Like it or not, we do a fair amount of primary care medicine in the emergency department. Therefore, we need to know some of the basics about primary care. One of the most fundamental concepts is the use of aspirin for prevention of MI either before the first one (primary) OR after (secondary) your patient has had a heart attack or stroke. Spoiler alert… 2018 was not a good year for aspirin. It would seem our beloved miracle drug has not been able to escape the rigors of time and medical reversal; much as we have seen with so many other treatments in medicine. Don’t panic, using our beloved aspirin during and after an acute MI hasn’t changed (see you don’t even need a towel!). But whom in the ED, do we need to discharge on a daily aspirin? How good is aspirin in the PRIMARY prevention of cardiovascular disease? Well the holiday season of 2018 has gifted us with 3 trials to help us answer these burning questions.
NOTE: SKIP TO THE BOLDED TEXT AT THE END IF YOU WANT THE ULTRA SUMMARY
First a little back story. I was born at a very young age…oh sorry not my back-story, the aspirin in prevention back-story. To understand the controversy we need to define a few terms. The first is MACE, which stands for major adverse cardiac events defined as MI (aka myocardial infraction, aka heart attack), stroke, and vascular death (and sometimes arrhythmias are thrown in to the definition as well). MACE is what separates the terms Primary prevention from Secondary Prevention. The people without MACE are the people we are PRIMARILY trying to prevent bad things from happening. If they HAVE had MACE then we are trying to SECONDARILY prevent a repeat of bad things. As I said above the role of aspirin has been well established in SECONDARY prevention (i.e. prior MI). This was established by the famous Antithrombotic Trialists’ Collaboration in 2009 in over 200,000 patients. The use of aspirin in the PRIMARY prevention however has been somewhat controversial despite 30 years of studies! The harm from aspirin is mostly due bleeding and over the years we have had better and better medications to treat vascular pathology (specifically statins, neuropathy and myopathy aside).
OK so now that we are again confident that aspirin is great SECONDARILY (once you have a heart attack), we need to figure out if it is useful for PRIMARILY preventing heart attacks (BEFORE you have one). Below we discuss the THREE trials that help us figure this out.
The first trial we will discuss is the ARRIVE trial. ARRIVE was done in seven countries, including the US mostly in primary care offices. Eligible patients were either males aged 55 years and older with >1 risk factors or females aged 60 years and older with >2 risk factors. The study also checks all the usual boxes for doing a study the right way including randomized, double blind, placebo-controlled, multicenter, and intention to treat analysis. Patients had a moderate vascular risk but NO MACE, so all primary prevention and were randomized to get aspirin or placebo. The primary outcome was a time to event analysis for the composite of who did get MACE. GI bleeding was the major safety outcomes. They enrolled about 12,500 pts and randomized about 6300 to each group. For the primary outcome of MACE the aspirin group had 4.3% vs. 4.5% MACE (HR of 0.8-1.1; p=0.6). For the GI bleeding outcome aspirin had 0.97% vs. 0.46% in the placebo group (HR 2.11, 1.36–3.28; p=0·0007). So, aspirin had no difference in MACE but doubled the bleeding.
In order to see if we can find a subgroup of people the MIGHT benefit with primary prevention of aspirin we turn to the ASCEND trial. This jolly good UK trial looked specifically at diabetics for primary prevention. They enrolled men and women at least 40 yo who had a diagnosis of diabetes and followed them for 7 years. The primary outcome, which was modified DURING recruitment (naughty, naughty!) was MACE and the primary safety outcome was any major bleeding (ICH, GI, etc.). The trial was a randomized, placebo controlled and intention to treat study. The trial included 15000 pts. and randomized 7740 to each group (I know that math doesn’t add up but work with me here). For the primary outcome of MACE, the study found a 1% benefit to aspirin overall, with 8.5% for aspirin and 9.6% for placebo (RR of 0.88 with p=0.01). However, that 1% difference occurred only in the first 3 years (2.6% vs. 3.5%) but after 3 years there was no further difference (2.7% vs. 2.7%). The “any” major bleeding risk however was 4.1% in the aspirin group and 3.2 in the placebo group (RR 1.29 with p=0.003). So even if we don’t look at these groups by year (and the subgroups were NOT pre-specified so we shouldn’t – More naughtiness!); the benefit to aspirin for primary prevention was 1% and the harm was 1% making it a wash. This looks like a job for shared decision making in the first 3 years…
The last study we will discuss looks at another at risk group, the elderly. The ASPREE trial involved men and women from Australia and the United States who were 70 years of age or older (or ≥65 years of age among minorities in the United States). Again this was a randomized controlled trial of aspirin or placebo of approximately 19,000 (only 2500 from the US) “relatively healthy” elderly people who were followed for about 5 years. The primary end point was disability-free survival, which was defined as survival free from dementia or persistent physical disability. The primary composite end point was derived from the first end-point events of death, dementia, and persistent physical disability. Of note the trial was stopped early because “it was extremely unlikely that continuation of the trial intervention would reveal a benefit with regard to the primary end point”. Unfortunately, this trial makes the naughty list for listing two primary outcomes “The primary end point was disability-free survival… The primary composite end point was derived from the first end-point events of death, dementia, and persistent physical disability”. Then they go on to mistakenly list not survival but mortality. About 9500 were allocated to each group. They list “any cause of death” as 5.9% with aspirin and 5.2 with placebo, so no difference. They list CV disease including stroke as 1.0% for aspirin vs 1.2% for placebo. They list major hemorrhage as 0.3% for aspirin and 0.3% for placebo. They also go on to say in the abstract that there were more cancer related deaths in the aspirin group but that isn’t really an appropriate conclusion since we don’t even know if this is an a priori secondary outcome or just statistical jujitsu after the fact.
So to summarize these three large trials: ARRIVE had no change in MACE but increased bleeding; ASCEND had a decrease in MACE but with an equal and opposite increase in bleeding; and ASPREE had no change in mortality, no change in MACE and no change in bleeding. So does the patient with chest pain but without MACE get an aspirin forthright?
I would say no to that…and to all a good night!
1. Gaziano, J. 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: 1036–46.
2. Bowman, L. Effects of Aspirin for Primary Prevention in Persons with Diabetes Mellitus. N Engl J Med 2018;379: 1529-39. ASCEND Study Collaborative Group.
3. McNeil J. Effect of Aspirin on All-Cause Mortality in the Healthy Elderly. N Engl J Med 2018;379: 1519-28. ASPREE Investigator Group