When researchers ask an important question, randomize people into a placebo-controlled trial, and collect and report results, society wins—regardless of the findings.
One of the core problems with clinical science is that "positive" studies earn more praise than neutral studies. This is silly because knowing what does not work is as vital as knowing what does work.
Now let's talk aspirin (ASA) to prevent cardiac events in people without heart disease. Two major trials presented at the European Society of Cardiology (ESC) Congress 2018 inform this decision. Since millions of people take ASA in hopes of improving health, this is big news.
The Trials
In ASCEND,[1] more then 15,000 middle-aged patients with diabetes but no evident heart disease were randomized to 100 mg of ASA or placebo. In ARRIVE,[2] more than 12,500 adults with (presumed) moderate risk but no evident heart disease were randomized to 100 mg of ASA or placebo. Both studies used composite primary endpoints of major cardiac events and safety endpoints of bleeding.
I spoke with the principal investigators (PIs), Jane Armitage from Oxford University, United Kingdom (ASCEND), and J. Michael Gaziano (ARRIVE) from Brigham and Women's Hospital, Boston, Massachusetts.
Ten Take-Away Lessons
1. There have been oodles of ASA studies. Why do more?
Both PIs explained that there is a knowledge deficit for ASA use in patients at moderate risk. Numerous studies have confirmed ASA's benefit after a cardiac event or intervention—secondary prevention. Fewer studies have addressed primary prevention, and those that did so have included patients at super-low risk. ASCEND and ARRIVE aimed to address the role of ASA for primary prevention in patients with higher cardiac risk. This is a vital question because more and more patients are living with risk factors and moderate risk.
2. The top-line results were neutral.
In ARRIVE, the intention-to-treat analysis showed no reduction of events with ASA. In ASCEND, the authors came to a "no net benefit" conclusion for ASA because its reduction in cardiac events (about 1.1%) was countered by bleeding events (0.9%).
3. Both trials confirmed the biological effect of ASA on reduction of cardiac events.
In ASCEND, during an average of 7.4 years of follow-up, ASA reduced the primary endpoint by 12% in relative terms and 1.1% in absolute terms. These findings met statistical significance.
The ARRIVE trial was more complex. During an average of 5 years of follow-up, in the intention-to-treat analysis, ASA did not reduce events. Gaziano told me that because of the pragmatic nature of ARRIVE, there were many dropins (controls who started taking ASA) and dropouts (active arm patients who stopped taking ASA). When analyzed according to who actually took ASA, also known as the per protocol analysis, MI rates were significantly reduced, and the 19% relative reduction in the composite primary endpoint nearly met statistical significance (P = .07).
4. Both trials confirmed the biological effect of ASA on bleeding.
In ASCEND, ASA increased the rate of major bleeding by 29% in relative terms and 0.9% in absolute terms. Most bleeding was from the gastrointestinal (GI) tract. In ARRIVE, ASA doubled the rate of GI bleeding in relative terms but by only 0.5% in absolute terms.
5. ASA did not influence severe events.
In both trials, ASA had no effect on overall mortality, nor did it increase fatal bleeding.
6. Cardiac event rates in ARRIVE were lower than expected.
In ARRIVE, the observed rate of cardiac events was only one third of what was expected (550 vs 1488 events). Although the authors tried to enroll higher-risk patients, including only those with multiple risk factors, the cohort ended up being a low-risk group.
7. Risk calculators overestimate event rates in western societies.
Both Gaziano and Armitage told me that secular trends and increased use of preventive therapies are decreasing cardiac event rates. By secular trends, they mean that societal efforts, such as lower rates of smoking and removal of trans-fats from the food supply, have led to a heart-healthier environment. In addition, greater use of preventive therapies—statins and antihypertensive meds, for instance—have also contributed to lower rates of cardiac disease. These developments increase the difficulty of running trials for primary prevention but are decidedly good news for patients.
Gaziano did make the distinction that calculators that use typical risk factors may be more accurate in societies with increasing rates of heart disease, such as China.
8. Diabetes is a different disease these days.
Armitage told me that in the past, the big fear with diabetes was cardiovascular complications. But in ASCEND, far more deaths resulted from nonvascular causes (61% vs 39%). This, too, is good news, and is likely due to societal trends and better risk factor management.
9. No weight-based effects of ASA were seen.
A recent post hoc analysis[3] of primary prevention ASA trials provocatively found that low doses of aspirin (75 to 100 mg) were effective only in patients weighing less than 70 kg and had no benefit in the 80% of men and nearly 50% of all women weighing 70 kg or more (about 154 lbs).
Neither ASCEND nor ARRIVE found any heterogeneous treatment effect based on weight. Gaziano noted that almost 80% of the ARRIVE participants had a body mass index greater than 25 kg/m2. He said they plan further analyses based on weight. In ASCEND, the trend actually went in the opposite direction: ASA produced a lower rate of events in those heavier than 70 kg. Armitage sternly warned that we should be "very cautious" in the interpretation of post hoc studies.
10. ASA had no effects on cancer prevention.
In the discussion section of ASCEND, the authors cited multiple meta-analyses of low-dose ASA that suggest a possible reduction in GI cancer with long-term use. And the US Preventive Services Task Force concludes with moderate certainty that the net benefit of aspirin use to decrease colorectal cancer incidence in adults age 50 to 59 years is moderate.
The ASCEND trial found no difference in the rate of GI cancer. Gaziano told me they saw no cancer prevention signal in ARRIVE. Both trialists warned that if ASA prevents cancer, the effects would appear after 10 years of use, which is longer than the average follow-up of either study.
Conclusion
When I asked Armitage what she would recommend to a middle-aged patient with diabetes, she responded that rather than take ASA, it would be better to work hard on risk factor modification. Gaziano echoed the message from their concluding paragraph and said ASA use remains a decision that should involve a thoughtful discussion between a clinician and a patient. His feeling was that avoiding a cardiac event was worth the risk of having a GI bleed.
For now, I am closer to Armitage's view: A thoughtful look at ASA use in patients with these risk profiles shows little benefit and little harm. Since people don't have endless reserves of effort, it seems wiser to emphasize more important matters, such as maintaining an ideal weight, seeking physical fitness, taking blood pressure medications, and not smoking.
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Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.
Cite this: John M. Mandrola. Ten Things I Learned About Aspirin at ESC - Medscape - Aug 28, 2018.
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