First-line medical management of stable angina generally involves a beta-blocker (BB) or calcium channel blocker (CCB), with other classes of medication being added if symptom control is inadequate. Evidence supporting the appropriate choice of a second-line agent is currently unclear. The objective of this systematic review was to quantify the clinical benefit of BB, CCBs, long-acting nitrates (LANs), ranolazine, trimetazidine, ivabradine or nicorandil added to first-line monotherapy for stable coronary artery disease.
Methods
Randomised controlled trials comparing the efficacy of antianginal therapies in patients with stable angina refractory to first-line therapy were identified from a literature search. Exercise tolerance test (ETT) data and clinical outcomes were extracted and combined in a series of meta-analyses.
Results
A total of 46 qualifying studies were identified, evaluating 71 treatment comparisons. The combination of ranolazine added to CCB or BB showed positive outcomes across all outcomes assessed. Other combinations of BB, CCB, LAN and trimetazidine showed significant benefits for most but not all outcomes. Ivabradine demonstrated benefits for ETT assessments but these were not matched in clinical domains. No qualifying studies were identified for nicorandil in an add-on role.
Conclusion
Across a range of commonly assessed exercise and clinical outcomes, the effectiveness of BB+CCB used in combination is broadly confirmed. Ranolazine used with BB or CCB showed benefits across all outcomes assessed, while LAN and trimetazidine used with BB or CCB have shown benefits across some outcomes. Ivabradine added to BB shows inconsistent effects from a single study, whilst there is no relevant evidence for nicorandil.
National Institute for Health and Clinical Excellence (NICE). CG126 Stable angina. Manchester: National Clinical Guidelines Centre, 2011.
2.
MontalescotGSechtemUAchenbachS. 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 J2013; 34: 2949–3003.
3.
FihnSDGardinJMAbramsJ. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the diagnosis and management of patients with stable ischemic heart disease: 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. J Am Coll Cardiol2012; 60: e44–e164.
4.
KleinWWJacksonGTavazziL. Efficacy of monotherapy compared with combined antianginal drugs in the treatment of chronic stable angina pectoris: A meta-analysis. Coron Artery Dis2002; 13: 427–436.
5.
HozoSPDjulbegovicBHozoI. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol2005; 5: 13–13.
6.
DerSimonianRLairdN. Meta-analysis in clinical trials. Control Clin Trials1986; 7: 177–188.
7.
AkhrasFJacksonG. Efficacy of nifedipine and isosorbide mononitrate in combination with atenolol in stable angina. Lancet1991; 338: 1036–1039.
8.
DonaldsonKMDawkinsKDWallerDG. A comparison of nisoldipine and nifedipine, in combination with atenolol, in the management of myocardial ischaemia. Eur Heart J1993; 14: 534–539.
9.
DunselmanPLiemAHVerdelG. Addition of felodipine to metoprolol vs replacement of metoprolol by felodipine in patients with angina pectoris despite adequate beta-blockade. Results of the Felodipine ER and Metoprolol CR in Angina (FEMINA) Study. Working Group on Cardiovascular Research, The Netherlands (WCN). Eur Heart J1997; 18: 1755–1764.
10.
DunselmanPHVan KempenLHBouwensLH. Value of the addition of amlodipine to atenolol in patients with angina pectoris despite adequate beta blockade. Am J Cardiol1998; 81: 128–132.
11.
El-TamimiHDaviesGJ. Optimal control of myocardial ischaemia: The benefit of a fixed combination of atenolol and nifedipine in patients with chronic stable angina. Br Heart J1992; 68: 291–295.
12.
EmanuelssonHEgstrupKNikusK. Antianginal efficacy of the combination of felodipine-metoprolol 10/100 mg compared with each drug alone in patients with stable effort-induced angina pectoris: A multicenter parallel group study. The TRAFFIC Study Group. Am Heart J1999; 137: 854–862.
13.
FoaleRA. Atenolol versus the fixed combination of atenolol and nifedipine in stable angina pectoris. Eur Heart J1993; 14: 1369–1374.
14.
FoxKMMulcahyDFindlayI. The Total Ischaemic Burden European Trial (TIBET). Effects of atenolol, nifedipine SR and their combination on the exercise test and the total ischaemic burden in 608 patients with stable angina. The TIBET Study Group. Eur Heart J1996; 17: 96–103.
15.
HumenDPO'BrienPPurvesP. Effort angina with adequate beta-receptor blockade: Comparison with diltiazem alone and in combination. J Am Coll Cardiol1986; 7: 329–335.
16.
HungJLambIHConnollySJ. The effect of diltiazem and propranolol, alone and in combination, on exercise performance and left ventricular function in patients with stable effort angina: A double-blind, randomized, and placebo-controlled study. Circulation1983; 68: 560–567.
