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

Phase 4Active Not RecruitingNCT03417388

University of Florida2,476 enrolled

Overview

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.

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.

Interventions

High dose potent statinDRUG

The IMT-assigned women will receive high-dose, potent statin (atorvastatin 40-80 mg/d or rosuvastatin 20-40mg) class of lipid-lowering medications.

ACE-I (lisinopril) or ARB (losartan)DRUG

Angiotensin converting enzyme inhibitors (ACE inhibitors) and angiotensin receptor blockers (ARBs) are widely prescribed for primary hypertension.

Aspirin 81 enteric coated tablet dailyDRUG

Will be recommended to IMT women without contraindications or bleeding risk.

Lifestyle CounselingBEHAVIORAL

The PACE Lifestyle Assessment Intervention which is a program to assist with smoking cessation, weight loss, and exercise.

Quality of Life QuestionnairesBEHAVIORAL

Quality of Life Questionnaires will be obtained.

Eligibility

Sex: FEMALEMin age: 18 YearsMax age: 100 Years

Medical Language ↔ Plain English

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)

Locations (81)

Cardiology Associates of Mobile, Inc.

Mobile, Alabama, United States

Dignity Health-Mercy Gilbert Medical Center

Gilbert, Arizona, United States

Dignity Health-St. Joseph

Phoenix, Arizona, United States

University of Arizona

Tucson, Arizona, United States

University of Arkansas

Little Rock, Arkansas, United States

Outcomes

Primary Outcomes

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

Time frame: Within 5 years

Secondary Outcomes

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.

Time frame: 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.

Time frame: 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.