Women's IschemiA TRial to Reduce Events In Non-ObstRuctive CAD (WARRIOR)

The Ischemia-IMT (Ischemia-Intensive Medical Treatment Reduces Events in Women with Non-Obstructive CAD), subtitle: Women's Ischemia Trial to Reduce Events in Non-Obstructive CAD (WARRIOR) trial is a multicenter, prospective, randomized, blinded outcome evaluation (PROBE design) evaluating intensive statin/ACE-I (or ARB)/aspirin treatment (IMT) vs. usual care (UC) in 4,422 symptomatic women patients with symptoms and/or signs of ischemia but no obstructive CAD. The hypothesis is that IMT will reduce major adverse coronary events (MACE) 20% vs. UC. The primary outcome is first occurrence of MACE as death, nonfatal MI, nonfatal stroke/transient ischemic attack (TIA) or hospitalization for heart failure or angina. Secondary outcomes include quality of life, time to "return to duty"/work, health resource consumption, angina, cardiovascular (CV) death and primary outcome components. Events will be adjudicated by an experienced Clinical Events Committee (CEC). Follow-up was planned to be 3-years using 50 sites: primarily VA and Active Duty Military Hospitals/Clinics and a National Patient-Centered Clinical Research Network (PCORnet) clinical data research network (CDRN)(OneFlorida Consortium). The number of sites were increased and follow up was modified to continue until the last patient enrolled was followed until trial follow up was completed. Recruitment was complete January 6, 2024.

This study is being conducted to determine whether intensive medication treatment to modify risk factors and vascular function in women patients with coronary arteries showing no flow limit obstruction but with cardiac symptoms (i.e., chest pain, shortness of breath) will reduce the patient's likelihood of dying, having a heart attack, stroke/TIA or being hospitalized for cardiac reasons. The results will provide evidence data necessary to inform future guidelines regarding how best to treat this growing population of patients, and ultimately improve the patient's cardiac health and quality of life and reduce health-care costs.

Study Overview

• Status: Active, not recruiting
• Conditions: Coronary Artery Disease
• Intervention / Treatment: Drug: High dose potent statin; Drug: ACE-I (lisinopril) or ARB (losartan); Behavioral: Lifestyle Counseling; Behavioral: Quality of Life Questionnaires; Drug: Aspirin 81 enteric coated tablet daily

Detailed Description

WARRIOR trial is a multi-site, PROBE design, that will evaluate an intensive statin/ACE-I (or ARB)/aspirin treatment strategy (IMT) vs. primary prevention risk factor therapy treatment strategy (UC) in 4,422 symptomatic (chronic angina or equivalent) women with non-obstructive CAD (<50% diameter narrowing).

There will be ~80 US sites, including VA/ military and OneFlorida CDRN sites, with a proven record in prior trials. The investigators will use web-based, real-time data entry, and management University of Florida Data Management System (UFDMS) for site selection, screening, participant eligibility confirmation, enrollment, and randomization. Participants will be recruited from screened women with symptoms suspected to be ischemic with non-obstructive CAD by invasive coronary angiogram or CT angiogram. The high dose statin (atorvastatin or rosuvastatin) and ACE-I (lisinopril) [or ARB (losartan)] are generic commonly used medications previously demonstrated effective for improving angina, stress testing, myocardial perfusion and coronary microvascular flow reserve in small size trials in this population. Additionally, aspirin will also be recommended to IMT participants without contraindications or excess bleeding risk, however aspirin will not be provided by the study. Both the groups will also receive Lifestyle Counseling (PACE Assessment), and the same visit schedule and "face-time" with site staff to reduce bias. Events will be adjudicated by the Clinical Events Committee (CEC), according to objective criteria and masked to treatment assignment clues.

