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

• Sponsor: University of Florida (Other)
• Overall Status: Recruiting
• CT.gov ID: NCT03417388
• Collaborator: United States Department of Defense (U.S. Fed)
• Enrollment: 4,422
• Locations: 84
• Arms: 2
• Anticipated Duration (Months): 70.6
• Patients Per Site: 52.6
• Patients Per Site Per Month: 0.7

Study Details

Study Description

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 ~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 Design

• Study Type: Interventional
• Anticipated 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.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: Feb 9, 2018
• Anticipated Primary Completion Date: Sep 30, 2023
• Anticipated Study Completion Date: Dec 30, 2023

Arms and Interventions

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 ; 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 Names: PACE Lifestyle Intervention ; Behavioral: Quality of Life Questionnaires; Quality of Life Questionnaires will be obtained.; Other Names: 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 Names: QOL

Outcome Measures

Primary Outcome Measures

1. 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).

2. 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).

3. 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.

4. 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.

5. 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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 100 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cardiology Associates of Mobile, Inc.	Mobile	Alabama	United States	36608
2	Dignity Health-Mercy Gilbert Medical Center	Gilbert	Arizona	United States	85297
3	Dignity Health-St. Joseph	Phoenix	Arizona	United States	85013
4	University of Arizona	Tucson	Arizona	United States	85721
5	University of Arkansas	Little Rock	Arkansas	United States	72205
6	Cedars-Sinai Heart Institute	Los Angeles	California	United States	90048
7	UCLA Medical Center	Los Angeles	California	United States	90095
8	Loma Linda University Health	Redlands	California	United States	92354
9	Lundquist Institute for Biomedical Innovation at Harbor UCLA Medical Center	Torrance	California	United States	90502
10	Georgetown University	Washington	District of Columbia	United States	20057
11	Clearwater Cardiovascular Consultants Clinical Research	Clearwater	Florida	United States	33756
12	South Palm Cardiovascular Research Institute	Delray Beach	Florida	United States	33446
13	Family Medicine at Eastside Community Practice	Gainesville	Florida	United States	32206
14	Family Medicine at Hampton Oaks Medical Plaza (Adults and Peds)	Gainesville	Florida	United States	32607
15	Internal Medicine at Tower Hill	Gainesville	Florida	United States	32607
16	Family Medicine at Haile Plantation (Adults & Peds)	Gainesville	Florida	United States	32608
17	Malcom Randall VA Medical Center	Gainesville	Florida	United States	32608
18	Cardiovascular Clinic at UF Health UF	Gainesville	Florida	United States	32610
19	Internal Medicine at UF Health Medical Plaza	Gainesville	Florida	United States	32610
20	Spring Hill Cardiology	Gainesville	Florida	United States	32610
21	Family Medicine at 4th Ave	Gainesville	Florida	United States	32611
22	Family Medicine at Old Town (Adults and Peds)	Gainesville	Florida	United States	32680
23	Baptist Health	Jacksonville	Florida	United States	32207
24	University of Florida, Jacksonville	Jacksonville	Florida	United States	32209
25	Naval Hospital Jacksonville	Jacksonville	Florida	United States	32214
26	Mayo Clinic Jacksonville	Jacksonville	Florida	United States	32224
27	UF Primary Care at Lake City SW	Lake City	Florida	United States	32024
28	UF Primary Care at Lake City West	Lake City	Florida	United States	32024
29	Charles H. Croft MDPA	Melbourne	Florida	United States	32901
30	Daytona Heart Group	Multiple Locations	Florida	United States	32114
31	Southwest Florida Research Institute	Naples	Florida	United States	34102
32	Cardiovascular Instititute of Central Florida	Ocala	Florida	United States	34471
33	Ocala Research Institute Inc.	Ocala	Florida	United States	34480
34	Advent Health Orlando	Orlando	Florida	United States	32803
