Delicate Balance: Aspirin Reduces Events, Increases Bleeding

Batya Swift Yasgur MA, LSW

June 13, 2019

Aspirin for primary prevention reduces nonfatal ischemic events but significantly increases nonfatal bleeding events, a new meta-analysis suggests.

Investigators analyzed 15 randomized controlled trials (RCTs), comparing approximately 83,000 patients taking aspirin with 82,000 control patients and found that aspirin and control were associated with similar rates of all-cause death, cardiovascular (CV) death, and non-CV death, but aspirin was associated with a lower risk for nonfatal myocardial infarction (MI) and transient ischemic attack (TIA).

In contrast, aspirin (especially at higher doses) was associated with a 32% relative increase in intracranial bleeding risk (including hemorrhagic stroke) and a more than 50% increase in the risk of major GI bleeding.

There were no differences between the aspirin and control groups in total cancer and cancer-related deaths during the study period.

"We analyzed 15 carefully selected RCTs, including over 165,000 participants, and based on a very careful analysis, we concluded that use of aspirin for primary prevention reduces nonfatal ischemic events but increases nonfatal bleeding events, some with quite major significance," senior author Jawahar Mehta, MD, PhD, Distinguished Professor of Medicine and Physiology and Biophysics and Stebbins Chair in Cardiology, University of Arkansas for Medical Sciences, Little Rock, told theheart.org | Medscape Cardiology.

"We came to a decision that the use of aspirin for primary prevention should be tailored to individual patients who are high risk of developing a cardiovascular event," he said.

The study was published online June 10 in the Journal of the American College of Cardiology.

Variable Findings

Aspirin for secondary prevention of MI, stroke, or TIA is well established, but the efficacy of aspirin for primary prevention varies among RCTs, creating "significant variability in societal guidelines," the authors state.

"Aspirin is commonly used for primary prevention for cardiovascular disease in a variety of subjects, but studies have shown that repeated use of aspirin may not be appropriate and may even be harmful," Mehta said.

To investigate the question, the researchers identified 9838 citations on the subject and narrowed their review to 15 studies comparing participants treated with aspirin to control subjects.

The included studies encompassed a total of 165,502 participants (n = 83,529; mean age, 61.6 ± 5.6 years; and n = 81,973; mean age, 61.5 ± 5.5 years, respectively). Included were findings from the recently reported ASPREE, ASCEND, and ARRIVE trials. "The current meta-analysis represents the largest and most contemporary examination of long-term outcomes with aspirin use for primary prevention of CVD," the authors note.

Study populations in the aspirin and control groups were "well balanced" for CV risk factors.

The main efficacy outcomes included all-cause death, CV death, MI, stroke, TIA, and major adverse CV events (MACE), and safety outcomes included major bleeding, intracranial bleeding, fatal bleeding, and major GI bleeding, with all outcomes analyzed by intention-to-treat (ITT).

The researchers also evaluated cancer incidence and cancer-related death.

Five trials were deemed at low risk and 10 at intermediate risk for bias; however, the body of evidence for outcomes reached a "level of high quality."

"Modest" Protection

Aspirin was associated with similar all-cause death (4.75% vs 4.82%; risk ratio [RR], 0.97; 95% CI, 0.93 - 1.01; P = .13; I2 = 0%) and non-CV death (3.3% vs 3.3%; RR, 0.98; 95% CI, 0.92 - 1.05; P = .53; I2 = 29%).

There was a "modest" reduction in CV death with aspirin, compared with the control group, but it was not considered to be statistically significant.

Aspirin use was associated with lower risk for total MI (2.07% vs 2.35%; RR, 0.85; 95% CI, 0.76 to 0.95; P = .003; I2 = 60%), which was driven by a lower risk of nonfatal MI in the aspirin group, compared with the control group (1.37% vs 1.62%; RR, 0.82; 95% CI, 0.72 - 0.94; P = .005; I2 = 58%).

The risks of fatal MI, angina pectoris, coronary revascularization, and symptomatic peripheral arterial disease were similar in both groups.

Total stroke rates, including fatal and nonfatal stroke, were likewise similar in the aspiring and control groups (1.82% vs 1.86%; RR, 0.97; 95% CI, 0.89 - 1.04; P = .37; I= 10%; RR, 1.03; 95% CI, 0.84 - 1.26; P = .81; and RR, 0.94; 95% CI, 0.85 - 1.02; P = 0.15, respectively).

By contrast, the risk for TIA was lower in the aspirin than in the control group (1.06% vs 1.33%; RR, 0.79; 95% CI, 0.71 - 0.89; < .001; I2 = 0%).

