Chronic stable angina treatment newer antianginal agents: Difference between revisions
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__NOTOC__ | __NOTOC__ | ||
{{Chronic stable angina}} | {{Chronic stable angina}} | ||
{{CMG}}; '''Associate Editor(s)-In-Chief:''' {{CZ}}; [[John Fani Srour, M.D.]]; [[WikiDoc Scholars#WikiDoc Scholars with Distinction|Jinhui Wu, M.D.]]; [[Lakshmi Gopalakrishnan|Lakshmi Gopalakrishnan, M.B.B.S.]] | {{CMG}}; '''Associate Editor(s)-In-Chief:''' {{CZ}}; [[John Fani Srour, M.D.]]; [[WikiDoc Scholars#WikiDoc Scholars with Distinction|Jinhui Wu, M.D.]]; [[Lakshmi Gopalakrishnan|Lakshmi Gopalakrishnan, M.B.B.S.]]; {{AA}} | ||
==Overview== | ==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]]. | [[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== | ==Newer Anti-anginal Agents== | ||
===Mechanisms of Benefit=== | |||
*[[Ranolazine]] alters the trans-cellular late sodium current which remains open in pathologic states, such as [[ischemia]] and [[heart failure]].<ref name="pmid16717165">Chaitman BR (2006) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=16717165 Ranolazine for the treatment of chronic angina and potential use in other cardiovascular conditions.] ''Circulation'' 113 (20):2462-72. [http://dx.doi.org/10.1161/CIRCULATIONAHA.105.597500 DOI:10.1161/CIRCULATIONAHA.105.597500] PMID: [http://pubmed.gov/16717165 16717165]</ref> 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.<ref name="pmid15302796">Antzelevitch C, Belardinelli L, Zygmunt AC, Burashnikov A, Di Diego JM, Fish JM et al. (2004) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=15302796 Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties.] ''Circulation'' 110 (8):904-10. [http://dx.doi.org/10.1161/01.CIR.0000139333.83620.5D DOI:10.1161/01.CIR.0000139333.83620.5D] PMID: [http://pubmed.gov/15302796 15302796]</ref><ref name="pmid18929234">Stone PH (2008) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=18929234 Ranolazine: new paradigm for management of myocardial ischemia, myocardial dysfunction, and arrhythmias.] ''Cardiol Clin'' 26 (4):603-14. [http://dx.doi.org/10.1016/j.ccl.2008.06.002 DOI:10.1016/j.ccl.2008.06.002] PMID: [http://pubmed.gov/18929234 18929234]</ref> Therefore, inhibition of this effect results in improvement of [[ischemia]] and anginal symptoms.<ref name="pmid8026023">Haigney MC, Lakatta EG, Stern MD, Silverman HS (1994) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=8026023 Sodium channel blockade reduces hypoxic sodium loading and sodium-dependent calcium loading.] ''Circulation'' 90 (1):391-9. PMID: [http://pubmed.gov/8026023 8026023]</ref><ref name="pmid8387886">Ver Donck L, Borgers M, Verdonck F (1993) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=8387886 Inhibition of sodium and calcium overload pathology in the myocardium: a new cytoprotective principle.] ''Cardiovasc Res'' 27 (3):349-57. PMID: [http://pubmed.gov/8387886 8387886]</ref> | *[[Ranolazine]] alters the trans-cellular late sodium current which remains open in pathologic states, such as [[ischemia]] and [[heart failure]].<ref name="pmid16717165">Chaitman BR (2006) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=16717165 Ranolazine for the treatment of chronic angina and potential use in other cardiovascular conditions.] ''Circulation'' 113 (20):2462-72. [http://dx.doi.org/10.1161/CIRCULATIONAHA.105.597500 DOI:10.1161/CIRCULATIONAHA.105.597500] PMID: [http://pubmed.gov/16717165 16717165]</ref> 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.<ref name="pmid15302796">Antzelevitch C, Belardinelli L, Zygmunt AC, Burashnikov A, Di Diego JM, Fish JM et al. (2004) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=15302796 Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties.] ''Circulation'' 110 (8):904-10. [http://dx.doi.org/10.1161/01.CIR.0000139333.83620.5D DOI:10.1161/01.CIR.0000139333.83620.5D] PMID: [http://pubmed.gov/15302796 15302796]</ref><ref name="pmid18929234">Stone PH (2008) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=18929234 Ranolazine: new paradigm for management of myocardial ischemia, myocardial dysfunction, and arrhythmias.] ''Cardiol Clin'' 26 (4):603-14. [http://dx.doi.org/10.1016/j.ccl.2008.06.002 DOI:10.1016/j.ccl.2008.06.002] PMID: [http://pubmed.gov/18929234 18929234]</ref> Therefore, inhibition of this effect results in improvement of [[ischemia]] and anginal symptoms.<ref name="pmid8026023">Haigney MC, Lakatta EG, Stern MD, Silverman HS (1994) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=8026023 Sodium channel blockade reduces hypoxic sodium loading and sodium-dependent calcium loading.] ''Circulation'' 90 (1):391-9. PMID: [http://pubmed.gov/8026023 8026023]</ref><ref name="pmid8387886">Ver Donck L, Borgers M, Verdonck F (1993) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=8387886 Inhibition of sodium and calcium overload pathology in the myocardium: a new cytoprotective principle.] ''Cardiovasc Res'' 27 (3):349-57. PMID: [http://pubmed.gov/8387886 8387886]</ref> | ||
