Highlighting the Impact of Nonobstructive Angina on Women

The WARRIOR trial investigated women exhibiting ischemic symptoms without obstructive coronary artery disease (OCAD). Although the trial found that intensive medical therapy did not significantly decrease the initial occurrence of major cardiovascular events, it was underpowered to definitively confirm this outcome.

“This trial is neutral and should not be interpreted as negative,” stated Eileen Handberg, PhD, a professor of medicine at the University of Florida in Orlando. “Our adherence levels were insufficient, and we lacked the power to fully test our primary hypothesis.”

During her presentation at the American College of Cardiology Scientific Session 2025 in Chicago, she emphasized, “These findings should not suggest that statins or antihypertensive medications should be discontinued for women with cardiovascular risk factors.”

The WARRIOR trial stands out as the first large-scale, randomized study to focus on women experiencing signs of ischemia but without arterial obstructions—a condition termed ischemia with no OCAD, Handberg explained.

This population is substantial; in the United States, approximately 4-5 million women seek medical attention after reporting ischemic symptoms like chest pain, breathlessness, and dizziness, often necessitating further investigation through coronary CT angiograms or invasive coronary angiography. Alarmingly, around half of these women are found to not have OCAD.

Addressing Angina Hospitalizations

“Our findings reveal a significant burden on patients and physicians associated with this condition, highlighted by a high rate of recurrent angina-related hospitalizations. Women with these symptoms are consuming considerable healthcare resources, often presenting with hypertension and high cholesterol that require aggressive management,” Handberg remarked.

Handberg urged, “It’s crucial that we acknowledge these women’s experiences. We must eliminate biases about their pain presentation and ensure their symptoms receive the follow-up care they deserve. These women face comorbidities and should be receiving appropriate risk-reduction strategies. While those in our study were relatively well-managed at baseline—a hopeful sign—we must strive for further enhancements in their care.”

The trial analyzed 2,476 women (average age: 60) across 71 medical centers in the U.S. Nearly half of the participants were classified as obese, and most presented various cardiovascular risk factors, including high low-density lipoprotein cholesterol (LDL-C) and a familial history of coronary disease.

Participants were randomly assigned to either intensive medical therapy—which included a high-intensity statin, an ACE inhibitor or angiotensin receptor blocker at the maximum tolerated dose, and low-dose aspirin—or to usual care, which relied on the discretion of their treating physicians for prescriptions and treatments.

After five years of follow-up, there was no significant difference between the intensive therapy group and the usual care group concerning the primary composite endpoint, which consisted of the first occurrence of death, myocardial infarction, stroke, transient ischemic attack, or hospitalization for heart failure or angina.

In both groups, approximately 16% of participants experienced an event related to the composite endpoint within five years, with no substantial differences noted in secondary endpoints or analyzed subgroups.

Impact of the COVID-19 Pandemic on Recruitment

The trial’s underperformance in terms of power was partly due to challenges in patient recruitment during the COVID-19 pandemic.

“Our trial had to pause for six months during the nationwide lockdown, severely affecting our ability to keep study sites active and accessible to staff and patients. When clinical trials encounter delays, it can cause a loss of momentum, requiring significant effort to rekindle interest,” Handberg explained. Ultimately, the study did not meet its goal of enrolling 4,422 participants.

Additionally, a lower-than-expected baseline angina level diminished the potential impact on angina symptoms and related quality of life. The control group also exhibited relatively good baseline management, with 70% on statins, about half on ACE inhibitors or angiotensin receptor blockers, and 40% on beta blockers.

The open-label trial design likely led to unexpected “contamination,” where participants did not adhere strictly to the assigned treatment pathways, a situation anticipated to some extent. Initially, 16% of the usual care group was on intensive medications, while 52% of the intensive therapy group failed to comply with their assigned regimens. Furthermore, adherence declined over time in both groups.

However, a sensitivity analysis taking these factors into account indicated a hazard ratio of 0.74 for the primary endpoint among those adhering to their assigned treatments, suggesting a 25% reduction in cardiovascular events potentially favoring intensive therapy.

Moreover, while the reduction in LDL-C was modest, patients receiving intensive medical therapy showed a significantly greater average decrease of 7.6 mg/dL compared to those receiving usual care, though there was no notable difference in blood pressure management.

Key Takeaways

“It’s a common misconception that a trial failing to meet its endpoint lacks significance or teachable moments. That couldn’t be further from the truth in this context,” asserted Pamela Douglas, MD, a professor of research in cardiovascular diseases at Duke University. “We have highlighted the importance of this population, the prevalence of this condition, and our limited understanding, alongside the considerable burden it imposes.”

Throughout the trial, 17% of participants required hospitalization—a striking statistic, Douglas noted.

“The trial design was ambitious,” Douglas remarked. “This pragmatic approach—essential for advancements moving forward—should not be conflated with traditional efficacy trials, which tend to enforce strict controls and seamless intervention but at the expense of participant comfort and logistical demands on researchers.”

Various ancillary studies are currently being conducted to further examine coronary anatomy among participants, and blood samples will be analyzed to investigate disease mechanisms and potential new treatment targets, Handberg reported.

“These ongoing studies will significantly enhance our understanding of this growing cohort of women and their symptom management challenges,” she concluded.

Overall, the WARRIOR study marks a significant milestone as the largest trial focused on a population of women whose conditions remain poorly understood, noted Kim Eagle, MD, from the University of Michigan School of Public Health.

“The complexities underlying this condition—whether they stem from vascular reactivity, lipid issues, spasms, or inflammation—continue to perplex us, and insights could emerge from the ongoing substudies,” he added.

The WARRIOR trial received funding from the US Department of Defense, with Handberg, Douglas, and Eagle reporting no relevant financial conflicts.