Author + information
- Received December 5, 2018
- Revision received March 10, 2019
- Accepted March 12, 2019
- Published online June 10, 2019.
- Hesham K. Abdelaziz, MD, PhDa,b,∗,
- Marwan Saad, MD, PhDb,c,∗@MarwanSaadMD,
- Naga Venkata K. Pothineni, MDc,
- Michael Megaly, MD, MSd,e,
- Rahul Potluri, MDf,
- Mohammed Saleh, MDg,
- David Lai Chin Kon, MDa,
- David H. Roberts, MDa,
- Deepak L. Bhatt, MD, MPHh@DLBHATTMD,
- Herbert D. Aronow, MD, MPHi@herbaronowMD,
- J. Dawn Abbott, MDi@JDawnAbbott1 and
- Jawahar L. Mehta, MD, PhDc,∗ (, )@chandu991
- aLancashire Cardiac Center, Blackpool Victoria Hospital, Blackpool, United Kingdom
- bDepartment of Cardiovascular Medicine, Ain Shams University, Cairo, Egypt
- cDivision of Cardiovascular Medicine, University of Arkansas for Medical Sciences and The Central Arkansas Veterans Healthcare System, Little Rock, Arkansas
- dMinneapolis Heart Institute, Abbott Northwestern Hospital, Minneapolis, Minnesota
- eHennepin Healthcare, Minneapolis, Minnesota
- fAston Medical School, School of Medical Sciences, Aston University, Birmingham, United Kingdom
- gDepartment of Medicine, Creighton University, Omaha, Nebraska
- hBrigham and Women’s Hospital Heart & Vascular Center, Harvard Medical School, Boston, Massachusetts
- iDivision of Cardiovascular Medicine, The Warren Alpert Medical School of Brown University and Lifespan Cardiovascular Institute, Providence, Rhode Island
- ↵∗Address for correspondence:
Dr. Jawahar L. Mehta, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, Arkansas 72205.
Background The efficacy and safety of aspirin for primary prevention of cardiovascular disease (CVD) remain debatable.
Objectives The purpose of this study was to examine the clinical outcomes with aspirin for primary prevention of CVD after the recent publication of large trials adding >45,000 individuals to the published data.
Methods Randomized controlled trials comparing clinical outcomes with aspirin versus control for primary prevention with follow-up duration of ≥1 year were included. Efficacy outcomes included all-cause death, cardiovascular (CV) death, myocardial infarction (MI), stroke, transient ischemic attack (TIA), and major adverse cardiovascular events. Safety outcomes included major bleeding, intracranial bleeding, fatal bleeding, and major gastrointestinal (GI) bleeding. Random effects DerSimonian-Laird risk ratios (RRs) for outcomes were calculated.
Results A total of 15 randomized controlled trials including 165,502 participants (aspirin n = 83,529, control n = 81,973) were available for analysis. Compared with control, aspirin was associated with similar all-cause death (RR: 0.97; 95% confidence interval [CI]: 0.93 to 1.01), CV death (RR: 0.93; 95% CI: 0.86 to 1.00), and non-CV death (RR: 0.98; 95% CI: 0.92 to 1.05), but a lower risk of nonfatal MI (RR: 0.82; 95% CI: 0.72 to 0.94), TIA (RR: 0.79; 95% CI: 0.71 to 0.89), and ischemic stroke (RR: 0.87; 95% CI: 0.79 to 0.95). Aspirin was associated with a higher risk of major bleeding (RR: 1.5; 95% CI: 1.33 to 1.69), intracranial bleeding (RR: 1.32; 95% CI: 1.12 to 1.55), and major GI bleeding (RR: 1.52; 95% CI: 1.34 to 1.73), with similar rates of fatal bleeding (RR: 1.09; 95% CI: 0.78 to 1.55) compared with the control subjects. Total cancer and cancer-related deaths were similar in both groups within the follow-up period of the study.
Conclusions Aspirin for primary prevention reduces nonfatal ischemic events but significantly increases nonfatal bleeding events.
