Aspirin (75 to 100 mg) compared with no aspirin in the primary prevention of cardiovascular disease and cancer

Outcomes	Number of participants (studies), follow-up	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Anticipated absolute effects over 10 years
				Risk with placebo	Risk difference with aspirin*
Total mortality Follow-up: range 3.8 to 10 years^[1-4]	161,660 (13 RCTs)	⊕⊕⊕ MODERATE due to imprecision^¶	RR 0.97 (0.93 to 1.02)	60-year-old person^Δ
				83 per 1000^Δ	2 fewer per 1000 (6 fewer to 2 more)
Myocardial infarction (MI) Nonfatal events Follow-up: range 3.8 to 10 years^[1,2,4]	142,566 (12 RCTs)	⊕⊕⊕⊕ HIGH	RR 0.83 (0.76 to 0.90)	Low cardiovascular risk population^◊
				27 per 1000^§	5 fewer per 1000 (6 fewer to 3 fewer)
				Moderate cardiovascular risk population^◊
				83 per 1000^§	14 fewer per 1000 (20 fewer to 8 fewer)
				High cardiovascular risk population^◊
				136 per 1000^§	23 fewer per 1000 (33 fewer to 14 fewer)
Stroke Includes nonfatal ischemic and hemorrhagic strokes Follow-up: range 3.8 to 10 years^[1,2,4]	127,433 (12 RCTs)	⊕⊕⊕ MODERATE due to imprecision^¶	RR 0.95 (0.85 to 1.06)	Low cardiovascular risk population^◊
				23 per 1000^§	1 fewer per 1000 (3 fewer to 1 more)
				Moderate cardiovascular risk population^◊
				65 per 1000^§	3 fewer per 1000 (10 fewer to 4 more)
				High cardiovascular risk population^◊
				108 per 1000	5 fewer per 1000 (16 fewer to 6 more)
Major extracranial bleed^¶¶ Follow-up: range 3.8 to 10 years^[1,2,4-6]	155,911 (11 RCTs)	⊕⊕⊕⊕ HIGH	RR 1.46 (1.32 to 1.62)	Low cardiovascular risk population^‡
				8 per 1000^§	4 more per 1000 (3 more to 5 more)
				Moderate cardiovascular risk population^‡
				24 per 1000^§	11 more per 1000 (8 more to 15 more)
				High cardiovascular risk population^‡
				40 per 1000^§	18 more per 1000 (13 more to 25 more)
Colorectal cancer (incidence) Follow-up: median 18.3 years^[7]	14,033 (4 RCTs)	⊕⊕ LOW due to imprecision^† and risk of bias^ΔΔ	HR 0.76 (0.60 to 0.96)	Low colorectal cancer risk population: Anticipated absolute effect over 20 years^◊◊
				30 per 1000**	7 fewer per 1000 (12 fewer to 1 fewer)
				Moderate colorectal cancer risk population
				53 per 1000**	12 fewer per 1000 (21 fewer to 2 fewer)
				High colorectal cancer risk population
				100 per 1000**	23 fewer per 1000 (39 fewer to 4 fewer)

GRADE Working Group grades of evidence:

High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect.
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of the effect.

CI: confidence interval; RR: risk ratio; HR: hazard ratio; NCI: National Cancer Institute.
* The risk difference in the aspirin group (and its 95% CI) is based on the estimated risk in the comparison group and the relative effect of the intervention (and its 95% CI).
¶ The 95% CI for the absolute effect includes no benefit of aspirin. We did not rate down for risk of bias, but this was a borderline decision. Three of the trials did not blind patients, caregivers, or outcome adjudicator. Sensitivity analyses in meta-analysis by Raju et al^[8] did not show evidence of risk of bias.
Δ Control group risk estimate for 10-year mortality applies to a 60-year-old person (male or female) and comes from population-based data from Statistics Norway. Mortality increases with age (eg, 50-year-old male; 40 deaths per 1000 in 10 years) and is lower in females than in males (eg, 2.5% in women aged 50 years versus 4% in men aged 50 years).
◊ Risk groups correspond to low (5%), medium (15%), and high risk (25%) according to the Framingham score (or other risk tool) to estimate 10-year risk.
§ Control group risk estimates in low, moderate, and high cardiovascular risk groups are based on the Framingham score. We have used data from an individual patient data meta-analysis to provide estimated risks for patient-important outcomes not covered by the Framingham risk score. We have also adjusted for 20% overestimation associated with Framingham risk score.
‡ In the individual patient data meta-analysis, risk for future major bleeding correlated with risk for future cardiovascular events. Therefore, we make the assumption that a patient at low, medium, or high risk of future cardiovascular events (determined by Framingham score) will be at low, medium, or high risk of future major bleeding events, respectively.
† The 95% CI for absolute effect borders no benefit of aspirin.
** Moderate control group risk estimate derived from meta-analysis by Rothwell et al.^[7]
¶¶ Major extracranial bleeds are usually from the gastrointestinal tract and are most often defined in those requiring transfusion or resulting in death.
ΔΔ Treatment with aspirin during the included studies ranged from 2.6 to 6.9 years. Colorectal cancer incidence was determined using cancer and death registries for a median of 18.3 years without knowledge of post-treatment period aspirin use.
◊◊ Control group risk estimates based on NCI Colorectal Cancer Risk Predictor Tool.

References:

Guirguis-Blake JM, Evans CV, Senger CA, et al. Aspirin for the primary prevention of cardiovascular events: a systematic evidence review for the US Preventive Services Task Force: evidence synthesis No 131. AHRQ Publication No. 13-05195-EF-1. Agency for Healthcare Research and Quality, 2015.
ASCEND Study Collaborative Group. Effects of aspirin for primary prevention in persons with diabetes mellitus. N Engl J Med 2018; 379:1529.
McNeil JJ, Nelson MR, Woods RL, et al. Effect of aspirin on all-cause mortality in the healthy elderly. N Engl J Med 2018; 379:1519.
Gaziano JM, Brotons C, Coppolecchia R, 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. Lancet 2018; 392:1036.
Ikeda Y, Shimada K, Teramoto T, et al. Low-dose aspirin for primary prevention of cardiovascular events in Japanese patients 60 years or older with atherosclerotic risk factors: a randomized clinical trial. JAMA 2014; 312:2510.
McNeil JJ, Wolfe R, Woods RL, et al. Effect of aspirin on cardiovascular events and bleeding in the healthy elderly. N Engl J Med 2018; 379:1509.
Rothwell PM, Wilson M, Elwin CE, et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet 2010; 376:1741.
Raju N, Sobieraj-Teague M, Hirsh J, et al. Effect of aspirin on cardiovascular and all-cause mortality in primary prevention of cardiovascular disease: a meta-analysis of randomized controlled trials. Am J Med 2011; 124:621.

Adapted from: Vandvik PO, Lincoff AM, Gore JM, et al. Primary and Secondary Prevention of Cardiovascular Disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e637S.

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Aspirin (75 to 100 mg) compared with no aspirin in the primary prevention of cardiovascular disease and cancer