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*[[Molsidomine]] is a long acting [[vasodilator]] shown to reduce the incidence of anginal attacks by undergoing metabolism to form SIN-1 that subsequently releases [[nitric oxide]].<ref name="pmid15676171">Messin R, Opolski G, Fenyvesi T, Carreer-Bruhwyler F, Dubois C, Famaey JP et al. (2005) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=15676171 Efficacy and safety of molsidomine once-a-day in patients with stable angina pectoris.] ''Int J Cardiol'' 98 (1):79-89. [http://dx.doi.org/10.1016/j.ijcard.2004.01.007 DOI:10.1016/j.ijcard.2004.01.007] PMID: [http://pubmed.gov/15676171 15676171]</ref> | *[[Molsidomine]] is a long acting [[vasodilator]] shown to reduce the incidence of anginal attacks by undergoing metabolism to form SIN-1 that subsequently releases [[nitric oxide]].<ref name="pmid15676171">Messin R, Opolski G, Fenyvesi T, Carreer-Bruhwyler F, Dubois C, Famaey JP et al. (2005) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=15676171 Efficacy and safety of molsidomine once-a-day in patients with stable angina pectoris.] ''Int J Cardiol'' 98 (1):79-89. [http://dx.doi.org/10.1016/j.ijcard.2004.01.007 DOI:10.1016/j.ijcard.2004.01.007] PMID: [http://pubmed.gov/15676171 15676171]</ref> | ||
==Indication== | ===Indication=== | ||
*[[Ranolazine]] is effective as both monotherapy <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> and combination therapy <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> for the treatment and prevention of anginal episodes, however is not effective to relieve an episode of angina that has already begun. | *[[Ranolazine]] is effective as both monotherapy<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> and combination therapy<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> 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 [[Chronic stable angina treatment beta blockers|beta-blockers]] and hence indicated symptomatic patients with a contra-indication to beta-blocker therapy.<ref name="pmid16214830">Tardif JC, Ford I, Tendera M, Bourassa MG, Fox K, INITIATIVE Investigators (2005) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=16214830 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. [http://dx.doi.org/10.1093/eurheartj/ehi586 DOI:10.1093/eurheartj/ehi586] PMID: [http://pubmed.gov/16214830 16214830]</ref> | *[[Ivabradine]] has shown to be as effective as [[Chronic stable angina treatment beta blockers|beta-blockers]] and hence indicated symptomatic patients with a contra-indication to beta-blocker therapy.<ref name="pmid16214830">Tardif JC, Ford I, Tendera M, Bourassa MG, Fox K, INITIATIVE Investigators (2005) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=16214830 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. [http://dx.doi.org/10.1093/eurheartj/ehi586 DOI:10.1093/eurheartj/ehi586] PMID: [http://pubmed.gov/16214830 16214830]</ref> | ||
*In patients with stable angina, [[trimetazidine]] has shown to improve exercise parameters and reduce the incidence of anginal episodes.<ref name="pmid11336628">Cross HR (2001) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=11336628 Trimetazidine for stable angina pectoris.] ''Expert Opin Pharmacother'' 2 (5):857-75. [http://dx.doi.org/10.1517/14656566.2.5.857 DOI:10.1517/14656566.2.5.857 ] PMID: [http://pubmed.gov/11336628 11336628]</ref> It is also shown to be effective both in monotherapy or when used in combination with [[Chronic stable angina | *In patients with stable angina, [[trimetazidine]] has shown to improve exercise parameters and reduce the incidence of anginal episodes.