17.
JenkinsRMNagleRE. The symptomatic and objective effects of nifedipine in combination with beta-blocker therapy in severe angina pectoris. Postgrad Med J1982; 58: 697–700.
18.
JohnstonDLLesowayRHumenDP. Clinical and hemodynamic evaluation of propranolol in combination with verapamil, nifedipine and diltiazem in exertional angina pectoris: A placebo-controlled, double-blind, randomized, crossover study. Am J Cardiol1985; 55: 680–687.
19.
KawanishiDTReidCLMorrisonEC. Response of angina and ischemia to long-term treatment in patients with chronic stable angina: A double-blind randomized individualized dosing trial of nifedipine, propranolol and their combination. J Am Coll Cardiol1992; 19: 409–417.
20.
KennyJKiffPHolmesJ. Beneficial effects of diltiazem and propranolol, alone and in combination, in patients with stable angina pectoris. Br Heart J1985; 53: 43–46.
21.
Madjlessi-SimonTFilletteFMary-KrauseM. Effects of amlodipine on transient myocardial ischemia in patients with a severe coronary condition treated with a beta-blocker. Eur Heart J1995; 16: 1780–1788.
22.
MeyerTEAdnamsCCommerfordP. Comparison of the efficacy of atenolol and its combination with slow-release nifedipine in chronic stable angina. Cardiovasc Drugs Ther1993; 7: 909–913.
23.
O'KeefeJCCreamerJEBanimSO. Efficacy of nisoldipine combined with beta-adrenergic-blocking drugs in the treatment of chronic stable angina. Clin Cardiol1987; 10: 345–350.
24.
ParameshwarJKeeganJMulcahyD. Atenolol or nicardipine alone is as efficacious in stable angina as their combination: A double blind randomised trial. Int J Cardiol1993; 40: 135–141.
25.
PehrssonSKRingqvistIEkdahlS. Monotherapy with amlodipine or atenolol versus their combination in stable angina pectoris. Clin Cardiol2000; 23: 763–770.
26.
RonnevikPKSilkeBOstergaardO. Felodipine in addition to beta-adrenergic blockade for angina pectoris. a multicentre, randomized, placebo-controlled trial. Eur Heart J1995; 16: 1535–1541.
27.
RossinenJPartanenJNieminenMS. Amlodipine in patients with stable angina pectoris treated with beta-blockers. Double-blind comparison with placebo. Scand Cardiovasc J1998; 32: 41–48.
28.
SangiorgioPDiPGSavonittoS. Felodipine in chronic stable angina: A randomized, double-blind, placebo-controlled, crossover study. Eur Heart J1990; 11: 1011–1017.
29.
SavonittoSArdissionoDEgstrupK. Combination therapy with metoprolol and nifedipine versus monotherapy in patients with stable angina pectoris. Results of the International Multicenter Angina Exercise (IMAGE) Study. J Am Coll Cardiol1996; 27: 311–316.
30.
StraussWEParisiAF. Randomized, placebo-controlled evaluation of lidoflazine in patients receiving beta-blocker therapy with propranolol: Improvement in anginal symptoms and exercise tolerance with combined drug therapy. Am J Cardiol1984; 53: 1003–1007.
31.
StraussWEParisiAF. Superiority of combined diltiazem and propranolol therapy for angina pectoris. Circulation1985; 71: 951–957.
32.
ToalCBMotroMBairdMG. Effectiveness of nifedipine GITS in combination with atenolol in chronic stable angina. Can J Cardiol1999; 15: 1103–1109.
33.
TweddelACBeattieJMMurrayRG. The combination of nifedipine and propranolol in the management of patients with angina pectoris. Br J Clin Pharmacol1981; 12: 229–233.
34.
UusitaloAArstilaMBaeEA. Metoprolol, nifedipine, and the combination in stable effort angina pectoris. Am J Cardiol1986; 57: 733–737.
35.
WoodmanseyPAStewartAGMoriceAH. Amlodipine in patients with angina uncontrolled by atenolol. A double blind placebo controlled cross over trial. Eur J Clin Pharmacol1993; 45: 107–111.
36.
HumenDPKostukWJ. Clinical response and effects on left ventricular function of isosorbide dinitrate added to propranolol or diltiazem monotherapy in patients with chronic stable angina. Can J Cardiol1991; 7: 74–80.
37.
JensenGTrautnerFRasmussenS. Haemodynamic and clinical effects of isosorbide-dinitrate in patients with severe effort angina on beta-blocking treatment. Eur J Clin Pharmacol1983; 24: 169–172.
38.
SvendsenJHAldershvileJAbildgaardU. Efficacy of controlled-release isosorbide-5-mononitrate as adjunctive treatment to beta-blocking agents in patients with stable angina pectoris. J Cardiovasc Pharmacol1989; 14: 358–363.
