Given the bleeding seen in the study, US guidelines that have been open to using aspirin in this setting need to be revisited, one expert says.

MUNICH, Germany (UPDATED)—Aspirin reduces serious vascular events when used for primary CV prevention in patients with diabetes, but the cost in terms of major bleeding appears to be too high to support its use in that setting, findings from the ASCEND trial suggest.

Over a mean follow-up of 7.4 years, serious vascular events occurred in 8.5% of aspirin-treated patients and 9.6% of placebo-treated patients (rate ratio 0.88; 95% CI 0.79-0.97). At the same time, however, aspirin treatment raised the risk of major bleeding (4.1% vs 3.2%; rate ratio 1.29; 95% CI 1.09-1.52), Jane Armitage (University of Oxford, England) reported here at the European Society of Cardiology (ESC) Congress 2018.

The findings, published simultaneously online in the New England Journal of Medicine, show that there was no group of patients in which the benefits clearly outweighed the risks, Armitage said at a press conference. She pointed out, too, that aspirin did not reduce the risk of any type of cancer during the study period, contrary to analyses of older aspirin trials.

“When we looked at the balance of benefits versus risks we see that the absolute benefits from avoiding serious vascular events were largely counterbalanced by the increased risk of bleeding,” Armitage concluded.

Most of the 15,480 patients in the trial had their other cardiovascular risk factors well managed, with high rates of statin and antihypertensive treatment, good glycemic control, and a low rate of smoking, Armitage said.

“One of the messages from this trial is that these people can be very well treated and their event rate can come down,” she said. “But for these diabetic patients, we could show no added benefit of them taking aspirin in addition to their other medications.”

Serving as a discussant after Armitage’s presentation, Sigrun Halvorsen, MD, PhD (Oslo University Hospital, Norway), did not rule out the possibility that aspirin could be beneficial for primary prevention in some patients with diabetes.

“Based on the results of this largest study on aspirin in the primary prevention of CVD in diabetes, the mere presence of diabetes does not appear sufficient for aspirin to entail a benefit clearly exceeding the risk of bleeding,” she said. “However, most of the individuals in this study were of low risk. I would like to see more details on higher-risk individuals, both in this and in other trials, before excluding any role for ASA in primary prevention in diabetes.”

The results are sure to cause more waves in the United States than in Europe, because American guidelines have been more open to the idea of using aspirin for primary CV prevention in patients with diabetes. A 2011 update to the American Heart Association (AHA) guidelines for the prevention of CVD in women, for instance, says aspirin is reasonable in women with diabetes unless contraindicated. And a 2015 scientific statement on the prevention of CVD in adults with type 2 diabetes from the AHA and the American Diabetes Association says low-dose aspirin is reasonable in certain patients depending on their 10-year CVD risk and bleeding risk.

In contrast, the 2016 European guidelines on CVD prevention contain a class III recommendation against using antiplatelet therapy—including aspirin—in people with diabetes who do not have CVD.

AHA spokesperson Ileana Piña, MD (Montefiore Weiler Hospital, New York, NY), said the ASCEND findings should give pause to clinicians who have been using aspirin for primary CV prevention in their diabetic patients.

Piña is a co-author on the 2011 AHA guidance for women, and she told TCTMD, “We said that we didn’t have a lot of evidence in women, but we thought that these were patients at a high vascular risk. We need to go back and take a look at that again.”

Weighing Vascular Benefit and Bleeding Risk

The ASCEND trial was a 2x2 factorial trial that included patients 40 and older with diabetes and no evidence CVD at baseline. Patients were randomized both to enteric-coated aspirin 100 mg daily or placebo and to supplementation with 1-gram capsules of omega-3 fatty acids or placebo. Armitage reported the aspirin results, with the fish oil results revealed in a separate presentation at the meeting.

The mean age of the included patients was 63 years, and 63% were men. The vast majority of patients (94%) had type 2 diabetes.

Serious vascular events included MI, stroke/TIA, and vascular death, excluding intracranial hemorrhage, which was included in the major bleeding endpoint. Major bleeding also encompassed sight-threatening bleeding in the eye, GI bleeding, and other serious bleeding.

The observed reduction in serious vascular events in the aspirin arm was similar to that seen in a 2009 meta-analysis of aspirin for primary prevention from the Antithrombotic Trialists’ Collaboration, Armitage et al note in their paper, adding that ASCEND differs from the trials included in that analysis in that there was extensive use of cardioprotective treatments in ASCEND.

“Hence, the present trial provides a direct assessment of the balance of the benefits and hazards of aspirin use in a contemporary context,” they write, calculating that 91 patients would need to be treated to prevent one serious vascular event during follow-up and 112 would need to be treated to cause a major bleed.

Armitage presented an analysis of patients divided by 5-year risk of serious vascular events at baseline, showing that risks of both vascular events and major bleeding increase as baseline risk rises. At all levels of risk, major bleeding risk largely matches risk of vascular events, although Armitage acknowledged substantially uncertainty in the estimates.

Should These Patients Stop Taking Aspirin?

In a discussion at the press conference, Armitage said it is challenging to compare a major bleed with a vascular event.

“In general, there has been this feeling that vascular events—because they often can be disabling—are more important, but these are serious bleeds. And, of course, particularly among elderly patients, we know that people do die of serious gastrointestinal bleeds in particular,” she said. “But it is a dilemma and I don’t think we have any simple answer.”

Halvorsen agreed that a discussion should be had about whether vascular events and bleeding should be weighted equally. “Most major bleedings . . . were GI bleeds in this study and these can be largely prevented by [proton pump inhibitors], in contrast to death and strokes that are irreversible events,” she said.

Though it varies, a substantial number of patients with diabetes seem to be taking aspirin for primary CV prevention, with Armitage citing two studies showing proportions of 17% to 30%. She said rates are likely higher in the United States.

Asked whether these patients should stop taking aspirin, Armitage highlighted the role of shared decision-making.

“If you are well managed with diabetes [and] you’ve got your other risk factors under control, I think you need to consider very carefully whether or not for you the benefits of aspirin do outweigh the risks,” she said. “And I think that that’s a decision that will have to happen between patient and doctor.”

ASCEND is one of two large primary-prevention trials of daily aspirin presented at ESC 2018 today. The ARRIVE trial, conducted in more than 12,000 moderate-risk individuals (but excluding diabetes patients) found no benefit of aspirin for preventing major cardiovascular events in patients initially assessed as being at a 10-20% 10-year risk for CVD.