Clinical trial NCT03417388: Women's IschemiA TRial to Reduce Events In Non-ObstRuctive CAD
Official title: Women's IschemiA TRial to Reduce Events In Non-ObstRuctive CAD
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE4
Conditions: Coronary Artery Disease
Keywords: Coronary Angiography
Coronary CT Angiogram
Ischemia
Non-obstructive CAD
Lead sponsor: University of Florida
Sponsor class: OTHER
Collaborators: name: United States Department of Defense
First posted: 2018-01-31
Enrollment: 2476
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This will be a PROBE design, that will evaluate an intensive statin/ACE-I (or ARB) treatment strategy (IMT) vs. primary prevention risk factor therapy treatment strategy (UC) in symptomatic (chronic angina or equivalent) women with non-obstructive CAD.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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)

Primary outcomes:
measure: All Cause Death incidents reported between the two groups
timeFrame: 3 years
measure: Non-fatal myocardial infarction (MI) incidents reported between the two groups
timeFrame: 3 years
measure: Stroke/TIA incidents reported between the two groups
timeFrame: 3 years
measure: Hospitalizations for cardiovascular events reported between the two groups
timeFrame: 3 years
measure: Hospitalizations for heart failure incidents reported between the two groups
timeFrame: 3 years
Secondary outcomes:
Other outcomes:
Locations:
city: Mobile
country: United States
facility: Cardiology Associates of Mobile, Inc.
state: Alabama
city: Gilbert
country: United States
facility: Dignity Health-Mercy Gilbert Medical Center
state: Arizona
city: Phoenix
country: United States
facility: Dignity Health-St. Joseph
state: Arizona
city: Tucson
country: United States
facility: University of Arizona
state: Arizona
city: Little Rock
country: United States
facility: University of Arkansas
state: Arkansas
city: Los Angeles
country: United States
facility: Cedars-Sinai Heart Institute
state: California
city: Los Angeles
country: United States
facility: UCLA Medical Center
state: California
city: Torrance
country: United States
facility: Lundquist Institute for Biomedical Innovation at Harbor UCLA Medical Center
state: California
city: Washington
country: United States
facility: Georgetown University
state: District of Columbia
city: Clearwater
country: United States
facility: Clearwater Cardiovascular Consultants Clinical Research
state: Florida
city: Delray Beach
country: United States
facility: South Palm Cardiovascular Research Institute
state: Florida
city: Gainesville
country: United States
facility: Family Medicine at Eastside Community Practice
state: Florida
city: Gainesville
country: United States
facility: Family Medicine at Hampton Oaks Medical Plaza (Adults and Peds)
state: Florida
city: Gainesville
country: United States
facility: Internal Medicine at Tower Hill
state: Florida
city: Gainesville
country: United States
facility: Family Medicine at Haile Plantation (Adults & Peds)
state: Florida
city: Gainesville
country: United States
facility: Malcom Randall VA Medical Center
state: Florida
city: Gainesville
country: United States
facility: Cardiovascular Clinic at UF Health UF
state: Florida
city: Gainesville
country: United States
facility: Internal Medicine at UF Health Medical Plaza
state: Florida
city: Gainesville
country: United States
facility: Spring Hill Cardiology
state: Florida
city: Gainesville
country: United States
facility: Family Medicine at 4th Ave
state: Florida
city: Gainesville
country: United States
facility: Family Medicine at Old Town (Adults and Peds)
state: Florida
city: Jacksonville
country: United States
facility: Baptist Health
state: Florida
city: Jacksonville
country: United States
facility: University of Florida, Jacksonville
state: Florida
city: Jacksonville
country: United States
facility: Naval Hospital Jacksonville
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic Jacksonville
state: Florida
city: Lake City
country: United States
facility: UF Primary Care at Lake City SW
state: Florida
city: Lake City
country: United States
facility: UF Primary Care at Lake City West
state: Florida
city: Melbourne
country: United States
facility: Charles H. Croft MDPA
state: Florida
city: Multiple Locations
country: United States
facility: Daytona Heart Group
state: Florida
city: Naples
country: United States
facility: Southwest Florida Research Institute
state: Florida
city: Ocala
country: United States
facility: Cardiovascular Instititute of Central Florida
state: Florida
city: Ocala
country: United States
facility: Ocala Research Institute Inc.
