Evidence evolving on aspirin as prevention

For many years, the conventional wisdom was clear: An aspirin a day keeps heart attacks and strokes away. But while this still rings true for secondary prevention of cardiovascular disease (CVD), research has raised more questions than answers for primary prevention, with the results of three randomized trials in 2018 further challenging aspirin's utility for this indication.

Overall, the trials, ARRIVE (Aspirin to Reduce Risk of Initial Vascular Events), ASCEND (A Study of Cardiovascular Events iN Diabetes), and ASPREE (Aspirin in Reducing Events in the Elderly), presented a clear theme: In patients who have not had a prior cardiovascular event, aspirin's protective effects are modest and may not necessarily outweigh its potential downsides (namely, risk of bleeding and hemorrhagic stroke). With these new results in hand, it is time to rethink aspirin's role in primary prevention, said Laurence S. Sperling, MD, FACP, professor in preventive cardiology and director of the Emory Heart Disease Prevention Center at Emory University in Atlanta.

“You would think that in 2019, if there was any medicine we knew how to use well, it would be aspirin. … This is one of the oldest compounds known to mankind, from the bark of the willow tree, dating all the way back to Galen and Hippocrates,” he said. “And yet, today, despite the randomized controlled clinical trials we have and all the evidence we have about potential benefits, the individualized risk-benefit still remains unclear.”

Experts explained what has changed (and why) and offered take-home points for internists that may be practice-changing.

The evidence is in

Many physicians have long prescribed aspirin for primary CVD prevention. For example, in 2013, more than one-third of eligible Mississippi residents without CVD were taking aspirin daily for primary prevention, according to results of a CDC analysis published in September 2017 by Preventing Chronic Disease.

This study determined eligibility for using aspirin for primary prevention of CVD based on 2009 recommendations from the U.S. Preventive Services Task Force (USPSTF). Those Grade A recommendations encouraged daily aspirin for primary prevention in men ages 45 to 79 years and in women ages 55 to 79 years when the potential benefit of reducing myocardial infarctions and ischemic strokes, respectively, outweighed the risk of gastrointestinal (GI) hemorrhage.

The most recent recommendations are more limited. In 2016, the USPSTF updated (and downgraded) its endorsement to a Grade B recommendation for starting low-dose aspirin for primary prevention of CVD in adults ages 50 to 59 years with a 10% or greater 10-year CVD risk. These patients should not be at increased risk for bleeding, should have a life expectancy of at least 10 years, and must be willing to take low-dose aspirin daily for at least 10 years, the USPSTF said. The recommendations become Grade C (i.e., encourage individual decision making) for the same population at ages 60 to 69 years. In adults younger than age 50 years or ages 70 years and older, the USPSTF determined the evidence to be insufficient to weigh the benefits and harms.

The 2018 trials looked at three distinct populations: patients with moderate CVD risk, patients with diabetes, and patients ages 70 years and older (≥ages 65 years for black and Hispanic patients). In the ARRIVE trial, which was funded by Bayer, researchers randomized 12,456 patients with moderate CVD risk and no prior events to receive 100 mg of aspirin or placebo and compared cardiovascular events between groups. In the ASCEND trial, 15,480 patients with diabetes but no prior CVD were randomized to receive either 100 mg or placebo, with first serious vascular event as the primary outcome. Finally, ASPREE randomly assigned elderly adults without CVD to 100 mg of aspirin or placebo and compared outcomes including major hemorrhage and CVD.

In the first trial, ARRIVE, there was no significant difference in cardiovascular events between groups, and aspirin was associated with an increased risk of GI bleeding compared to placebo, according to results published in September 2018 by the Lancet. In the second, ASCEND, published in October 2018 by the New England Journal of Medicine (NEJM), aspirin had a modest effect in preventing serious vascular events, but the authors determined the benefits to be counterbalanced by the bleeding risk. Finally, in ASPREE, also published by NEJM in October 2018, aspirin did not reduce the risk of CVD and significantly increased risk of major hemorrhage compared to placebo.

A systematic review and meta-analysis of 13 randomized trials, including these recent three, found that among nearly 165,000 participants without CVD, aspirin use was associated with a reduced risk of cardiovascular events (hazard ratio, 0.89) and an increased risk of major bleeding (hazard ratio, 1.43). The estimated number needed to treat to prevent one cardiovascular event was 265, while the number needed to harm to cause one major bleeding event was 210, according to results published online in January 2019 by JAMA.

Surveys about shared decision making have shown that many doctors don't discuss the downsides of interventions very well with patients, noted Michael Pignone, MD, MACP, MPH, chair of the department of internal medicine and professor in the departments of internal medicine, oncology, and population health at The University of Texas at Austin Dell Medical School. “It seems so straightforward to take an aspirin, but there are potential benefits and potential harms,” he said.

However, weighing the benefits and harms isn't as simple as comparing the number needed to treat with the number needed to harm, Dr. Pignone said. “It is not sufficient to just add up and compare the number of heart attacks prevented versus number of GI bleeds caused, as those two types of events have different levels of severity and implications for future health,” he noted.

For Darren A. DeWalt, MD, FACP, the new evidence provides two major takeaways for primary CVD prevention: Don't start people on aspirin after age 70, and use aspirin carefully in a way that addresses its modest benefit and real downsides. “I'm not to the point where we should just stop prescribing aspirin, but I'm closer to that than I was before,” he said.

Physicians have questioned aspirin's role in primary prevention for several years, and the new trials add a bit more certainty, said Dr. DeWalt, distinguished professor and chief of the division of general medicine and clinical epidemiology at the University of North Carolina School of Medicine in Chapel Hill. “I think a lot of internists out in the community have been told to put people on aspirin for a long time, so this may be something that they need to wrestle with a little bit,” he said.

