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ASCEND: Aspirin, omega-3 supplements fail for primary prevention in diabetes
MUNICH — In a large cohort of patients with diabetes but no prior CVD, aspirin prevented vascular events but caused major bleeding events, and an omega-3 fatty acid supplement did not prevent vascular events, researchers from the ASCEND study reported at the European Society of Cardiology Congress.
The researchers randomly assigned 15,480 patients with diabetes and no CVD history (mean age, 63 years; 63% men) to receive aspirin 100 mg per day or placebo, and to receive 1 g per day of omega-3 fatty acids or olive oil placebo. Mean follow-up was 7.4 years. The findings were presented at the European Society of Cardiology Congress and published simultaneously in The New England Journal of Medicine.
Aspirin study
During follow-up, the primary outcome of serious vascular events — defined as MI, ischemic stroke, transient ischemic attack or CV death excluding any intracranial hemorrhage — occurred in 8.5% of the aspirin group vs. 9.6% of the placebo group (rate ratio = 0.88; 95% CI, 0.79-0.97), according to data presented here.
However, major bleeding events — defined as intracranial hemorrhage, sight-threatening bleeding in the eye, gastrointestinal bleeding or other serious bleeding — were more common with aspirin treatment, at 4.1% in the aspirin group vs. 3.2% in the placebo group (rate ratio = 1.29; 95% CI, 1.09-1.52). According to the researchers, this finding was driven by GI bleeding and other extracranial bleeding.
“Aspirin did, as expected, reduce the risk of serious vascular events, but also, as expected, significantly increased the risk of major bleeding, by 29%,” Jane Armitage, FRCP, FFPH, from the Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, said in a press release. “And when we look at the balance of benefits vs. risks, the absolute benefit from avoiding serious adverse events were largely counterbalanced by the increased risk of bleeding. We were not able to identify any particular group for whom the benefits clearly outweigh the risks.”
GI tract cancer occurred in 2% of each group, while any cancer occurred at a similar rate (aspirin group 11.6%; placebo group, 11.5%).
“There was no suggestion that aspirin reduced the risk of cancer,” Armitage said during the press conference.
Fatty acid study
“ASCEND is the largest and longest-duration of omega-3 fatty acid supplements ever,” Louise Bowman, MD, from the Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, said in the press release. “In this study, we demonstrated no effect on the primary outcome of serious vascular events and no effect on cancer or total all-cause mortality.”
During the study period, the primary outcome of serious vascular events occurred in 8.9% of the fatty acid group vs. 9.2% of the placebo group (rate ratio = 0.97; 95% CI, 0.87-1.05), according to the researchers.
The key secondary outcome of first serious vascular event or any arterial revascularization occurred in 11.4% of the fatty acid group vs. 11.5% of the placebo group (rate ratio = 1; 95% CI, 0.91-1.09).
There was also no difference between the groups in all-cause death (fatty acid group, 9.7%; placebo group, 10.2%; rate ratio = 0.95; 95% CI, 0.86-1.05) or in nonfatal serious adverse events.
The adherence rate was 76%.
“Overall, our results suggest that current guideline recommendations should perhaps be reconsidered in terms of omega-3 fatty acid supplements,” Bowman said during the press conference.
The 1-g dose was chosen “based on earlier studies that showed promise of the 1-g dose,” she said. “It seemed the sensible approach, given that is what was being recommended. But the question does remain, would a higher dose have been effective?” – by Erik Swain
References:
Armitage J, et al.
Bowman L, et al. Hot Line Session 2. Both presented at: European Society of Cardiology Congress; Aug. 25-29, 2018; Munich.
The ASCEND Study Collaborative Group. N Engl J Med. 2018;doi:10.1056/NEJMoa1804988.
The ASCEND Study Collaborative Group. N Engl J Med. 2018;doi:10.1056/NEJMoa1804989.
Disclosures: The study was supported in part by Abbott, Bayer, Mylan and Solvay. Armitage reports she has past or present research contracts with Bayer, Merck, Mylan and The Medicines Company. Bowman reports she received grants and/or nonfinancial support from Abbott, Bayer, Bayer Schering Pharma, Mylan and Solvay. Please see the study for a list of the other authors’ relevant financial disclosures.
