Women's IschemiA TRial to Reduce Events In Non-ObstRuctive CAD
- Conditions
- Coronary Artery Disease
- Interventions
- Drug: High dose potent statinDrug: ACE-I (lisinopril) or ARB (losartan)Drug: AspirinBehavioral: Lifestyle CounselingBehavioral: Quality of Life Questionnaires
- Registration Number
- NCT03417388
- Lead Sponsor
- University of Florida
- Brief Summary
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 will 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).
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.
- 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.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- Female
- Target Recruitment
- 2476
- 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
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Intensive Medical Treatment (IMT) High dose potent statin 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. Intensive Medical Treatment (IMT) Quality of Life Questionnaires 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. Intensive Medical Treatment (IMT) ACE-I (lisinopril) or ARB (losartan) 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. Intensive Medical Treatment (IMT) Lifestyle Counseling 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. Usual Care (UC) Quality of Life Questionnaires 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. Intensive Medical Treatment (IMT) Aspirin 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.
- Primary Outcome Measures
Name Time Method Non-fatal myocardial infarction (MI) incidents reported between the two groups 3 years Collection of all non-fatal MI's reported between the two groups will use the log rank test for comparison of outcomes. Although the power analysis required the exponential assumption, the actual statistical test is free of assumptions, as the null hypothesis is that the survival distributions for the two strategies are the same, and therefore the null hazard ratio is 1.00 (proportional hazards). MI definition follows universal criteria for Types 1-5 MI events. Specifically, the use of the "Third Universal Definition of Myocardial Infarction" detection of a rise and/or fall of cardiac biomarker values, with at least one value \>99th percentile upper reference limit and preferred biomarker is Cardiac troponin (cTn).
Stroke/TIA incidents reported between the two groups 3 years Collection of all strokes or transient ischemic attack (TIA) reported between the two groups will use the log rank test for comparison of outcomes. Although the power analysis required the exponential assumption, the actual statistical test is free of assumptions, as the null hypothesis is that the survival distributions for the two strategies are the same, and therefore the null hazard ratio is 1.00 (proportional hazards). The stroke definition is new onset neurological defect of central origin confirmed by brain imaging (CT or MRI) evidence of cerebral infarction or intracerebral hemorrhage. The definition of TIA is the same as stroke except no confirmation by brain imaging, but confirmed by a neurologist consult.
Hospitalizations for cardiovascular events reported between the two groups 3 years Collection of all hospitalization for cardiovascular events reported between the two groups will use the log rank test for comparison of outcomes. Although the power analysis required the exponential assumption, the actual statistical test is free of assumptions, as the null hypothesis is that the survival distributions for the two strategies are the same, and therefore the null hazard ratio is 1.00 (proportional hazards). Cardiovascular causes includes accelerated angina, persistent angina, unstable angina.
All Cause Death incidents reported between the two groups 3 years Collection of all deaths reported between the two groups will use the log rank test for comparison of outcomes. Although the power analysis required the exponential assumption, the actual statistical test is free of assumptions, as the null hypothesis is that the survival distributions for the two strategies are the same, and therefore the null hazard ratio is 1.00 (proportional hazards).
Hospitalizations for heart failure incidents reported between the two groups 3 years Collection of all hospitalizations for heart failure between the two groups will use the log rank test for comparison of outcomes. Although the power analysis required the exponential assumption, the actual statistical test is free of assumptions, as the null hypothesis is that the survival distributions for the two strategies are the same, and therefore the null hazard ratio is 1.00 (proportional hazards).
- Secondary Outcome Measures
Name Time Method
Trial Locations
- Locations (81)
Lutheran Health Physicians
🇺🇸Fort Wayne, Indiana, United States
Silver State Cardiology
🇺🇸Henderson, Nevada, United States
The Valley Hospital
🇺🇸Ridgewood, New Jersey, United States
Pinehurst Medical Clinic
🇺🇸Pinehurst, North Carolina, United States
The Christ Hospital
🇺🇸Cincinnati, Ohio, United States
Trihealth Heart Institute
🇺🇸Cincinnati, Ohio, United States
Midwest Heart and Vascular Specialists
🇺🇸Overland Park, Kansas, United States
Cardiology Associates of Mobile, Inc.
🇺🇸Mobile, Alabama, United States
Clearwater Cardiovascular Consultants Clinical Research
🇺🇸Clearwater, Florida, United States
Dignity Health-Mercy Gilbert Medical Center
🇺🇸Gilbert, Arizona, United States
Cedars-Sinai Heart Institute
🇺🇸Los Angeles, California, United States
UCLA Medical Center
🇺🇸Los Angeles, California, United States
South Palm Cardiovascular Research Institute
🇺🇸Delray Beach, Florida, United States
UF Primary Care at Lake City SW
🇺🇸Lake City, Florida, United States
Mayo Clinic Jacksonville
🇺🇸Jacksonville, Florida, United States
UF Primary Care at Lake City West
🇺🇸Lake City, Florida, United States
Daytona Heart Group
🇺🇸Multiple Locations, Florida, United States
Cardiovascular Instititute of Central Florida
🇺🇸Ocala, Florida, United States
Cardiovascular Center of Sarasota
🇺🇸Sarasota, Florida, United States
Advent Sebring
🇺🇸Sebring, Florida, United States
Guardian Research
🇺🇸Winter Park, Florida, United States
Midwest Cardiovascular Research and Education Foundation
🇺🇸Elkhart, Indiana, United States
University of Kentucky
🇺🇸Lexington, Kentucky, United States
Emory University
🇺🇸Atlanta, Georgia, United States
Cardiovascular Consultants of South Georgia, LLC.
