Microvascular Coronary Disease In Women: Impact Of Ranolazine

Interested women will be considered for the study if they meet inclusion and exclusion
criteria including review of baseline CMR, ECG and blood work (liver and kidney function).
The baseline CMR must be completed within 12 months previous to enrollment.

Eligible women with angina and CMR subendocardial perfusion abnormalities, defined as CMR
qualitative perfusion abnormalities of greater than or equal to 10% reported as abnormal
following blind review per protocol, will be consented and enrolled. The women will complete
baseline demographic and health history questionnaires, including the SAQ, Women's Ischemic
Syndrome Evaluation (WISE) angina frequency, DASI and SF-36.

This study is a double-blind, placebo controlled, cross-over design in which treatment order
to ranolazine and placebo will be randomly assigned. Note: The participant's usual medication
regimen will be continued throughout study participation. Following enrollment into the
study, participants will be randomized to treatment #1 (either placebo or ranolazine).
Ranolazine will be dosed as 500 mg orally twice daily for 2 weeks and, assuming tolerance,
followed by 1000 mg orally twice daily for an additional 2 weeks. If the participant is
unable to increase dose secondary to side effects, she will remain on 500 mg twice daily for
the second 2 week interval. The first end of treatment CMR (CMR 1) will be scheduled at the
end of the 4th week of treatment, approximately 4 hours after the morning dose of study drug.
At this visit (Vis 2), concurrent medications, symptoms, and adverse events will be reviewed.
Clinical measurements will be taken (weight, BP, waist and hip circumference) and
questionnaires will be completed (SAQ, WISE angina frequency, DASI and SF-36).

After the first course of study treatment, the patient will undergo a two week wash-out with
no study drug while continuing usual medication regimen. Following the washout period, study
participants will start the second cycle of study drug treatment (i.e., the other study drug
not received in treatment 1). At visit 3, participants will undergo baseline 2 measurements
which include concurrent medication and symptom assessment, clinical measurements (weight,
BP, waist and hip circumference) and will complete baseline 2 questionnaires (SAQ, WISE
angina frequency, DASI and SF-36). Study drug treatment #2 will follow the same escalation of
study drug dose as described above for treatment 1. The final study CMR (CMR 2) will be
scheduled at the end of the 4th week of treatment 2, approximately 4 hours after the morning
dose of study drug. At this visit (Vis 4), concurrent medications, symptoms, and adverse
events will be reviewed. Clinical measurements will be taken (weight, blood pressure, waist
and hip circumference) and questionnaires will be completed (SAQ, WISE angina frequency, DASI
and SF-36). [See Table 1 for a listing of all study procedures by visit.] The two post study
drug treatment CMRs will be performed at the same time of day, replicating temperature,
fasting state, adenosine dosing and infusion, magnet settings and using the same over-reader.
The dose of adenosine will be consistent for all study CMR tests: 140 mcg/kg over 5 minutes.

Inclusion Criteria:

1. Women with signs and symptoms of myocardial ischemia (chest pain, abnormal stress
testing, abnormal noninvasive testing) in the absence of obstructive coronary artery
disease (epicardial coronary stenosis <50% luminal diameter stenosis).

2. Women with ≥10% myocardial ischemia by CMR perfusion.

Exclusion Criteria:

1. Contraindications to withholding nitrates, beta-blockers, calcium channel agents,
ACE/ARB agents for 48 hours prior to testing.

2. Contraindications in CMR including AICD, pacemaker, untreatable claustrophobia or
known angio-edema.

3. Contraindications to ranolazine including hepatic insufficiency, prolonged QT, renal
failure.

4. Women taking drugs that inhibit CYP3A such as diltiazem, verapamil, ketoconazole,
macrolides or HIV protease inhibitors.

5. Women less than 18 years of age.

6. Women on drugs that prolong the QT interval such as Class Ia or III antiarrhythmic
agents, erythromycin, certain antipsychotics.

7. Pregnancy or breast feeding.

8. Life expectancy less than 6 months.