Clonal hematopoiesis of indeterminate potential (CHIP) did not appear to raise the risk for cardiovascular disease in older healthy adults treated with low-dose aspirin, but it was associated with an increased risk for bleeding, according to results of a substudy of the ASPREE trial.

The prespecified substudy of the double-blind, randomized trial was published in JAMA Cardiology.

“CHIP is associated with a higher risk of cardiovascular disease; however, primary prevention strategies to modify this risk are yet to be identified,” Zoe K. McQuilten, MBBS, PhD, from the School of Public Health and Preventive Medicine at Monash University in Melbourne, Australia, told Medscape Medical News. “Aspirin is a widely used therapy for secondary cardiovascular prevention but is not recommended for routine use in older adults for primary prevention as the risk of bleeding outweighs the benefits.”

As a result, McQuilten said this substudy aimed to clarify whether older adults with CHIP, who may represent a higher cardiovascular risk group, were more likely to benefit from aspirin for primary prevention than individuals without CHIP.

The trial took place at primary and community care facilities in the US and Australia.

The researchers randomly assigned participants to 100 mg aspirin daily or placebo and measured CHIP from blood specimens collected at trial entry.

Major adverse cardiovascular events included fatal and nonfatal ischemic stroke, nonfatal myocardial infarction and coronary heart disease death, and clinically significant bleeding.

Of the 9434 total participants (median age, 73.7 years; 54% women) who provided a sample at baseline, 23% had CHIP at variant allele fraction (VAF) of at least 2%, including 5.6% or participants with ≥ 10% VAF.

Not the Risk Factor We Thought It Was

Results showed that CHIP did not raise the risk for major adverse cardiovascular events at 2% to 10% VAF (adjusted hazard ratio [HR], 0.84; 95%CI, 0.68-1.03; P = .09) or 10% VAF or greater (adjusted HR, 0.80; 95%CI, 0.57-1.12; P = .19).

“The lack of association between CHIP and cardiovascular disease likely reflects the nature of the ASPREE cohort, who were healthy older individuals, aged older than 70 years in our substudy, and free of life-limiting disease at the time of entry into the study,” McQuilten explained. “This lower risk of cardiovascular disease likely explains the lack of benefit of aspirin.”

However, CHIP did increase the risk for clinically significant bleeding at 2%-10% VAF (adjusted HR, 1.24; 95% CI, 1.02-1.51; P = .03) and at ≥ 10% VAF (adjusted HR, 1.21; 95% CI, 0.85-1.73; P = .28).

“This increased risk of bleeding was irrespective of aspirin use,” McQuilten said. “Therefore, despite the higher baseline risk of bleeding in those with CHIP, aspirin can still be recommended in those with CHIP for other evidence-based indications, such as secondary prevention of cardiovascular disease.”

Aspirin also did not have an effect on the individual components of the composite major adverse cardiovascular events endpoint.

According to John W. McEvoy, MBBCh, BAO, MEd, MHS, PhD, established professor of preventive cardiology at the University of Galway, Galway, Ireland, the authors failed to detect an association between CHIP and cardiovascular disease, despite CHIP being touted as a novel blood-based biomarker of risk for heart disease and stroke.

“Thus, the main takeaway is that CHIP may not be the cardiovascular disease risk factor we thought it was,” McEvoy said.

A Call for More Robust Evaluation

In an accompanying editorial, Nicholas Chiu, MD, MPH, and Peter Libby, MD, both from Brigham and Women’s Hospital, Harvard Medical School, Boston, cautioned against overinterpreting subgroup signals, especially when they arise from a study null for its primary endpoint.

“The bleeding signal among CHIP carriers reported here should stimulate validation in subsequent studies and spur mechanistic studies to scrutinize its potential biological underpinnings,” Chiu and Libby wrote. “For now, the question of aspirin for primary prevention in JAK2 CHIP requires more robust evaluation — potentially via individual patient data meta-analyses to achieve adequate statistical power to study this rarer, though potentially more hazardous CHIP variant.”

“More broadly,” they continued, “although rife with challenges, the field must push beyond observational associations and post hoc analyses toward prospective interventional studies. At present, CHIP remains a risk factor in search of a roadmap — a diagnostic label without a clear therapeutic path forward. The red flag highlighted in this ASPREE substudy underscores the urgent need for more data to guide our management of CHIP, a newly recognized age-related cardiovascular risk factor bound to affect more of our patients in the future.”

McEvoy agreed that more data are necessary, noting that the study serves to motivate the need for more research on CHIP as a risk factor for cardiovascular disease in older adults before measurement of this biomarker should be considered by clinicians in their practice.

“The fact that the authors found CHIP to be associated with bleeding will, I think, not result in the measurement of CHIP being used in clinical practice to assess bleeding risk because there is likely significant residual confounding by age,” he said.

McQuilten reported receiving grants from the National Health and Medical Research Council during the conduct of the study. Chiu and McEvoy reported no relevant conflicts of interest. Libby reported being an unpaid consultant and scientific advisory board member for Baim Institute and Novartis; an unpaid consultant for Amgen, Beren Therapeutics, Esperion Therapeutics, Genentech, Kancera, Kowa Pharmaceuticals, Novo Nordisk, and Sanofi-Regeneron; scientific advisory board member for Abcentra, Caristo Diagnostics, CSL Behring, Elucid Bioimaging, Olatec Therapeutics, PlaqueTec, Polygon Therapeutics, TenSixteen Bio, Soley Therapeutics, and XBiotech Inc.; having a patent for use of IL-1 beta binding antibodies pending, a patent for treatment of brain ischemia-reperfusion injury pending, and a patent for use of canakinumab pending; on the board of directors of Abcentra; having a financial interest in XBiotech, TenSixteen Bio, Soley Therapeutics, and Abcentra; receiving funding support from the National Heart, Lung, and Blood Institute and RRM Charitable Fund; and receiving research funding to his laboratory in the last 2 years from Novartis, Novo Nordisk, and Genentech.

Brian Ellis is a freelance writer and editor who lives in Southwest Virginia.