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==Supportive trial data==
==Supportive trial data==
*In the '''MARISA''' trial, 191 patients with angina-limited exercise discontinued anti-anginal medications and were randomized to either [[ranolazine]] or placebo. The study reported patients with stable angina tolerated monotherapy better as evidenced by an increase in exercise performance and time to angina. However, the one-year survival did not decrease as expected ''(96.3 ± 1.7%)''.<ref name="pmid15093870">Chaitman BR, Skettino SL, Parker JO, Hanley P, Meluzin J, Kuch J et al. (2004) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=15093870 Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina.] ''J Am Coll Cardiol'' 43 (8):1375-82. [http://dx.doi.org/10.1016/j.jacc.2003.11.045 DOI:10.1016/j.jacc.2003.11.045] PMID: [http://pubmed.gov/15093870 15093870]</ref>
*In the '''MARISA''' trial, 191 patients with angina-limited exercise discontinued anti-anginal medications and were randomized to receive either, [[ranolazine]] or placebo treatments. The study reported patients with stable angina tolerated monotherapy better as evidenced by an increase in exercise performance and time to angina. However, the one-year survival did not decrease as expected ''(96.3 ± 1.7%)''.<ref name="pmid15093870">Chaitman BR, Skettino SL, Parker JO, Hanley P, Meluzin J, Kuch J et al. (2004) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=15093870 Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina.] ''J Am Coll Cardiol'' 43 (8):1375-82. [http://dx.doi.org/10.1016/j.jacc.2003.11.045 DOI:10.1016/j.jacc.2003.11.045] PMID: [http://pubmed.gov/15093870 15093870]</ref>


*In the '''CARISA''' trial, 823 patients with symptomatic chronic angina were randomized to either one of two doses of [[ranolazine]] or placebo. The study reported ranolazine offered additional anti-anginal and anti-ischemic efficacy as evidenced by increased exercise performance, time to angina and time to [[ST depression]] in patients with severe chronic angina who remain symptomatic while taking standard doses of [[atenolol]], [[amlodipine]], or [[diltiazem]]. There were no significant adverse long-term survival consequences over 1 to 2 years of therapy ''(One- and two-year survival rates of 98.4% and 95.9% respectively)''.<ref name="pmid14734593">Chaitman BR, Pepine CJ, Parker JO, Skopal J, Chumakova G, Kuch J et al. (2004) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=14734593 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'' 291 (3):309-16. [http://dx.doi.org/10.1001/jama.291.3.309 DOI:10.1001/jama.291.3.309] PMID: [http://pubmed.gov/14734593 14734593]</ref>
*In the '''CARISA''' trial, 823 patients with symptomatic chronic angina were randomized to receive either one of two doses of [[ranolazine]] or placebo. The study reported ranolazine offered additional anti-anginal and anti-ischemic efficacy as evidenced by increased exercise performance, time to angina and time to [[ST depression]] in patients with severe chronic angina who remain symptomatic while taking standard doses of [[atenolol]], [[amlodipine]], or [[diltiazem]]. There were no significant adverse long-term survival consequences over 1 to 2 years of therapy ''(One- and two-year survival rates of 98.4% and 95.9% respectively)''.<ref name="pmid14734593">Chaitman BR, Pepine CJ, Parker JO, Skopal J, Chumakova G, Kuch J et al. (2004) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=14734593 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'' 291 (3):309-16. [http://dx.doi.org/10.1001/jama.291.3.309 DOI:10.1001/jama.291.3.309] PMID: [http://pubmed.gov/14734593 14734593]</ref>


