Aspirin for primary cardiovascular prevention, RIP

SNOWMASS, COLO. – The decades-long belief that aspirin is beneficial for primary prevention of cardiovascular events was utterly dashed by three major randomized clinical trials during the space of a few short weeks in autumn 2018.


“Is aspirin safe and effective for primary prevention? The short answer here is no,” Patrick T. O’Gara, MD, declared at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
“Think of all those decades of aspirin therapy in the hopes of making ourselves healthier,” added Dr. O’Gara, professor of medicine at Harvard Medical School, Boston, and a past president of the American College of Cardiology.

He cited the results of three placebo-controlled randomized trials totaling more than 47,000 patients without known cardiovascular disease: ARRIVE, published in late September 2018, followed in October by ASPREE and ASCEND.
• ARRIVE. This double-blind study conducted in seven countries included 12,546 patients deemed at moderate cardiovascular risk, with an estimated 10-year cardiovascular event risk of 17%. Eligibility was restricted to men aged 55 and up and women aged 60 or older. After a median follow-up of 5 years, there was no difference between patients assigned to enteric-coated aspirin at 100 mg/day versus placebo in the incidence of major adverse cardiovascular events, with a hazard ratio of 0.96. However, GI bleeding events were 2.1-fold more common in the aspirin group (Lancet. 2018 Sep 22;392[10152]:1036-46).

• ASPREE. This double-blind trial, conducted in Australia and the United States, included 19,114 community-dwelling participants aged 70 years or older, or 65 years or older for Hispanics and blacks in the United States. After a median 4.7 years of follow-up, there was no difference in major adverse cardiovascular events between subjects randomized to 100 mg/day of enteric-coated aspirin and those on placebo. So, as in ARRIVE, no benefit. However, the rate of major hemorrhage was 38% greater in the aspirin group (N Engl J Med. 2018 Oct 18;379[16]:1509-18).
Moreover, the rate of all-cause mortality was 14% greater in the aspirin group, a statistically significant difference, compared with controls. Drilling down, the investigators showed that the major contributor to this excess mortality in the aspirin group was their 31% greater rate of cancer-related death (N Engl J Med. 2018 Oct 18;379[16]:1519-28).
“Remember, we used to think that taking aspirin reduced the incidence of GI cancer, and, in particular, colon adenocarcinoma? Well, here’s a very startling observation in 19,114 healthy elderly patients showing an increase in cancer-associated death with the use of aspirin,” commented Dr. O’Gara.

• ASCEND. This study randomized 15,480 subjects with diabetes but no known cardiovascular disease to 100 mg/day of aspirin or placebo and followed them for a mean of 7.4 years. There was a significant 12% relative risk reduction in the composite endpoint of serious vascular events in the aspirin group; however, the aspirin-treated patients also had a 29% greater rate of major bleeding events (N Engl J Med. 2018 Oct 18;379[16]:1529-39).

“So in dealing with our diabetic patients, we could perhaps say there is a small reduction in the risk of cardiovascular outcomes that is overwhelmed by more than a factor of two with regard to an increase in the risk of bleeding,” the cardiologist observed.
How did physicians get the aspirin story for primary prevention so wrong for so long? Dr. O’Gara pointed to the Physicians’ Health Study, conducted mainly back in the 1970s, as one of the benchmark studies that led to the widespread use of aspirin in this way.

“I think the aspirin story has now been put into sharp focus just within the course of the last 6 months and should force all of us to reassess what it is that we advise patients,” he concluded.
Dr. O’Gara’s presentation was the talk of the meeting, as many attendees hadn’t yet caught up with the latest aspirin data.

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During an Q&A session, Robert A. Vogel, MD, a preventive cardiology authority at the University of Colorado, Denver, was asked, given the new emphasis placed upon coronary artery calcium as a supplemental risk assessment tool in the latest guidelines, at what magnitude of coronary artery calcium score in a patient with no history of coronary disease he would give aspirin for secondary prevention.
“I know I don’t know the answer to that question,” Dr. Vogel replied. “I no longer reflexively give aspirin to, say, a 60-year-old with a calcium score of 200. I will give a statin. Statins in my book are so effective and safe that my threshold for giving a statin in a 60-year-old is virtually nothing. But with a calcium score of 2,000 or 5,000, I worry just like you worry.”

He noted that the primary prevention patients in the three recent major trials were mostly 60-70 years of age or older. It’s safe to assume that by that point in life many of them had silent atherosclerosis and would have had a non-zero coronary artery calcium score, had they been tested. And yet, aspirin didn’t provide any net benefit in those groups, unlike the drug’s rock-solid proven value in patients who have actually experienced a cardiovascular event.
Dr. O’Gara reported receiving funding from the National Heart, Lung and Blood Institute, the National Institute of Dental and Craniofacial Research, from Medtronic in conjunction with the ongoing pivotal APOLLO transcatheter mitral valve replacement trial, and from Edwards Lifesciences for the ongoing EARLY TAVR trial.

bjancin@mdedge.com

This article was updated 1/31/19.