• Study Type: Interventional
• Enrollment (Actual): 2476
• Phase: Phase 4

Contacts and Locations

Study Locations

• Puerto Rico
  • San Juan
    • San Juan, San Juan, Puerto Rico, 00921
      • VA Caribbean Healthcare System
• United States
  • Alabama
    • Mobile, Alabama, United States, 36608
      • Cardiology Associates of Mobile, Inc.
  • Arizona
    • Gilbert, Arizona, United States, 85297
      • Dignity Health-Mercy Gilbert Medical Center
    • Phoenix, Arizona, United States, 85013
      • Dignity Health-St. Joseph
    • Tucson, Arizona, United States, 85721
      • University of Arizona
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas
  • California
    • Los Angeles, California, United States, 90095
      • UCLA Medical Center
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Heart Institute
    • Torrance, California, United States, 90502
      • Lundquist Institute for Biomedical Innovation at Harbor UCLA Medical Center
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20057
      • Georgetown University
  • Florida
    • Clearwater, Florida, United States, 33756
      • Clearwater Cardiovascular Consultants Clinical Research
    • Delray Beach, Florida, United States, 33446
      • South Palm Cardiovascular Research Institute
    • Gainesville, Florida, United States, 32608
      • Malcom Randall VA Medical Center
    • Gainesville, Florida, United States, 32610
      • Cardiovascular Clinic at UF Health UF
    • Gainesville, Florida, United States, 32206
      • Family Medicine at Eastside Community Practice
    • Gainesville, Florida, United States, 32607
      • Family Medicine at Hampton Oaks Medical Plaza (Adults and Peds)
    • Gainesville, Florida, United States, 32607
      • Internal Medicine at Tower Hill
    • Gainesville, Florida, United States, 32608
      • Family Medicine at Haile Plantation (Adults & Peds)
    • Gainesville, Florida, United States, 32610
      • Internal Medicine at UF Health Medical Plaza
    • Gainesville, Florida, United States, 32610
      • Spring Hill Cardiology
    • Gainesville, Florida, United States, 32611
      • Family Medicine at 4th Ave
    • Gainesville, Florida, United States, 32680
      • Family Medicine at Old Town (Adults and Peds)
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Jacksonville
    • Jacksonville, Florida, United States, 32209
      • University of Florida, Jacksonville
    • Jacksonville, Florida, United States, 32207
      • Baptist Health
    • Jacksonville, Florida, United States, 32214
      • Naval Hospital Jacksonville
    • Lake City, Florida, United States, 32024
      • UF Primary Care at Lake City SW
    • Lake City, Florida, United States, 32024
      • UF Primary Care at Lake City West
    • Melbourne, Florida, United States, 32901
      • Charles H. Croft MDPA
    • Multiple Locations, Florida, United States, 32114
      • Daytona Heart Group
    • Naples, Florida, United States, 34102
      • Southwest Florida Research Institute
    • Ocala, Florida, United States, 34471
      • Cardiovascular Instititute of Central Florida
    • Ocala, Florida, United States, 34480
      • Ocala Research Institute Inc.
    • Orlando, Florida, United States, 32806
      • Orlando Health
    • Pensacola, Florida, United States, 32512
      • Naval Hospital Pensacola
    • Sarasota, Florida, United States, 34239
      • Cardiovascular Center of Sarasota
    • Sebring, Florida, United States, 33872
      • Advent Sebring
    • Tampa, Florida, United States, 33612
      • James A. Haley Veterans Hospital
    • Tampa, Florida, United States, 33614
      • BayCare Medical Group
    • Tampa, Florida, United States, 33613
      • AdventHealth Tampa - Pepin Heart Institute
    • Tampa, Florida, United States, 33613
      • Interventional Cardiac Consultants
    • Winter Park, Florida, United States, 32792