*'''MERLIN TIMI 36''' trial <ref name="pmid17804441">Scirica BM, Morrow DA, Hod H, Murphy SA, Belardinelli L, Hedgepeth CM et al. (2007) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=17804441 Effect of ranolazine, an antianginal agent with novel electrophysiological properties, on the incidence of arrhythmias in patients with non ST-segment elevation acute coronary syndrome: results from the Metabolic Efficiency With Ranolazine for Less Ischemia in Non ST-Elevation Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) randomized controlled trial.] ''Circulation'' 116 (15):1647-52. [http://dx.doi.org/10.1161/CIRCULATIONAHA.107.724880 DOI:10.1161/CIRCULATIONAHA.107.724880] PMID: [http://pubmed.gov/17804441 17804441]</ref> and its sub study <ref name="pmid19389561">Wilson SR, Scirica BM, Braunwald E, Murphy SA, Karwatowska-Prokopczuk E, Buros JL et al. (2009) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=19389561 Efficacy of ranolazine in patients with chronic angina observations from the randomized, double-blind, placebo-controlled MERLIN-TIMI (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Segment Elevation Acute Coronary Syndromes) 36 Trial.] ''J Am Coll Cardiol'' 53 (17):1510-6. [http://dx.doi.org/10.1016/j.jacc.2009.01.037 DOI:10.1016/j.jacc.2009.01.037] PMID: [http://pubmed.gov/19389561 19389561]</ref> are the most recent development in relation to [[ranolazine]]. In the MERLIN-TIMI 36 study, 6560 patients with prior chronic angina who received evidence based therapy (95% [[aspirin]], 78% [[statins]], 89% [[beta-blockers]], average 2.9 antianginal agents) were randomized to either [[ranolazine]] or placebo. The primary end point of all cause mortality or non-fatal [[MI]] during a median follow-up of 1 year was less frequent with ranolazine ''(HR:0.86; 95% CI:0.75 to 0.97; p=0.017)''. The study concluded that ranolazine not only improved anti-ischemic effects in the 3565 patients with prior chronic stable angina ''(HR:0.77; 95% CI:0.59 to 1.00; p=0.048)'', but also showed anti-arrythmic effects with decrease incidence of [[ventricular tachycardia]], [[SVT]] and ventricular pauses in ranolazine study group.
*'''MERLIN TIMI 36''' trial<ref name="pmid17804441">Scirica BM, Morrow DA, Hod H, Murphy SA, Belardinelli L, Hedgepeth CM et al. (2007) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=17804441 Effect of ranolazine, an antianginal agent with novel electrophysiological properties, on the incidence of arrhythmias in patients with non ST-segment elevation acute coronary syndrome: results from the Metabolic Efficiency With Ranolazine for Less Ischemia in Non ST-Elevation Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) randomized controlled trial.] ''Circulation'' 116 (15):1647-52. [http://dx.doi.org/10.1161/CIRCULATIONAHA.107.724880 DOI:10.1161/CIRCULATIONAHA.107.724880] PMID: [http://pubmed.gov/17804441 17804441]</ref> and its sub study<ref name="pmid19389561">Wilson SR, Scirica BM, Braunwald E, Murphy SA, Karwatowska-Prokopczuk E, Buros JL et al. (2009) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=19389561 Efficacy of ranolazine in patients with chronic angina observations from the randomized, double-blind, placebo-controlled MERLIN-TIMI (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Segment Elevation Acute Coronary Syndromes) 36 Trial.] ''J Am Coll Cardiol'' 53 (17):1510-6. [http://dx.doi.org/10.1016/j.jacc.2009.01.037 DOI:10.1016/j.jacc.2009.01.037] PMID: [http://pubmed.gov/19389561 19389561]</ref> are the most recent development in relation to [[ranolazine]]. In the MERLIN-TIMI 36 study, 6560 patients with prior chronic angina who received evidence based therapy (95% [[aspirin]], 78% [[statins]], 89% [[beta-blockers]], average 2.9 antianginal agents) were randomized to receive either, [[ranolazine]] or placebo. The primary end point of all cause mortality or non-fatal [[MI]] during a median follow-up of 1 year was less frequent with ranolazine ''(HR:0.86; 95% CI:0.75 to 0.97; p=0.017)''. The study concluded that ranolazine not only improved anti-ischemic effects in the 3565 patients with prior chronic stable angina ''(HR:0.77; 95% CI:0.59 to 1.00; p=0.048)'', but also showed anti-arrythmic effects with a decreased incidence of [[ventricular tachycardia]], [[SVT]] and ventricular pauses in ranolazine study group.