The role of aspirin for secondary prevention of myocardial infarction (MI), stroke, or transient ischemic attack (TIA) is well established (1–4). A serial cross-sectional study of 94,270 individuals from 2007 to 2015 reported that aspirin use for primary prevention of cardiovascular disease (CVD) averaged 43% (5). However, the efficacy and safety of aspirin for primary prevention varied among multiple randomized controlled trials (RCTs) (6–15), creating significant variability in societal guidelines (4,16–18).
The recently published 10-year follow-up of the JPAD 2 study (Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes) (19), as well as 3 large RCTs, ARRIVE (Aspirin to Reduce Risk of Initial Vascular Events) (20), ASCEND (A Study of Cardiovascular Events in Diabetes) (21), and ASPREE (Aspirin in Reducing Events in the Elderly) (22,23), added more data to the existing debate. Long-term aspirin use has also been associated with a reduction in cancer incidence and mortality (24,25). The current systematic review represents the most comprehensive analysis of the available data to evaluate the efficacy and safety of aspirin for primary prevention of CVD as well as its effect on cancer incidence and mortality within the period of follow-up.
Data sources, trial eligibility, and data extraction
This study was conducted according to PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines and is registered with the International Prospective Register for Systematic Reviews (PROSPERO: CRD42018115612). A systematic search of online databases was performed until September 2018 for RCTs. Online Figure 1 illustrates the search strategy.
Trials that: 1) compared aspirin (any dose) versus control (placebo or no aspirin) for primary prevention of CVD; and 2) reported outcomes of interest at minimum follow-up duration of 1 year were included. Details of inclusion/exclusion criteria and data extraction are provided in the Online Appendix.
Risk of bias and quality assessment
We utilized the Cochrane Collaboration tool to assess the risk of bias among included studies, and the GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) tool to assess quality of evidence for each outcome (26).
The main efficacy outcomes included all-cause death, cardiovascular (CV) death, MI, stroke, TIA, and major adverse cardiovascular events (MACE). Safety outcomes included major bleeding, intracranial bleeding, fatal bleeding, and major gastrointestinal (GI) bleeding. Cancer incidence and cancer-related death were evaluated. All outcomes were analyzed by an intention-to-treat. The Online Appendix provides details regarding study outcomes and definitions.
Data synthesis and statistical analysis
Categorical variables were reported as frequencies and percentages, continuous variables as mean ± SD. The DerSimonian and Laird model was utilized to calculate random-effects weighted incidences and summary risk ratios (RRs) (27), using study population size as its weight. Confidence intervals (CIs) were calculated at the 95% level for overall effect estimates. All p values were 2-tailed and were considered statistically significant if <0.05. The Higgins I2 statistic (28), and the Egger method (29) were used to evaluate for heterogeneity and publication bias, respectively. Numbers needed to treat (NNT) and to harm (NNH) were calculated; however, these numbers should be interpreted with caution as they are strongly dependent on the baseline risk for CVD in the participants of each trial. Annual risk of CV events was calculated for each study population (Online Appendix).
We performed multiple sensitivity and subgroup analyses for main efficacy and safety outcomes. Furthermore, random-effect meta-regression analyses were performed to evaluate for treatment modification effects in outcomes with baseline characteristics. Further details on secondary analyses are provided in the Online Appendix. All analyses were performed using STATA software version 14 (StataCorp, College Station, Texas).
Characteristics of the included studies
Our search yielded 9,838 citations (Online Figure 1). A total of 15 RCTs including 165,502 participants (aspirin n = 83,529, and control n = 81,973) were included (6–11,13–15,19–22,30,31). The estimated 10-year CV risk was high (i.e., ≥7.5%) in 11 studies, and low-intermediate in 4 trials. Three RCTs were conducted exclusively in men (6,7,9), and 1 was exclusively in women (11). Four RCTs enrolled only diabetic patients (13,19,21,30), whereas 1 excluded this population (20). The weighted mean duration of follow-up was 6.44 ± 2.04 years. Table 1 reports details of included trials.
Baseline characteristics of the included cohorts
Mean age was 61.6 ± 5.6 years in the aspirin group versus 61.5 ± 5.5 years in the control group. Study populations in aspirin and control groups were well balanced for various CV risk factors. Baseline patient demographics are detailed in Online Table 1.