<ref name="pmid11336628">Cross HR (2001) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=11336628 Trimetazidine for stable angina pectoris.] ''Expert Opin Pharmacother'' 2 (5):857-75. [http://dx.doi.org/10.1517/14656566.2.5.857 DOI:10.1517/14656566.2.5.857 ] PMID: [http://pubmed.gov/11336628 11336628]</ref> It is also shown to be effective both in monotherapy or when used in combination with [[Chronic stable angina medical therapy|standard anti-anginal agents]].<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 patients, refractory to optimal [[Chronic stable angina | *In patients, refractory to optimal [[Chronic stable angina medical therapy|medical therapy]] who are not candidates for [[Chronic stable angina revascularization|revascularization]], [[perhexiline]] may be indicated.<ref name="pmid6134684">White HD, Lowe JB (1983) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=6134684 Antianginal efficacy of perhexiline maleate in patients refractory to beta-adrenoreceptor blockade.] ''Int J Cardiol'' 3 (2):145-55. PMID: [http://pubmed.gov/6134684 6134684]</ref><ref name="pmid2180591">Cole PL, Beamer AD, McGowan N, Cantillon CO, Benfell K, Kelly RA et al. (1990) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=2180591 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: [http://pubmed.gov/2180591 2180591]</ref> | ||
==Dosage== | ===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. | 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== | ===Adverse Effects=== | ||
*[[Ranolazine]] by inhibiting the HERG channel causes [[Long QT syndrome| prolongation of QT interval]].<ref name="pmid15277312">Schram G, Zhang L, Derakhchan K, Ehrlich JR, Belardinelli L, Nattel S (2004) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=15277312 Ranolazine: ion-channel-blocking actions and in vivo electrophysiological effects.] ''Br J Pharmacol'' 142 (8):1300-8. [http://dx.doi.org/10.1038/sj.bjp.0705879 DOI:10.1038/sj.bjp.0705879] PMID: [http://pubmed.gov/15277312 15277312]</ref><ref name="pmid15378132">Antzelevitch C, Belardinelli L, Wu L, Fraser H, Zygmunt AC, Burashnikov A et al. (2004) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=15378132 Electrophysiologic properties and antiarrhythmic actions of a novel antianginal agent.] ''J Cardiovasc Pharmacol Ther'' 9 Suppl 1 ():S65-83. PMID: [http://pubmed.gov/15378132 15378132]</ref> Other mild side effects include [[nausea]], [[constipation]], [[headache]], [[dizziness]], [[palpitations]]. | *[[Ranolazine]] by inhibiting the HERG channel causes [[Long QT syndrome| prolongation of QT interval]].<ref name="pmid15277312">Schram G, Zhang L, Derakhchan K, Ehrlich JR, Belardinelli L, Nattel S (2004) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=15277312 Ranolazine: ion-channel-blocking actions and in vivo electrophysiological effects.] ''Br J Pharmacol'' 142 (8):1300-8. [http://dx.doi.org/10.1038/sj.bjp.0705879 DOI:10.1038/sj.bjp.0705879] PMID: [http://pubmed.gov/15277312 15277312]</ref><ref name="pmid15378132">Antzelevitch C, Belardinelli L, Wu L, Fraser H, Zygmunt AC, Burashnikov A et al. (2004) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=15378132 Electrophysiologic properties and antiarrhythmic actions of a novel antianginal agent.] ''J Cardiovasc Pharmacol Ther'' 9 Suppl 1 ():S65-83. PMID: [http://pubmed.gov/15378132 15378132]</ref> Other mild side effects include [[nausea]], [[constipation]], [[headache]], [[dizziness]], [[palpitations]]. | ||
*Side effects of [[perhexiline]] include [[hepatotoxicity]] and [[peripheral neuropathy]].<ref name="pmid15084367">Lee L, Horowitz J, Frenneaux M (2004) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=15084367 Metabolic manipulation in ischaemic heart disease, a novel approach to treatment.] ''Eur Heart J'' 25 (8):634-41. [http://dx.doi.org/10.1016/j.ehj.2004.02.018 DOI:10.1016/j.ehj.2004.02.018] PMID: [http://pubmed.gov/15084367 15084367]</ref> | *Side effects of [[perhexiline]] include [[hepatotoxicity]] and [[peripheral neuropathy]].<ref name="pmid15084367">Lee L, Horowitz J, Frenneaux M (2004) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=15084367 Metabolic manipulation in ischaemic heart disease, a novel approach to treatment.] ''Eur Heart J'' 25 (8):634-41. [http://dx.doi.org/10.1016/j.ehj.2004.02.018 DOI:10.1016/j.ehj.2004.02.018] PMID: [http://pubmed.gov/15084367 15084367]</ref> | ||
==Supportive Trial Data== | ===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%).<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> | ||