*In the '''ERICA trial''',565 patients with [[Chronic stable angina definition|stable coronary disease]] and more than three anginal attacks per week despite maximum recommended dosage of [[Chronic stable angina treatment calcium channel blockers|amlodipine]] (10 mg/day) and [[Chronic stable angina treatment nitrates|long acting nitrate therapy]], were randomized to receive either [[ranolazine]] or placebo to assess the effect of ranolazine on the frequency of anginal episode per week. Enrolled patients had a baseline anginal frequency of 5.63 episodes per week, and nitroglycerin consumption of 4.72 tablets per week. The study reported significant reduction in the frequency of anginal episodes between the two groups: 2.88 in the [[ranolazine]] group and 3.31 in the placebo group ''(p=0.028)''. In addition, there was also significant reduction in the nitroglycerin consumption observed between the two groups: 20.3 in the ranolazine group and 2.68 in the placebo group ''(p=0.014)''.<ref name="pmid16875985">Stone PH, Gratsiansky NA, Blokhin A, Huang IZ, Meng L, ERICA Investigators (2006) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=16875985 Antianginal efficacy of ranolazine when added to treatment with amlodipine: the ERICA (Efficacy of Ranolazine in Chronic Angina) trial.] ''J Am Coll Cardiol'' 48 (3):566-75. [http://dx.doi.org/10.1016/j.jacc.2006.05.044 DOI:10.1016/j.jacc.2006.05.044] PMID: [http://pubmed.gov/16875985 16875985]</ref>   
*In the '''ERICA trial''', 565 patients with [[Chronic stable angina definition|stable coronary disease]] and more than three anginal attacks per week despite maximum recommended dosage of [[Chronic stable angina treatment calcium channel blockers|amlodipine]] (10 mg/day) and [[Chronic stable angina treatment nitrates|long acting nitrate therapy]], were randomized to receive either [[ranolazine]] or placebo to assess the effect of ranolazine on the frequency of anginal episode per week. Enrolled patients had a baseline anginal frequency of 5.63 episodes per week, and nitroglycerin consumption of 4.72 tablets per week. The study reported significant reduction in the frequency of anginal episodes between the two groups: 2.88 tablets per week in the [[ranolazine]] group and 3.31 tablets per week in the placebo group ''(p=0.028)''. In addition, there was also significant reduction in the nitroglycerin consumption observed between the two groups: 20.3 tablets per week in the ranolazine group and 2.68 tablets per week in the placebo group ''(p=0.014)''.<ref name="pmid16875985">Stone PH, Gratsiansky NA, Blokhin A, Huang IZ, Meng L, ERICA Investigators (2006) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=16875985 Antianginal efficacy of ranolazine when added to treatment with amlodipine: the ERICA (Efficacy of Ranolazine in Chronic Angina) trial.] ''J Am Coll Cardiol'' 48 (3):566-75. [http://dx.doi.org/10.1016/j.jacc.2006.05.044 DOI:10.1016/j.jacc.2006.05.044] PMID: [http://pubmed.gov/16875985 16875985]</ref>   


*In a placebo-controlled trial, that evaluated the anti-anginal and anti-ischemic effects of '''[[ivabradine]]''', involved 360 patients with symptomatic chronic stable angina who were randomized to receive either ivabradine or placebo. The study reported that ivabradine produces a dose-dependent improvement in the exercise tolerance and time to the development of [[ischemia]] during exercise.<ref name="pmid12591750">Borer JS, Fox K, Jaillon P, Lerebours G, Ivabradine Investigators Group (2003) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=12591750 Antianginal and antiischemic effects of ivabradine, an I(f) inhibitor, in stable angina: a randomized, double-blind, multicentered, placebo-controlled trial.] ''Circulation'' 107 (6):817-23. PMID: [http://pubmed.gov/12591750 12591750]</ref>
*In a placebo-controlled trial, that evaluated the anti-anginal and anti-ischemic effects of '''[[ivabradine]]''', involved 360 patients with symptomatic chronic stable angina who were randomized to receive either ivabradine or placebo. The study reported that ivabradine produces a dose-dependent improvement in the exercise tolerance and time to the development of [[ischemia]] during exercise.<ref name="pmid12591750">Borer JS, Fox K, Jaillon P, Lerebours G, Ivabradine Investigators Group (2003) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=12591750 Antianginal and antiischemic effects of ivabradine, an I(f) inhibitor, in stable angina: a randomized, double-blind, multicentered, placebo-controlled trial.] ''Circulation'' 107 (6):817-23. PMID: [http://pubmed.gov/12591750 12591750]</ref>


*In the treatment of stable angina, a '''meta-analysis''' that evaluated the efficacy and tolerance of [[trimetazidine]], both in monotherapy and in combination with other antianginal agents, reported [[trimetazidine]] was well tolerated and significantly reduced the frequency of anginal attacks in coronary patients.<ref name="pmid12655281">Marzilli M, Klein WW (2003) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=12655281 Efficacy and tolerability of trimetazidine in stable angina: a meta-analysis of randomized, double-blind, controlled trials.] ''Coron Artery Dis'' 14 (2):171-9. [http://dx.doi.org/10.1097/01.mca.0000062799.53287.82 DOI:10.1097/01.mca.0000062799.53287.82] PMID: [http://pubmed.gov/12655281 12655281]</ref>
*In the treatment of stable angina, a '''meta-analysis''' that evaluated the efficacy and tolerance of [[trimetazidine]] both, in monotherapy and in combination with other antianginal agents, reported [[trimetazidine]] was well tolerated and significantly reduced the frequency of anginal attacks in coronary patients.<ref name="pmid12655281">Marzilli M, Klein WW (2003) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=12655281 Efficacy and tolerability of trimetazidine in stable angina: a meta-analysis of randomized, double-blind, controlled trials.] ''Coron Artery Dis'' 14 (2):171-9. [http://dx.doi.org/10.1097/01.mca.0000062799.53287.82 DOI:10.1097/01.mca.0000062799.53287.82] PMID: [http://pubmed.gov/12655281 12655281]</ref>


