A randomized, placebo-controlled trial of late Na current inhibition (ranolazine) in coronary microvascular dysfunction (CMD): Impact on angina and myocardial perfusion reserve

European Heart Journal

Volumn 37, Issue 19, 2016, Pages 1504-1513

  Merz, C Noel Bairey ^a   Handberg, Eileen M ^b   Shufelt, Chrisandra L ^a   Mehta, Puja K ^a   Minissian, Margo B ^a   Wei, Janet ^a   Thomson, Louise E J ^a   Berman, Daniel S ^a   Shaw, Leslee J ^c   Petersen, John W ^b   Brown, Garrett H ^b   Anderson, R David ^b   Shuster, Jonathan J ^b   Cook Wiens, Galen ^a   Rogatko, Andre ^a   Pepine, Carl J ^b  

^a CEDARS SINAI MEDICAL CENTER   (United States)

^b UNIVERSITY OF FLORIDA   (United States)

^c EMORY UNIVERSITY   (United States)

Author keywords

Eosinophils; Histopathology; Neutrophil extracellular traps; Neutrophils; Platelets; Stent thrombosis; Thrombus aspiration

Indexed keywords

ANGIOTENSIN RECEPTOR; BETA ADRENERGIC RECEPTOR BLOCKING AGENT; DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR; GADOLINIUM; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; NITRIC ACID DERIVATIVE; PLACEBO; RANOLAZINE; SODIUM CHANNEL BLOCKING AGENT;

ADULT; ANGINA PECTORIS; ARTICLE; ASSESSMENT OF HUMANS; BACKACHE; BODY MASS; BRADYCARDIA; BRONCHOSPASM; CARDIOVASCULAR MAGNETIC RESONANCE; CARDIOVASCULAR PARAMETERS; CONTRAST ENHANCEMENT; CONTROLLED STUDY; CORONARY ARTERY DISEASE; CORONARY FLOW RESERVE; CORONARY MICROVASCULAR DYSFUNCTION; COUGHING; CROSSOVER PROCEDURE; DIZZINESS; DOUBLE BLIND PROCEDURE; DRUG SAFETY; FAINTNESS; FEMALE; HEART EJECTION FRACTION; HEART INFARCTION; HEART RATE; HORMONE SUBSTITUTION; HUMAN; KIDNEY DISEASE; MAJOR CLINICAL STUDY; MALE; MEDICATION COMPLIANCE; MIDDLE AGED; MYOCARDIAL PERFUSION RESERVE; NAUSEA; NUCLEAR MAGNETIC RESONANCE SCANNER; PRESYNCOPE; PRIORITY JOURNAL; QUALITY OF LIFE; RANDOMIZED CONTROLLED TRIAL; RECTOCELE; SEATTLE ANGINA QUESTIONNAIRE; SODIUM CURRENT; THORAX PAIN; THROAT DISEASE; TREATMENT DURATION; CLINICAL TRIAL; DRUG ADMINISTRATION; HEART MUSCLE ISCHEMIA; HEMODYNAMICS; MAGNETIC RESONANCE ANGIOGRAPHY; MICROVASCULATURE; MULTICENTER STUDY; ORAL DRUG ADMINISTRATION; PATHOPHYSIOLOGY; PHYSIOLOGY; TREATMENT OUTCOME;

ADMINISTRATION, ORAL; ANGINA PECTORIS; CORONARY DISEASE; CROSS-OVER STUDIES; DOUBLE-BLIND METHOD; DRUG ADMINISTRATION SCHEDULE; FEMALE; HEMODYNAMICS; HUMANS; MAGNETIC RESONANCE ANGIOGRAPHY; MALE; MEDICATION ADHERENCE; MICROVESSELS; MIDDLE AGED; MYOCARDIAL ISCHEMIA; QUALITY OF LIFE; RANOLAZINE; SODIUM CHANNEL BLOCKERS; TREATMENT OUTCOME;

EID: 84975727145     PISSN: 0195668X     EISSN: 15229645     Source Type: Journal    
DOI: 10.1093/eurheartj/ehv647     Document Type: Article

References (48)

