Microvascular Coronary Disease In Women: Impact Of Ranolazine
NCT ID: NCT00570089
Last Updated: 2019-06-10
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE2
20 participants
INTERVENTIONAL
2007-04-30
2009-12-31
Brief Summary
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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).
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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
CROSSOVER
TREATMENT
DOUBLE
Study Groups
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Study Drug Ranexa, Then Placebo
Participants first received study drug Ranexa, 500mg, orally twice daily for 2 weeks, assuming tolerance, followed by 1000mg orally twice daily for an additional 2 weeks. If the participant is unable to increase dose secondary to side effects, she will remain on 500mg twice daily for the second 2-week interval.
After a washout period of 2 weeks, they then received Placebo tablet (matching Ranexa tablet).
Ranolazine
500mg, orally twice daily for 2 weeks, assuming tolerance, followed by 1000mg orally twice daily for an additional 2 weeks. If the participant is unable to increase dose secondary to side effects, she will remain on 500mg twice daily for the second 2-week interval.
Placebo
Placebo, 500mg, orally twice daily for 2 weeks, assuming tolerance, followed by 1000mg orally twice daily for an additional 2 weeks. If the participant is unable to increase dose secondary to side effects, she will remain on 500mg twice daily for the second 2-week interval.
Placebo, Then Study Drug Ranexa(Ranolazine)
Participants first received Placebo tablet (matching Ranexa tablet) for two weeks.
After washout period of 2 weeks, they then received Ranexa 500mg, orally twice daily for 2 weeks, assuming tolerance, followed by 1000mg orally twice daily for an additional 2 weeks. If the participant is unable to increase dose secondary to side effects, she will remain on 500mg twice daily for the second 2-week interval.
Ranolazine
500mg, orally twice daily for 2 weeks, assuming tolerance, followed by 1000mg orally twice daily for an additional 2 weeks. If the participant is unable to increase dose secondary to side effects, she will remain on 500mg twice daily for the second 2-week interval.
Placebo
Placebo, 500mg, orally twice daily for 2 weeks, assuming tolerance, followed by 1000mg orally twice daily for an additional 2 weeks. If the participant is unable to increase dose secondary to side effects, she will remain on 500mg twice daily for the second 2-week interval.
Interventions
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Ranolazine
500mg, orally twice daily for 2 weeks, assuming tolerance, followed by 1000mg orally twice daily for an additional 2 weeks. If the participant is unable to increase dose secondary to side effects, she will remain on 500mg twice daily for the second 2-week interval.
Placebo
Placebo, 500mg, orally twice daily for 2 weeks, assuming tolerance, followed by 1000mg orally twice daily for an additional 2 weeks. If the participant is unable to increase dose secondary to side effects, she will remain on 500mg twice daily for the second 2-week interval.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
2. Women with ≥10% myocardial ischemia by CMR perfusion.
Exclusion Criteria
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.
FEMALE
No
Sponsors
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CV Therapeutics
INDUSTRY
Cedars-Sinai Medical Center
OTHER
Responsible Party
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Noel Bairey Merz
Director
Principal Investigators
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Noel Bairey-Merz, MD
Role: PRINCIPAL_INVESTIGATOR
Cedars-Sinai Medical Center
Locations
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AHSP
Los Angeles, California, United States
Countries
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References
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Chaitman BR. Ranolazine for the treatment of chronic angina and potential use in other cardiovascular conditions. Circulation. 2006 May 23;113(20):2462-72. doi: 10.1161/CIRCULATIONAHA.105.597500. No abstract available.
Buchthal SD, den Hollander JA, Merz CN, Rogers WJ, Pepine CJ, Reichek N, Sharaf BL, Reis S, Kelsey SF, Pohost GM. Abnormal myocardial phosphorus-31 nuclear magnetic resonance spectroscopy in women with chest pain but normal coronary angiograms. N Engl J Med. 2000 Mar 23;342(12):829-35. doi: 10.1056/NEJM200003233421201.
Doyle M, Fuisz A, Kortright E, Biederman RW, Walsh EG, Martin ET, Tauxe L, Rogers WJ, Merz CN, Pepine C, Sharaf B, Pohost GM. The impact of myocardial flow reserve on the detection of coronary artery disease by perfusion imaging methods: an NHLBI WISE study. J Cardiovasc Magn Reson. 2003 Jul;5(3):475-85. doi: 10.1081/jcmr-120022263.
Hundley WG, Hamilton CA, Thomas MS, Herrington DM, Salido TB, Kitzman DW, Little WC, Link KM. Utility of fast cine magnetic resonance imaging and display for the detection of myocardial ischemia in patients not well suited for second harmonic stress echocardiography. Circulation. 1999 Oct 19;100(16):1697-702. doi: 10.1161/01.cir.100.16.1697.
