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

All-cause death will be used 1) CV death is insensitive in this population with non-obstructive CAD since death is less likely attributed to CV causes when no obstructive CAD is present; 2) all-cause death is resistant to ascertainment bias in this unblinded trial. CV death will be defined broadly to include both definite CV death and possible CV death (all deaths except those with definite non-CV cause, e.g., cancer, witnessed trauma and homicide).

The MI definition follows universal criteria for Types 1-5 MI events. Stroke/TIA definition is new onset neurological defect of central origin confirmed by brain imaging (CT or MRI) evidence of cerebral infarction or intracerebral hemorrhage.

Hospitalization for angina- Any hospitalization for angina, plus unstable angina or ACS.

Hospitalization for Heart Failure -required established objective criteria for heart failure.

All MACE events are adjudicated by a blinded Clinical Endpoint Committee

The analysis will be repeated for the following combinations of MACE events (1) composite outcome of CV-death, non-fatal MI, or non-fatal stroke/TIA; (2) composite outcome CV-death, non-fatal MI, resuscitated cardiac arrest, or hospitalization for angina or heart failure; (3) all-cause mortality; (4) CV-death (5) total MI [fatal plus non-fatal]; (6) resuscitated cardiac arrest; (7) hospitalization for angina; (8) hospitalization for HF; (9) total stroke/TIA [fatal plus non- fatal]; (10) composite outcome of CV-death, non-fatal MI, stroke/TIA, resuscitated cardiac arrest, or hospitalization for angina or heart failure.

The comparison of randomized treatment strategies for composite hierarchical endpoint will be conducted using win statistics (WS), including the win ratio (WR), win odds (WO), will be computed to compare two groups based on hierarchical order of clinical importance as follows: 1) all cause death within 5 yrs, 2) stroke within 5 yrs, 3) MI within 5 yrs, 4) number of hospitalization within 5 yrs, 5) first hospitalization for heart failure or chest pain within 5 yrs, and 6) average of SAQ7 at 6 months and 1-year. The WR method compares each patient in the intervention group with every patient in the control group, and the magnitude of the effect is computed as the ratio of the total number of pairwise "wins" to "losses" considering the predefined hierarchy of the outcomes. Since the WR does not account for ties that the WO will also be computed. The benefit of the IMT arm is indicated by an estimate of WS/WO test statistic with their respective 95% confidence intervals greater than 1.

QoL comparisons will adhere to the ITT principle. We will examine changes over time from baseline and identify the major determinants of those changes using regression analysis. Questionnaires, such as the SAQ scores, at each time point will be analyzed using linear mixed models with correlation within subjects over time. In case the outcome residuals do not have a normal distribution, a transformation will be considered (e.g. log, Box-Cox). Interaction of group and time effects will be examined to assess for different time trends between groups.

Evaluated over time by group.

DASI as assessed over time by group.

Measure of medication compliance between groups over time.

Assessment of healthy lifestyle intervention between groups over time.

Screening for PTSD over time between groups

Comparing health care resource utilization across time between groups.

Assessment of general anxiety over time between groups

Assessment of depression over time between groups

MACE is first occurrence of all cause death, non fatal MI, non fatal stroke or TIA, hospitalization for heart failure, hospitalization for chest pain/angina. Quality of life is being assessed using Seattle Angina Questionnaire, SAQ7 and all of the SAQ domains, PTSD is being assessed using the PCL5, functional capacity is being assessed using the Duke Activity Status Index, EQ-5D-3L, Depression is being assessed using the PHQ-8 and anxiety using the GAD-7

Using Andersen-Gill model with frailty to describe the repeated events: all-cause death, non-fatal MI, non-fatal stroke/TIA, or hospitalization for either angina or heart failure. Definitions of repeated events include 30 days between a documented MI and death as a standard definition for "Fatal MI" and >48hrs was a standard for exacerbation of ischemia (chest pain or ECG changes of ischemia) to call it a "new event" (e.g., either an MI, HF, or another exacerbation of ischemia).