state: Florida
city: Orlando
country: United States
facility: Orlando Health
state: Florida
city: Pensacola
country: United States
facility: Naval Hospital Pensacola
state: Florida
city: Sarasota
country: United States
facility: Cardiovascular Center of Sarasota
state: Florida
city: Sebring
country: United States
facility: Advent Sebring
state: Florida
city: Tampa
country: United States
facility: James A. Haley Veterans Hospital
state: Florida
city: Tampa
country: United States
facility: AdventHealth Tampa - Pepin Heart Institute
state: Florida
city: Tampa
country: United States
facility: Interventional Cardiac Consultants
state: Florida
city: Tampa
country: United States
facility: BayCare Medical Group
state: Florida
city: Winter Park
country: United States
facility: Guardian Research
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Thomasville
country: United States
facility: Cardiovascular Consultants of South Georgia, LLC.
state: Georgia
city: Chicago
country: United States
facility: Loyola University Chicago
state: Illinois
city: Fairview Heights
country: United States
facility: Medicoricium
state: Illinois
city: Urbana
country: United States
facility: Carle Foundation Hospital
state: Illinois
city: Elkhart
country: United States
facility: Midwest Cardiovascular Research and Education Foundation
state: Indiana
city: Fort Wayne
country: United States
facility: Lutheran Health Physicians
state: Indiana
city: Overland Park
country: United States
facility: Midwest Heart and Vascular Specialists
state: Kansas
city: Bowling Green
country: United States
facility: Western Kentucky Heart And Lung
state: Kentucky
city: Lexington
country: United States
facility: The Research Group of Lexington, LLC
state: Kentucky
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Bethesda
country: United States
facility: Walter Reed National Military Medical Center
state: Maryland
city: Pittsfield
country: United States
facility: Berkshire Medical Center
state: Massachusetts
city: Midland
country: United States
facility: Mid Michigan Health
state: Michigan
city: Duluth
country: United States
facility: Essentia Institute of Rural Health
state: Minnesota
city: Minneapolis
country: United States
facility: Minneapolis Heart Institute Foundation
state: Minnesota
city: Tupelo
country: United States
facility: Cardiology Associates Research, LLC
state: Mississippi
city: Tupelo
country: United States
facility: Cardiology Associates Research. LLC
state: Mississippi
city: Omaha
country: United States
facility: CHI Health Research Center
state: Nebraska
city: Henderson
country: United States
facility: Silver State Cardiology
state: Nevada
city: Ridgewood
country: United States
facility: The Valley Hospital
state: New Jersey
city: Cooperstown
country: United States
facility: Bassett Healthcare Network
state: New York
city: New York
country: United States
facility: NYU Langone
state: New York
city: New York
country: United States
facility: Weil Medical college of Cornell
state: New York
city: Richmond Hill
country: United States
facility: Jamaica Hospital Medical Center
state: New York
city: Apex
country: United States
facility: Peak Clinical Trials, LLC
state: North Carolina
city: Pinehurst
country: United States
facility: Pinehurst Medical Clinic
state: North Carolina
city: Cincinnati
country: United States
facility: The Christ Hospital
state: Ohio
city: Cincinnati
country: United States
facility: Trihealth Heart Institute
state: Ohio
city: Springfield
country: United States
facility: Heart House Research Foundation
state: Ohio
city: Austin
country: United States
facility: Seton Heart Institute
state: Texas
city: Austin
country: United States
facility: Austin Heart
state: Texas
city: Fort Sam Houston
country: United States
facility: Brooke Army Medical Center
state: Texas
city: San Antonio
country: United States
facility: San Antonio Endovascular and Heart Institute
state: Texas
city: Temple
country: United States
facility: Baylor Scott and White
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia Health System
state: Virginia
city: Richmond
country: United States
facility: Chippenham Hospital
state: Virginia
city: Roanoke
country: United States
facility: Carilion Clinic
state: Virginia
city: Morgantown
country: United States
facility: West Virginia University
state: West Virginia
city: San Juan
country: Puerto Rico
facility: VA Caribbean Healthcare System
Study officials:
affiliation: University of Florida
name: Carl J Pepine, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.