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*In the treatment of stable angina, a meta-analysis which evaluated the efficacy and tolerance of [[trimetazidine]], 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 which evaluated the efficacy and tolerance of [[trimetazidine]], 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, which reviewed 23 randomized controlled trials data comparing [[trimetazidine]] with placebo or other [[Chronic stable angina | *Another meta-analysis, which reviewed 23 randomized controlled trials data comparing [[trimetazidine]] with placebo or other [[Chronic stable angina medical therapy|conventional anti-anginal agents]], collectively involving 1,378 patients with [[Chronic stable angina definition|stable angina]], was used to assess the efficacy and tolerability of [[trimetazidine]]. Researchers reported 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, researchers concluded that [[trimetazidine]] was 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 medical therapy|conventional anti-anginal agents]]. It has also been associated with fewer dropouts related to adverse effects from [[trimetazidine]]. 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> | ||
== | ==2012 Chronic Angina Guidelines Update for the Management of Patients With Chronic Stable Angina (DO NOT EDIT)<ref name="pmid23166210">{{cite journal| author=Fihn SD, Gardin JM, Abrams J, Berra K, Blankenship JC, Dallas AP et al.| title=2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: executive summary: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. | journal=Circulation | year= 2012 | volume= 126 | issue= 25 | pages= 3097-137 | pmid=23166210 | doi=10.1161/CIR.0b013e3182776f83 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23166210 }} </ref>== | ||
==Ranolazine== | |||
{|class="wikitable" style="width:80%" | |||
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|colspan="1" style="text-align:center; background:LemonChiffon"| [[ACC AHA guidelines classification scheme#Classification of Recommendations|Class IIa]] | |||
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| bgcolor="LemonChiffon"|<nowiki>"</nowiki>'''1.''' [[Ranolazine]] can be useful when prescribed as a substitute for beta blockers for relief of symptoms in patients with SIHD if initial treatment with beta blockers leads to unacceptable side effects or is ineffective or if initial treatment with beta blockers is contraindicated<nowiki>"</nowiki>''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence:B ]])'' <nowiki>"</nowiki> | |||
|- | |||
| bgcolor="LemonChiffon"|<nowiki>"</nowiki>'''2.''' [[Ranolazine]] in combination with beta blockers can be useful when prescribed for relief of symptoms when initial treatment with beta blockers is not successful in patients with SIHD<nowiki>"</nowiki>''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence:A ]])'' <nowiki>"</nowiki> | |||
|} | |||
==References== | ==References== | ||
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[[Category:Ischemic heart diseases]] | [[Category:Ischemic heart diseases]] | ||
[[Category:Cardiology]] | [[Category:Cardiology]] | ||
[[Category:Emergency medicine]] | [[Category:Emergency medicine]] | ||
[[Category:Intensive care medicine]] | |||
[[Category:Up-To-Date]] | |||
[[Category:Up-To-Date cardiology]] | [[Category:Up-To-Date cardiology]] | ||
Latest revision as of 18:43, 31 October 2016
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Chronic stable angina Microchapters | ||
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Classification | ||
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Differentiating Chronic Stable Angina from Acute Coronary Syndromes | ||
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Diagnosis | ||
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Alternative Therapies for Refractory Angina | ||
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Discharge Care | ||
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Guidelines for Asymptomatic Patients | ||
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Case Studies | ||
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Chronic stable angina treatment newer antianginal agents On the Web | ||
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]; John Fani Srour, M.D.; Jinhui Wu, M.D.; Lakshmi Gopalakrishnan, M.B.B.S.; Aysha Anwar, M.B.B.S[3]
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.
