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

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.

Inclusion Criteria:

- Signs and symptoms of suspected ischemia prompting referral for further evaluation by
cardiac catheterization or coronary angiogram or coronary CT angiogram within 3 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).