For Dr. Pignone, a member of the USPSTF when the 2016 recommendations were finalized, the approach of using aspirin for primary CVD prevention in certain patients with a 10% or greater 10-year risk still makes sense. “[But] probably only after having already used other, perhaps less risky cardiovascular preventive strategies like statins, better blood pressure control, and, in people who are smokers, smoking cessation,” he said.

To assess CVD risk beyond what the standard 10-year risk estimator tool says, primary care doctors can look at additional risk-enhancing factors, such as metabolic syndrome and a family history of premature CVD, said Dr. Sperling, coauthor of a paper on risk-assessment tools to guide decision making, which was published in November 2018 by the Journal of the American College of Cardiology. “These risk enhancers, or evidence of significant subclinical atherosclerosis noted in a coronary calcium score, may become important in the decision making regarding aspirin use for primary prevention,” he said.

Some physicians have a firmer stance against aspirin, viewing it to be likely more harmful than helpful in most patients, especially when compared to newer primary prevention strategies. “In my own practice, I actually haven't prescribed aspirin for primary prevention in six to eight years. … I think these three trials confirm what many of us suspected,” said cardiologist Paul M Ridker, MD, MPH, an author on several of the original trials of aspirin for primary prevention.

One of the grayer areas in the new research is aspirin's potential effect on cancer risk. Aspirin has been associated with reduced risks of colorectal, liver, and ovarian cancer, and the 2016 USPSTF recommendation encouraged low-dose aspirin for primary prevention of colorectal cancer in addition to CVD in certain patients. But the ASPREE trial has shown an increase in cancer-related deaths in the aspirin group.

For now, experts said the jury is out. The overall evidence for aspirin's potential to reduce colorectal cancer risk is compelling, but the new trials don't provide any more evidence to suggest a broader benefit in terms of cancer prevention, said Dr. Pignone. “We need to be following these trial participants out over much longer periods of time, which is hard and expensive,” he said. “But even if they don't stay randomized, we ought to be getting follow-up with them over time to see if anything emerges.”

What's changed?

One important layer of the new studies is that the data are contemporary. It's not that the trials performed 25 years ago were wrong about aspirin; it's that interventions to reduce CVD risk have changed since then, said Dr. Ridker, director of the Center for Cardiovascular Disease Prevention at Brigham and Women's Hospital and professor of medicine at Harvard Medical School in Boston.

“What has changed dramatically in that 25 years is that we now do a much better job controlling blood pressure, we have far less smoking, people generally are healthier for other reasons, and we have much better control of cholesterol,” he said. Dr. DeWalt agreed, adding that although the effect of an aspirin a day on CVD risk seems to be a lukewarm 10% or so, “It's not zero.”

However, there are better options available today, he said. “Now that we have everybody on statins, aspirin's not so helpful anymore.” As Dr. Ridker said, echoing his October 2018 NEJM editorial, “The best strategy for using aspirin in primary prevention today may simply be to prescribe a statin instead.”

The new trials enrolled people with supposedly moderate CVD risk, but event rates were actually lower than anticipated, a potential effect of aggressively using statins and treating hypertension in current practice, noted Carlin S. Long, MD, FACP, professor of medicine and cardiology and director of the Center for the Prevention of Heart and Vascular Disease at the University of California, San Francisco.

“I think lower is better for LDL [cholesterol] and lower is better for blood pressure, and I think if we can get that into the primary care strategic thinking, then stuff like the daily baby aspirin may be gilding the lily to a certain extent,” he said.

One of the benefits of aspirin is that it's very cheap and widely available. But statins, too, have become very inexpensive, experts noted. When you compare the side effect profiles of the two drugs, it's clear which is the safer bet, said Dr. DeWalt. “Aspirin, hands down, is a more dangerous drug than statins. There's no question about it scientifically,” he said.

However, because aspirin is such an established medication and it's available over the counter, patients often have the perception that it's not a dangerous drug, Dr. DeWalt said. “It's our job as physicians to help to explain, but it often takes multiple conversations to get people to try a statin,” he said, noting that myalgias are often patients' biggest fear.

These conversations are a good place to dispel myths and make clear the sterling safety profile of statins, experts said. About 95% of people don't get muscle pain with statins, and even if they do, the side effects go away after stopping the drug, Dr. Pignone noted. “I do point out to patients that, if you've never taken the statin and you're worried that you're going to get muscle pain, why not try it and find out before deciding against the benefits?” he said.

Still, some patients who have been doing well on aspirin for primary prevention for years may be “true believers” who don't want to change their regimen, and that's OK, Dr. Long said. In these patients, he considers the use of GI-protective agents, such as proton-pump inhibitors, and has a conversation about weight-based dosing, as patients who weigh more than 150 pounds or so might need a higher dose to reap benefits.

On the flip side, a patient may be excited about discontinuing aspirin and having to take one fewer pill. “I think you can definitely defend that approach, as well,” said Dr. Long. But it's important to note that if patients have been on aspirin successfully, they shouldn't stop it without talking to their doctor, Dr. Pignone added. “There is some moderately strong evidence to suggest that stopping aspirin increases your short-term risk of events,” he said.

All told, doctors should avoid falling into the trap of interpreting the most recent trial as the definitive conclusion, Dr. Pignone said. “There's nothing that makes the last trial that's been published the best trial,” he said.

In the meantime, 2018 may have marked the end of an era for what used to be called “the wonder drug.”