Newer Anti-anginal Agents
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]
- Molsidomine is a long acting vasodilator shown to reduce the incidence of anginal attacks by undergoing metabolism to form SIN-1 that subsequently releases nitric oxide.[9]
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]
- In patients, refractory to optimal medical therapy who are not candidates for revascularization, perhexiline may be indicated.[13][14]
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
- Ranolazine by inhibiting the HERG channel causes prolongation of QT interval.[15][16] Other mild side effects include nausea, constipation, headache, dizziness, palpitations.
- Side effects of perhexiline include hepatotoxicity and peripheral neuropathy.[17]
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 treatments. 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, researchers enrolled a total population of 565 patients who were classified with stable coronary disease and more than three anginal attacks per week, despite recommended dosage of amlodipine (10 mg/day) and long acting nitrate therapy. Patients were randomized to receive either, 1,000 mg of ranolazine (n=281) or placebo (n=284) treatments twice a day for 6 weeks to assess the effect of ranolazine on the frequency of anginal episodes per week. The enrolled patients had a baseline anginal frequency of 5.63 (+/- 0.18) episodes per week and nitroglycerin consumption of 4.72 (+/- 0.21) tablets per week. The study reported significant reduction in the frequency of anginal episodes between the two groups: 2.88 (+/- 0.19, p=0.028) episodes per week in the ranolazine group and 3.31 (+/- 0.22, p=0.028) episodes per week in the placebo group. In addition, there was also significant reduction in the nitroglycerin consumption observed between the two groups: 2.03 (+/- 0.20, p=0.014) tablets per week in the ranolazine group and 2.68 (+/- 0.22, p=0.014) tablets per week in the placebo group.[20]
- In a placebo-controlled trial, researchers enrolled 360 patients with symptomatic chronic stable angina to evaluate the anti-anginal and anti-ischemic effects of ivabradine. Patients were randomized to receive either, ivabradine or placebo treatments. Researchers 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 which evaluated the efficacy and tolerance of trimetazidine, 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, which reviewed 23 randomized controlled trials data comparing trimetazidine with placebo or other conventional anti-anginal agents, collectively involving 1,378 patients with stable angina, was used to assess the efficacy and tolerability of trimetazidine. Researchers reported 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, researchers concluded that trimetazidine was 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 related to adverse effects from trimetazidine. 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]
2012 Chronic Angina Guidelines Update for the Management of Patients With Chronic Stable Angina (DO NOT EDIT)[23]
Ranolazine
| Class IIa |
| "1. Ranolazine can be useful when prescribed as a substitute for beta blockers for relief of symptoms in patients with SIHD if initial treatment with beta blockers leads to unacceptable side effects or is ineffective or if initial treatment with beta blockers is contraindicated"(Level of Evidence:B ) " |
| "2. Ranolazine in combination with beta blockers can be useful when prescribed for relief of symptoms when initial treatment with beta blockers is not successful in patients with SIHD"(Level of Evidence:A ) " |
References
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 6.0 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
- ↑ 7.0 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
- ↑ 8.0 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
- ↑ 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
- ↑ 10.0 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
- ↑ 11.0 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
- ↑ 12.0 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ Fihn SD, Gardin JM, Abrams J, Berra K, Blankenship JC, Dallas AP; et al. (2012). "2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: executive summary: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons". Circulation. 126 (25): 3097–137. doi:10.1161/CIR.0b013e3182776f83. PMID 23166210.