Quality assessment and risk of bias of the included trials
A total of 5 trials were deemed at low risk and 10 at intermediate risk for bias. The body of evidence for outcomes reached a level of high quality (Online Tables 2 and 3). No significant risk of bias was demonstrated by the Egger test for any of the outcomes.
All-cause, CV, and non-CV death
Aspirin was associated with similar all-cause death (4.75% vs. 4.82%; RR: 0.97; 95% CI: 0.93 to 1.01; p = 0.13; I2 = 0%) and non-CV death (3.3% vs. 3.3%; RR: 0.98; 95% CI: 0.92 to 1.05; p = 0.53; I2 = 29%). There was a modest nonstatistically significant reduction in CV death with aspirin compared with the control group (1.46% vs. 1.52%; RR: 0.93; 95% CI: 0.86 to 1.00; p = 0.064; I2 = 0%) (Figure 1).
Aspirin use was associated with lower risk of total MI (2.07% vs. 2.35%; RR: 0.85; 95% CI: 0.76 to 0.95; p = 0.003; I2 = 60%), driven by a lower risk of nonfatal MI (1.37% vs. 1.62%; RR: 0.82; 95% CI: 0.72 to 0.94; p = 0.005; I2 = 58%) compared with the control group. The risks of fatal MI (RR: 0.93; 95% CI: 0.79 to 1.11; p = 0.43; I2 = 13%), angina pectoris (RR: 0.92; 95% CI: 0.79 to 1.08; p = 0.30; I2 = 0%), coronary revascularization (RR: 0.96; 95% CI: 0.87 to 1.05; p = 0.36; I2 = 0%), and symptomatic peripheral arterial disease (5.95% vs. 6.28%; RR: 0.88; 95% CI: 0.70 to 1.09; p = 0.24; I2 = 9%) were similar in both groups (Figure 2, Online Figure 2).
The risk of TIA was lower in the aspirin (1.06% vs. 1.33%; RR: 0.79; 95% CI: 0.71 to 0.89; p < 0.001; I2 = 0%) compared with the control group. Total stroke rates (1.82% vs. 1.86%; RR: 0.97; 95% CI: 0.89 to 1.04; p = 0.37; I2 = 10%), including fatal (RR: 1.03; 95% CI: 0.84 to 1.26; p = 0.81), and nonfatal stroke (RR: 0.94; 95% CI: 0.85 to 1.02; p = 0.15) were similar in the 2 groups. Further analysis revealed a lower risk of ischemic stroke (1.29% vs. 1.49%; RR: 0.87; 95% CI: 0.79 to 0.95; p = 0.002; I2 = 0%), but a trend toward a higher risk of hemorrhagic stroke (0.29% vs. 0.23%; RR: 1.21; 95% CI: 0.99 to 1.47; p = 0.059; I2 = 0%) with aspirin versus control (Figure 3, Online Figure 3). The NNTs to prevent 1 event of MI, TIA, and ischemic stroke were 357, 370, and 500, respectively.
Major adverse cardiovascular events
A composite of nonfatal MI, nonfatal stroke, TIA, or CV death utilizing data from 6 RCTs was lower with aspirin compared with the control group (3.86% vs. 4.24%, RR: 0.903; 95% CI: 0.85 to 0.96; p = 0.001).
Major bleeding events
Aspirin use for primary prevention was associated with a significant increase in the risk of major bleeding (1.47% vs. 1.02%; RR: 1.50; 95% CI: 1.33 to 1.69; p < 0.001; I2 = 25%), intracranial bleeding including hemorrhagic stroke (0.42% vs. 0.32%; RR: 1.32; 95% CI: 1.12 to 1.55; p = 0.001; I2 = 0%), and major GI bleeding (0.80% vs. 0.54%; RR: 1.52; 95% CI: 1.34 to 1.73; p < 0.001; I2 = 0%) compared with the control group (Figure 4). Fatal bleeding was reported in 5 trials (8,10,16,17,26) and was similar in the 2 groups (0.23% vs. 0.19%; RR: 1.09; 95% CI: 0.78 to 1.55; p = 0.6; I2 = 0%). The NNHs to cause a major bleeding event and intracranial bleeding were 222 and 1,000, respectively.