39.
FriedensohnAMeshulamRSchlesingerZ. Randomized double-blind comparison of the effects of isosorbide dinitrate retard, verapamil sustained-release, and their combination on myocardial ischemic episodes. Cardiology1991; 79: S31–S40.
40.
VlaySCOlsonLC. Nifedipine and isosorbide dinitrate alone and in combination for patients with chronic stable angina: A double-blind crossover study. Am Heart J1990; 120: 303–307.
41.
ChaitmanBRPepineCJParkerJO. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: A randomized controlled trial. JAMA2004; 291: 309–316.
42.
StonePHGratsianskyNABlokhinA. Antianginal efficacy of ranolazine when added to treatment with amlodipine: The ERICA (Efficacy of Ranolazine in Chronic Angina) trial. J Am Coll Cardiol2006; 48: 566–575.
43.
KosiborodMArnoldSVSpertusJA. 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 Cardiol2013; 61: 2038–2045.
44.
BrochierMDemangeJDuclouxG. Value of the combination of trimetazidine and a calcium inhibitor in the treatment of chronic coronary insufficiency. Double-blind controlled study versus placebo.). Ann Cardiol Angeiol (Paris)1986; 35: 49–56.
45.
ChazovEILepakchinVKZharovaEA. Trimetazidine in Angina Combination Therapy–the TACT study: Trimetazidine versus conventional treatment in patients with stable angina pectoris in a randomized, placebo-controlled, multicenter study. Am J Ther2005; 12: 35–42.
46.
ChutzDS. Value of addition of trimetazidine to calcium antagonist treatment in chronic coronary insufficiency. Gaz Med (Paris)1984; 91: S93–S95.
47.
DanchinNMarzilliMParkhomenkoA. Efficacy comparison of trimetazidine with therapeutic alternatives in stable angina pectoris: A network meta-analysis. Cardiology2011; 120: 59–72.
48.
LevyS. Combination therapy of trimetazidine with diltiazem in patients with coronary artery disease. Group of South of France Investigators. Am J Cardiol1995; 76: 12B–16B.
49.
ManchandaSCKrishnaswamiS. Combination treatment with trimetazidine and diltiazem in stable angina pectoris. Heart1997; 78: 353–357.
50.
SellierPBroustetJP. Assessment of anti-ischemic and antianginal effect at trough plasma concentration and safety of trimetazidine MR 35 mg in patients with stable angina pectoris: A multicenter, double-blind, placebo-controlled study. Am J Cardiovasc Drugs2003; 3: 361–369.
51.
SzwedHSadowskiZElikowskiW. 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 J2001; 22: 2267–2274.
52.
TardifJCPonikowskiPKahanT. Efficacy of the I(f) current inhibitor ivabradine in patients with chronic stable angina receiving beta-blocker therapy: A 4-month, randomized, placebo-controlled trial. Eur Heart J2009; 30: 540–548.
53.
The Committee for Medicinal Products for Human Use (CHMP). Guideline on the clinical investigation of anti-anginal medicinal products in stable angina pectoris. CPMP/EWP/234/95/rev.1. London: European Medicines Agency, June 2006.
54.
WiklundIComerfordMBDimenasE. The relationship between exercise tolerance and quality of life in angina pectoris. Clin Cardiol1991; 14: 204–208.
55.
LongworthLBuxtonMJSculpherM. Estimating utility data from clinical indicators for patients with stable angina. Eur J Health Econ2005; 6: 347–353.
56.
GoldsmithKADyerMTBuxtonMJ. Mapping of the EQ-5D index from clinical outcome measures and demographic variables in patients with coronary heart disease. Health Qual Life Outcomes2010; 8: 54–54.
57.
ChestnutLGKellerLRLambertWE. Measuring heart patients' willingness to pay for changes in angina symptoms. Med Decis Making1996; 16: 65–77.
58.
Shu deFDongBRLinXF. Long-term beta blockers for stable angina: Systematic review and meta-analysis. Eur J Prev Cardiol2012; 19: 330–341.
59.
Bangalore S, Steg G, Deedwania P, et al.; REACH Registry Investigators. Beta-blocker use and clinical outcomes in stable outpatients with and without coronary artery disease. JAMA 2012; 308: 1340–1349.
60.
TimmisADChaitmanBRCragerM. Effects of ranolazine on exercise tolerance and HbA1c in patients with chronic angina and diabetes. Eur Heart J2006; 27: 42–48.
61.
ChisholmJWGoldfineABDhallaAK. Effect of ranolazine on A1C and glucose levels in hyperglycemic patients with non-ST elevation acute coronary syndrome. Diabetes Care2010; 33: 1163–1168.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
