Aspirin for Primary Prevention

Tiffany Cheng, Pharm.D., Fairview Pharmacy Services

Background:​​ Aspirin is commonly used to reduce the risk of cardiovascular events. Use in secondary prevention is well established, while primary prevention has been controversial.​ ​Currently, guidelines are recommending aspirin therapy for primary prevention if patients have diabetes and/or an additional risk for cardiovascular disease (CVD) such as ≥10% 10-year risk of CVD, family history of CVD, hypertension, dyslipidemia, and smoking. However, Zhang et al. concluded patients with diabetes on aspirin therapy did not reduce the risk of CVD without increasing the risk of major bleeding.​ ​After reviewing five additional studies on primary prevention of CVD and colorectal cancer (CRC), the U.S. Preventive Services Task Force (USPSTF) updated their recommendations to recommend aspirin for primary prevention with increased risk of CVD.​ ​New studies have been published looking at aspirin therapy for primary prevention: ASCEND, ASPREE, and ARRIVE trials.

Evidence:​​ A 2009 meta-analysis by Zhang et al. reviewed seven prospective randomized controlled trials comparing aspirin therapy to placebo in patients with diabetes for primary prevention. Aspirin therapy non-significantly reduced major cardiovascular (CV) events (RR 0.92 [95% CI 0.83-1.02]; P=0.11), all-cause mortality (0.95 [95% CI 0.85-1.06]; P=0.33), CV mortality (0.95 [95% CI 0.71-1.27]; P=0.71), stroke (0.83 [95% CI 0.63-1.10]; P=0.20), and myocardial infarction (MI) (0.85 [95% CI 0.65-1.11]; P=0.24). Aspirin also non-significantly increased the risk of major bleeding (2.46 [95% CI 0.70-8.61]; P=0.16).

The ASPREE trial was a randomized controlled trial that compared enteric-coated aspirin 100 mg once daily to placebo in 19,114 participants who were ≥70 years (≥65 years in African American or Hispanic populations) with no history of CVD, dementia, or disability. After five years, aspirin therapy was found to have no significant difference on the primary composite outcome (death, dementia, or persistent physical disability) (1.01 [95% CI 0.92 - 1.11]; P=0.79) or reducing CV events (0.95 [95% CI 0.83 - 1.08]). Subgroup analysis also resulted in non-significant differences. Aspirin did significantly increase the risk of major bleeding (1.38 [95% CI 1.18 - 1.62]; P<0.001) and risk of death from any cause (1.14 [95% CI 1.01 - 1.29]).

The ASCEND trial was a randomized controlled trial that compared enteric-coated aspirin 100 mg once daily to placebo in 15,480 participants who were ≥40 years with diabetes and no history of CVD. After a mean follow-up of 7.4 years, aspirin significantly reduced the risk of serious vascular events (0.88 [95% CI 0.79 - 0.97]; P=0.01). However, the risk of major bleed was also significantly greater in aspirin group (1.29 [95% CI 1.09 - 1.52]; P=0.003).

The ARRIVE trial was a randomized controlled trial that compared enteric-coated aspirin 100 mg daily to placebo in 12,546 participants who were men ≥55 years with two to four CV risk factors and women ≥60 years with three or more CV risk factors. After a five year follow-up, there was a non-significant difference in composite CV event rate (0.96 [95% CI 0.81 to 1.13]; P=0.6038).​ ​The risk of gastrointestinal (GI) bleed significantly increased (2.11 [95% CI 1.36 to 3.28]; P=0.0007). There was a non-significant difference in the GI bleed event rate compared to the expected event rate.

Discussion:​​ The USPSTF has a grade B recommendation to start low dose aspirin for primary prevention of CVD and CRC in adults 50 to 59 years old with ≥10% 10-year CV risk who also have a low bleed risk, life expectancy of at least ten years, and the desire to take aspirin. The USPSTF has a grade C recommendation to consider the risk and benefits individually in 60 to 69 years old with ≥10% 10-year CV risk. The meta-analysis by Zhang et al. concluded non-significant differences in all outcomes between aspirin and placebo therapy. However, meta-regression to appraise the impact of gender suggested a potential risk reduction of stroke in women with diabetes and MI in men with diabetes. For this reason, more research is needed to understand how gender may impact MI and stroke risk with aspirin therapy. The ASPREE trial found aspirin to significantly increase the risk of major bleeding and risk of death. The researchers suggested cancer to confound the high mortality rate in the aspirin group. The ASCEND trial found a significant reduction in vascular events and increased risk of bleeding events. A limitation to the ARRIVE study was the underestimation of CV risk. The study aimed for patients with a moderate 10-year CV risk score. Instead, the study population had a low CV risk. There was no reduction in CV events with aspirin therapy, and yet there was a two-fold risk of GI bleeding.

Clinical Impact:​​ From the new primary prevention studies, there is insufficient evidence to support the use of aspirin in primary prevention for patients ≥70 years or patients without diabetes and an estimated 10-year CV risk score <20% and a high bleed risk. There may be a shift in aspirin therapy in primary prevention of CVD guideline recommendations in the future.

References:
1. Gaziano, J., 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. ​The Lancet.​ 2018;​392(​ 10152), 1036-1046. DOI: 10.1016/S0140-6736(18)31924-X.
2. Bibbins-Domingo, K., Grossman, D., Curry, S., et al. Aspirin Use for the Primary Prevention of Cardiovascular Disease and Colorectal Cancer: U.S. Preventive Services Task Force Recommendation Statement. ​Annals of Internal Medicine.​ 2016;164(12), 836-845. DOI: 10.7326/M16-0577.
3. Zhang, C., Sun, A., Zhang, P., et al. Aspirin for primary prevention of cardiovascular events in patients with diabetes: A meta-analysis. ​Diabetes Research and Clinical Practice​. 2009;87(2):211-218. doi:10.1016/j.diabres.2009.09.029.
4. McNeil, J., Woods, R., Nelson, et al. Effect of Aspirin on Disability-free Survival in the Healthy Elderly. ​The New England Journal of Medicine. 2​ 018;​379​(16), 1499-1508. DOI: 10.1056/NEJMoa1800722.
5. Bowman, L., Mafham, M., Wallendszus, K., et al. Effects of Aspirin for Primary Prevention in Persons with Diabetes Mellitus. ​The New England Journal of Medicine. ​2018;​379(​ 16), 1529-1539. DOI: 10.1056/NEJMoa1804988.
6. McNeil, J., Wolfe, R., Woods, R., et al. Effect of Aspirin on Cardiovascular Events and Bleeding in the Healthy Elderly. ​The New England Journal of Medicine. 2​ 018​;379​(16), 1509-1518. DOI: 10.1056/NEJMoa1805819.
7. McNeil, J., Nelson, R., Woods, R., et al. Effect of Aspirin on All-Cause Mortality in the Healthy Elderly. ​The New England Journal of Medicine. 2​ 018​;379​(16), 1519-1528. DOI: 10.1056/NEJMoa1803955.