Aspirin was associated with increased risk of GI ulcers (RR: 1.37; 95% CI: 1.07 to 1.76; p = 0.013; I2 = 80%) compared with the control group.
At a mean follow-up of 6.46 years, cancer incidence (6.1% vs. 6.2%; RR: 0.99; 95% CI: 0.93 to 1.06; p = 0.85; I2 = 24%) and cancer-related death (1.95% vs. 1.89%; RR: 0.99; 95% CI 0.82 to 1.20; p = 0.92; I2 = 80%) were similar in both groups (Online Figure 4).
Female sex was associated with a favorable treatment effect on total stroke (p = 0.046). Meta-regression across the year of publication showed favorable treatment effect on nonfatal MI in older compared with recent studies (p = 0.05). Other baseline characteristics, including age, hypertension, diabetes, or statin use, demonstrated no modification of any efficacy or safety outcomes (Online Table 4).
In our pre-specified sensitivity analyses of: 1) populations who received low-dose aspirin ≤100 mg/day; 2) populations with estimated 10-year ASCVD risk ≥7.5%; and 3) outcomes reported at follow-up ≥5 years, aspirin remained associated with a lower risk of total MI, nonfatal MI, TIA, ischemic stroke, and MACE compared with the control group.
All-cause death was lower with aspirin only at follow-up ≥5 years (RR: 0.95; 95% CI: 0.90 to 0.99; p = 0.032), likely derived by consistent effects on non-CV death (RR: 0.95; 95% CI: 0.89 to 1.0; p = 0.08) and CV death (RR: 0.95; 95% CI: 0.87 to 1.03; p = 0.3). In populations with a high estimated 10-year ASCVD risk, aspirin showed a trend toward lower CV death (RR: 0.92; 95% CI: 0.84 to 1.0; p = 0.06); however, all-cause death remained similar (RR: 0.97; 95% CI: 0.91 to 1.02; p = 0.26). In all other sensitivity analyses, all-cause and CV death were similar between both groups. Risk of major bleeding was higher with aspirin versus control among all sensitivity analyses.
In populations who received low-dose aspirin (≤100 mg/day), there was a significant reduction in total stroke (RR: 0.92; 95% CI: 0.85 to 0.99; p = 0.04) and nonfatal stroke (RR: 0.88; 95% CI: 0.80 to 0.96; p = 0.007), a finding that was not observed when trials with all doses were pooled. To further explore this effect, we performed a subgroup analysis comparing low-dose (≤100 mg/day) versus high-dose (≥300 mg/day) aspirin, and observed an association between high-dose aspirin and increased risk of total stroke (RR: 1.19; 95% CI: 1.0 to 1.4; p = 0.05), and a 57% relative increase in the risk of hemorrhagic stroke (RR: 1.57; 95% CI: 0.89 to 2.77) (Online Figure 5).
The current analysis demonstrates similar outcomes in terms of all-cause death (RR: 0.96; 95% CI: 0.91 to 1.00 vs. RR: 0.96; 95% CI: 0.85 to 1.10), CV death (RR: 0.91; 95% CI: 0.82 to 1.00 vs. RR: 0.89; 95% CI: 0.6 to 1.3), and total stroke (RR: 0.91; 95% CI: 0.76 to 1.1 vs. RR: 0.98; 95% CI: 0.88 to 1.1) with aspirin versus control in patients with or without diabetes. The risk of MI was lower with aspirin in subjects without diabetes but not in those with diabetes (RR: 0.8; 95% CI: 0.66 to 0.98; p = 0.03 vs. RR: 0.90; 95% CI: 0.75 to 1.07; p = 0.23), but without a significant subgroup interaction (pinteraction = 0.48).