1. Pepine CJ, Ferdinand KC, Shaw L, Light-McGroary KA, Shah R, Gulati M, Duvernoy C,Walsh MN, Bairey Merz CN. Emergence of non-obstructive coronary artery disease: A woman's problem and need for change in definition on angiography. J Am Coll Cardiol 2015;66:1918-1933.
2. Jespersen L, Abildstrom SZ, Hvelplund A, Galatius S, Madsen JK, Pedersen F, Hojberg S, Prescott E. Symptoms of angina pectoris increase the probability of disability pension and premature exit from the workforce even in the absence of obstructive coronary artery disease. Eur Heart J 2013;34:3294-3303.
3. Shaw LJ, Merz CN, Pepine CJ, Reis SE, Bittner V, Kip KE, Kelsey SF, Olson M, Johnson BD, Mankad S, Sharaf BL, Rogers WJ, Pohost GM, Sopko G, Women's Ischemia Syndrome Evaluation I. The economic burden of angina in women with suspected ischemic heart disease: results from the National Institutes of Health-National Heart, Lung, and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation. Circulation 2006;114:894-904.
4. 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. 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;109:2993-2999.
5. Pepine CJ. Ischemic heart disease in women. J Am Coll Cardiol 2006;47(3 Suppl): S1-S3.
6. von Mering GO, Arant CB, Wessel TR, McGorray SP, Bairey Merz CN, Sharaf BL, Smith KM, Olson MB, Johnson BD, Sopko G, Handberg E, Pepine CJ, Kerensky RA. Abnormal coronary vasomotion as a prognostic indicator of cardiovascular events in women: results from the National Heart, Lung, and Blood Institute-Sponsored Women's Ischemia Syndrome Evaluation (WISE). Circulation 2004;109:722-725.
7. Murthy VL, Naya M, Taqueti VR, Foster CR, Gaber M, Hainer J, Dorbala S, Blankstein R, Rimoldi O, Camici PG, Di Carli MF. Effects of sex on coronary microvascular dysfunction and cardiac outcomes. Circulation 2014;129:2518-2527.
8. Chaitman BR. Ranolazine for the treatment of chronic angina and potential use in other cardiovascular conditions. Circulation 2006;113:2462-2472.
9. Chaitman BR, Pepine CJ, Parker JO, Skopal J, Chumakova G, Kuch J, Wang W, Skettino SL,Wolff AA. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: A randomized controlled trial. JAMA 2004;291:309-316.
10. Chaitman BR, Skettino SL, Parker JO, Hanley P, Meluzin J, Kuch J, Pepine CJ, Wang W, Nelson JJ, Hebert DA, Wolff AA. Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol 2004;43:1375-1382.
11. Timmis AD, Chaitman BR, Crager M. Effects of ranolazine on exercise tolerance and HbA1c in patients with chronic angina and diabetes. Eur Heart J 2006;27: 42-48.
12. Wenger NK, Chaitman B, VetrovecGW. Gender comparison of efficacy and safety of ranolazine for chronic angina pectoris in four randomized clinical trials. Am J Cardiol 2007;99:11-18.
13. Rousseau MF, Pouleur H, Cocco G, Wolff AA. Comparative efficacy of ranolazine versus atenolol for chronic angina pectoris. Am J Cardiol 2005;95:311-316.
14. Stone PH, Gratsiansky NA, Blokhin A, Huang IZ, Meng L. Antianginal efficacy of ranolazine when added to treatment with amlodipine: The ERICA (Efficacy of Ranolazine in Chronic Angina) trial. J Am Coll Cardiol 2006;48:566-575.
15. Kosiborod M, Arnold SV, Spertus JA, McGuire DK, Li Y, Yue P, Ben-Yehuda O, Katz A, Jones PG, Olmsted A, Belardinelli L, Chaitman BR. Evaluation of ranolazine in patients with type 2 diabetes mellitus and chronic stable angina. Results from the TERISA randomized clinical trial (type 2 diabetes evaluation of ranolazine in subjects with chronic stable angina). J Am Coll Cardiol 2013;61:2038-2045.