*Another '''meta-analysis''' that reviewed 23 randomized controlled trials comparing [[trimetazidine]] with placebo, or other [[Chronic stable angina pharmacotherapy overview|conventional anti-anginal agents]], involved 1,378 patients with [[Chronic stable angina definition|stable angina]], to assess the efficacy and tolerability of [[trimetazidine]]. There was a significant reduction in the number of weekly anginal episodes ''(mean difference -1.44, 95% CI -2.10 to -0.79; p<0.0001)'' and improved exercise time to 1 mm [[ST segment depression]] ''(p=0.0002)'' observed in the [[trimetazidine]] group. One of the four small trials involving 263 patients, favored [[trimetazidine]] over [[Chronic stable angina treatment nitrates|nitrates]] and the remaining three trials favored other anti-anginal agents. Thus, the study concluded that [[trimetazidine]] has shown to be effective in the treatment of [[Chronic stable angina definition|stable angina]] compared with placebo, alone or when used in combination with [[Chronic stable angina pharmacotherapy overview|conventional anti-anginal agents]], and associated fewer dropouts that were observed with [[trimetazidine]] were due to its adverse effects. Furthermore, the study proposed the need for large, long term trials comparing trimetazidine with other anti-anginal drugs to establish the clinical role of [[trimetazidine]].<ref name="pmid16235330">Ciapponi A, Pizarro R, Harrison J (2005) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=16235330 Trimetazidine for stable angina.] ''Cochrane Database Syst Rev''  (4):CD003614. [http://dx.doi.org/10.1002/14651858.CD003614.pub2 DOI:10.1002/14651858.CD003614.pub2] PMID: [http://pubmed.gov/16235330 16235330]</ref>
*Another '''meta-analysis''' that reviewed 23 randomized controlled trials comparing [[trimetazidine]] with placebo or other [[Chronic stable angina pharmacotherapy overview|conventional anti-anginal agents]], involved 1,378 patients with [[Chronic stable angina definition|stable angina]], to assess the efficacy and tolerability of [[trimetazidine]]. There was a significant reduction in the number of weekly anginal episodes ''(mean difference -1.44, 95% CI -2.10 to -0.79; p<0.0001)'' and improved exercise time to 1 mm [[ST segment depression]] ''(p=0.0002)'' observed in the [[trimetazidine]] group. One of the four small trials involving 263 patients, favored [[trimetazidine]] over [[Chronic stable angina treatment nitrates|nitrates]] and the remaining three trials favored other anti-anginal agents. Thus, the study concluded that [[trimetazidine]] has shown to be effective in the treatment of [[Chronic stable angina definition|stable angina]] when compared with placebo, alone or when used in combination with [[Chronic stable angina pharmacotherapy overview|conventional anti-anginal agents]]. It has also been associated with fewer dropouts resulting from [[trimetazidine]] and its adverse effects. Furthermore, the study proposed the need for large, long term trials comparing trimetazidine with other anti-anginal drugs to establish the clinical role of [[trimetazidine]].<ref name="pmid16235330">Ciapponi A, Pizarro R, Harrison J (2005) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=16235330 Trimetazidine for stable angina.] ''Cochrane Database Syst Rev''  (4):CD003614. [http://dx.doi.org/10.1002/14651858.CD003614.pub2 DOI:10.1002/14651858.CD003614.pub2] PMID: [http://pubmed.gov/16235330 16235330]</ref>


