Experts Debate Aspirin for Primary Prevention in Type 2 Diabetes

"Aspirin should be reserved for secondary prevention in type 2 diabetes" was the title of a debate at the International Diabetes Federation's 2021 virtual meeting.

The use of daily low-dose aspirin for secondary cardiovascular prevention in people with type 2 diabetes who have had a previous myocardial infarction (MI) or stroke is supported by multiple studies and strongly endorsed by professional societies. The American Diabetes Association (ADA), for example, earlier this year recommended 75-162 mg/day aspirin for that indication.

More controversial is the use of aspirin for primary cardiovascular prevention in patients with no previous cardiovascular events.

For such individuals, ADA says that such use "may be considered" among those who are at increased cardiovascular risk "after a comprehensive discussion with the patient on the benefits versus the comparable increased risk of bleeding."

And the 2019 joint guidelines by the European Society of Cardiology (ESC) and European Association for the Study of Diabetes (EASD) recommend that 75-100 mg/day of aspirin "may be considered" for primary prevention in the absence of clear contraindications in people with type 2 diabetes at high or very high cardiovascular risk, but not in those at moderate risk.

And ESC/EASD advises that when low-dose aspirin is used, proton pump inhibitors (PPIs) be considered to prevent gastrointestinal bleeding, one of the most common side effects of aspirin.

And more recently, draft guidance from the US Preventive Services Task Force (USPSTF) suggests that aspirin for primary prevention is not helpful and should be avoided, at least in people over 60, as reported by Medscape Medical News. Younger age groups got a grade C recommendation, meaning that the decision to take or not take aspirin should be individualized with the understanding that the net benefit is small.

At the IDF debate on December 9, the "yes" argument for only reserving aspirin as secondary prevention for people with diabetes was made by Jane Armitage, MD, professor of clinical trials and epidemiology and honorary consultant in health and medicine at the University of Oxford, UK.

She led the 2018 ASCEND trial, which showed that aspirin reduced the risk for serious vascular events by 12% but also increased the risk for major bleeding by 29%. That trial informed both US and European guidelines.

Taking the opposing view was Bianca Rocca, MD, PhD, associate professor of pharmacology at the Catholic University School of Medicine in Rome, Italy. Rocca is an author of the ESC/EASD guidelines.

Her arguments were based on evidence showing that aspirin has a clear additive benefit beyond that of statins and antihypertensive therapy in preventing a first heart attack in people at intermediate-high cardiovascular risk, that the safety estimate in trials is influenced by the definition used for major bleeding, and that the gastrointestinal (GI) bleeding risk can be mitigated with drugs.

Aspirin Should Be Reserved for Secondary Cardiovascular Prevention

Armitage began by noting that cardiovascular risk has fallen substantially in recent years in developed countries due to the widespread use of statins and antihypertensive medications.

"These can halve cardiovascular risk safely in healthy people, and therefore should be the primary things to consider when you want to reduce cardiovascular risk," she noted.

In contrast, "aspirin is not an entirely safe drug because it increases the risk of bleeding. So, if we add such treatments to otherwise well people...the risk of harm must be very small and the benefits must be much larger than the harms."

In addition to ASCEND, there have been six more primary prevention trials of aspirin in the modern statin/antihypertensive era that have enrolled people at intermediate cardiovascular risk, as opposed to healthier people in earlier trials. Of these, ASCEND was the only one to show clear and statistically significant reductions in vascular events, she pointed out.

A 2019 meta-analysis of those seven trials plus six older ones, which randomized 164,225 participants, of whom 19% had diabetes, found an 11% reduction in ischemic event risk.

But that benefit was counterbalanced by a 43% increased risk in major bleeding and a 56% greater risk in major GI bleeding. Those translated to a 5 per 10,000 person-year reduction in serious vascular events, but a 6-7 per 10,000 person-year increase in the risk of major bleeding.

But of course, these estimates depend on background event rates, age, and baseline disease.

"The key question is whether or not we can find a sort of sweet spot to find the people in whom the benefits of aspirin might substantially outweigh the risks. But at the moment, we're not in a position to do that," Armitage said.

