WARRIOR Underscores Burden of Nonobstructive Angina in Women

In women with signs of ischemia but no obstructive coronary artery disease (OCAD), intensive medical therapy did not reduce the first occurrence of a major cardiovascular event in the WARRIOR trial, but the trial was underpowered to show a definitive result.

“This is a neutral trial and should not be considered a negative trial,” said study investigator Eileen Handberg, PhD, professor of medicine at the University of Florida in Orlando. “We had insufficient adherence and power to test the primary hypothesis.”

“These results should not be interpreted as endorsing discontinuation of statins or antihypertensive medications among women with cardiovascular risk factors,” she explained during her presentation of the results at the American College of Cardiology Scientific Session 2src25 in Chicago.

The WARRIOR trial is important because it is the first large, randomized study to be conducted in a population of women who experience signs and symptoms of ischemia but who have been found not to have an obstruction in their coronary arteries, a condition known as ischemia with no OCAD, she explained.

This is a large population. In the United States, an estimated 4-5 million women seek medical advice after reporting symptoms of cardiac ischemia, 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 OCAD.

Hospitalizations for Angina

“Our results show a high patient and physician burden associated with this condition, with a very high rate of recurrent angina hospitalizations. These women are using a lot of healthcare resources. They have hypertension and elevated cholesterol that need to be aggressively treated,” Handberg said. 

“We need to pay attention to these women. We need to get rid of the bias of the pain being a little bit different, and we should not dismiss their symptoms and say they don’t need follow-up. They do need follow-up,” she added. “These women have comorbidities, and they should be getting reasonable risk-reduction strategies. The women in this study were relatively well treated at baseline, which is a good sign that we’re moving in that direction, but there’s a lot of need for improvement.”

The WARRIOR trial assessed 2476 women (average age, 6src years) at 71 medical centers in the United States. About half the trial population had obesity and most had other cardiovascular risk factors, such as hypertension, high low-density-lipoprotein cholesterol (LDL-C), or a family history of coronary disease.

Patients were randomly assigned to receive intensive medical therapy, which consisted of a high-intensity statin, an ACE inhibitor or angiotensin receptor blocker at the maximally tolerated dose, and low-dose aspirin. The other half received usual care, meaning that decisions about prescriptions and other treatments were left to the discretion of the treating physician.

After 5 years of follow-up, there was no significant difference between the two groups in the primary endpoint, which was a composite of the first occurrence of death, myocardial infarction, stroke or transient ischemic attack, or hospitalization for heart failure or angina. 

About 16% of patients in both groups experienced an event in the composite endpoint at 5 years. There were no significant differences between intensive medical therapy and usual care for any of the secondary endpoints or subgroups analyzed.

COVID Pandemic Affected Recruitment

The trial was underpowered because the team had difficulty recruiting patients during the COVID-19 pandemic.

“The trial had to close for 6 months when the country shut down, and it greatly impacted our ability to keep sites active, with staff and patients not being able to come to healthcare facilities. And when trials stop, they lose inertia, and then you have to rebuild the enthusiasm,” Handberg explained. This resulted in the trial falling well short of its goal of enrolling 4422 participants.

There was also a lower level of angina at baseline than anticipated, which reduced the capacity to improve angina symptoms and related quality of life. And patients in the control group were relatively well treated at baseline, with 7src% taking statins, about half taking an ACE inhibitor or angiotensin receptor blocker, and 4src% taking a beta blocker.

In addition, the open-label design likely resulted in higher-than-anticipated trial “contamination,” which occurs when patients are not treated in line with the assigned strategy.

This was expected to some extent. It was assumed that patients assigned to usual care would be taking some intensive medications, and that patients assigned to intensive medical therapy would not take some of their assigned medications. However, this occurred more often than anticipated.

“Initially, 16% of usual-care patients were receiving intensive medications and 52% of the intensive group were not adherent to the assigned strategy,” Handberg reported. Plus, “adherence in both arms declined further over time.”

However, in a sensitivity analysis that took this into account, the estimated hazard ratio for the primary endpoint was src.74 for intensive medication in those who were compliant with assigned treatments, suggesting a 25% reduction in cardiovascular events, which is “potentially supportive of an effect for intensive treatment,” she said.

The reduction in LDL-C was modest but significantly lower in patients assigned to intensive medical therapy than to usual care, with a time-averaged difference of 7.6 mg/dL, but there was no detectable difference in blood pressure control between groups.

Important Messages

“We tend to think if a trial doesn’t meet its endpoint, it’s not important, and that we can’t learn from it, but that couldn’t be more untrue in this setting,” said Pamela Douglas, MD, professor of research in cardiovascular diseases at Duke University in Durham, North Carolina. “We have heard how important this population is, how common this disease is, how little we know about it, and how high the burden is.”

During the course of the trial, 17% of patients required hospitalization. “That is more than one in six, an incredibly informative figure,” she said.

The study design was “ambitious,” Douglas said. “This pragmatic design — which is what needs to happen going forward — should not be confused with a pure efficacy trial, where things are tightly controlled, and the intervention is designed and delivered seamlessly but at great cost to participants and to study investigators.” 

Several ancillary studies are underway to assess, more closely, the coronary anatomy of the participants, and blood samples will be analyzed to explore mechanisms of disease and possible new therapeutic targets, Handberg reported.

“These ongoing substudies will continue to contribute to improve our understanding of this growing patient population and its symptom burden,” she added.

The WARRIOR study was an achievement, in that it was the largest trial ever in this group of women who are not well understood, said Kim Eagle, MD, from the University of Michigan School of Public Health in Ann Arbor.

“The physiology of this condition continues to mystify us. Is it vascular reactivity? Is it lipids? Is it spasm? Is it inflammation? Some of those nuances will perhaps come from the substudies of this trial,” he added.

The WARRIOR trial was funded by the US Department of Defense. Handberg, Douglas, and Eagle report no relevant financial disclosures.