      • Guardian Research
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
    • Thomasville, Georgia, United States, 31792
      • Cardiovascular Consultants of South Georgia, LLC.
  • Illinois
    • Chicago, Illinois, United States, 60660
      • Loyola University Chicago
    • Fairview Heights, Illinois, United States, 62208
      • Medicoricium
    • Urbana, Illinois, United States, 61801
      • Carle Foundation Hospital
  • Indiana
    • Elkhart, Indiana, United States, 46514
      • Midwest Cardiovascular Research and Education Foundation
    • Fort Wayne, Indiana, United States, 46804
      • Lutheran Health Physicians
  • Kansas
    • Overland Park, Kansas, United States, 66211
      • Midwest Heart and Vascular Specialists
  • Kentucky
    • Bowling Green, Kentucky, United States, 42103
      • Western Kentucky Heart And Lung
    • Lexington, Kentucky, United States, 40506
      • University of Kentucky
    • Lexington, Kentucky, United States, 40503
      • The Research Group of Lexington, LLC
  • Maryland
    • Bethesda, Maryland, United States, 20889
      • Walter Reed National Military Medical Center
  • Massachusetts
    • Pittsfield, Massachusetts, United States, 01201
      • Berkshire Medical Center
  • Michigan
    • Midland, Michigan, United States, 48670
      • Mid Michigan Health
  • Minnesota
    • Duluth, Minnesota, United States, 55805
      • Essentia Institute of Rural Health
    • Minneapolis, Minnesota, United States, 55407
      • Minneapolis Heart Institute Foundation
  • Mississippi
    • Tupelo, Mississippi, United States, 38801
      • Cardiology Associates Research, LLC
    • Tupelo, Mississippi, United States, 38801
      • Cardiology Associates Research. LLC
  • Nebraska
    • Omaha, Nebraska, United States, 68124
      • CHI Health Research Center
  • Nevada
    • Henderson, Nevada, United States, 89052
      • Silver State Cardiology
  • New Jersey
    • Ridgewood, New Jersey, United States, 07450
      • The Valley Hospital
  • New York
    • Cooperstown, New York, United States, 13326
      • Bassett Healthcare Network
    • New York, New York, United States, 10016
      • NYU Langone
    • New York, New York, United States, 10065
      • Weil Medical college of Cornell
    • Richmond Hill, New York, United States, 11418
      • Jamaica Hospital Medical Center
  • North Carolina
    • Apex, North Carolina, United States, 27502
      • Peak Clinical Trials, LLC
    • Pinehurst, North Carolina, United States, 38274
      • Pinehurst Medical Clinic
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • The Christ Hospital
    • Cincinnati, Ohio, United States, 45242
      • Trihealth Heart Institute
    • Springfield, Ohio, United States, 45505
      • Heart House Research Foundation
  • Texas
    • Austin, Texas, United States, 78705
      • Seton Heart Institute
    • Austin, Texas, United States, 78756
      • Austin Heart
    • Fort Sam Houston, Texas, United States, 78234
      • Brooke Army Medical Center
    • San Antonio, Texas, United States, 78258
      • San Antonio Endovascular and Heart Institute
    • Temple, Texas, United States, 76508
      • Baylor Scott and White
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Health System
    • Richmond, Virginia, United States, 23225
      • Chippenham Hospital
    • Roanoke, Virginia, United States, 24017
      • Carilion Clinic
  • West Virginia
    • Morgantown, West Virginia, United States, 26508
      • West Virginia University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Signs and symptoms of suspected ischemia prompting referral for further evaluation by cardiac catheterization or coronary angiogram or coronary CT angiogram within 5 years from consent
• Willing to provide written informed consent
• Non-obstructive CAD defined as 0 to 49% diameter reduction of a major epicardial vessel or a FFR>0.80

