COMMENTARY

Aspirin in Primary Prevention: Lessons From ARRIVE

Interviewer: John M. Mandrola, MD; Interviewee: J. Michael Gaziano, MD, MPH

Disclosures

August 28, 2018

John M. Mandrola, MD: Hi, everyone. This is John Mandrola from theheart.org | Medscape Cardiology. I'm here at the European Society of Cardiology meeting in Munich, Germany. I'm pleased to welcome Dr Mike Gaziano from the Brigham and Women's Hospital, who is primary investigator of the ARRIVE trial,[1] studying aspirin for primary prevention. Welcome.

J. Michael Gaziano, MD, MPH: Nice to be here.

Mandrola: Can you tell us about the topline results of this trial?

Gaziano: I sure can. We did a trial of aspirin in the current era among individuals at moderate risk. We did not find a reduction overall in major cardiovascular events. We found bleeding rates that were very low, but there was a twofold increased risk of bleeding. However, what we found (which is what others have seen) is that in the subgroup of individuals who were compliant, the biology of aspirin works. We found an almost halving of the risk for myocardial infarction in a secondary analysis.

Mandrola: Excellent. Tell us why this study and the ASCEND trial[2] were done.

Gaziano: There are three trials about to release results, two of them here at this meeting. The ARRIVE trial and the ASCEND trial were done because there was a gap in knowledge. We have a large number of trials in people who have acute events like heart attacks or acute procedures like stents; in long-term secondary prevention, people with vascular disease. We also have a few trials in individuals who haven't had first events, but those tended to be in very healthy people at low risk.

At least in the United States, the area where we recommend that patients might be benefiting from aspirin is those at moderate risk, but there weren't any trials in that area. We set out to do a trial in people who were at moderate risk, based on a collection of risk factors. ASCEND chose people at moderate risk because they had diabetes, and the ASPREE trial [yet to be presented] is a study in people over 70, also at a higher-than-average risk.

Mandrola: The risk in between? Not low risk and not super high risk?

Gaziano: Exactly.

Mandrola: Tell us: You mentioned in the topline results about this no benefit or no difference in intention-to-treat (ITT) analysis, but there is a biological effect if you look at people who actually take aspirin. My people in electrophysiology go crazy about the difference between ITT and as-treated analysis.

Gaziano: I think we have to be very cautious; we would not draw definite conclusions from an as-treated analysis. Remember, there are over 400 trials of aspirin and we need to understand both biology and the practical aspects of a trial. We set out to do a trial in individuals who were at moderate risk, and by all of our estimations, they were at higher risk than in the other studies. The previous studies were low risk because individuals started off with very few risk factors. In this study, we included men over 55 with two or more risk factors and women over 60 with three or more risk factors. They had an estimated risk of—about a 14% chance of having a heart attack or a 17% chance of having a CVD event.

However, during the study, their observed risk was much lower. Why was that? It was because we treated their blood pressure aggressively. Two thirds of them were getting blood pressure treatment, half of them were getting lipid-lowering treatment. In addition, people were going on aspirin during the study. If you developed chest pain or stable angina, that wasn't an endpoint, and you were potentially put on aspirin. The first issue was that we had far fewer events. We expected to have almost 1500 events and we got 550.

Mandrola: That's remarkable.

Gaziano: That's good news for the patients. We had far fewer events than we would have predicted. In this situation, people were taking aspirin in the background. It's one thing when you're studying a drug that's a new, investigational drug, where it's not possible to get it. When you drop out of the study, you're dropping out. But with a common drug like aspirin, we had drop-ins, and they tended to be the higher-risk patients.

The other thing is that we have some context. In this case, the per-protocol analysis tells us, at least biologically, that aspirin doesn't work any differently in the high-risk and the low-risk patients, which we wouldn't expect. It's more difficult to show an effect in the modern era when we're doing all of these other things (including aspirin) in the background.

Mandrola: Like you said, it's good news because these were patients who had high risk; you expected them to have more events and you only got a third of the events, perhaps because of this background therapy.

Gaziano: Exactly.

Mandrola: You made slightly different conclusions in your paper than the ASCEND authors made in theirs about aspirin's net benefit. Can you talk about that?

Gaziano: Yes. There were a couple of differences. First was that we had far more cardiovascular events, about 550. Our major safety was gastrointestinal bleeding because we had included hemorrhagic stroke in our stroke outcomes; it was included in the composite. There wasn't really any imbalance in hemorrhagic stroke: There were 11 in the placebo group and eight in the aspirin group. Our bleeding rate was much lower than what they saw in the ASCEND trial.