When the researchers conducted further analysis, they found a lower risk for ischemic stroke (1.29% vs 1.49%; RR, 0.87; 95% CI, 0.79 - 0.95; P = .002; I2 = 0%), but a trend toward a higher risk for hemorrhagic stroke (0.29% vs 0.23%; RR, 1.21; 95% CI, 0.99 - 1.47; P = .059; I2 = 0%) in the aspirin vs the control group.

Data from five RCTs showed a composite of nonfatal MI, nonfatal stroke, TIA, and CV death to be lower in the aspirin than the control group (3.86% vs 4.24%; RR, 0.903; 95% CI, 0.85 - 0.96; P = .001).

The authors note that the NNTs to prevent one event of MI, nonfatal MI, TIA, and ischemic stroke were 357, 400, 370, and 500, respectively.

Risk/Benefit Conversation

Major bleeding events were significantly higher in the aspirin than in the control group (1.47% vs 1.02%; RR, 1.50; 95% CI, 1.33 - 1.69; < .001; I2 = 25%).

In particular, aspirin was associated with more intracranial bleeding than control, including hemorrhagic stroke (0.42% vs 0.32%; RR, 1.32; 95% CI, 1.12 - 1.55; P = .001; I2 = 0%), and with more major GI bleeding (0.80% vs 0.54%; RR, 1.52; 95% CI, 1.34 - 1.73; P < .001; I2 = 0%).

However, rates of fatal bleeding were similar in the two groups (0.23% vs 0.19%; RR, 1.09; 95% CI, 0.78 -c1.55; P = .6; I2 = 0%).

Aspirin was also associated with increased risk for GI ulcers, compared with the control group (RR, 1.37; 95% CI, 1.07 - 1.76; P = .013; I2 = 80%).

Cancer incidence and cancer-related deaths were similar in both groups at a mean follow-up of 6.46 years.

A meta-regression analysis found female sex to be associated with a favorable treatment effect on total stroke (P = .046).

Secondary analyses revealed that aspirin may reduce all-cause death after 5 years of follow-up, and that the trend toward lower risk for CV death with aspirin is observed only in populations with high estimated 10-year ASCVD risk.

Secondary analyses also showed that the lower risk for total and nonfatal stroke with aspirin use was found only with low-dose aspirin.

Physicians considering using aspirin for primary prevention "should discuss the small benefits and significant bleeding risks with the patient," Mehta commented.

Additionally, when aspirin is used for primary prevention, he said, "it should be given in a dose of less than 100 mg/day."

Unequal Disability

Commenting on the study for theheart.org | Medscape Cardiology, Michael Pignone, MD, MPH, professor and chair, Department of Internal Medicine, and assistant dean for veterans affairs, Dell Medical School, Austin, Texas, said that the "provider needs to obtain the information to assess CVD risk and risk of [GI] bleeding in patients in the potentially eligible age range."

Pignone, who was not involved with the study, noted that this only applies to primary prevention, as patients with known CVD are at high risk.

Moreover, "if the patient has moderate or greater CVD risk — meaning a 10-year risk over 10% after other therapies have been applied — and is not at increased bleeding risk (under age 70 and no history of GI bleeding or other strong risk factors for bleeding), then discuss aspirin prevention with the patient," said Pignone, who is the author of an accompanying editorial.

"At this point, the main deciding factors are the patient's tolerance for risk in both ways — risk of causing and adverse bleeding event and risk of not preventing a CVD event — and how they feel about the hassle of taking another pill daily," he said.

Also commenting on the study for theheart.org | Medscape Cardiology, Brian Sliver, MD, interim chair and professor of neurology, UMass Memorial Medical Center University, Massachusetts Medical School, Boston, said the size of the study is "substantial, with more than 160,000 [patients] included" and "adds to the literature with the addition of more studies in the meta-analyses."

Silver, who was not involved with the study, said that he views the results as "mixed and not compelling to initiate aspirin for primary prevention."

However, he noted, "one statistic that is not calculable from the available data is disability related to the outcome event."

For example, "one intracranial hemorrhage could be more disabling than a minor MI, so the two events cannot be necessarily considered as equal."

"If there was a way to measure the impact on function, that would be most helpful in the decision analysis," Silver noted.

The authors conclude that "these findings suggest that the decision to use aspirin for primary prevention should be tailored to the individual patient, based on estimated ASCVD risk and perceived bleeding risk, as well as patient preferences regarding types of event prevented, versus potential bleeding caused."

Mehta has served as consultant to Bayer, Boehringer Ingelheim, AstraZeneca, MedImmmune, and Pfizer; and has received grant support from Bayer, Boehringer Ingelheim, AstraZeneca, and the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development. The other authors' disclosures are listed on the original paper. No disclosures listed for Pignone. Silver discloses no competing interests.

J Am Coll Cardiol. Published online June 10, 2019. Abstract, Editorial

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