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There has been a debate about the value of aspirin as a prophylactic agent since I was an intern, which was a long time ago. Although aspirin seems to work very well in patients who have disease, its prophylactic value has been jumbled.
ASCEND is a well-designed randomized prospective trial. The aspirin was purely preventative, but the population was at higher risk because they had diabetes. How I interpret the findings is that you trade a lower incidence of ischemic events for a higher incidence of bleeding. This raises all kinds of questions. If I say to one of my patients, would you rather have an MI or a GI bleed, they would probably take the GI bleed. But people tend to equate these two, despite infarctions being more likely to be fatal. I don’t think they’re exactly equal. In the authors’ analysis, the number needed to treat to receive benefit was smaller than the number needed to treat to have harm. It would be an easier decision if this were all GI bleeding. But I worry about intracranial bleeding. Those were very small, but not zero.
The bottom line is that there is no role for aspirin as a prophylactic agent that has been documented at this point in time. But given the fact that most people would trade bleeding, which is usually treatable, for a reduction in major ischemic events, I tend to risk-stratify patients. If they are diabetic with no other risk factors, I probably go easy. If they are diabetic with risk for bleeding, then there is no way I would prescribe aspirin. But if they are diabetic and without risk for bleeding but have other risk factors such as hypertension, smoking or family history, I will tell them I will give them aspirin and it will reduce their risk for MI, and if it causes bleeding we will deal with it.
The omega-3 fatty acid portion was also well-done. The primary endpoint was negative. Frankly, I stopped recommending omega-3 fatty acids for my patients a number of years ago based on other negative trials. This is yet another negative trial in a higher-risk group of patients than usually studied. The 1-g dose may have been too small. People who take these supplements usually take 2 to 4 g per day. These are not very expensive, but they’re not cheap, especially for those using pharmaceutical-grade supplements. And then you get expensive urine.
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Even though the trial was done with very good intentions, and it studied diabetic patients supposedly at high risk, the overall event rate was low, which was surprising. I don’t know of any diabetes prospective trial that has had that kind of event rate. That tells me there may have been some selection bias. Most patients had a low or moderate vascular risk score. You get what you select for.
Omega-3 fatty acids have never been convincingly proven to reduce risk on top of statins. In this study, 70% of patients were on statins. So it is not entirely surprising that no benefit was found on top of statins.
Another problem with the trial is that the dose of omega-3 fatty acids was low at 1 g per day. Most of the trials being conducted now are with a dose of 3 to 4 g per day. It’s purely speculation, but we may have seen different results if the dose were higher. These days, most clinicians who prescribe omega-3 fatty acids prescribe 2 to 4 g per day. Of course, this study was started a long time ago, and hindsight is 20/20. We have learned so much more since the study began.
The aspirin portion of the trial provides some exciting data. I was pleased to see that aspirin does reduce the vascular event rate, but it is counterbalanced by the bleeding risk. We have many ways of balancing the risks against the benefits. Also of note, there are data from Germany showing that enteric-coated aspirin does not provide as good antiplatelet efficacy in diabetic patients. Extended-release aspirin may be a different story.
I don’t think these results will change guidelines. We have never recommended omega-3 fatty acids for diabetic patients, and that will continue until there are convincing data otherwise. This does provide further data that aspirin provides benefit in diabetic patients, which we have been saying all along.
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ASCEND was a well-done study with 12,000 patients. The investigators did a terrific job of conducting a pragmatic trial. We are not as good at these in the U.S. They were able to have pretty complete datasets using electronic records that talk to each other, which we in the U.S. do not have.
I have a lot of patients who tell me that they want to take omega-3 fatty acid supplements, and I tell them to eat fish; it tastes better. When I see diabetic women with HF, they do not do well, and I tell them not to spend the money on supplements, and to eat fish at least three times per week. It’s part of the Mediterranean diet. If they eat fish, then maybe they are not eating steak or fatty foods. The total substitution in their diet may help.
I will be talking to the American Heart Association guideline committee about looking into this issue. This is a well-done randomized trial that meets our criteria for inclusion in guidelines.