Daily aspirin for primary prevention of heart disease is a practice under scrutiny. Based on the new 2019 ACC/AHA CVD prevention guidelines, is this patient a candidate?
Mr. Campbell is 57-years-old and presents to your clinic for routine annual follow-up. He has a history of hypothyroidism and hyperlipidemia and is currently taking levothyroxine; he is asymptomatic. He admits to smoking about 5 cigarettes daily and drinks 1-2 glasses of wine daily.
His physical exam is notable for obesity (BMI 31) with central adiposity; he is in no distress. He works as a manager at an office payroll company and doesn’t pursue regular cardiovascular exercise. He was adopted so family history is unknown.
Results of most recent relevant laboratory studies
He asks you many questions about his risk factors for “a heart attack” and how he can modify these. In particular, he wants to know if he should start taking a daily aspirin to “protect his heart.”
Question. What do you advise him about the role of aspirin in primary prevention of atherosclerotic cardiovascular disease (ASCVD)?
A. Low-dose (81 mg) aspirin may be considered for primary prevention of ASCVD in select adults aged 40-70 years who are not at increased bleeding risk.
B. Low-dose aspirin is recommended routinely for primary prevention of ASCVD in all male adults age >55 years and women age >60 years, unless the bleeding risk is very high.
C. Low-dose but not regular-strength (325 mg) aspirin, can be reasonable to use for primary prevention in an adult who has had a prior bleeding episode.
D. Low-dose aspirin should be used routinely in the primary prevention of ASCVD in select adults aged 40-70 years who are not at increased bleeding risk.
Answer: A. Low-dose (81 mg) aspirin may be considered for primary prevention of ASCVD in select adults aged 40-70 years who are not at increased bleeding risk.
Low-dose aspirin (75-100 mg) has been used routinely in the past for the prevention of ASCVD and works by irreversibly inhibiting platelet function and preventing atherothrombosis. Although aspirin was commonly used in men aged >55 years and women aged >65 years who were at low bleeding risk, the practice is no longer recommended based on the recently updated 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease.1
Multiple recent studies, including 3 pivotal randomized controlled trials (ARRIVE2, ASPREE3, ASCEND4 ) published in the New England Journal of Medicine and Lancet, have demonstrated lack of net clinical benefit of aspirin in primary prevention. Therefore, it is now a Class IIb indication to consider aspirin for the primary prevention of ASCVD in select adults aged 40-70 years who are not at increased bleeding risk1(option A) but routine use in all adults is not recommended1(option C).
Mr Campbell is a current smoker and has a calculated 10-year ASCVD risk score of 16.8% (moderate) and is determined not to be at increased bleeding risk, so aspirin 81 mg daily would be a reasonable option to lower his ASCVD risk. However, given the observed increased risk for bleeding, the option should be discucssed with the patient in the context of the absence of net clinical benefit.
Aspirin should not be used routinely in adults aged >70 years (Class III) or in adults who are at increased bleeding risk (Class III). Aspirin should continue to be prescribed in all adults for secondary prevention (ie, patients with established cardiovascular disease, prior stroke, myocardial infarction [MI], coronary artery bypass grafting [CABG], peripheral arterial disease [PAD]). In these patients, the benefit outweighs the risk.1
Mr Campbell is curious about the trials that were conducted on use of aspirin and how the results might affect him. Of the 3 trials you mentioned that have shaped revisions to the ACC/AHA ASCVD prevention guidelines, the ARRIVE2 trial is the most relevant to him.
You recall that >12 000 men aged at least 55 years and women aged ≥60 years, all with average CV risk and no prior bleeding events or diabetes, were randomized to 100 mg aspirin or placebo daily and followed up for a median of 5 years for primary prevention (moderate CV risk). The ARRIVE primary composite endpoint was time to first occurrence of CV death, MI, unstable angina, stroke, or transient ischemic attack.2
Question: What do you explain to Mr Campbell as the main findings of the ARRIVE trial?
A. Serious adverse events were higher in the placebo group than the aspirin group.
B. Gastrointestinal (GI) bleeding occurred more frequently in the aspirin group than in the placebo group.
C. The incidence of serious adverse events was higher with placebo compared to aspirin.
D. The overall event rate was higher than expected.
Answer: B. GI bleeding in ARRIVE occurred more in the aspirin group than in the placebo group.2
In the ARRIVE trial, GI bleeding events (mostly mild) occurred in 0.97% of patients in the aspirin group versus 0.46% in the placebo group.2 The overall incidence rate of serious adverse events as well as of adverse events was similar in both treatment groups (see Table for expanded results). There was no significant reduction in the rate of the primary endpoint seen in the aspirin vs the placebo groups.2 The overall event rate in ARRIVE was actually quite low. The authors speculate that the result may reflect the success of current CV prevention strategies which, in turn, suggests that the ARRIVE cohort was actually more of a low-risk population.2
Mr. Campbell then asks your advice about whether his older brother, 72-years-old, should be taking aspirin. He says he’s pretty healthy and not taking any other medication-but, he’s 72.