*In the '''TRIMPOL II trial''', 426 patients with stable, effort-induced angina and documented [[coronary artery disease]] were randomized to receive either [[trimetazidine]] or placebo, to assess the anti-ischemic efficacy and tolerability of [[trimetazidine]] when used in combination with a [[Chronic stable angina treatment beta blockers|beta blocker]] in patients with stable effort angina. At 12-week follow-up, the combined trimetazidine-beta blocker group showed significant improvement in the time to 1 mm [[ST segment depression]] during exercise, time to onset of angina and mean weekly number of anginal episodes. Thus, the study concluded that [[trimetazidine]] combined with a [[Chronic stable angina treatment beta blockers|beta blocker]] is useful in patients with stable angina that is insufficiently controlled by [[Chronic stable angina treatment beta blockers|beta blocker]] monotherapy.<ref name="pmid11728147">Szwed H, Sadowski Z, Elikowski W, Koronkiewicz A, Mamcarz A, Orszulak W et al. (2001) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=11728147 Combination treatment in stable effort angina using trimetazidine and metoprolol: results of a randomized, double-blind, multicentre study (TRIMPOL II). TRIMetazidine in POLand.] ''Eur Heart J'' 22 (24):2267-74. [http://dx.doi.org/10.1053/euhj.2001.2896 DOI:10.1053/euhj.2001.2896] PMID: [http://pubmed.gov/11728147 11728147]</ref>
*In the '''TRIMPOL II trial''', 426 patients with stable, effort-induced angina and documented [[coronary artery disease]] were randomized to receive either [[trimetazidine]] or placebo, to assess the anti-ischemic efficacy and tolerability of [[trimetazidine]] when used in combination with a [[Chronic stable angina treatment beta blockers|beta blocker]] in patients with stable effort angina. At 12-week follow-up, the combined trimetazidine-beta blocker group showed significant improvement in the time to 1 mm [[ST segment depression]] during exercise, time to onset of angina and mean weekly number of anginal episodes. Thus, the study concluded that [[trimetazidine]] combined with a [[Chronic stable angina treatment beta blockers|beta blocker]] is useful in patients with stable angina that is insufficiently controlled by [[Chronic stable angina treatment beta blockers|beta blocker]] monotherapy.<ref name="pmid11728147">Szwed H, Sadowski Z, Elikowski W, Koronkiewicz A, Mamcarz A, Orszulak W et al. (2001) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=11728147 Combination treatment in stable effort angina using trimetazidine and metoprolol: results of a randomized, double-blind, multicentre study (TRIMPOL II). TRIMetazidine in POLand.] ''Eur Heart J'' 22 (24):2267-74. [http://dx.doi.org/10.1053/euhj.2001.2896 DOI:10.1053/euhj.2001.2896] PMID: [http://pubmed.gov/11728147 11728147]</ref>

Revision as of 16:09, 14 November 2011

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [5]; Associate Editor(s)-In-Chief: Cafer Zorkun, M.D., Ph.D. [6]; John Fani Srour, M.D.; Jinhui Wu, M.D.; Lakshmi Gopalakrishnan, M.B.B.S.

Overview

Ranolazine is a one of the newer FDA approved anti-anginal medication for management of chronic stable angina. Perhexiline is another anti-anginal, primarily used in Australia and New Zealand, being studied for use in the United States and UK. In patients with chronic stable angina, other effective agents with anti-anginal and anti-ischemic properties are ivabradine,trimetazidine and molsidomine.

Mechanisms of benefit

  • Ranolazine alters the trans-cellular late sodium current which remains open in pathologic states, such as ischemia and heart failure.[1] The persistent opening of late sodium channel leads to intracellular sodium and calcium overload and a subsequent increase in diastolic stiffness. This stiffness can lead to compression of the intramural vessels that supply the myocardium with blood and oxygen.[2][3] Therefore, inhibition of this effect results in improvement of ischemia and anginal symptoms.[4][5]
  • Ivabradine selectively inhibits the pacemaker If activity of the sinus node and therefore is negatively chronotropic both at rest and during activity. Ivabradine also produces a dose-dependent improvement in exercise tolerance and time to development of ischemia during exercise.[6][7]
  • Trimetazidine is a cyto-protective metabolic anti-anginal agent that promotes aerobic glycolysis by inhibiting anaerobic glycolysis and fatty acid metabolism. This mechanism ensures the proper functioning of ionic pumps and transmembranous sodium-potassium flow while maintaining cellular homeostasis in ischemic cells.[8]

Indication

  • Ranolazine is effective as both monotherapy [10] and combination therapy [11] for the treatment and prevention of anginal episodes, however is not effective to relieve an episode of angina that has already begun.
  • Ivabradine has shown to be as effective as beta-blockers and hence indicated symptomatic patients with a contra-indication to beta-blocker therapy.[7]
  • In patients with stable angina, trimetazidine has shown to improve exercise parameters and reduce the incidence of anginal episodes.[8] It is also shown to be effective both in monotherapy or when used in combination with standard anti-anginal agents. [12]

Dosage

In asymptomatic patients, an initial dose of 500 mg twice daily of ranolazine may be required and a dose of 1000 mg twice daily may be required in symptomatic patients.