Aspirin was associated with a lower risk of MI than control in men, but not in women (RR: 0.69; 95% CI: 0.58 to 0.83; p < 0.001 vs. RR: 0.92; 95% CI: 0.78 to 1.1; p = 0.35; pinteraction = 0.03). Otherwise, sex did not affect the outcomes of all-cause death (RR: 0.96; 95% CI: 0.87 to 1.00 vs. RR: 0.92; 95% CI: 0.78 to 1.10), CV death (RR: 0.93; 95% CI: 0.82 to 1.00 vs. RR: 0.9; 95% CI: 0.75 to 1.10), total stroke (RR: 1.19; 95% CI: 0.96 to 1.12 vs. RR: 0.95; 95% CI: 0.81 to 1.12), and major bleeding (RR: 1.44; 95% CI: 1.21 to 1.73 vs. RR: 1.48; 95% CI: 1.25 to 1.75) with aspirin versus control.
Aspirin was associated with a lower risk of all-cause death (RR: 0.94; 95% CI: 0.88 to 1.00; p = 0.05 vs. RR: 0.99; 95% CI: 0.91 to 1.08; p = 0.88; pinteraction = 0.24), total MI (RR: 0.84; 95% CI: 0.73 to 0.97; p = 0.01 vs. RR: 0.85; 95% CI: 0.70 to 1.03; p = 0.1; pinteraction = 0.89), and nonfatal MI (RR: 0.77; 95% CI: 0.63 to 0.94; p = 0.01 vs. RR: 0.87; 95% CI: 0.72 to 1.05; p = 0.16; pinteraction = 0.37) in fair- versus high-quality trials, but without significant pinteraction. Major bleeding remained significantly higher with aspirin versus control regardless of study quality (Online Figure 6).
The current meta-analysis represents the largest and most contemporary examination of long-term outcomes with aspirin use for primary prevention of CVD. Our primary analysis found that: 1) aspirin is not associated with a reduction in all-cause or non-CV death, but is associated with a modest, nonstatistically significant relative reduction of 7% in CV death; 2) aspirin (even ≤100 mg/day) is associated with lower rates of MI (NNT = 357), nonfatal MI (NNT = 400), TIA (NNT = 370), and ischemic stroke (NNT = 500); 3) aspirin use is associated with a significant increase in the risk of nonfatal major bleeding events, regardless of dose or population characteristics; and 4) aspirin does not affect the incidence of cancer or risk of cancer death within a median follow-up period of 6.46 years. Secondary analyses revealed that: 1) aspirin may reduce all-cause death after 5 years of follow-up; 2) the trend toward lower risk of CV death with aspirin is only observed in populations with high estimated 10-year ASCVD risk; and 3) lower risk of total and nonfatal stroke with aspirin use is observed only when low-dose aspirin (≤100 mg/day) is utilized.
Aspirin and primary prevention of death
Prior meta-analyses of aspirin use for primary prevention have provided conflicting evidence regarding its effect on all-cause death (1,32–34). In the current analysis, although aspirin did not reduce all-cause death, a modest nonstatistically significant relative reduction of 7% in CV death was observed. Furthermore, in populations followed for >5 years (mean 6.7 years), a potential benefit for all-cause death was noticed. In a previous meta-analysis, a similar finding was attributed to reduction in nonvascular rather than vascular death (24). A uniform reduction in all-cause death may be challenging to demonstrate in primary prevention trials due to heterogeneity of populations studied and the high incidence of nonvascular death (>60% of all deaths), in particular, nonvascular noncancer death (20% to 25% of all deaths) (35). It remains plausible that misattribution of cause of death occurred. Although some trials restricted the definition of CV death to a composite of fatal MI and fatal stroke (13,14,30), others included other causes (e.g., sudden cardiac death, heart failure, and pulmonary embolism) (6,7,11,19,21–23). Further evaluation of temporal distribution and actual cause of death in participants enrolled in recent RCTs would provide additional insight.
Aspirin and primary prevention of CV events
We observed a significant reduction in total and nonfatal MI with aspirin. The lack of effect on fatal MI has been previously established (6,7,11,19–21,23). Among cerebrovascular outcomes, we noted a benefit with aspirin use in primary prevention of TIA and ischemic stroke; however, this benefit was offset by an increase in rates of hemorrhagic stroke, resulting in a similar overall rate of stroke in the 2 groups. This is in concordance with prior meta-analyses (32–34). Only the WHS (Women’s Health Study), a trial of aspirin 100 mg every other day in middle-age female health professionals, showed a significant reduction in ischemic stroke with aspirin (11). Interestingly, a meta-regression analysis of our study shows possible modification in the incidence of stroke in women. It should be noted that most of these trials were designed with power calculation for composite endpoints, thereby making it difficult to detect significant differences between treatment groups for the less common, individual outcomes.
