publishing Group

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ISIS-2 Trial (1998)

• Administration of aspirin within 24 hours to patients presenting with acute MI.

• ASA 162 mg alone demonstrated significant differences in 30-day mortality that persisted 10 years out.

• Led to class 1 recommendation for all patients with suspected STEMI to receive aspirin 162-325 mg.

2009 antithrombotic Trialists’ Collaboration

• Meta-analysis, 16 secondary prevention trials (17,000 patients at high average risk)

• Compared long term aspirin only vs control.

• Demonstrated statistically significant reduction in major coronary events including non-fatal MI and CHD mortality.

• Demonstrated statistically significant reduction in stroke

• Statistically higher risk of major extracranial bleed.

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Aspirin for Primary Prevention

• 1994: meta-analysis of about 30,000 patients with “low risk”

• Demonstrated statistically significant reduction in non-fatal MI

• Accompanied by non-significant increase risk of stroke

• Non-significant reduction in vascular events at 5 years.

• 2002: Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients by Antithrombotic Trialists’ Collaboration

• 135,000 patients

• Antiplatelet therapy vs control

• Antiplatelet therapy reduced the combined outcome of any serious vascular event by about one quarter; non-fatal myocardial infarction was reduced by one third, non-fatal stroke by one quarter, and vascular mortality by one sixth (with no apparent adverse effect on other deaths)

• No individual data regarding clinical outcomes with Asa alone, only composite outcome against adjusted control.

Antiplatelet better Antiplatelet worse

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From: Aspirin for the Primary Prevention of Cardiov ascular Events: Recommendation and Rationale

Ann Intern Med. 2002;136(2):157-160. doi:10.7326/00 03-4819-136-2-200201150-00015

• 2009 Antithrombotic Trialists’ Collaboration

• Meta-analysis (95, 000 patients at low-average risk)

• Compared long-term asa to control

• Six primary prevention trials

• British Doctor’s Study (1978-1979, 500 mg daily)

• US Physicans’ Health Study (1981-1984, 325 mg QOD)

• Thrombosis Prevention Trial (1989-1994, 75 mg daily)

• Hypertension Optimal Treatment Trial (1992-1994, 75 mg daily)

• Primary Prevention Project (1993-1998, 100 mg daily)

• Women’s Health Study (1992-1995, 100 mg alternate days)

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The Lancet 2009 373, 1849-1860DOI: (10.1016/S0140-6736(09)60503-1)

• Noted increase in gastrointestinal and other extracranial bleeds by about half (0.10 vs 0.07% per year)

Other Notable Primary Prevention Trials

• 2008: Ogawa et Al.: low dose asa for primary prevention in diabetics in Japan. More atherosclerotic (although not significantly) events occurred in the nonaspirin group. Significantly more fatal coronary/cerebral vascular events occurred in the nonaspiringroup(secondary endpoint)

• 2008: POPADAD: No significant difference between asa and no asause in patients age 40 and above with diabetes.

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Other Notable Primary Prevention Trials

• 2010: Aspirin for Prevention of Cardiovascular Events in a General Population Screened for a Low Ankle Brachial Index

• 3350 patients, double blinded RCT to asa vs placebo. No significant difference in primary composite endpoint of all initial vascular events and all cause mortality.

A Study of Cardiovascular Events in Diabetes (ASCEND) Trial

• 15,840 patients

• Randomly assigned to placebo vs asa 100 mg daily

• Primary efficacy outcome, first major vascular event (MI, stroke/tia, death from any vascular cause (excluding hemorrhage)

• Primary safety outcome was the first major bleeding event.

• Mean follow up of 7.4 years

• Men or women > 40 years

• Adherence about 70%

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• Overall, on the basis of the absolute percentage differences between the groups in the incidence of serious vascular events (1.1 percentage points lower in the aspirin group than in the placebo group) and in bleeding events (0.9 percentage points higher in the aspirin group), 91 patients would need to be treated to avoid a serious vascular event over a period of 7.4 years, and 112 to cause a major bleeding event.

• Of note remember only 70% adherence with both groups

Aspirin in Reducing Events in the Elderly (ASPREE)

• 2010-2014

• 19,114 patients

• Randomized, double blinded, placebo controlled

• Age 70 years or older (or 65 and older if African American/Hispanic)

• Prespecified secondary endpoint of cardiovascular disease (fatal coronary heart disease, nonfatal MI, fatal or nonfatal stroke, hospitalization for heart failure)

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Discussion

• The rate of the prespecified secondary end point of cardiovascular disease (a composite that accounted for all cardiovascular events, including stroke due to intracranial hemorrhage and hospital admission for cardiac failure) was not significantly lower with low-dose aspirin than with placebo.

