ARRIVE, ASCEND and the Future of Aspirin

September 6, 2018

The future role of aspirin in primary prevention of cardiovascular disease is unclear, and not for lack of scrutiny at ESC 2018.

“An aspirin a day keeps the doctor away,” an age-old adage revised to support stroke prevention, may no longer be relevant in light of new data presented at the European Society of Cardiology (ESC) Scientific Congress 2018 in Munich, Germany. Of course we have known for some time-and data continue to support us-that aspirin is highly effective in secondary prevention of cardiovascular disease (ie, in patients who have already had an adverse vascular event). However, aspirin’s benefit in primary prevention is controversial and its use has generally been recommended for those who are considered at particularly high risk for CVD, such as patients with diabetes, smokers, or those with multiple CV risk factors. (There are also observational data that show a lower risk of colon cancer with aspirin therapy.)

Results of 2 large randomized controlled trials looking at the benefit of aspirin in primary prevention were presented at ESC: ASCEND (A study of cardiovascular events in diabetes ) and ARRIVE (Aspirin to reduce risk of initial vascular events. ASCEND assessed 15 480 persons with diabetes with no baseline cardiovascular disease whereas ARRIVE assessed 12 546 patients who had multiple cardiovascular risk factors and were deemed at “moderate cardiovascular risk.” Notably, ARRIVE excluded patients with diabetes and those at high risk for bleeding.

ASCEND trial design, baseline characteristics, primary outcomes and brief discussion are summarized as follows:

  - Design: 40+y with diabetes and no CV disease
  - Characteristics: mean age 63y, 63% male, 83% overweight, 62% with HTN, 25% on insulin
  - Randomized to: ASA 100 mg daily or placebo
  - Mean followup: 7.4y

  - Primary efficacy outcome: first serious vascular event (MI, CVA, TIA, death from vascular cause) excluding ICH.

      - Reduction in event rate of 1.1%, RR 0.88 (0.79 - 0.97), p=0.01. NNT = 91.

  - Primary safety outcome: 1st major bleeding event (ICH, GIB, bleeding in eye, other
serious bleeding

      - Increase in event rate of 0.9%, RR 1.29 (1.09 - 1.52), p=0.003.  NNH=128.

Next: ASCEND conclusions

ASCEND concluded that although aspirin reduced the rate of first serious vascular events, there was significantly more major bleeding that essentially cancelled out this benefit with the NNT and NNH. Note that there was some crossover so at the end of the study, the difference in medical therapy between the groups was 69%. 

Discussants of the trial at the meeting suggested that the study population may be substantially low risk because the majority had other CVD risk factors well managed (eg, high rates of statin and antihypertensive therapy, good glycemic control, low smoking rates) and were therefore perhaps not reflective of a high-risk primary prevention population that may benefit. The authors reported that there was no difference when data were examined by low-, intermediate-, and high-risk subgroups.

Discussants of the trial ... suggested that the study population may be substantially low risk because the majority had other CVD risk factors well managed...

Also discussed was the idea that vascular events and bleeding events should be “weighted” differently as vascular events are often irreversible whereas bleeding events can be reversed (although the severity of these events was argued to be similar). Of note, GI cancer (2.0% vs 2.0%) and all cancers (11.6% vs 11.5%) were no different between the groups, although event rates were low and the study was likely to have been underpowered. 

This study left us wondering about the balance between efficacy and safety with respect to starting aspirin in diabetic patients. Once this study (which was published in the NEJM) was presented, there was much anticipation of the ARRIVE trial, which targeted a population at higher risk of vascular events and without diabetes.

Next: ARRIVE

ARRIVE trial design, baseline characteristics, primary outcomes and brief discussion are summarized as follows:  - Design: men>55y and women >60y, excluded diabetes or high risk of bleeding
  - Characteristics: mean age 10-year risk of first acute CV event “moderate” (10% to 20%.
  - Randomized to: ASA 100 mg daily or placebo
  - Median FU: 5.0 y

  - Primary efficacy outcome: time to first occurrence of CVD, MI, UA, CVA, TIA; Intention to treat 4.3% (aspirin) vs 4.5% (placebo) HR 0.96 (0.81-1.13, p=0.603). 

     - Lower rate of MI with aspirin although difference was not statistically significant.

-Safety outcomes: GIB (0.97% vs. 0.46% (placebo), HR 2.11; 95% CI 1·36–3·28; p=0·0007 and serious adverse events (20.2% vs. 20.9% (placebo)).

Discussion about the ARRIVE results shared some of the thinking about ASCEND, as discussants commented on the neutral trial (which was thought to be due to the high rate of crossovers).  There was also a very low overall event rate, despite a “moderate risk” population in an era of highly effective primary preventive strategies which may have limited the power to detect differences.

Overall, the audience left ESC 2018 wondering what role, if any, remains for aspirin in primary prevention populations. While the negative results have some second-guessing the value of a drug used liberally for CVD prevention for 4 decades, experts point to a swing back toward more judicious practice and emphasize that there are still select populations that benefit from aspirin therapy and that patients need to be assessed on an individual case-by-case basis.

References:

 -  ASCEND Study Collaborative Group. Effects of aspirin for primary prevention in persons with diabetes mellitus. New Engl J Med. 2018;Epub ahead of print.

  - Gaziano JM, Brotons C, Coppolecchia R, et al. Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo-controlled trial. Lancet. 2018;Epub ahead of print.

  - Capodanno C, Angiolillo DJ. Aspirin for primary prevention of cardiovascular disease. Lancet. 2018;Epub ahead of print.