Another more detailed meta-analysis is currently being conducted by the Antithrombotic Trialists' Collaboration to shed more light on the issue, she noted.

Complicating the benefit versus risk calculation further, Armitage said, is evidence from a 2009 meta-analysis of the earlier aspirin primary prevention trials that show the risk factors for both cardiovascular events and for bleeding are similar, including male sex, diabetes, smoking, and 20-mmHg higher blood pressure.

"We are well familiar with the increased risk of cardiovascular events in our diabetic patients, but perhaps a little less familiar with the fact that our diabetic patients are also at increased risk of major GI bleeding...This is the difficulty that we face, and I would make a very strong argument that, at the moment, aspirin use should be confined to people in secondary prevention and not primary prevention," Armitage concluded.

Aspirin Safe for High-Risk Patients to Reduce First Event Risk

Rocca began by noting that diabetes significantly increases the risk of a first major atherothromboembolic event by approximately twofold compared to those without diabetes, even with current therapies. "So, the problem is, how can we safety prevent the first serious vascular event in each individual patient with type 2 diabetes?"

She pointed to a recent individual patient data meta-analysis of 18,162 intermediate-to-high-risk subjects, including about 40% with diabetes, randomized to fixed-dose combinations of a statin plus two or more antihypertensive drugs versus controls (placebo or usual care) with or without aspirin added to the mix.

The aspirin added significant benefit compared to the fixed-dose combination alone, with a risk reduction of 47% for the primary endpoint of time to first occurrence of a composite of cardiovascular death, MI, stroke, or arterial revascularization, and a 5-year number needed to treat of 37 with the combination including aspirin.

In this case, there was no significant increased bleeding risk with aspirin. There was a slight increase in GI bleeding, from 0.2% to 0.4%, but it wasn't significant with a 5-year number needed to harm of 554, Rocca noted.

Rocca called the ASCEND trial "a great contribution to understanding whether aspirin is worthwhile using in primary prevention," noting that about 75% of participants were taking statins and 60% were taking antihypertensive drugs, so it was "a well-controlled population."

In fact, she noted, in ASCEND there were no increased risks for intracranial hemorrhage, fatal hemorrhages, or sight-threatening eye bleeding with aspirin use. The overall 0.9% absolute increase in major bleeding was mostly driven by serious GI bleeding.

The bleeding classification used in ASCEND was the five-level system derived by the Bleeding Academic Research Consortium (BARC), whereas trials that led to the approval of ticagrelor and others have used the much simpler three-level thrombosis in myocardial infarction (TIMI) definition of "major," "minor," and "minimal" bleeding, she explained.

A 2019 study found that use of the BARC definition led to a more than threefold increase in the number of bleedings classified as "major" when applied to a large trial comparing antithrombotic medications.

Rocca also pointed out that GI bleeding is preventable. In a large randomized, placebo-controlled trial, use of the PPI pantoprazole reduced gastrointestinal bleeding in patients receiving low-dose anticoagulation and/or aspirin for stable cardiovascular disease, with no evidence of cardiovascular harm.

"These may further optimize the efficacy to safety balance of giving aspirin in primary prevention in addition to secondary prevention," she said.

Finally, she also pointed to the relevance of patient preference. A 2017 article suggesting that "minor" or "minimal" bleeding might be perceived by patients as having a lower impact than an MI, ischemic stroke, or transient ischemic attack.

Armitage's institution has a staff policy of not accepting personal payments from industry. She was the principal investigator of ASCEND, which was sponsored by the University of Oxford and funded by the British Heart Foundation and the UK Medical Research Council. Drug and packaging costs were provided by Bayer, Solvay, Abbott, and Mylan. Rocca has received speaker fees from SOBI, conducted an investigator-initiated study for Bayer AG (on rivaroxaban), and has a grant from the Italian Medicine Agency for an investigator-initiated phase 2 trial on low-dose aspirin.

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape, with other work appearing in The Washington Post, NPR's Shots blog, and Diabetes Forecast magazine. She is on Twitter: @MiriamETucker.

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