🇺🇸Thomasville, Georgia, United States
Carle Foundation Hospital
🇺🇸Urbana, Illinois, United States
Loyola University Chicago
🇺🇸Chicago, Illinois, United States
The Research Group of Lexington, LLC
🇺🇸Lexington, Kentucky, United States
Cardiology Associates Research, LLC
🇺🇸Tupelo, Mississippi, United States
Minneapolis Heart Institute Foundation
🇺🇸Minneapolis, Minnesota, United States
Mid Michigan Health
🇺🇸Midland, Michigan, United States
Essentia Institute of Rural Health
🇺🇸Duluth, Minnesota, United States
NYU Langone
🇺🇸New York, New York, United States
Austin Heart
🇺🇸Austin, Texas, United States
Jamaica Hospital Medical Center
🇺🇸Richmond Hill, New York, United States
Weil Medical college of Cornell
🇺🇸New York, New York, United States
Peak Clinical Trials, LLC
🇺🇸Apex, North Carolina, United States
Baylor Scott and White
🇺🇸Temple, Texas, United States
Heart House Research Foundation
🇺🇸Springfield, Ohio, United States
West Virginia University
🇺🇸Morgantown, West Virginia, United States
VA Caribbean Healthcare System
🇵🇷San Juan, Puerto Rico
San Antonio Endovascular and Heart Institute
🇺🇸San Antonio, Texas, United States
Brooke Army Medical Center
🇺🇸Fort Sam Houston, Texas, United States
Carilion Clinic
🇺🇸Roanoke, Virginia, United States
Dignity Health-St. Joseph
🇺🇸Phoenix, Arizona, United States
James A. Haley Veterans Hospital
🇺🇸Tampa, Florida, United States
AdventHealth Tampa - Pepin Heart Institute
🇺🇸Tampa, Florida, United States
Interventional Cardiac Consultants
🇺🇸Tampa, Florida, United States
BayCare Medical Group
🇺🇸Tampa, Florida, United States
Walter Reed National Military Medical Center
🇺🇸Bethesda, Maryland, United States
CHI Health Research Center
🇺🇸Omaha, Nebraska, United States
Lundquist Institute for Biomedical Innovation at Harbor UCLA Medical Center
🇺🇸Torrance, California, United States
University of Arizona
🇺🇸Tucson, Arizona, United States
Medicoricium
🇺🇸Fairview Heights, Illinois, United States
Western Kentucky Heart And Lung
🇺🇸Bowling Green, Kentucky, United States
University of Virginia Health System
🇺🇸Charlottesville, Virginia, United States
Bassett Healthcare Network
🇺🇸Cooperstown, New York, United States
Chippenham Hospital
🇺🇸Richmond, Virginia, United States
Orlando Health
🇺🇸Orlando, Florida, United States
Seton Heart Institute
🇺🇸Austin, Texas, United States
University of Arkansas
🇺🇸Little Rock, Arkansas, United States
Georgetown University
🇺🇸Washington, District of Columbia, United States
Baptist Health
🇺🇸Jacksonville, Florida, United States
University of Florida, Jacksonville
🇺🇸Jacksonville, Florida, United States
Charles H. Croft MDPA
🇺🇸Melbourne, Florida, United States
Cardiology Associates Research. LLC
🇺🇸Tupelo, Mississippi, United States
Naval Hospital Jacksonville
🇺🇸Jacksonville, Florida, United States
Southwest Florida Research Institute
🇺🇸Naples, Florida, United States
Ocala Research Institute Inc.
🇺🇸Ocala, Florida, United States
Naval Hospital Pensacola
🇺🇸Pensacola, Florida, United States
Berkshire Medical Center
🇺🇸Pittsfield, Massachusetts, United States
Family Medicine at Eastside Community Practice
🇺🇸Gainesville, Florida, United States
Family Medicine at 4th Ave
🇺🇸Gainesville, Florida, United States
Family Medicine at Hampton Oaks Medical Plaza (Adults and Peds)
🇺🇸Gainesville, Florida, United States
Internal Medicine at Tower Hill
🇺🇸Gainesville, Florida, United States
Family Medicine at Haile Plantation (Adults & Peds)
🇺🇸Gainesville, Florida, United States
Malcom Randall VA Medical Center
🇺🇸Gainesville, Florida, United States
Spring Hill Cardiology
🇺🇸Gainesville, Florida, United States
Cardiovascular Clinic at UF Health UF
🇺🇸Gainesville, Florida, United States
Internal Medicine at UF Health Medical Plaza
🇺🇸Gainesville, Florida, United States
Family Medicine at Old Town (Adults and Peds)
🇺🇸Gainesville, Florida, United States