Exclusion Criteria:

• History of noncompliance (with medical therapy, protocol, or follow-up)
• History of non-ischemic dilated or hypertrophic cardiomyopathy
• Documented acute coronary syndrome(ACS) within previous 30 days
• Left ventricular ejection fraction (LVEF) <40%, New York Heart Association heart failure (NYHA HF) class III-IV, or hospitalization for Reduced ejection fraction (HFrEF) within 180 days
• Stroke within previous 180 days or intracranial hemorrhage at any time
• End-stage renal disease, on dialysis, or estimated glomerular filtration rate (eGFR) <30 ml/min.
• Severe valvular disease or likely to require surgery/Transcatheter aortic valve replacement (TVAR) within 3 years
• Life expectancy <3-yrs. due to non-cardiovascular comorbidity
• Enrolled in a competing clinical trial
• Prior intolerance to both an ACE-I and ARB
• If intolerant to a statin unless taking a PCSK9 as a statin replacement by their clinical provider
• Pregnancy (all pre-menopausal females must have negative urine pregnancy test if randomized to IMT before study drugs are prescribed. If they have not gone through menopause, had a hysterectomy, oophorectomy, or sterilization such as tubal ligation procedure)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intensive Medical Treatment (IMT); The IMT-assigned women will receive high dose potent statin, and moderate dose of an ACE-I (lisinopril) or ARB (losartan). Aspirin will also be recommended to IMT women without contraindications or bleeding risk. This group will also receive Lifestyle Counseling (PACE Assessment), Quality of Life questionnaires, and the same visit schedule and "face-time" with site staff to reduce bias.	Drug: High dose potent statin; The IMT-assigned women will receive high-dose, potent statin (atorvastatin 40-80 mg/d or rosuvastatin 20-40mg) class of lipid-lowering medications.; Other Names: atorvastatin or rosuvastatin; Drug: ACE-I (lisinopril) or ARB (losartan); Angiotensin converting enzyme inhibitors (ACE inhibitors) and angiotensin receptor blockers (ARBs) are widely prescribed for primary hypertension.; Other Names: ACE-I or ARB; Behavioral: Lifestyle Counseling; The PACE Lifestyle Assessment Intervention which is a program to assist with smoking cessation, weight loss, and exercise.; Other Names: PACE Lifestyle Intervention; Behavioral: Quality of Life Questionnaires; Quality of Life Questionnaires will be obtained.; Other Names: QOL; Drug: Aspirin 81 enteric coated tablet daily; Will be recommended to IMT women without contraindications or bleeding risk.; Other Names: Aspirin
Active Comparator: Usual Care (UC); The UC-assigned women will maintain standard of care. This group will also receive Lifestyle Counseling (PACE Assessment), Quality of Life questionnaires, and the same visit schedule and "face-time" with site staff to reduce bias.	Behavioral: Quality of Life Questionnaires; Quality of Life Questionnaires will be obtained.; Other Names: QOL

