Intensive Medical Therapy Does Not Improve Outcomes in Women with INOCA

The landmark WARRIOR trial has concluded an intensive medical therapy among women with ischemia without obstructive coronary artery disease (INOCA) did not significantly improve outcomes relative to usual care.

Billed by investigators as the largest, randomized, pragmatic outcome trial for INOCA, results of the study suggest there were no statistically significant differences in major adverse cardiovascular events with the use of intensive medical therapy. However, investigators also point out study results demonstrate the level of diagnostic and treatment confusion surrounding this condition for clinicians.1,2

“We do not consider this to be a definitive trial at this point; however, it is nevertheless informative for the field,” said principal investigator Carl J. Pepine, MD, professor of medicine at the University of Florida.1 “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.”

Presented at American College of Cardiology (ACC) 2025 Annual Scientific Sessions and funded by the US Department of Defense, the trial was launched in 2018 and had initially planned to enroll 4422 participants, but as a result of the COVID-19 pandemic, all study activities were paused for approximately 6 months and some study sites.1,2

In total, 2476 women from 71 sites in the US were included in the study. Per trial protocol, women with symptoms and/or signs of ischemia and no obstructive coronary artery disease (CAD) as determined by either invasive coronary angiography (n=1353) or coronary computed tomography angiography (n=1123) were randomized to receive either an intensive medical therapy strategy or usual care. Intensive medical therapy was defined as a high-intensity statin, maximally tolerated dose of an ACE inhibitor or ARB, and low-dose aspirin.1

Patients were followed every 6 months for up to 5 years and the primary outcome was the first occurrence of major adverse cardiovascular events (MACE), defined as death, nonfatal myocardial infarction, nonfatal stroke/transient ischemic attack, or hospitalization for heart failure or angina. Secondary outcomes of interest for the study included individual MACE events, total MACE events, and angina as assessed by the Seattle Angina Questionnaire, as well as quality of life measures.1

Among the 2476 women enrolled in the study, 1239 were randomized to intensive medical therapy and 1237 were randomized to usual care. Baseline characteristics were similar between the intensive medical therapy and usual care groups. The intensive medical therapy group had a mean age of 64.2 years, with 37.6% aged 65 years or older, while the usual care group had a mean age of 64.1 years, with 39.4% aged 65 years or older. Statin use was similar (70.9% in intensive medical therapy vs 69.9% in usual care), though high-intensity statins were prescribed more frequently in the intensive medical therapy group. Use of ACE inhibitors or ARBs was greater in the intensive medical therapy group (53.2% vs 48.2%). In contrast, beta-blockers and calcium channel blockers were more frequently prescribed in the usual care group (25.8% vs 28.4%).1

Results of the study suggested 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 (HR, 1.13, 95% CI, 0.94 to 1.37; P=.20). When assessing individual components of MACE, results indicated 27 deaths from any cause in the intensive medical therapy group and 17 in the usual care group, cardiovascular deaths occurred among 4 in the intensive medical therapy group and 5 in the usual care group, and hospitalization for chest pain occurred in 305 patients receiving intensive medical therapy and 298 patients receiving usual care. Investigators noted there were 7 instances of hospitalization for heart failure was uncommon in the intensive medical therapy group and 6 in the usual care group, with non-fatal heart attacks occurring in 14 patients in each group.1

Investigators called attention to multiple limitations within their study to consider when interpreting findings. These included under enrollment, inclusion of CCTA lowering MACE risk profile, the open-label design resulting in greater contamination than expected, and elevated baseline Seattle Angina Questionnaire reduced capacity to improve angina and angina-related quality of life.1

“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,” Pepine added.2 “It represents an important societal burden in terms of cardiovascular outcomes, quality of life and health care costs and resources.”

References:

1. E Handberg, CJ Pepine, NB Merz, et al. Primary And Secondary Outcomes Of The Women’s Ischemia Trial To Reduce Events In Non Obstructive Coronary Artery Disease. Presented at: American College of Cardiology (ACC.25) Annual Scientific Session. March 29 – 31, 2025. Chicago, Il.

2. American College of Cardiology. Women with Chest Pain May Not Need Intensive Medical Therapy - American College of Cardiology. American College of Cardiology. Published March 29, 2025. Accessed March 29, 2025. https://www.acc.org/About-ACC/Press-Releases/2025/03/29/14/18/Women-with-Chest-Pain-May-Not-Need-Intensive-Medical-Therapy.