Microvascular Coronary Disease In Women: Impact Of Ranolazine

Microvascular Coronary Disease In Women: Impact Of Ranolazine

1. To evaluate the impact of ranolazine extended-release tablets in women with subendocardial ischemia due to microvascular endothelial dysfunction on myocardial ischemia (Cardiac Magnetic Resonance (CMR) extent, severity.
2. To evaluate the impact of ranolazine extended-release tablets in women with subendocardial ischemia due to microvascular endothelial dysfunction on the outcomes of angina (Seattle Angina Questionnaire (SAQ), WISE angina frequency, Duke Activity Status Inventory(DASI) and SF-36).

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.