Expert Review: Coronary Heart Disease

Relative efficacy of antianginal drugs used as add-on therapy in patients with stable angina: A systematic review and meta-analysis.

Background and knowledge gap
Stable angina is a form of coronary artery disease. Its potential to progress requires the most appropriate treatment in order to reduce the incapacitating effect of an acute angina attack and to avoid long-term cardiovascular events. With or without revascularization, pharmacological treatment is an essential component of this treatment strategy, which also involves lifestyle and diet.
The pharmacological management of stable angina consists on a combination of at least a drug for angina relief plus drugs to improve prognosis, as well as use ofsublingual nitroglycerin for chest pain management. It is recommended that either a betablocker (BB) or a calcium channel blocker (CCB) to a short-acting nitrate be added as first-line treatment to control heart rate and symptoms. If the symptoms are not controlled, it is advised to switch to the other option (CCB or BB) or to combine a b-blocker and a dihidropiridine CCB1,2.
Novel classes of treatment with different mechanisms of action have been developed in the last years, including nicorandil, ivabradine, trimetazidine and ranolazine. These drugs, as well as the traditional long acting nitrates (LAN), are currently approved as second-line treatments and have dynamically entered the clinical practice. However, their long-term effects are still under investigation and evidence supporting the appropriate choice of a second-line agent is currently unclear

Aim of the Study
The objective of this meta-analysis was to quantify the relative clinical efficacy of BB, CCB, ranolazine, LAN, nicorandil or ivabradine added on to first line therapy.
Outcomes evaluated included:
a) Tolerance exercise test: total exercise duration, time to ST depression (1mm), time to angina presentation
b) Weekly number of angina episodes
c) Weekly number of short-acting nitrate administration for chest pain relief

A comprehensive literature search was carried out to identify randomised controlled trials comparing the use of a licensed antianginal therapy versus an agent from another drug class, in patients with stable angina who were symptomatic on first line therapy with either a BB or CCB. Exercise tolerance test (ETT) data and clinical outcomes were extracted and combined in a series of meta-analyses.

The search identified 46 qualifying studies evaluating 71 treatment comparisons. The most frequent combinations evaluated were CCB added to BB (n=37) and BB added to CCB (n=12). The remaining comparisons evaluated LAN added to either BB or CCB (n=8), ivabradine added to BB (n=1) and ranolazine added to either BB or CCB (n=3). No qualifying studies were identified for nicorandil in an add-on role.
The combination of ranolazine added to CCB or BB showed positive outcomes across all outcomes assessed. Of note, relative reduction of weekly angina attacks was 25% with Ranolazine, higher than that observed with the addition of CCB to BB (18%), LAN to either BB or CCB (19%), or trimetazidine to either BB or CCB (21%).
Other combinations of BB, CCB, LAN and trimetazidine showed some heterogeneity across the studies included, with significant benefits for most but not all outcomes. The only study including Ivabradine just demonstrated benefits for ETT assessments, not correlated with clinical domains.

Clinical Impact:
The results of this study support current recommendations for BB+CCB combination in in patients with persistent symptoms despite monotherapy.
In addition, the combination of either BB or CCB with ranolazine shows significant improvement in exercise and clinical outcomes.

Corresponding author from original paper
Dr Jonathan Belsey, JB
Medical Ltd, The Old Brickworks, Chapel Lane, Little Cornad, Sudbury, CO10 OPB, United Kingdom
Electronic address:


1.- Montalescot G, Sechtem U, Achenbach S, Andreotti F, Arden C, Budaj A, et al. the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J. 2013 ;34(38):2949-3003
2.- Fihn SD, Gardin JM, Abrams J, Berra K, Blankenship JC, Dallas AP, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stableischemic 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. Circulation. 2012;126(25):e354-4

Citation: Citation: Belsey J, Savelieva I, Mugelli A, Camm AJ. Relative efficacy of antianginal drugs used as add-on therapy in patients with stable angina: A systematic review and meta-analysis. Eur J Prev Cardiol. 2014. pii: 2047487314533217. [Epub ahead of print]

Leave a Reply

Your email address will not be published. Required fields are marked *