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The primary outcome is MACE, defined as first occurrence of all-cause death, non-fatal MI, non-fatal stroke, or hospitalization for angina or HF.	All-cause death will be used 1) CV death is insensitive in this population with non-obstructive CAD since death is less likely attributed to CV causes when no obstructive CAD is present; 2) all-cause death is resistant to ascertainment bias in this unblinded trial. CV death will be defined broadly to include both definite CV death and possible CV death (all deaths except those with definite non-CV cause, e.g., cancer, witnessed trauma and homicide). The MI definition follows universal criteria for Types 1-5 MI events. Stroke/TIA definition is new onset neurological defect of central origin confirmed by brain imaging (CT or MRI) evidence of cerebral infarction or intracerebral hemorrhage. Hospitalization for angina- Any hospitalization for angina, plus unstable angina or ACS. Hospitalization for Heart Failure -required established objective criteria for heart failure. All MACE events are adjudicated by a blinded Clinical Endpoint Committee	Within 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Components of MACE	The analysis will be repeated for the following combinations of MACE events (1) composite outcome of CV-death, non-fatal MI, or non-fatal stroke/TIA; (2) composite outcome CV-death, non-fatal MI, resuscitated cardiac arrest, or hospitalization for angina or heart failure; (3) all-cause mortality; (4) CV-death (5) total MI [fatal plus non-fatal]; (6) resuscitated cardiac arrest; (7) hospitalization for angina; (8) hospitalization for HF; (9) total stroke/TIA [fatal plus non- fatal]; (10) composite outcome of CV-death, non-fatal MI, stroke/TIA, resuscitated cardiac arrest, or hospitalization for angina or heart failure.	Within 5 years
Composite hierarchical MACE endpoint	The comparison of randomized treatment strategies for composite hierarchical endpoint will be conducted using win statistics (WS), including the win ratio (WR), win odds (WO), will be computed to compare two groups based on hierarchical order of clinical importance as follows: 1) all cause death within 5 yrs, 2) stroke within 5 yrs, 3) MI within 5 yrs, 4) number of hospitalization within 5 yrs, 5) first hospitalization for heart failure or chest pain within 5 yrs, and 6) average of SAQ7 at 6 months and 1-year. The WR method compares each patient in the intervention group with every patient in the control group, and the magnitude of the effect is computed as the ratio of the total number of pairwise "wins" to "losses" considering the predefined hierarchy of the outcomes. Since the WR does not account for ties that the WO will also be computed. The benefit of the IMT arm is indicated by an estimate of WS/WO test statistic with their respective 95% confidence intervals greater than 1.	Within 5 years
Seattle Angina Questionnaire (SAQ).	QoL comparisons will adhere to the ITT principle. We will examine changes over time from baseline and identify the major determinants of those changes using regression analysis. Questionnaires, such as the SAQ scores, at each time point will be analyzed using linear mixed models with correlation within subjects over time. In case the outcome residuals do not have a normal distribution, a transformation will be considered (e.g. log, Box-Cox). Interaction of group and time effects will be examined to assess for different time trends between groups.	Study entry and every six months until end of follow up (up to 72 months)
EQ-5D-3L	Evaluated over time by group.	Study entry and every six months until end of follow up (up to 72 months)
Duke Activity Status Inventory (DASI)	DASI as assessed over time by group.	Study entry and every six months until end of follow up (up to 72 months)
Modified Morisky Medicine Scale Take your medication	Measure of medication compliance between groups over time.	Study entry and every six months until end of follow up (up to 72 months)
PACE (Programs of All-Inclusive Care for the Elderly).	Assessment of healthy lifestyle intervention between groups over time.	Study entry and every six months until end of follow up (up to 72 months)
PCL-5 (Screening for PTSD).	Screening for PTSD over time between groups	Study entry and every six months until end of follow up (up to 72 months)
Health care utilization and cost effectiveness	Comparing health care resource utilization across time between groups.	Study entry and every six months until end of follow up (up to 72 months)
GAD 7	Assessment of general anxiety over time between groups	Study entry and every six months until end of follow up (up to 72 months)
PHQ 8	Assessment of depression over time between groups	Study entry and every six months until end of follow up (up to 72 months)
MACE and Quality of Life outcomes will also be stratified by enrollment assessment of non-obstructive CAD using noninvasive CCTA vs invasive coronary angiography	MACE is first occurrence of all cause death, non fatal MI, non fatal stroke or TIA, hospitalization for heart failure, hospitalization for chest pain/angina. Quality of life is being assessed using Seattle Angina Questionnaire, SAQ7 and all of the SAQ domains, PTSD is being assessed using the PCL5, functional capacity is being assessed using the Duke Activity Status Index, EQ-5D-3L, Depression is being assessed using the PHQ-8 and anxiety using the GAD-7	Within 5 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
An analysis of MACE with repeated events considering the number of previous events as a time-dependent covariate will be performed	Using Andersen-Gill model with frailty to describe the repeated events: all-cause death, non-fatal MI, non-fatal stroke/TIA, or hospitalization for either angina or heart failure. Definitions of repeated events include 30 days between a documented MI and death as a standard definition for "Fatal MI" and >48hrs was a standard for exacerbation of ischemia (chest pain or ECG changes of ischemia) to call it a "new event" (e.g., either an MI, HF, or another exacerbation of ischemia).	Within 5 years