We also demonstrate a reduction in total and nonfatal stroke in populations who received low-dose aspirin ≤100 mg/day, but an increase in total stroke driven primarily by higher incidence of hemorrhagic stroke with aspirin ≥300 mg/day. A dose-related increase in bleeding with aspirin is well established (36). Furthermore, prior studies have shown higher mortality with hemorrhagic versus ischemic stroke (1). Our results illustrate a critical association between aspirin dose and risk of total stroke, favoring lower doses for primary prevention of stroke. The current analysis shows that to prevent 1 MI, TIA, or ischemic stroke event, 357, 370, and 500 persons would require treatment, respectively.
In recent RCTs (19–21,23), the modest reduction in CV events or lack of benefit with aspirin suggests a role for other primary prevention strategies that are being employed in the patient population, and is supported by a trend toward a lower estimated 10-year ASCVD risk in these RCTs (mean 8.3%) when compared with older studies (mean 14.4%). For example, in the ASCEND study, the mean systolic blood pressure in the aspirin group was 136 mm Hg, with >75% of population receiving statins, and only 8% actively smoking (21). In the ARRIVE trial, almost 50% of patients were on statins, >65% on antihypertension medications, and less than one-third were smokers (20). Our meta-regression showing a favorable treatment effect on nonfatal MI in older versus recent trials supports this theory and follows the general trend of reduction/plateauing of the burden of CVD worldwide (37).
Primary prevention strategies in healthy adults are multifaceted. These subjects are more likely to be health-conscious, to engage in healthy lifestyle practices such as regular exercise, and to consume a heathy diet as well as other over-the-counter compounds that may have antiplatelet effects, and also tend to have higher rates of statin intake, which have been shown to have an effect on coagulation cascade and inhibit thrombin production. Demonstrating an incremental benefit of aspirin on a background of aggressive primary prevention measures is challenging and may explain the lack of a net benefit in this population. Furthermore, the lack of data regarding percentage of statin use in many of the included trials hindered a comprehensive analysis about its role in modification of outcomes with aspirin. The ongoing ACCEPT-D (Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes) will provide important insight into the role of aspirin on a background of statin therapy for the primary prevention of CVD in a diabetic population (38).
Sex differences in the efficacy of aspirin for primary prevention remain a matter of debate (1,32,34,39). Although our analysis demonstrates a possible sex difference in the benefit with aspirin, the heterogeneity in population characteristics, in particular, the baseline risk of ASCVD, may have contributed to the results. In another subgroup analysis, we did not observe benefit of aspirin in primary prevention of MI in diabetic populations. The biological plausibility of this observation could be based on possible aspirin resistance and increase in platelet turnover in diabetic patients (40–43). Although this was recently challenged by the ASCEND trial, it is important to note that the risk of nonfatal MI was similar between aspirin and control groups in high-risk diabetic patients in this trial.
Safety of aspirin use in primary prevention
Our analysis shows an increased risk for major bleeding (NNH = 222) with aspirin use for primary prevention, a finding that remains consistent even when restricting the analysis to low-dose aspirin trials. However, fatal bleeding was similar in both groups. Aspirin (especially at higher doses) was associated with a 32% relative increase in intracranial bleeding risk (including hemorrhagic stroke) as well as >50% increase in the risk of major GI bleeding. Such findings are similar to results from prior studies (1,33,36,44).
Although certain baseline characteristics such as older age, male sex, history of GI ulcers, elevated mean BP, and NSAID use, have shown to increase the risk of aspirin-related bleeding (36,45), our meta-regression analysis failed to demonstrate any effect modification of major bleeding by baseline characteristics. Patient-level metanalysis would be helpful to further investigate these effects.
