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Aspirin for Primary Prevention of Cardiovascular Events
Two new studies push the pendulum away from aspirin prophylaxis.
The scene is all too familiar in primary care practice. Aspirin is on the medication list of a new patient with well-controlled hypertension and hyperlipidemia and no history of clinically evident cardiovascular (CV) disease. You ask how he came to be taking aspirin, and he replies, “I started doing this on my own. … Isn't aspirin supposed to prevent heart attacks and strokes?” Or, maybe you don't even ask — you just tacitly endorse the aspirin use. Two new studies, published in August 2018 and supported by Bayer, might help us navigate some of these cases.
In the first trial (ARRIVE; NEJM JW Gen Med Oct 1 2018 and Lancet 2018 Aug 26; [e-pub]), about 12,000 nondiabetic patients were randomized to 100 mg of aspirin or placebo daily. Enrolled men were 55 or older and had ≥2 CV risk factors; enrolled women were 60 or older and had ≥3 CV risk factors. During average follow-up of 5 years, aspirin conferred no CV benefit: The incidence of a composite endpoint that included myocardial infarction (MI) and stroke was about 4% in both groups. Gastrointestinal bleeding was slightly, but statistically significantly, more common with aspirin (1% vs. 0.5%; P=0.0007).
In the second trial (ASCEND; NEJM JW Gen Med Oct 1 2018 and N Engl J Med 2018 Aug 26; [e-pub]), 15,000 middle-aged or older diabetic patients were randomized to daily aspirin (100 mg) or placebo. During average follow-up of ≈7 years, the incidence of serious vascular events was 1 percentage point lower in the aspirin group than in the placebo group (8.5% vs. 9.6%; P=0.01), but the incidence of major bleeding events was 1 percentage point higher with aspirin (4.1% vs. 3.2%; P=0.003).
In sum, among nondiabetic patients with CV risk factors, aspirin conferred no benefit and was associated with slight harm. Among diabetic patients, the tradeoff between small probabilities of benefit and harm was a close call. Notably, a large proportion of patients in both studies were taking statins and antihypertensive drugs, and only a small proportion were current smokers. Thus, one could reasonably conclude that these studies examined the incremental benefit of aspirin, added to other standard preventive interventions.
What did the U.S. Preventive Services Task Force (USPSTF) say about primary prevention with aspirin in its 2016 guideline (NEJM JW Gastroenterol Sep 2016 and Ann Intern Med 2016; 164:836)? Based on data from 11 randomized trials published between 1989 and 2014, the USPSTF recommends low-dose aspirin for adults (age range, 50–59) whose 10-year CV risk exceeded 10% and who are not at excess risk for bleeding. For people in their 60s, the USPSTF judges the benefits and harms as too closely balanced to merit a decisive recommendation and found that evidence was inadequate to address younger or older age groups. The USPSTF recommends the American College of Cardiology (ACC) calculator for estimating baseline CV risk, and the guideline provides a table for estimating life-years gained per 10,000 people taking aspirin (stratified by age and CV risk). However, the ACC calculator's accuracy is controversial (NEJM JW Gen Med Apr 15 2015 and Ann Intern Med 2015; 162:266), and the aforementioned table incorporates decision analytic modeling that might not reflect the incremental benefit of aspirin in contemporary patients who already are addressing CV risk through pharmacologic and lifestyle measures.
At least two other sources of uncertainty merit attention. First, there is growing interest in prophylactic aspirin to prevent colorectal cancer — a projected benefit that was incorporated into the USPSTF recommendation. Aspirin did not lower rates of colorectal cancer in either ASCEND or ARRIVE, but the duration of these studies might have been too short to demonstrate lower cancer incidence. Second, a recently published meta-analysis suggested that higher-dose aspirin (e.g., ≥325 mg) might be necessary to confer CV benefit in overweight people; however, because higher-dose aspirin has been associated with higher risk for serious bleeding, tradeoffs remain uncertain (NEJM JW Gen Med Aug 15 2018 and Lancet 2018; 392:387).
Wrap-Up
In my view, the new studies should push the pendulum away from aspirin prophylaxis for primary prevention — at least in moderate-risk patients. Differences between benefits and harms are likely to be razor thin, and balancing one adverse CV event against one bleeding event is not straightforward. For example, a fatal MI is more lethal than a minimally symptomatic gastrointestinal bleed, whereas some bleeding events (e.g., severe intracranial hemorrhage) are more lethal than some ischemic CV events (e.g., transient ischemic attack). Prospectively, we can't predict which of those outcomes would apply to any given patient.
As it happens, several days after ASCEND was published, a 50-year-old man with type 2 diabetes and hyperlipidemia (treated with insulin, metformin, and atorvastatin) came in for a routine visit. Aspirin was also on his medication list, but in previous visits, I had regarded it with benign neglect. I pulled up the ASCEND paper online, we discussed the results together, and he made an informed decision to discontinue aspirin. If he had deferred the decision to me (“Dr. Brett, I'll do whatever you think is best”), I would have made the same call.