16. Task Force M, Montalescot G, Sechtem U, Achenbach S, Andreotti F, Arden C, Budaj A, Bugiardini R, Crea F, Cuisset T, Di Mario C, Ferreira JR, Gersh BJ, Gitt AK, Hulot JS, Marx N, Opie LH, Pfisterer M, Prescott E, Ruschitzka F, Sabate M, Senior R, Taggart DP, van der Wall EE, Vrints CJ, Guidelines ESCCfP, Zamorano JL, Achenbach S, Baumgartner H, Bax JJ, Bueno H, Dean V, Deaton C, Erol C, Fagard R, Ferrari R, Hasdai D, Hoes AW, Kirchhof P, Knuuti J, Kolh P, Lancellotti P, Linhart A, Nihoyannopoulos P, Piepoli MF, Ponikowski P, Sirnes PA, Tamargo JL, Tendera M, Torbicki A, WijnsW, Windecker S, Document R, Knuuti J, Valgimigli M, Bueno H, Claeys MJ, Donner-Banzhoff N, Erol C, Frank H, Funck-Brentano C, Gaemperli O, Gonzalez-Juanatey JR, Hamilos M, Hasdai D, Husted S, James SK, Kervinen K, Kolh P, Kristensen SD, Lancellotti P, Maggioni AP, Piepoli MF, Pries AR, Romeo F, Ryden L, Simoons ML, Sirnes PA, Steg PG, Timmis A, Wijns W, Windecker S, Yildirir A, Zamorano JL. 2013 ESC guidelines on the management of stable coronary artery disease: The Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J 2013;34:2949-3003.
17. Pepine CJ. Angina pectoris in a contemporary population: characteristics and therapeutic implications. TIDES Investigators. Cardiovasc Drugs Ther 1998;12(Suppl 3): 211-216.
18. Goykhman P, Mehta PK, Agarwal M, Shufelt C, Slomka PJ, Yang Y, Xu Y, Shaw LJ, Berman DS, Merz NB, Thomson LE. Reproducibility of myocardial perfusion reserve- variations in measurements from post processing using commercially available software. Cardiovasc Diagn Ther 2012;2:268-277.
19. Ishimori ML, Martin R, Berman DS, Goykhman P, Shaw LJ, Shufelt C, Slomka PJ, Thomson LE, Schapira J, Yang Y, Wallace DJ, Weisman MH, Bairey Merz CN. Myocardial ischemia in the absence of obstructive coronary artery disease in systemic lupus erythematosus. JACC Cardiovasc Imaging 2011;4:27-33.
20. Thomson LE, Wei J, Agarwal M, Haft-Baradaran A, Shufelt C, Mehta PK, Gill EB, Johnson BD, Kenkre T, Handberg EM, Li D, Sharif B, Berman DS, Petersen JW, Pepine CJ, Bairey Merz CN. Cardiac magnetic resonance myocardial perfusion reserve index is reduced in women with coronary microvascular dysfunction. A National Heart, Lung, and Blood Institute-sponsored study from the Women's Ischemia Syndrome Evaluation. Circ Cardiovasc Imaging 2015;3:153-160.
21. Nelson MD, Szczepaniak LS, Wei J, Haftabaradaren A, Bharadwaj M, Sharif B, Mehta P, Zhang X, Thomson LE, Berman DS, Li D, Bairey Merz CN. Diastolic dysfunction in women with signs and symptoms of ischemia in the absence of obstructive coronary artery disease: A hypothesis-generating study. Circ Cardiovasc Imaging 2014;7:510-516.
22. 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;4:514-522.
23. Spertus JA, Winder JA, Dewhurst TA, Deyo RA, Prodzinski J, McDonell M, Fihn SD. Development and evaluation of the Seattle Angina Questionnaire: A new functional status measure for coronary artery disease. J Am Coll Cardiol 1995;25: 333-341.
24. Chan PS, Jones PG, Arnold SA, Spertus JA. Development and validation of a short version of the Seattle angina questionnaire. Circ Cardiovasc Qual Outcome 2014;7: 640-647.
25. Hlatky MA, Boineau RE, Higginbotham MB, Lee KL, Mark DB, Califf RM, Cobb FR, Pryor DB. A brief self-administered questionnaire to determine functional capacity (the Duke Activity Status Index). Am J Cardiol 1989;64:651-654.
26. Anderson C, Laubscher S, Burns R. Validation of the Short Form 36 (SF-36) health survey questionnaire among stroke patients. Stroke 1996;27:1812-1816.
27. Hays R, Sherbourne C, Mazel R. User's Manual for the Medical Outcomes Study (MOS) Core: Measures of Health-related Quality of Life. MR-162-RC. Santa Monica: RAND; 1994. p. 172.
28. Ware J, Johnston S, Davies A, Brook R. Conceptualization and Measurement of Health for Adults in the Health Insurance Study. Santa Monica: RAND; 1987. p. 180.
29. Handberg EM, Eastwood JA, Eteiba W, Johnson BD, Krantz DS, Thompson DV, Vaccarino V, Bittner V, Sopko G, Pepine CJ, Merz NB, Rutledge TR. Clinical implications of theWomen's Ischemia Syndrome Evaluation: inter-relationships between symptoms, psychosocial factors and cardiovascular outcomes. Women's Health 2013;9:479-490.
30. Nabel EG, Ganz P, Gordon JB, Alexander RW, Selwyn AP. Dilation of normal and constriction of atherosclerotic coronary arteries caused by the cold pressor test. Circulation 1988;77:43-52.
31. Chih S, Macdonald PS, Feneley MP, Law M, Graham RM, McCrohon JA. Reproducibility of adenosine stress cardiovascular magnetic resonance in multi-vessel symptomatic coronary artery disease. J Cardiovasc Magn Reson 2010; 12:42.