Cancer incidence and mortality
Our analysis shows no reduction in the risk of cancer or cancer-related death with aspirin use in primary prevention, even on secondary analysis restricted to long-term follow-up trials (≥5 years). The discrepancy between our results and prior meta-analyses that showed potential lower risk of cancer and cancer death with aspirin (24,35,46) can be attributed to the inconsistency of results in recent RCTs reporting similar risk of cancer-related outcomes in aspirin versus control and the need for even longer follow-up to see any potential effect on cancer (20–22).
Benefit versus risk prediction tool for aspirin use in primary prevention
The clinical dilemma of identifying the population that would benefit from aspirin in primary prevention still persists. In 2016, the U.S. Preventive Service Task Force utilized a decision-analysis model to estimate the magnitude of net benefit with aspirin based on age, sex, and 10-year CVD risk using the American Heart Association/American College of Cardiology risk calculator (47). The U.S. Preventive Service Task Force indicated that a net benefit in life expectancy is expected for most men and women started on aspirin at age 40 to 59 years and 60 to 69 years if they are at high risk for CVD. However, overestimation of CVD risk with this calculator in real-world is a current concern (48). In addition, the current analysis demonstrates a potential reduction of net benefit with aspirin in the contemporary era. Furthermore, a valid prediction tool for estimating the bleeding risk with aspirin in primary prevention is lacking, and only a single risk prediction tool for GI complications with aspirin is available (49). Our study calls for an updated decision-analysis model that incorporates the new evidence and utilizes a comprehensive risk prediction tool for GI bleeding. This would improve the precision of the model to define an appropriate ischemic versus bleeding risk threshold, based on which an adequately validated benefit-risk prediction tool can be calibrated to determine individuals in whom the benefits of using aspirin for primary prevention outweigh the risks.
Study strengths and limitations
The current study aims to provide comprehensive and updated data about efficacy and safety of aspirin in primary prevention of CVD. Since the submission of our paper, 2 meta-analyses have been published (50,51). Our study, however, provides further insight through more comprehensive subgroup, sensitivity, and meta-regression analyses. In particular, the current study emphasizes: 1) a potential benefit with aspirin on all-cause death on long-term follow-up >5 years; 2) a trend toward lower CV death in population with high ASCVD risk; 3) a favorable treatment effect with aspirin on nonfatal MI in older compared with recent studies; and 4) a difference in the outcome of stroke with a low-dose (≤100 mg/day) versus high-dose (≥300 mg/day) aspirin. We included only RCTs to avoid bias associated with observational studies. However, our study has limitations. The main limitations are the heterogeneity in the definition of composite outcomes among trials, as well as the heterogenous quality of studies included. To overcome these limitations, we analyzed individual outcomes separately, and MACE was examined only from studies with a homogenous definition. We further performed multiple secondary analyses to enhance the quality of our analysis. Another limitation to be acknowledged is that the use of summary estimates of absolute risk reduction and NNT/NNH is suboptimal when pooling data to perform a meta-analysis. Hence, we performed our analysis primarily using summary estimates of RRs. Finally, the lack of patient-level data precluded a more robust analysis.
Aspirin use for primary prevention decreased nonfatal ischemic events and increased nonfatal bleeding events (Central Illustration). The benefits were more pronounced when estimated ASCVD risk was ≥7.5% over 10 years. These findings suggest that the decision to use aspirin for primary prevention should be tailored to the individual patient based on estimated ASCVD risk and perceived bleeding risk, as well as patient preferences regarding types of events prevented versus potential bleeding caused. When aspirin is used for primary prevention, a low dose (≤100 mg/day) should be recommended.
COMPETENCY IN MEDICAL KNOWLEDGE: Aspirin reduces the risk of first nonfatal MI and stroke, but increases the risk of bleeding. The decision to use aspirin for primary prevention should be based on a patient’s risk of CV events and bleeding and the dose should not exceed 100 mg daily.
TRANSLATIONAL OUTLOOK: Longer-term follow-up studies are needed to better characterize individuals for whom the benefit of aspirin for primary prevention outweighs the risk of bleeding, and to assess potential effects on incident cancer and all-cause mortality.
↵∗ Drs. Abdelaziz and Saad contributed equally to this work and are joint first authors.