I think, in general, that the pooled analysis is really the way to get the best estimate for how much benefit you're going to get for aspirin in terms of cardiovascular disease (and we have to even consider cancer these days), and the best estimate for the impact on bleeding.

We chose not to do a risk-benefit comparison in our study for those reasons. The other issue is that we tend to trade these off, one against another. Personally, I think many others might not value a heart attack or a debilitating stroke the same way you might a nonfatal GI bleed. The vast majority of bleeds that we saw in our study were mild and there was no difference in fatal events. We ultimately had six severe GI bleeding events.

Mandrola: When I read ASCEND, they basically said there is a real benefit to aspirin, but there's a harm from bleeding, and they said it's not effective for primary prevention.

Gaziano: Yes, I think that's where we are today. I think the nice thing about ASCEND was that it shows, again, the biology of aspirin in a diabetic population. Even in the current era, the participants in ASCEND were also getting statins and blood pressures medication, and I assume, to some degree, perhaps some aspirin in the background, though it might have been a little bit less because it was a UK study. The biology of aspirin works the same; it prevents cardiovascular events and it causes bleeding. I still think the answer is, how do you balance those in any particular patient?

Mandrola: I want to ask you about the prediction of events in the modern era. We have a lot of talk about these pooled cohort equations where we say, "You're this amount of risk." Your study, which shows fewer events than expected, throws a wrench in that, doesn't it?

Gaziano: I think it's good news. I would say it's good news that rates are falling for good reason. All three legs of the stool are in play here. There are secular trends that are happening, that happen in the population at large; there are treatments like aggressive treatment of blood pressure and cholesterol risk factors; and then there's treatment on the backend. People are getting to the hospital and not dying of events, etc. That's really good news in parts of the world.

These risk calculators seem to overestimate the risk that's at least part of the equation. It makes it hard for a trialist but it's good news for the public. That may not be the same everywhere around the world. I've had some good discussions with people doing the same kinds of risk calculations in a place like China, where coronary heart disease and stroke rates are rising and where there isn't as widespread treatment.

Mandrola: Another question about this recent meta-analysis[3] is about the heterogeneous treatment effect of aspirin based on body mass index, showing that it's more effective in smaller people than in larger people. What did you find in your study and what do you think?

Gaziano: I was a coauthor on that paper in the Lancet, and those kinds of exploratory analyses are good to generate some new hypotheses that need to be further explored in other studies. Can we add some information from ASCEND and from ARRIVE in that regard? Unfortunately, because we chose people with high risk, the vast majority of our subjects were in the overweight category; the median BMI was 28.5. The same thing occurred in the ASCEND trial, so unfortunately I think the number of individuals in the lower weight category (< 70 kg or 154 lb) are going to be limited.

Mandrola: Too few patients that are thin, to say?

Gaziano: Yes. Whether we're going to be able to add meaningful information to that analysis remains to be seen. We certainly are going to look more carefully. Most of what we know about dose doesn't come from in-study comparison; it's actually comparing across studies. Fortunately, there is a study that is in the United States that is looking at two doses. ADAPTABLE is a study that's looking at two doses of aspirin. As long as they have sufficient people in various weight strata, I think that will be a better study to tell us whether dose really does modify the effect, within study comparison.

Mandrola: Final question. I want to ask you about this whole business about cancer prevention with low-dose aspirin. There are some data from ARRIVE and ASCEND on that.

Gaziano: Right. ARRIVE and ASCEND looked at cancer outcomes within the study. Like many of the primary and secondary prevention trials, there wasn't an effect within the study. The aspirin effect appears to emerge maybe about a decade after the start of treatment and even after people have stopped the treatment. It seems to have a long latent period. Primary prevention studies that have the capacity to look longer—that's where the best data will come.

It's a fairly consistent finding, so much so that the US Preventive Task Force thinks—and I agree with them—that when you're sitting down with a patient, which is the best way to make the decision about who should be on aspirin, that cancer is an important consideration. The potential long-term benefits in reducing colorectal cancer should be considered alongside the potential shorter intermediate gains of prevention of cardiovascular events and weighed against the shorter-term bleeding risk, which, actually in most trials, seems to go down over time.

Mandrola: Thank you so much for joining us. It's been a great conversation.

Gaziano: It was my pleasure.

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