Efficacy of Aspirin for Primary Prevention in Adults With High-Risk Type 2 Diabetes

Should anyone be taking aspirin for primary prevention?

In 2019, the American College of Cardiology and American Heart Association guidelines on primary prevention reversed prior recommendations, highlighting that aspirin should not be used for primary prevention in adults over the age of 70 years or those with increased bleeding risk and that aspirin may be used in adults between the ages of 40 and 70 years who have higher risk of subsequent cardiovascular events. The US Preventive Services Task Force subsequently highlighted that the use of aspirin in this higher-risk population is individually based (balancing the risk of bleeding and ischemia) and that the net benefit is likely small.

Diving into the studies that led to these recommendations requires us to go back a few decades. In the 1980s, two large trials were undertaken to explore the effects of high-dose aspirin in male physicians. One of these trials showed no benefit (BMD), whereas the other (PHS) was stopped early due to futility but demonstrated a reduction in a secondary endpoint of myocardial infarction. Fast-forward to the twenty-first century; there was a barrage of clinical trials that attempted to find a high-risk population in which there would be a net positive benefit of daily aspirin when balancing the risk of major bleeding events. Regardless of the population, these large studies (JPP, ARRIVE, ASPREE, ASCEND) continued to demonstrate that aspirin had minimal to no effect on cardiovascular outcomes, but was associated with a real increase in bleeding.

With the current recommendations, patients and clinicians are still left wondering who falls into the category of "adults aged between 40 and 70 years at high risk of cardiovascular events." The guidelines try to help by suggesting that this may include individuals with a Framingham Risk Score of 10% or greater. Looking to large datasets that could provide the answer to this seemingly difficult question, the authors of this study analyzed patient data from the ACCORD trial. The ACCORD trial was a randomized clinical trial of patients aged between 40 and 79 years with type 2 diabetes and additional risk factors for cardiovascular disease. Participants were randomized to either intensive risk factor modification (glycemic, hypertension, and dyslipidemia control) or standard of care. The trial was stopped early due to increased mortality observed in the intensive glycemic control group.

Of the 10,251 total participants, 6330 participants with no history of ischemic heart disease and with available information on aspirin use were included in the analysis. When you consider the average age and burden of comorbidities of this cohort, most, if not all, participants would fall into this high-risk population with a Framingham Risk Score of >10%. Nearly half of these participants were taking daily aspirin during the study period. After 5 years of follow-up, there was no difference in major cardiovascular complications (cardiovascular death, myocardial infarctions, or stroke), with an event rate of 6.5% in the aspirin group and 6.9% in the no aspirin group (adjusted HR, 0.94; 95% CI, 0.78–1.14).

There now exist several randomized controlled trials and non-randomized observational studies that have shown no clear benefit of daily aspirin for the primary prevention of cardiovascular events. There is no question that the best way to reduce an individual’s risk of cardiovascular events is to adjust the known strong modifiable risk factors, including smoking, hypertension, diabetes, obesity, dyslipidemia, and sedentary lifestyles. But it remains elusive as to whether we can identify which group of patients without evident atherosclerotic cardiovascular disease will benefit from daily aspirin. Until then, the question remains: Should anyone be taking aspirin for primary prevention?