• Of note the observed rates of cardiovascular disease were lower than anticipated by about half.

• About 2/3 of the participants were still taking the assigned trial intervention

• MACE was not a prespecified secondary endpoint.

Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo-controlled trial

• 2007-2016

• 12,546 patients deemed average cardiovascular risk

• High risk of GI bleeding, diabetes were excluded.

• Asa 100 mg daily vs placebo

• Primary efficacy endpoint: time to first CV death, MI, unstable angina, stroke, or TIA.

• Safety endpoints: hemorrhagic events and incidence of other adverse events.

Results

• Primary endpoint occurred in 269 (4·29%) patients in the aspirin group versus 281 (4·48%) patients in the placebo group (hazard ratio [HR] 0·96; 95% CI 0·81–1·13; p=0·6038)

• Gastrointestinal bleeding events (mostly mild) occurred in 61 (0·97%) patients in the aspirin group versus 29 (0·46%) in the placebo group (HR 2·11; 95% CI 1·36–3·28; p=0·0007).

• Again, overall event rate was lower than expected in this moderate risk group, which calls into question how “moderate risk” were the patients (based on scoring system).

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So Where Are We Now?

2016 USPSTF Recommendation Statement

• The USPSTF recommends initiating low-dose aspirin use for the primary prevention of CVD and CRC in adults aged 50 to 59 years who have a 10% or greater 10-year CVD risk, are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin daily for at least 10 years. (B recommendation)

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References

• ASCEND Study Collaborative Group. "Effects of aspirin for primary prevention in persons with diabetes mellitus."New England Journal of Medicine 379.16 (2018): 1529-1539.

• Baigent Colin, Collins Rory, Appleby Paul, Parish Sarah, Sleight Peter, Peto Richard et al. ISIS-2: 10 year survival among patients with suspected acute myocardial infarction in randomised comparison of intravenous streptokinase, oral aspirin, both, or neither BMJ 1998; 316 :1337

• Belch Jill, MacCuish Angus,Campbell Iain,Cobbe Stuart, Taylor Roy, Prescott Robin et al. The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease BMJ 2008; 337 :a1840

• Bibbins-Domingo K, on behalf of the U.S. Preventive Services Task Force. Aspirin Use for the Primary Prevention of Cardiovascular Disease and Colorectal Cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. [Epub ahead of print 12 April 2016]164:836–845. doi: 10.7326/M16-0577

• De Gaetano, G., and Collaborative Group of the Primary Prevention Project. "Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice. Collaborative Group of the Primary Prevention Project." Lancet (London, England) 357.9250 (2001): 89.

• Donna K. Arnett, Roger S. Blumenthal, Michelle A. Albert, Andrew B. Buroker, Zachary D. Goldberger, Ellen J. Hahn, Cheryl Dennison Himmelfarb, Amit Khera, Donald Lloyd-Jones, J. William McEvoy, Erin D. Michos, Michael D. Miedema, Daniel Muñoz,Sidney C. Smith, Salim S. Virani, Kim A. Williams, Joseph Yeboah, Boback Ziaeian. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease. J Am Coll Cardiol. 2019 Sep, 74 (10) e177-e232.

• Fowkes, F. Gerald R., et al. "Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: a randomized controlled trial." Jama 303.9 (2010): 841-848.

• Gaziano, J. Michael, et al. "Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo-controlled trial." The Lancet 392.10152 (2018): 1036-1046.

• Hansson, Lennart, et al. "Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial." The Lancet 351.9118 (1998): 1755-1762.

• McNeil, John J., et al. "Effect of aspirin on cardiovascular events and bleeding in the healthy elderly." New England Journal of Medicine 379.16 (2018): 1509-1518.

• Ogawa, Hisao, et al. "Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial." Jama 300.18 (2008): 2134-2141.

• Piepoli MF, Hoes AW, Agewall S, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J. 2016;37(29):2315–2381. doi:10.1093/eurheartj/ehw106

• Trialists’Collaboration, Antithrombotic. "Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients." Bmj 324.7329 (2002): 71-86.