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.
ASCEND: Aspirin, fish oil flop in diabetes
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.
This article was updated 1/31/19.