Adverse effects

Supportive trial data

  • In the MARISA trial, 191 patients with angina-limited exercise discontinued anti-anginal medications and were randomized to receive either, ranolazine or placebo treatments. The study reported patients with stable angina tolerated monotherapy better as evidenced by an increase in exercise performance and time to angina. However, the one-year survival did not decrease as expected (96.3 ± 1.7%).[10]
  • In the CARISA trial, 823 patients with symptomatic chronic angina were randomized to receive either one of two doses of ranolazine or placebo. The study reported ranolazine offered additional anti-anginal and anti-ischemic efficacy as evidenced by increased exercise performance, time to angina and time to ST depression in patients with severe chronic angina who remain symptomatic while taking standard doses of atenolol, amlodipine, or diltiazem. There were no significant adverse long-term survival consequences over 1 to 2 years of therapy (One- and two-year survival rates of 98.4% and 95.9% respectively).[11]
  • MERLIN TIMI 36 trial[18] and its sub study[19] are the most recent development in relation to ranolazine. In the MERLIN-TIMI 36 study, 6560 patients with prior chronic angina who received evidence based therapy (95% aspirin, 78% statins, 89% beta-blockers, average 2.9 antianginal agents) were randomized to receive either, ranolazine or placebo. The primary end point of all cause mortality or non-fatal MI during a median follow-up of 1 year was less frequent with ranolazine (HR:0.86; 95% CI:0.75 to 0.97; p=0.017). The study concluded that ranolazine not only improved anti-ischemic effects in the 3565 patients with prior chronic stable angina (HR:0.77; 95% CI:0.59 to 1.00; p=0.048), but also showed anti-arrythmic effects with a decreased incidence of ventricular tachycardia, SVT and ventricular pauses in ranolazine study group.
  • In the ERICA trial, 565 patients with stable coronary disease and more than three anginal attacks per week despite maximum recommended dosage of amlodipine (10 mg/day) and long acting nitrate therapy, were randomized to receive either ranolazine or placebo to assess the effect of ranolazine on the frequency of anginal episode per week. Enrolled patients had a baseline anginal frequency of 5.63 episodes per week, and nitroglycerin consumption of 4.72 tablets per week. The study reported significant reduction in the frequency of anginal episodes between the two groups: 2.88 tablets per week in the ranolazine group and 3.31 tablets per week in the placebo group (p=0.028). In addition, there was also significant reduction in the nitroglycerin consumption observed between the two groups: 20.3 tablets per week in the ranolazine group and 2.68 tablets per week in the placebo group (p=0.014).[20]
  • In a placebo-controlled trial, that evaluated the anti-anginal and anti-ischemic effects of ivabradine, involved 360 patients with symptomatic chronic stable angina who were randomized to receive either ivabradine or placebo. The study reported that ivabradine produces a dose-dependent improvement in the exercise tolerance and time to the development of ischemia during exercise.[6]
  • In the treatment of stable angina, a meta-analysis that evaluated the efficacy and tolerance of trimetazidine both, in monotherapy and in combination with other antianginal agents, reported trimetazidine was well tolerated and significantly reduced the frequency of anginal attacks in coronary patients.[12]
  • Another meta-analysis that reviewed 23 randomized controlled trials comparing trimetazidine with placebo or other conventional anti-anginal agents, involved 1,378 patients with stable angina, to assess the efficacy and tolerability of trimetazidine. There was a significant reduction in the number of weekly anginal episodes (mean difference -1.44, 95% CI -2.10 to -0.79; p<0.0001) and improved exercise time to 1 mm ST segment depression (p=0.0002) observed in the trimetazidine group. One of the four small trials involving 263 patients, favored trimetazidine over nitrates and the remaining three trials favored other anti-anginal agents. Thus, the study concluded that trimetazidine has shown to be effective in the treatment of stable angina when compared with placebo, alone or when used in combination with conventional anti-anginal agents. It has also been associated with fewer dropouts resulting from trimetazidine and its adverse effects. Furthermore, the study proposed the need for large, long term trials comparing trimetazidine with other anti-anginal drugs to establish the clinical role of trimetazidine.[21]
  • In the TRIMPOL II trial, 426 patients with stable, effort-induced angina and documented coronary artery disease were randomized to receive either trimetazidine or placebo, to assess the anti-ischemic efficacy and tolerability of trimetazidine when used in combination with a beta blocker in patients with stable effort angina. At 12-week follow-up, the combined trimetazidine-beta blocker group showed significant improvement in the time to 1 mm ST segment depression during exercise, time to onset of angina and mean weekly number of anginal episodes. Thus, the study concluded that trimetazidine combined with a beta blocker is useful in patients with stable angina that is insufficiently controlled by beta blocker monotherapy.[22]

