ASCEND: Aspirin Not Needed for Primary Prevention in Diabetes

August 27, 2018

MUNICH — The benefit of aspirin on reducing vascular events did not outweigh the increased risk for serious bleeding in a new large primary prevention trial in patients with diabetes.  

In the ASCEND trial, aspirin significantly reduced the risk for serious vascular events by 12% but also significantly increased the risk for major bleeding by 29%. No effect on gastrointestinal or any other cancer was seen.

"I think we now have to consider very carefully whether aspirin is necessary," concluded co-lead investigator, Jane Armitage, MD, professor of clinical trials and epidemiology and honorary consultant in public health medicine at the University of Oxford, United Kingdom.

"In our trial, patients generally had good control of blood sugar, blood pressure and cholesterol and a high percentage of nonsmokers, so under these circumstances I would say that aspirin is not needed," she concluded.

Armitage presented the trial here at the European Society of Cardiology (ESC) 2018 Congress. It was also published simultaneously in the New England Journal of Medicine (NEJM)

As background, Armitage noted that aspirin is well established as beneficial in secondary prevention of heart disease and it is fairly well accepted not to be beneficial for general primary prevention, but diabetic patients represent a high-risk primary prevention group and its effect on this population is uncertain. She said European guidelines currently suggest that aspirin may be considered on an individual basis for primary prevention in diabetic patients and the US guidelines encourage its use a little more strongly.

Commenting on the study for theheart.org | Medscape Cardiology, Ileana L. Piña, MD, MPH, professor of medicine and associate chief of cardiology at Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York City, and a spokesperson for the American Heart Association, said, "ASCEND was a very nicely done trial.  It gives us pause to look at the guidelines again."

ASCEND

The ASCEND trial involved 15,480 UK patients with diabetes aged 40 years or older (average, 63 years) with no baseline cardiovascular disease. They were randomly assigned to aspirin 100 mg daily or placebo and followed for an average 7.4 years.  

After some crossovers, the difference in antiplatelet use between the two groups at the end of the study was 69%.

The primary efficacy outcome was the first serious vascular event (myocardial infarction, stroke or transient ischemic attack, or death from any vascular cause, excluding any confirmed intracranial hemorrhage). The primary safety outcome was the first major bleeding event (intracranial hemorrhage, sight-threatening bleeding event in the eye, gastrointestinal bleeding, or other serious bleeding).

Results showed that the aspirin group experienced significantly fewer serious vascular events but significantly more major bleeding events.

Table. ASCEND: Aspirin Results 

Endpoint Aspirin (%) Placebo (%) Rate Ratio (95% Confidence Interval) P Value
Serious vascular events 8.5 9.6 0.88 (0.79 - 0.97) .01
Major bleeding 4.1 3.2 1.29 (1.09 - 1.52) .003

 

Overall, 91 patients would need to be treated to avoid a serious vascular event over a period of 7.4 years, and 112 to cause a major bleeding event, Armitage reported.

Some cardiologists believe there may still be a place for aspirin in certain primary prevention patients with diabetes. 

Discussant of the study at the ESC Hotline session, Sigrun Halvorsen, MD, University of Oslo, Norway, pointed out that the average cardiovascular risk of patients in this study (1.3% per year) was lower than anticipated and that only 17% of the population was considered high risk. 

"I would like to see more data in this high- risk population before totally excluding any role for aspirin in primary prevention," she said.

Professor Manel Sabate, Hospital Clinic, Barcelona, Spain, told theheart.org | Medscape Cardiology that diabetic patients encompass a broad spectrum of disease.

"We have to try to individualize which patient may benefit from aspirin," he said. "Maybe we have to create scores to identify patients at high risk of bleeding and those at high risk of vascular events. Those at higher risk of vascular events include those with a longer history of diabetes, those not well controlled (HbA1c [hemoglobin A1c] levels > 8) and those with microvascular complications, which may indicate the heart is more at risk. I would still consider aspirin for these patients."

However, Armitage reported that similar balances of benefits and risks were seen in all the various subgroups investigated, including patients at low, intermediate, and high risk for heart disease. 

"There is no group where the benefit clearly outweighed the risk," she stated.

Co-chair of the ESC press conference on ASCEND, François Schiele, MD, University of Franche-Comté, Besançon, France, challenged Armitage as to whether a major bleed was equivalent to a serious vascular event. "I myself would rather have a major bleed as these are usually treatable whereas a major vascular event normally has permanent consequences" he said.

Armitage replied, "We haven't specifically done that analysis, and, yes, there is a feeling that a vascular event is more important than a bleed, but our bleeding endpoint was serious bleeds — serious enough to put people in hospital — and people can die from these serious bleeds. But, yes, this is a dilemma."

"What we've been able to do in this trial is count the bleeding very carefully, and we clearly show that bleeding increased with vascular risk and this needs to be more appreciated than it has in the past," she added. 

In the NEJM paper, the researchers point out that approximately half the excess of bleeding was in the gastrointestinal (GI) tract, with approximately one third in the upper GI tract, but that less than a quarter of participants were receiving proton-pump inhibitors (PPIs). They add: "It is possible that bleeding rates among aspirin users might be lower if PPIs were routinely used in these persons."

What About Cancer Risk?

Because previous studies have suggested that aspirin may be associated with a reduced risk for cancer — in particular, GI tract cancer — the ASCEND researchers also looked at this.  But results showed no significant difference between the aspirin and placebo groups in the incidence of GI  tract cancer (2.0% vs 2.0%), or all cancers (11.6% vs 11.5%).  

"Previous observational studies and meta-analyses of selected randomized trials have suggested a reduced risk of GI cancer with aspirin but the observational studies have not been able to adjust for all confounding," Armitage said. "And the meta-analyses have only included selected trials. We have 7.5 years of follow-up, and we found no evidence of a reduction in the incidence of GI cancer or of cancer at any other site, even during the later years of follow-up. However, there were not enough cancer cases to obtain reliable power, so longer-term follow-up for these outcomes is planned."

ASCEND was a 2 x 2 factorial study that also investigated the effect of fish oil on vascular events in diabetic patients and found no benefit.

The ASCEND trial was supported by grants to the University of Oxford from the Medical Research Council, Cancer Research UK, British Heart Foundation, Bayer, Solvay, Abbott, and Mylan. Armitage reports grants from Medical Research Council, Cancer Research UK, British Heart Foundation, Bayer, Solvay and Abbott and Mylan during the conduct of the study.

European Society of Cardiology (ESC) 2018 Congress. Presented August 26, 2018.

N Engl J Med. Published online August 26, 2018. Abstract

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