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

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ClinicalTrials.gov Identifier: NCT03417388
Recruitment Status : Recruiting
First Posted : January 31, 2018
Last Update Posted : June 10, 2019
Sponsor:
Collaborator:
United States Department of Defense
Information provided by (Responsible Party):
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.


Condition or disease Intervention/treatment Phase
Coronary Artery Disease Drug: High dose potent statin Drug: ACE-I (lisinopril) or ARB (losartan) Drug: Aspirin Behavioral: Lifestyle Counseling Behavioral: Quality of Life Questionnaires Phase 4

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 ~50 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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 4422 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
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.
Masking: Single (Outcomes Assessor)
Masking Description: The Clinical Events Committee (CEC) will be masked to all treatment assignment.
Primary Purpose: Treatment
Official Title: Women's IschemiA TRial to Reduce Events In Non-ObstRuctive CAD
Actual Study Start Date : February 9, 2018
Estimated Primary Completion Date : December 30, 2021
Estimated Study Completion Date : December 30, 2022

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 Name: 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 Name: ACE-I or ARB

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

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

Behavioral: Quality of Life Questionnaires
Quality of Life Questionnaires will be obtained.
Other Name: QOL

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 Name: QOL




Primary Outcome Measures :
  1. All Cause Death incidents reported between the two groups [ Time Frame: 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).

  2. Non-fatal myocardial infarction (MI) incidents reported between the two groups [ Time Frame: 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).

  3. Stroke/TIA incidents reported between the two groups [ Time Frame: 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.

  4. Hospitalizations for cardiovascular events reported between the two groups [ Time Frame: 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.

  5. Hospitalizations for heart failure incidents reported between the two groups [ Time Frame: 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).



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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 <50% diameter reduction of a major epicardial vessel.

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.
  • Patients who have a Class 1 indication for high intensity statin therapy
  • 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 5 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 serum 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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03417388


Contacts
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Contact: Dana D Leach, ARNP-BC 352-273-8933 dana.leach@medicine.ufl.edu
Contact: Debra Landers 352-273-7901 debra.landers@medicine.ufl.edu

Locations
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United States, Alabama
Alabama Heart and Vascular Medicine Recruiting
Tuscaloosa, Alabama, United States, 35406
Principal Investigator: Kimberly Skelding, MD         
United States, California
Cedars-Sinai Heart Institute Recruiting
Los Angeles, California, United States, 90048
Contact: Sophie Yoo, MS    310-423-3300    jihye.yoo@cshs.org   
Principal Investigator: Chrisandra Shufelt, MD         
LA BioMedical Recruiting
Torrance, California, United States, 90502
Principal Investigator: Matthew Budoff, MD         
United States, Florida
Clearwater Cardiovascular Consultants Clinical Research Recruiting
Clearwater, Florida, United States, 33756
Principal Investigator: A-Hamid Hakki, MD         
South Palm Cardiovascular Research Institute Recruiting
Delray Beach, Florida, United States, 33446
Principal Investigator: Gustavo Cardenas, MD         
Family Medicine at Eastside Community Practice Recruiting
Gainesville, Florida, United States, 32206
Family Medicine at Hampton Oaks Medical Plaza (Adults and Peds) Recruiting
Gainesville, Florida, United States, 32607
Internal Medicine at Tower Hill Recruiting
Gainesville, Florida, United States, 32607
Family Medicine at Haile Plantation (Adults & Peds) Recruiting
Gainesville, Florida, United States, 32608
Cardiovascular Clinic at UF Health UF Recruiting
Gainesville, Florida, United States, 32610
Internal Medicine at UF Health Medical Plaza Recruiting
Gainesville, Florida, United States, 32610
UF Health at the University of Florida Recruiting
Gainesville, Florida, United States, 32610
Cardiology West at Doctors Park Recruiting
Gainesville, Florida, United States, 32611
Family Medicine at 4th Ave Recruiting
Gainesville, Florida, United States, 32611
Family Medicine at Old Town (Adults and Peds) Recruiting
Gainesville, Florida, United States, 32680
Baptist Health Recruiting
Jacksonville, Florida, United States, 32207
Principal Investigator: Ruple Galani, MD         
Naval Hospital Jacksonville Recruiting
Jacksonville, Florida, United States, 32214
UF Primary Care at Lake City SW Recruiting
Lake City, Florida, United States, 32024
UF Primary Care at Lake City West Recruiting
Lake City, Florida, United States, 32024
Novel Clinical Research Recruiting
Miami, Florida, United States, 33186
Contact: Heber L Varela, MD    786-773-2737      
Daytona Heart Group Recruiting
Multiple Locations, Florida, United States, 32114
Contact: Glenn Rayos, MD    386-258-8722      
Ocala Research Institute Inc. Recruiting
Ocala, Florida, United States, 34480
Contact: Rakesh Prashad, MD    352-412-5989      
Orlando Health Recruiting
Orlando, Florida, United States, 32806
Principal Investigator: Arnold Einhorn, MD         
Naval Hospital Pensacola Recruiting
Pensacola, Florida, United States, 32512
Principal Investigator: Carrie Gray, MD         
AdventHealth Tampa - Pepin Heart Institute Recruiting
Tampa, Florida, United States, 33613
Contact: Charles R Lambert, MD    813-615-7527      
Interventional Cardiac Consultants Recruiting
Tampa, Florida, United States, 33613
Contact: Carlos J Bayron, MD    727-842-9526      
United States, Kentucky
University of Kentucky Recruiting
Lexington, Kentucky, United States, 40506
Principal Investigator: Gretchen Wells, MD         
United States, Nevada
Silver State Cardiology Recruiting
Henderson, Nevada, United States, 89052
Principal Investigator: Leonard Parilak, MD         
United States, Ohio
Heart House Research Foundation Recruiting
Springfield, Ohio, United States, 45505
Principal Investigator: Sayed T Rizvi, MD         
Sponsors and Collaborators
University of Florida
United States Department of Defense
Investigators
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Principal Investigator: Carl J Pepine, MD University of Florida

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Responsible Party: University of Florida
ClinicalTrials.gov Identifier: NCT03417388     History of Changes
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 )
First Posted: January 31, 2018    Key Record Dates
Last Update Posted: June 10, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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

Keywords provided by University of Florida:
Coronary Angiography
Coronary CT Angiogram
Ischemia
Non-obstructive CAD

Additional relevant MeSH terms:
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Coronary Artery Disease
Myocardial Ischemia
Coronary Disease
Ischemia
Heart Diseases
Cardiovascular Diseases
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Pathologic Processes
Aspirin
Atorvastatin
Rosuvastatin Calcium
Lisinopril
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Losartan
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Platelet Aggregation Inhibitors
Cyclooxygenase Inhibitors
Enzyme Inhibitors