Vote on and Suggest Revisions to the Current Guidelines

Sources

References

  1. ↑ Chaitman BR (2006) Ranolazine for the treatment of chronic angina and potential use in other cardiovascular conditions. Circulation 113 (20):2462-72. DOI:10.1161/CIRCULATIONAHA.105.597500 PMID: 16717165
  2. ↑ Antzelevitch C, Belardinelli L, Zygmunt AC, Burashnikov A, Di Diego JM, Fish JM et al. (2004) Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties. Circulation 110 (8):904-10. DOI:10.1161/01.CIR.0000139333.83620.5D PMID: 15302796
  3. ↑ Stone PH (2008) Ranolazine: new paradigm for management of myocardial ischemia, myocardial dysfunction, and arrhythmias. Cardiol Clin 26 (4):603-14. DOI:10.1016/j.ccl.2008.06.002 PMID: 18929234
  4. ↑ Haigney MC, Lakatta EG, Stern MD, Silverman HS (1994) Sodium channel blockade reduces hypoxic sodium loading and sodium-dependent calcium loading. Circulation 90 (1):391-9. PMID: 8026023
  5. ↑ Ver Donck L, Borgers M, Verdonck F (1993) Inhibition of sodium and calcium overload pathology in the myocardium: a new cytoprotective principle. Cardiovasc Res 27 (3):349-57. PMID: 8387886
  6. ↑ 6.0 6.1 Borer JS, Fox K, Jaillon P, Lerebours G, Ivabradine Investigators Group (2003) Antianginal and antiischemic effects of ivabradine, an I(f) inhibitor, in stable angina: a randomized, double-blind, multicentered, placebo-controlled trial. Circulation 107 (6):817-23. PMID: 12591750
  7. ↑ 7.0 7.1 Tardif JC, Ford I, Tendera M, Bourassa MG, Fox K, INITIATIVE Investigators (2005) Efficacy of ivabradine, a new selective I(f) inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J 26 (23):2529-36. DOI:10.1093/eurheartj/ehi586 PMID: 16214830
  8. ↑ 8.0 8.1 Cross HR (2001) Trimetazidine for stable angina pectoris. Expert Opin Pharmacother 2 (5):857-75. DOI:10.1517/14656566.2.5.857 PMID: 11336628
  9. ↑ Messin R, Opolski G, Fenyvesi T, Carreer-Bruhwyler F, Dubois C, Famaey JP et al. (2005) Efficacy and safety of molsidomine once-a-day in patients with stable angina pectoris. Int J Cardiol 98 (1):79-89. DOI:10.1016/j.ijcard.2004.01.007 PMID: 15676171
  10. ↑ 10.0 10.1 Chaitman BR, Skettino SL, Parker JO, Hanley P, Meluzin J, Kuch J et al. (2004) Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol 43 (8):1375-82. DOI:10.1016/j.jacc.2003.11.045 PMID: 15093870
  11. ↑ 11.0 11.1 Chaitman BR, Pepine CJ, Parker JO, Skopal J, Chumakova G, Kuch J et al. (2004) 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 291 (3):309-16. DOI:10.1001/jama.291.3.309 PMID: 14734593
  12. ↑ 12.0 12.1 Marzilli M, Klein WW (2003) Efficacy and tolerability of trimetazidine in stable angina: a meta-analysis of randomized, double-blind, controlled trials. Coron Artery Dis 14 (2):171-9. DOI:10.1097/01.mca.0000062799.53287.82 PMID: 12655281
  13. ↑ White HD, Lowe JB (1983) Antianginal efficacy of perhexiline maleate in patients refractory to beta-adrenoreceptor blockade. Int J Cardiol 3 (2):145-55. PMID: 6134684
  14. ↑ Cole PL, Beamer AD, McGowan N, Cantillon CO, Benfell K, Kelly RA et al. (1990) Efficacy and safety of perhexiline maleate in refractory angina. A double-blind placebo-controlled clinical trial of a novel antianginal agent. Circulation 81 (4):1260-70. PMID: 2180591
  15. ↑ Schram G, Zhang L, Derakhchan K, Ehrlich JR, Belardinelli L, Nattel S (2004) Ranolazine: ion-channel-blocking actions and in vivo electrophysiological effects. Br J Pharmacol 142 (8):1300-8. DOI:10.1038/sj.bjp.0705879 PMID: 15277312
