Resources

  1. Gaziano JMet al. Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE) Lancet. 2018 Sep 22;392(10152):1036-1046 (PubMed)
  2. ASCEND Study Collaborative Group. Effects of Aspirin for Primary Prevention in Persons with Diabetes Mellitus. N Engl J Med. 2018 Aug 26 (early online)
  3. McNeil JJ et al. Effect of Aspirin on Disability-free Survival in the Healthy Elderly (ASPREE). Send to N Engl J Med. 2018 Sep 16 (early online)











Transcript

Dr. Frank Domino:

Several patients have been asking about whether they should be taking aspirin. There have been a bunch of articles in the newspaper recently and many patients are starting to question if this is worthwhile. Bill is your typical 62-year-old male. He has hypertension and diabetes, both are well-controlled in medication. He has never had a heart attack or stroke, he stays fit, exercising several times a week. The question is, should Bill take aspirin?

Hi, this is Frank Domino, Professor in the Department of Family Medicine and Community Health at the University of Massachusetts Medical School, and joining me today is Alan Ehrlich, Associate Professor in the Department of Family Medicine and Community Health at the University of Massachusetts Medical School and Executive Editor for DynaMed. Alan, thanks for coming to talk about aspirin.

Alan Ehrlich:

Thanks, Frank.

Dr. Domino:

So, can you tell us a little bit about aspirin for primary prevention and secondary prevention and what do those terms actually mean?

Alan Ehrlich:

Well, it's important to distinguish between primary and secondary prevention when thinking about the use of aspirin. For primary prevention we're trying to prevent some type of event in the first place. And so, in this case we're typically talking about cardiovascular disease, although aspirin has been used to try and prevent cancers, notably colorectal cancer, but for cardiovascular disease we know risk factors like hypertension and diabetes and elevated cholesterol all contribute to your chances of having a heart attack or a stroke and we modify those risk factors to try and prevent that in the first place and that's primary prevention, and aspirin can be used in that role.

If you've already had a heart attack or a stroke and we're trying to prevent recurrence or further morbidity, now you're talking about secondary prevention, and aspirin has a very clear role for secondary prevention. The benefit in people who've already had a heart attack for taking aspirin is clear and that is really distinguished. It's almost an order of magnitude difference how much benefit you get, at least based on the previously published data.

Dr. Domino:

So, Alan, thanks for that. The news has been full of information about a variety of trials, can you take them one at a time and lead us through what they tell us?

Alan Ehrlich:

Sure. There were three major trials that were published in big journals, Lancet, New England Journal, that looked at aspirin for primary prevention in different populations. Probably the most notable one was ASPREE trial. And in this trial they randomized about 19,000 healthy community dwelling adults, primarily over the age of 70 in Australia and the United States; although in the US they did enroll some people starting at 65 who were either Black or Hispanic. All these patients were presumably healthy, they were without any known cardiovascular disease, dementia or any type of disability and they were randomized to aspirin, 100 milligrams orally once a day versus placebo. They were looking at disability-free survival as their primary outcome and what they found was that in the patients who took aspirin, the all-cause mortality was actually slightly higher. This was, obviously, quite a surprise. They also did a post-hoc analysis; this was to look at why was it higher. And, in this case, they found it was driven by an increase in cancer deaths, including a higher rate of colorectal cancer death.

Dr. Domino:

So, just to be clear, the aspirin group had a higher rate of cancer deaths and colorectal cancer deaths? I thought aspirin was supposed to be protective about colorectal cancer?

Alan Ehrlich:

There were two other trials that are worth noting, one was the ARRIVE trial. It randomized 12,500 adults who were over the age of 55 for men and over 60 for women, who had moderate cardiovascular risk. This was on the basis of a 10-year risk of coronary heart disease, between 10% and 20% and that would meet the criteria that we typically use for who should be getting statins, who should be getting aspirin. They were randomized again to 100 milligrams of aspirin once a day versus placebo and the primary outcome here was the time to first occurrence of cardiovascular death, myocardial infarction, unstable angina, stroke or TIA. There was no difference in that primary outcome and there was an increase in the risk of GI bleeding by about half a percent. Finally, there was the ASCEND trial, and the ASCEND trial was looking specifically at patients with diabetes who were over the age of 40 who had no known atherosclerotic cardiovascular disease. They randomized about 15,000 patients to aspirin versus placebo, again using the 100 milligram dose. And there was also a secondary part of the trial that was looking at marine n-3 three fatty acids.

Comparing aspirin to placebo for serious vascular events, there was a slight benefit favoring the aspirin, but this was driven primarily by lower rates of TIA. And if you think about it, TIAs aren't permanent damage, they get better anyhow, and then this was offset by, again, an increase in major bleeding of about 1%. So, you have three trials that show either no or very limited benefit in populations that are very typical for who we normally would treat with aspirin, and these were all large trials, each of them had more than 10,000 patients. So it's really a bit of an eye-opener.

Dr. Domino:

So it sounds like the only group that may have had a benefit were those over the age of 40 with diabetes and that benefit was just a reduction in TIAs. Outside of that we increased the rates of bleeding, including intra-cerebral and GI bleeding, and may have increased the risk of cancer.

Alan Ehrlich:

Yeah. I think, again, that cancer death is probably the most questionable of the outcomes, but certainly there's no question aspirin will increase your rates of bleeding, and so, any benefit needs to offset that by a substantial margin.

Dr. Domino:

Alan, what do we do? We have these three trials that are very telling and we have a US Preventive Services Task Force guideline that's somewhat different. How do you rectify this?

Alan Ehrlich:

So, the USPS Task Force gives aspirin for primary prevention a grade B for patients who are 50 to 59 years old and a grade C for 60 to 69. And they focus on the two outcomes of preventing cardiovascular disease and prevention of colorectal cancer. For patients who are less than 50 and over 70, they give an I or insufficient recommendation, and so that would certainly apply to the ASPREE trial where they were looking at the elderly patients and that would tend to reinforce the sense that it probably doesn't help patients in that age group. I think for the younger age group you need to really look at what is the risk of cardiovascular disease that you're trying to offset. And in the ASPREE trial, what happened was the actual rates of cardiovascular disease were less than they had anticipated. And so, the authors had speculated well, maybe if you have more risk it might have some benefit, but again, that's just speculation. So, I think we need to be able to have a talk with our patients about the value of aspirin and what is more important to them, potentially preventing cardiovascular events or increasing your risk of bleeding?

Dr. Domino:

Well, thank you, Alan. This was a complex set of studies, they made national news and they stood in contrast to current guidelines. So, I really appreciate you coming today and helping us figure out how to help our friend Bill. Practice pointer, when considering aspirin for primary prevention of cardiovascular outcomes, recognize there is limited data about its efficacy and possibly worse data about its harm. Have an informed consent discussion with your patients on how best to prevent cardiovascular outcomes in adults. Join us next time when we discuss the role of alcohol consumption on nocturnal leg cramps in seniors.