An intensive three-drug regimen of heart medications did not significantly impact the rate of serious cardiovascular events at five years in women who experienced signs and symptoms of ischemia, or insufficient blood flow to the heart muscle, but had no blockages in their heart's arteries, according to research presented at the American College of Cardiology's Annual Scientific Session (ACC.25).
Each year in the United States, an estimated 4 million to 5 million women visit hospitals and clinicians' offices reporting signs of reduced blood flow to the heart such as chest pain, shortness of breath and dizziness severe enough to undergo evaluation with coronary CT angiogram or invasive coronary angiography. About half of these women are found not to have obstructive coronary artery disease (CAD).
In this first large, randomized controlled trial in women without obstructive CAD, called WARRIOR, researchers compared intensive medical therapy versus usual care.
Obstructive CAD occurs when a buildup of plaque causes the heart's arteries to become narrowed or partially blocked. It is a primary driver of heart attacks, heart failure and other serious heart problems. However, even without obstructive CAD, people who experience signs and symptoms of ischemia can experience reduced quality of life and an increased risk of serious cardiac events. Several small studies have suggested these patients may benefit from heart medications like statins, low-dose aspirin and angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) drugs.
This condition is highly prevalent and is the common reason for an unplanned visit to a primary care provider or the emergency department among women. It represents an important societal burden in terms of cardiovascular outcomes, quality of life and health care costs and resources."
Carl J. Pepine, MD, professor of medicine at the University of Florida and study's principal investigator
The trial enrolled 2,476 women at 71 medical centers in the United States. The average age of participants was 60 years and almost 90% of participants were White. Most participants were post-menopausal, about half had obesity and most had other cardiovascular risk factors such as high blood pressure (hypertension), high low-density lipoprotein (LDL) cholesterol or a family history of CAD.
Patients were randomly assigned to receive intensive medical therapy, which consisted of a high-intensity statin, an ACE inhibitor or ARB at the maximally tolerated dose and low-dose aspirin. The other half received usual care, meaning that decisions about prescriptions or other treatments were left to the discretion of the treating physician.
There was no significant difference between groups in terms of the study's primary endpoint, a composite of the first occurrence of death, non-fatal heart attack, non-fatal stroke or transient ischemic attack, or hospitalization for heart failure or angina. At five years, this composite endpoint had occurred in about 16% of patients in both study arms. There were also no differences observed between intensive medical therapy and usual care for any secondary endpoints or subgroups that were analyzed.
One important aspect of the study is that about half of the patients who were randomized to usual care were ultimately prescribed the same medications as those assigned to intensive medical therapy, meaning that a large portion of those in the control arm received a treatment regimen similar to patients in the intervention arm. In addition, many participants were already taking one or more of the study drugs before enrolling in the study, with 70% taking statins, about half taking an ACE inhibitor or ARB and 40% taking beta blockers at baseline.
"The trial demonstrates the diagnostic and treatment confusion around this condition; for example, clinicians at some sites felt more strongly about these women being on statins," Pepine said.
While the trial does not move the needle in terms of informing guidelines, researchers said that it does provide valuable insights on feasibility and medication tolerability, adherence and prescribing practices that can help to inform future trials on the optimal treatment for women experiencing signs of ischemia without CAD.
Researchers also said the trial was negatively impacted by the COVID-19 pandemic. All study activities were paused for about six months in the early part of the pandemic and some sites did not resume activities due to staffing limitations. As a result of this, the trial fell short of its goal of enrolling 4,422 participants.
"We do not consider this to be a definitive trial at this point; however, it is nevertheless informative for the field," Pepine said. "We also expect that secondary analyses and ancillary studies will yield important information on the pathophysiology and treatment of this condition. Future trials can move forward from an enlightened position."
Several ancillary studies are assessing both quality of life and cardiovascular outcomes using AI-enabled coronary analysis in patients who underwent coronary CT angiogram to define coronary anatomy for inclusion in the trial. In addition, the WARRIOR biorepository collected blood samples from study participants that will be utilized to explore mechanisms of disease and possible new therapeutic targets. The researchers plan to continue these ancillary studies to provide further insights.
The study was funded by the U.S. Department of Defense.
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