  16. ↑ Antzelevitch C, Belardinelli L, Wu L, Fraser H, Zygmunt AC, Burashnikov A et al. (2004) Electrophysiologic properties and antiarrhythmic actions of a novel antianginal agent. J Cardiovasc Pharmacol Ther 9 Suppl 1 ():S65-83. PMID: 15378132
  17. ↑ Lee L, Horowitz J, Frenneaux M (2004) Metabolic manipulation in ischaemic heart disease, a novel approach to treatment. Eur Heart J 25 (8):634-41. DOI:10.1016/j.ehj.2004.02.018 PMID: 15084367
  18. ↑ Scirica BM, Morrow DA, Hod H, Murphy SA, Belardinelli L, Hedgepeth CM et al. (2007) Effect of ranolazine, an antianginal agent with novel electrophysiological properties, on the incidence of arrhythmias in patients with non ST-segment elevation acute coronary syndrome: results from the Metabolic Efficiency With Ranolazine for Less Ischemia in Non ST-Elevation Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) randomized controlled trial. Circulation 116 (15):1647-52. DOI:10.1161/CIRCULATIONAHA.107.724880 PMID: 17804441
  19. ↑ Wilson SR, Scirica BM, Braunwald E, Murphy SA, Karwatowska-Prokopczuk E, Buros JL et al. (2009) Efficacy of ranolazine in patients with chronic angina observations from the randomized, double-blind, placebo-controlled MERLIN-TIMI (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Segment Elevation Acute Coronary Syndromes) 36 Trial. J Am Coll Cardiol 53 (17):1510-6. DOI:10.1016/j.jacc.2009.01.037 PMID: 19389561
  20. ↑ Stone PH, Gratsiansky NA, Blokhin A, Huang IZ, Meng L, ERICA Investigators (2006) Antianginal efficacy of ranolazine when added to treatment with amlodipine: the ERICA (Efficacy of Ranolazine in Chronic Angina) trial. J Am Coll Cardiol 48 (3):566-75. DOI:10.1016/j.jacc.2006.05.044 PMID: 16875985
  21. ↑ Ciapponi A, Pizarro R, Harrison J (2005) Trimetazidine for stable angina. Cochrane Database Syst Rev (4):CD003614. DOI:10.1002/14651858.CD003614.pub2 PMID: 16235330
  22. ↑ Szwed H, Sadowski Z, Elikowski W, Koronkiewicz A, Mamcarz A, Orszulak W et al. (2001) Combination treatment in stable effort angina using trimetazidine and metoprolol: results of a randomized, double-blind, multicentre study (TRIMPOL II). TRIMetazidine in POLand. Eur Heart J 22 (24):2267-74. DOI:10.1053/euhj.2001.2896 PMID: 11728147
  23. ↑ Fox K, Garcia MA, Ardissino D, Buszman P, Camici PG, Crea F; et al. (2006). [url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16735367 [1] "Guidelines on the management of stable angina pectoris: executive summary: The Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology"] Check |url= value (help). Eur Heart J. 27 (11): 1341–81. doi:10.1093/eurheartj/ehl001. PMID 16735367.
  24. ↑ Gibbons RJ, Chatterjee K, Daley J, Douglas JS, Fihn SD, Gardin JM et al. (1999) ACC/AHA/ACP-ASIM guidelines for the management of patients with chronic stable angina: executive summary and recommendations. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Patients with Chronic Stable Angina). Circulation 99 (21):2829-48. [2] PMID: 10351980
  25. ↑ Gibbons RJ, Abrams J, Chatterjee K, Daley J, Deedwania PC, Douglas JS et al. (2003) ACC/AHA 2002 guideline update for the management of patients with chronic stable angina--summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina). Circulation 107 (1):149-58.[3] PMID: 12515758
  26. ↑ Fraker TD, Fihn SD, Gibbons RJ, Abrams J, Chatterjee K, Daley J et al. (2007)2007 chronic angina focused update of the ACC/AHA 2002 Guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Writing Group to develop the focused update of the 2002 Guidelines for the management of patients with chronic stable angina. Circulation 116 (23):2762-72.[4] PMID: 17998462

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