32. Elkington AG, Gatehouse PD, Ablitt NA, Yang GZ, Firmin DN, Pennell DJ. Interstudy reproducibility of quantitative perfusion cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2005;7:815-822.
33. Agarwal M, Shufelt C, Mehta PK, Gill E, Berman DS, Li D, Sharif B, Li N, Bairey Merz CN, Thomson LE. Cardiac risk factors and myocardial perfusion reserve in women with microvascular coronary dysfunction. Cardiovasc Diagn Ther 2013;3: 146-152.
34. Pepine CJ, Anderson RD, Sharaf BL, Reis SE, Smith KM, Handberg EM, Johnson BD, Sopko G, Bairey Merz CN. Coronary microvascular reactivity to adenosine predicts adverse outcome in women evaluated for suspected ischemia results from the National Heart, Lung and Blood Institute WISE (Women's Ischemia Syndrome Evaluation) study. J Am Coll Cardiol 2010;55:2825-2832.
35. Schrimpf D, Pilz LR. Adaptive randomization procedures for the web-based randomization system RANDI2. Int J Clin Pharmacol Ther 2012;50:85-86.
36. Holm S. A simple sequentially rejective multiple test procedure. Scand J Statist 1979; 6:65-70.
37. Pocock S. Clinical Trials-a Practical Approach. Chichester-New York-Brisbane- Toronto-Singapore: John Wiley & Sons; 1983, p265 S.
38. De Bruyne B, Baudhuin T, Melin JA, Pijls NH, Sys SU, Bol A, Paulus WJ, Heyndrickx GR, Wijns W. Coronary flow reserve calculated from pressure measurements in humans. Validation with positron emission tomography. Circulation 1994;89:1013-1022.
39. Hozumi T, Yoshida K, Akasaka T, Asami Y, Ogata Y, Takagi T, Kaji S, Kawamoto T, Ueda Y, Morioka S. Noninvasive assessment of coronary flow velocity and coronary flow velocity reserve in the left anterior descending coronary artery by Doppler echocardiography: comparison with invasive technique. J Am Coll Cardiol 1998;32:1251-1259.
40. Letienne R, Vie B, Puech A, Vieu S, Le Grand B, JohnGW. Evidence that ranolazine behaves as a weak beta1-and beta2-adrenoceptor antagonist in the rat [correction of cat] cardiovascular system. Naunyn Schmiedebergs Arch Pharmacol 2001;363: 464-471.
41. Zhao G,Walsh E, Shryock JC, Messina E, Wu Y, Zeng D, Xu X, Ochoa M, Baker SP, Hintze TH, Belardinelli L. Antiadrenergic and hemodynamic effects of ranolazine in conscious dogs. J Cardiovasc Pharmacol 2011;57:639-647.
42. Tagliamonte E, Rigo F, Cirillo T, Astarita C, Quaranta G, Marinelli U, Caruso A, Romano C, Capuano N. Effects of ranolazine on noninvasive coronary flow reserve in patients with myocardial ischemia but without obstructive coronary artery disease. Echocardiography 2015;32:516-521.
43. Villano A, Di Franco A, Nerla R, Sestito A, Tarzia P, Lamendola P, Di Monaco A, Sarullo FM, Lanza GA, Crea F. Effects of ivabradine and ranolazine in patients with microvascular angina pectoris. Am J Cardiol 2013;112:8-13.
44. Stone AA, Shiffman S, Schwartz JE, Broderick JE, Hufford MR. Patient noncompliance with paper diaries. Bmj 2002;324:1193-1194.
45. Zhou JZ, Bi X, Yang H, Dharmakumar R, Arsanjani R, Bairey Merz C, Berman DS, Li D, Sharif B. First-pass perfusion CMR with reduced dark-rim artifact and instantaneous image reconstruction using optimized cartesian sampling and apodization. J Cardiovasc Magn Reson 2015;17(Supple 1):P001 (in press).
46. Nelson MD, Shaw J, Wei J, Mehta P, Motwani M, Thomson L, Berman DS, Thompson R, Li D, Bairey Merz CN, Sharif B. Subclinical left ventricular systolic and diastolic dysfunction in women with signs and symptoms of ischemia but no obstructive coronary artery disease: Novel insight using 'CINE' tracking in the NHLBI WISE study. Soc Cardiovasc Magn Reson; (under review).
47. Cocco G, Rousseau MF, Bouvy T, Cheron P, Williams G, Detry JM, Pouleur H. Effects of a new metabolic modulator, ranolazine, on exercise tolerance in angina pectoris patients treated with beta-blocker or diltiazem. J Cardiovasc Pharmacol 1992;20:131-138.
48. HayashidaW, van Eyll C, Rousseau MF, Pouleur H. Effects of ranolazine on left ventricular regional diastolic function in patients with ischemic heart disease. Cardiovasc Drugs Ther 1994;8:741-747.