Collaborators and Investigators

• Sponsor: Cedars-Sinai Medical Center
• Collaborators: United States Department of Defense; University of Florida
• Investigators: Principal Investigator: Carl J Pepine, MD, University of Florida

Publications and helpful links

General Publications

• Ya'Qoub L, Elgendy IY, Pepine CJ. Non-obstructive Plaque and Treatment of INOCA: More to Be Learned. Curr Atheroscler Rep. 2022 Sep;24(9):681-687. doi: 10.1007/s11883-022-01044-4. Epub 2022 Jul 4.
• Handberg EM, Merz CNB, Cooper-Dehoff RM, Wei J, Conlon M, Lo MC, Boden W, Frayne SM, Villines T, Spertus JA, Weintraub W, O'Malley P, Chaitman B, Shaw LJ, Budoff M, Rogatko A, Pepine CJ. Rationale and design of the Women's Ischemia Trial to Reduce Events in Nonobstructive CAD (WARRIOR) trial. Am Heart J. 2021 Jul;237:90-103. doi: 10.1016/j.ahj.2021.03.011. Epub 2021 Mar 18.
• Pepine CJ, Handberg E, Cooper-DeHoff R, Cook-Wiens G, Diniz MA, Frayne S, Lo MC, Smith SM, Harris B, Wei J, Chaitman BR, Spertus JA, Berry C, Weintraub W, Bairey Merz CN. Women's IschemiA TRial to Reduce Events In Non-ObstRuctive CAD (WARRIOR): a randomised controlled trial. Open Heart. 2026 Apr 3;13(1):e004115. doi: 10.1136/openhrt-2026-004115.
• Lakshmanan S, Wei J, Cook-Wiens G, Pepine CJ, Handberg EM, Shaw LJ, Budoff M, Merz CNB. Comparison of risk profiles of participants in the Women's IschemiA TRial to Reduce events In non-ObstRuctive CAD (WARRIOR) trial, using Coronary Computed Tomography Angiography vs Invasive Coronary Angiography. Prog Cardiovasc Dis. 2024 May-Jun;84:90-93. doi: 10.1016/j.pcad.2024.03.008. Epub 2024 Mar 26.

Study record dates

Study Major Dates

• Study Start (Actual): February 9, 2018
• Primary Completion (Estimated): September 14, 2026
• Study Completion (Estimated): September 14, 2026

Study Registration Dates

• First Submitted: January 24, 2018
• First Submitted That Met QC Criteria: January 24, 2018
• First Posted (Actual): January 31, 2018

Study Record Updates

• Last Update Posted (Actual): May 29, 2026
• Last Update Submitted That Met QC Criteria: May 27, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Ischemia; Coronary Angiography; Coronary CT Angiogram; Non-obstructive CAD
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Heart Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Disease; Myocardial Ischemia; Pathological Conditions, Signs and Symptoms; Ischemia; Coronary Artery Disease; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fatty Acids; Lipids; Azoles; Hydrocarbons; Hydrocarbons, Cyclic; Hydrocarbons, Aromatic; Imidazoles; Amides; Pyrimidines; Phenols; Benzene Derivatives; Hydrocarbons, Halogenated; Pyrroles; Heptanoic Acids; Sulfonamides; Sulfones; Salicylates; Hydroxybenzoates; Fluorobenzenes; Hydrocarbons, Fluorinated; Tetrazoles; Biphenyl Compounds; Dipeptides; Atorvastatin; Rosuvastatin Calcium; Aspirin; Losartan; Lisinopril
• Other Study ID Numbers: IRB201701142 -A; W81XWH-17-2-0030 (Other Grant/Funding Number: Department of Defense); OCR17268 (Other Identifier: UF OnCore); IRB201802734 (Other Identifier: UF IRB + VA); IRB201701434 (Other Identifier: UF IRB-01)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No