Hundley WG, Hillis LD, Hamilton CA, Applegate RJ, Herrington DM, Clarke GD, Braden GA, Thomas MS, Lange RA, Peshock RM, Link KM. Assessment of coronary arterial restenosis with phase-contrast magnetic resonance imaging measurements of coronary flow reserve. Circulation. 2000 May 23;101(20):2375-81. doi: 10.1161/01.cir.101.20.2375.
Hundley WG, Morgan TM, Neagle CM, Hamilton CA, Rerkpattanapipat P, Link KM. Magnetic resonance imaging determination of cardiac prognosis. Circulation. 2002 Oct 29;106(18):2328-33. doi: 10.1161/01.cir.0000036017.46437.02.
Johnson BD, Shaw LJ, Buchthal SD, Bairey Merz CN, Kim HW, Scott KN, Doyle M, Olson MB, Pepine CJ, den Hollander J, Sharaf B, Rogers WJ, Mankad S, Forder JR, Kelsey SF, Pohost GM; National Institutes of Health-National Heart, Lung, and Blood Institute. Prognosis in women with myocardial ischemia in the absence of obstructive coronary disease: results from the National Institutes of Health-National Heart, Lung, and Blood Institute-Sponsored Women's Ischemia Syndrome Evaluation (WISE). Circulation. 2004 Jun 22;109(24):2993-9. doi: 10.1161/01.CIR.0000130642.79868.B2. Epub 2004 Jun 14.
Kim RJ, Wu E, Rafael A, Chen EL, Parker MA, Simonetti O, Klocke FJ, Bonow RO, Judd RM. The use of contrast-enhanced magnetic resonance imaging to identify reversible myocardial dysfunction. N Engl J Med. 2000 Nov 16;343(20):1445-53. doi: 10.1056/NEJM200011163432003.
Kim WY, Danias PG, Stuber M, Flamm SD, Plein S, Nagel E, Langerak SE, Weber OM, Pedersen EM, Schmidt M, Botnar RM, Manning WJ. Coronary magnetic resonance angiography for the detection of coronary stenoses. N Engl J Med. 2001 Dec 27;345(26):1863-9. doi: 10.1056/NEJMoa010866.
Nagel E, Lehmkuhl HB, Bocksch W, Klein C, Vogel U, Frantz E, Ellmer A, Dreysse S, Fleck E. Noninvasive diagnosis of ischemia-induced wall motion abnormalities with the use of high-dose dobutamine stress MRI: comparison with dobutamine stress echocardiography. Circulation. 1999 Feb 16;99(6):763-70. doi: 10.1161/01.cir.99.6.763.
Nagel E, Klein C, Paetsch I, Hettwer S, Schnackenburg B, Wegscheider K, Fleck E. Magnetic resonance perfusion measurements for the noninvasive detection of coronary artery disease. Circulation. 2003 Jul 29;108(4):432-7. doi: 10.1161/01.CIR.0000080915.35024.A9. Epub 2003 Jul 14.
Panting JR, Gatehouse PD, Yang GZ, Grothues F, Firmin DN, Collins P, Pennell DJ. Abnormal subendocardial perfusion in cardiac syndrome X detected by cardiovascular magnetic resonance imaging. N Engl J Med. 2002 Jun 20;346(25):1948-53. doi: 10.1056/NEJMoa012369.
Schwitter J, DeMarco T, Kneifel S, von Schulthess GK, Jorg MC, Arheden H, Ruhm S, Stumpe K, Buck A, Parmley WW, Luscher TF, Higgins CB. Magnetic resonance-based assessment of global coronary flow and flow reserve and its relation to left ventricular functional parameters: a comparison with positron emission tomography. Circulation. 2000 Jun 13;101(23):2696-702. doi: 10.1161/01.cir.101.23.2696.
Wahl A, Paetsch I, Gollesch A, Roethemeyer S, Foell D, Gebker R, Langreck H, Klein C, Fleck E, Nagel E. Safety and feasibility of high-dose dobutamine-atropine stress cardiovascular magnetic resonance for diagnosis of myocardial ischaemia: experience in 1000 consecutive cases. Eur Heart J. 2004 Jul;25(14):1230-6. doi: 10.1016/j.ehj.2003.11.018.
Mehta PK, Goykhman P, Thomson LE, Shufelt C, Wei J, Yang Y, Gill E, Minissian M, Shaw LJ, Slomka PJ, Slivka M, Berman DS, Bairey Merz CN. Ranolazine improves angina in women with evidence of myocardial ischemia but no obstructive coronary artery disease. JACC Cardiovasc Imaging. 2011 May;4(5):514-22. doi: 10.1016/j.jcmg.2011.03.007.
Other Identifiers
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IRB 10465
Identifier Type: -
Identifier Source: org_study_id
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