At Last: Megatrial To Compare Secondary-Prevention ASA Dosages

Deborah Brauser

May 07, 2015

DURHAM, NC — There's little scientific rhyme or reason to the daily aspirin dosages commonly used in secondary prevention, but that could change in the near future as plans get under way for a 3-year prospective randomized trial with a planned enrollment estimated at 20,000 patients with cardiovascular disease. The megatrial comparing a standard aspirin tablet with a "baby aspirin" daily will be led by the hardened clinical trial specialists at Duke University[1].

The independent, nonprofit Patient-Centered Outcomes Research Institute (PCORI) announced approval this week of $14 million to fund the new multisite study, which will be called Aspirin Dosing: A Patient-centric Trial Assessing Benefits and Long-term Effectiveness (ADAPTABLE). Its aim is to determine whether daily use of standard 325-mg aspirin or of 81-mg ("baby") aspirin is more effective in reducing death and hospitalization from MI or stroke in 20,000 patients with atherosclerotic CVD.It will not be assessing which dose may be more effective in primary prevention.

"I think as a field, we've been advocating for larger, simpler clinical trials to answer important questions," co–principal investigator Dr Matthew T Roe (Duke Clinical Research Institute, Durham, NC) told heartwire from Medscape, noting they hope to start patient recruitment before the end of the year.

"We feel this has the potential for a major health impact and could open up a vast array of future studies," added co–PI and Duke colleague Dr Adrian F Hernandez.

When asked for comment, Dr Steven R Steinhubl (Scripps Translational Science Institute, La Jolla, CA) said the study is exciting and looks to be "a perfect use of this kind of resource" in regard to PCORI.

"This isn't a tiny trial with a surrogate end point. It's a really well-powered, large, meaningful trial. When it's done, for the first time ever, we'll be able to definitively say 'this is the right dose,' " said Steinhubl, who is not involved with the research.

Long-Standing Questions

Although aspirin has been commonly used for decades by people with heart disease to ward off MI and stroke, the question of dosing has come up time and again.

It's kind of remarkable to still not know what the right dose is.

Past studies have shown a link between higher doses and increased risk of gastrointestinal bleeding. However, research has also been unclear as to whether the lower dose is safer and/or as effective in this patient population—all of which are issues the current investigators hope to clear up.

"I think US practice is more dominated by concerns about stent-related complications, and that is perhaps why high doses of aspirin are being used. At least that's my theory," said Roe. "However, there's also quite a wide variety in practices and hospitals."

Steinhubl noted that the question about dosing for primary prevention is also "surprisingly unclear" as well as controversial. However, "in secondary prevention we know it's beneficial. So if we purely want to answer the dosing question, then that's the perfect population to assess."

Still, "325 mg is a totally made-up dose because in the 1900s it happened to be what stuck well together into a pill that Bayer could patent. It had nothing to do with its antiplatelet effect," he said, adding that some of the earliest studies examined doses as low as 30 mg a day. "But because 325 mg is considered adult-strength aspirin, it became commonly used. And many cardiologists have used it mostly out of habit."

He pointed out that "even the baby aspirin was just arbitrarily a quarter of the adult aspirin" and said that both doses preceded identification of aspirin as an antiplatelet agent by 50 to 60 years. "We're now using it as an antiplatelet but at doses that happen to be conveniently available in the United States, and not based on what's best for the patient, because it's never been well-studied," said Steinhubl. "It's kind of remarkable to still not know what the right dose is."

First Study of Its Kind

ADAPTABLE will be the first study conducted through PCORI's national Patient-Centered Clinical Research Network (PCORnet), which was established "to conduct much-needed health-outcome studies more quickly and efficiently, less expensively, and with greater potential impact than is now possible," notes the organization, which was authorized by Congress in 2010.

"There is a definite need for pragmatic clinical trials in our society, which PCORnet has been set up to do," said Roe, noting that the National Institutes of Health (NIH) does not have the infrastructure in place for a large-scale sharing of data from electronic health records, like PCORnet has, to facilitate the conduct of a trial like ADAPTABLE. And "pharmaceutical companies want to run trials around their products and not around the process itself," he added.

Six clinical data networks from PCORnet will contribute researchers, clinicians, and patients from Chicago, Kansas City, New Orleans, Nashville, Pittsburgh, and New York City. The goal is to randomly assign 20,000 patients to receive 81 or 325 mg daily of aspirin and to follow them for 30 months to assess risks and benefits.

All participants will have significant coronary artery blockage or have experienced a past MI. Subgroup analysis will examine patients with and without chronic kidney disease and diabetes.

"It's estimated that identifying the dosage of aspirin that works best for these patients could prevent as many as 88,800 deaths worldwide each year," notes PCORI.

"Hopefully, 81 mg will show itself to be at least as effective as an antithrombotic agent and much safer," added Steinhubl. "But no matter what the results are, for the first time ever we're going to have a really excellent study to definitively answer these questions. It could turn out that the doses are equivalent, and all the other stuff is speculation, but at least we'll have an answer. And that's tremendous."

A full list of financial disclosures for all Duke CRI faculty can be found on the organization's website. Steinhubl reports no relevant financial relationships.

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