Dr. Bhatt has served on the Advisory Board of Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, PhaseBio, and Regado Biosciences; has served on the Board of Directors of Boston VA Research Institute, Society of Cardiovascular Patient Care, and TobeSoft; has served as Chair of the American Heart Association Quality Oversight Committee, NCDR-ACTION Registry Steering Committee, and VA CART Research and Publications Committee; has served on Data Monitoring Committees for Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic, Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi-Sankyo), and Population Health Research Institute; has received honoraria from American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice-Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim), Belvoir Publications (Editor-in-Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), HMP Global (Editor-in-Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), and WebMD (CME steering committees); has served as Deputy Editor of Clinical Cardiology; has received research funding from Abbott, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi, Synaptic, and The Medicines Company; has received royalties from Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); has served as Site Co-Investigator for Biotronik, Boston Scientific, St. Jude Medical (now Abbott), and Svelte; has served as a Trustee of the American College of Cardiology; and has performed unfunded research for FlowCo, Merck, Novo Nordisk, PLx Pharma, and Takeda. Dr. Abbott has received research grants with no direct compensation from Sinomed, Abbott Vascular, Biosensors Research, Bristol-Myers Squibb, AstraZeneca, and CSL Behring. Dr. Mehta has served as consultant to Bayer, Boehringer Ingelheim, AstraZeneca, MedImmmune, and Pfizer; and has received grant support from Bayer, Boehringer Ingelheim, and AstraZeneca, and the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development (Washington, DC) (grant No BX-000282-05). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Listen to this manuscript's audio summary by Editor-in-Chief Dr. Valentin Fuster on JACC.org.
- Abbreviations and Acronyms
- cardiovascular disease
- major adverse cardiovascular events
- myocardial infarction
- transient ischemic attack
- Received December 5, 2018.
- Revision received March 10, 2019.
- Accepted March 12, 2019.
- 2019 American College of Cardiology Foundation
- Smith S.C.,
- Benjamin E.J.,
- Bonow R.O.,
- et al.
- Kernan W.N.,
- Ovbiagele B.,
- Black H.R.,
- et al.
- Van’t Hof J.R.,
- Duval S.,
- Walts A.,
- Kopecky S.L.,
- Luepker R.V.,
- Hirsch A.T.
- Peto R.,
- Gray R.,
- Collins R.,
- et al.
- The Medical Research Council’s General Practice Research Framework
- Belch J.,
- MacCuish A.,
- Campbell I.,
- et al.
- Goldstein L.B.,
- Bushnell C.D.,
- Adams R.J.,
- et al.
- Pignone M.,
- Alberts M.J.,
- Colwell J.A.,
- et al.
- Saito Y.,
- Okada S.,
- Ogawa H.,
- et al.
- Gaziano J.M.,
- Brotons C.,
- Coppolecchia R.,
- et al.
- Bowman L.,
- Mafham M.,
- Wallendszus K.,
- et al.,
- for the ASCEND Study Collaborative Group
- McNeil J.J.,
- Nelson M.R.,
- Woods R.L.,
- et al.
- McNeil J.J.,
- Wolfe R.,
- Woods R.L.,
- et al.
- Higgins J.P.T.,
- Altman D.G.,
- Gotzsche P.C.,
- et al.
- Higgins J.P.T.,
- Thompson S.G.,
- Deeks J.J.,
- Altman D.G.
- Egger M.,
- Davey Smith G.,
- Schneider M.,
- Minder C.
- Goicoechea M.,
- de Vinuesa S.G.,
- Quiroga B.,
- et al.
- Xie M.,
- Shan Z.,
- Zhang Y.,
- et al.
- Roth G.A.,
- Johnson C.,
- Abajobir A.,
- et al.
- De Berardis G.,
- Sacco M.,
- Evangelista V.,
- et al.
- Mylotte D.,
- Kavanagh G.F.,
- Peace A.J.,
- et al.
- Chubak J.,
- Whitlock E.P.,
- Williams S.B.,
- et al.
- Rana J.S.,
- Tabada G.H.,
- Solomon M.D.,
- et al.
- Zheng S.L.,
- Roddick A.J.
- Mahmoud A.N.,
- Gad M.M.,
- Elgendy A.Y.,
- Elgendy I.Y.,
- Bavry A.A.