You try to tell him that you would need to examine his brother and to make another appointment for his brother but he persists. Reluctantly, you try to remember the results of the ASPREE3 trial, which tested aspirin in primary prevention in individuals >70 years (or >65 years for Black/Hispanic).
Question: Which of the following were the conclusions of the ASPREE trial?
A. Low-dose aspirin increased cancer-related mortality.
B. Low-dose aspirin increased major bleeding.
C. Low dose aspirin did not result in fewer major adverse cardiovascular events (MACE).
D. None of the above.
E. All of the above.
Answer: E. All of the above
The ASPREE study randomized 19 114 healthy individuals with a median age of 74 years, 56% female and 11% with diabetes to receive either 100 mg of enteric coated aspirin or placebo daily.3 Among these healthy elderly patients, low-dose aspirin therapy was not beneficial in reducing disability-free survival or MACE after about 5 years but it did increase major bleeding, including intracranial and upper GI bleeding.3 (See Table for expanded results). There was also a relative increase in cancer deaths and overall deaths, with overall rates being low.
Finally, Mr Campbell asks you about his younger sister (55-years-old) who was diagnosed with type 2 diabetes about 3 years ago. Did any of the studies test aspirin for primary prevention of heart disease in diabetic patients?
You are now almost behind schedule but press on and tell him about ASCEND,4 which was a trial of aspirin 100 mg vs placebo in 15 480 patients with any type of diabetes and without CV disease, (primary prevention) followed for 7.4 years.
Question: What do you tell Mr Campbell about the results of the ACSCEND study?
A. That serious vascular events occurred in a significantly lower percentage of participants in the aspirin group than in the placebo group.
B. That major bleeding events occurred more often in the aspirin group, as compared with the placebo group.
C. Most of the bleeding events in the trial were GI and other extracranial bleeding.
D. There was no significant difference between the aspirin group and the placebo group in the incidence of GI tract cancer or all cancers.
E. None of the above.
F. All of the above.
Answer: F. All of the above
ASCEND investigators randomized a total of 15 480 participants (men and women aged ≥40 years) to either daily aspirin or placebo.4 During a mean follow-up of 7.4 years, serious vascular events occurred in a significantly lower percentage of participants in the aspirin group (8.5%) vs the placebo group (9.6%). In contrast, major bleeding events occurred in 4.1% of participants in the aspirin group, as compared with 3.2% in the placebo group, with most of the excess being GI and other extracranial bleeding.4 There was no significant difference between the aspirin group and the placebo group in the incidence of gastrointestinal tract cancer or all cancers; long-term follow-up for these outcomes is planned.4 (See Table for expanded results.)
Finally, Mr Campbell seems satisfied.After a discussion with him about the relative merits of daily aspirin it is agreed that he will begin taking 81 mg/day to reduce his risk of thromboembolic risk. You also counsel him on his own role in reducing his CV risk by modifying his current lifestyle, including quitting smoking, losing weight, eating less saturated fat, decreasing alcohol intake, and putting exercise in to his daily rountine.
Payal Kohli, MD, FACC, is a noninvasive cardiologist in clinical practice in Denver, Colo. Dr. Kohli graduated magna cum laude from Harvard Medical School, completed her residency in Internal Medicine at the Harvard Medical School/Brigham and Women’s Hospital in Boston, Mass, and completed her fellowship in cardiovascular disease at the University of California San Francisco. She also completed advanced fellowships in cardiovascular disease prevention and advanced echocardiography from UCSF. She has a special interest in the cardiovascular care of women but enjoys treating a variety of cardiovascular conditions.
1. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease. A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. Originally published https://doi.org/10.1161/CIR.0000000000000678
2. Gaziano JM, Brotons C, Coppolecchia R, et al, for the ARRIVE Executive Committee. 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;392(10152):1036-1046. doi: 10.1016/S0140-6736(18)31924-X.
3. McNeil JJ, Nelson MR, Woods RL, et al, on behalf of the ASPREE Investigator Group. Effect of aspiring on all-cause mortality in the healthy elderly. N Engl J Med 2018;379:1519-28.
4. The ASCEND Collaborative Study Group. Effects of aspirin for primary prevention in persons with diabetes mellitus. N Engl J Med 2018; 379:1529-1539.