35	Orlando Health	Orlando	Florida	United States	32806
36	Naval Hospital Pensacola	Pensacola	Florida	United States	32512
37	Cardiovascular Center of Sarasota	Sarasota	Florida	United States	34239
38	Advent Sebring	Sebring	Florida	United States	33872
39	James A. Haley Veterans Hospital	Tampa	Florida	United States	33612
40	AdventHealth Tampa - Pepin Heart Institute	Tampa	Florida	United States	33613
41	Interventional Cardiac Consultants	Tampa	Florida	United States	33613
42	BayCare Medical Group	Tampa	Florida	United States	33614
43	Guardian Research	Winter Park	Florida	United States	32792
44	Emory University	Atlanta	Georgia	United States	30322
45	Cardiovascular Consultants of South Georgia, LLC.	Thomasville	Georgia	United States	31792
46	Loyola University Chicago	Chicago	Illinois	United States	60660
47	Medicoricium	Fairview Heights	Illinois	United States	62208
48	Carle Foundation Hospital	Urbana	Illinois	United States	61801
49	Midwest Cardiovascular Research and Education Foundation	Elkhart	Indiana	United States	46514
50	Lutheran Health Physicians	Fort Wayne	Indiana	United States	46804
51	Midwest Heart and Vascular Specialists	Overland Park	Kansas	United States	66211
52	Western Kentucky Heart And Lung	Bowling Green	Kentucky	United States	42103
53	The Research Group of Lexington, LLC	Lexington	Kentucky	United States	40503
54	University of Kentucky	Lexington	Kentucky	United States	40506
55	Tulane University Heart and Vascular Institute	New Orleans	Louisiana	United States	70112
56	Walter Reed National Military Medical Center	Bethesda	Maryland	United States	20889
57	Berkshire Medical Center	Pittsfield	Massachusetts	United States	01201
58	Mid Michigan Health	Midland	Michigan	United States	48670
59	Essentia Institute of Rural Health	Duluth	Minnesota	United States	55805
60	Minneapolis Heart Institute Foundation	Minneapolis	Minnesota	United States	55407
61	Cardiology Associates Research, LLC	Tupelo	Mississippi	United States	38801
62	Cardiology Associates Research. LLC	Tupelo	Mississippi	United States	38801
63	CHI Health Research Center	Omaha	Nebraska	United States	68124
64	Silver State Cardiology	Henderson	Nevada	United States	89052
65	The Valley Hospital	Ridgewood	New Jersey	United States	07450
66	Bassett Healthcare Network	Cooperstown	New York	United States	13326
67	NYU Langone	New York	New York	United States	10016
68	Weil Medical college of Cornell	New York	New York	United States	10065
69	Jamaica Hospital Medical Center	Richmond Hill	New York	United States	11418
70	Peak Clinical Trials, LLC	Apex	North Carolina	United States	27502
71	Pinehurst Medical Clinic	Pinehurst	North Carolina	United States	38274
72	The Christ Hospital	Cincinnati	Ohio	United States	45219
73	Trihealth Heart Institute	Cincinnati	Ohio	United States	45242
74	Heart House Research Foundation	Springfield	Ohio	United States	45505
75	Seton Heart Institute	Austin	Texas	United States	78705
76	Austin Heart	Austin	Texas	United States	78756
77	Brooke Army Medical Center	Fort Sam Houston	Texas	United States	78234
78	San Antonio Endovascular and Heart Institute	San Antonio	Texas	United States	78258
79	Baylor Scott and White	Temple	Texas	United States	76508
80	University of Virginia Health System	Charlottesville	Virginia	United States	22908
81	Chippenham Hospital	Richmond	Virginia	United States	23225
82	Carilion Clinic	Roanoke	Virginia	United States	24017
83	West Virginia University	Morgantown	West Virginia	United States	26508
84	VA Caribbean Healthcare System	San Juan		Puerto Rico	00921

Sponsors and Collaborators

• University of Florida
• United States Department of Defense

Investigators

• Principal Investigator: Carl J Pepine, MD, University of Florida

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Florida
• ClinicalTrials.gov Identifier: NCT03417388
• Other Study ID Numbers: IRB201701142 -A; W81XWH-17-2-0030; OCR17268; IRB201802734; IRB201701434
• First Posted: Jan 31, 2018
• Last Update Posted: Sep 16, 2021
• Last Verified: Sep 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• 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: Coronary Artery Disease; Ischemia; Aspirin; Losartan; Lisinopril; Atorvastatin; Rosuvastatin Calcium

Study Results

No Results Posted as of Sep 16, 2021