Anti-anginal drugs: Systematic review and clinical implications

Highlights

• Medical treatment of stable angina is based on drugs classified as first or second line treatment.

• Is the categorization in first and second line antianginal treatment scientifically supported?

• We found a paucity of data comparing the efficacy of antianginal agents.

• The categorization of antianginal drug in first and second line is not confirmed.

Abstract

Background

The cornerstone of the treatment of patients affected by stable angina is based on drugs administration classified as first (beta-blockers, calcium channel blockers, short acting nitrates) or second line treatment (long-acting nitrates, ivabradine, nicorandil, ranolazine and trimetazidine). However, few data on comparison between different classes of drugs justify that one class of drugs is superior to another.

Methods

We performed a systematic review of the literature following PRISMA guidelines. Inclusion criteria: i) paper published in English; ii) diagnosis of stable coronary disease; iii) randomized clinical trial; iv) comparison of two anti-angina drugs; v) a sample size >100 patients; vi) a follow-up lasting at least 2 weeks; vii) paper published after 1999, when a meta-analysis of trials comparing beta-blockers, calcium antagonists, and nitrates for stable angina of Heidenreich et al. was published. Outcome: to establish whether the categorization in first and second line antianginal treatment is scientifically supported.

Results

Eleven trials fulfilled inclusion criteria. The results show that there is a paucity of data comparing the efficacy of antianginal agents. The little data available show that there are not compounds superior to others in terms of improvement in exercise test duration, frequency of anginal attacks, need for sub-lingual nitroglycerin.

Conclusion

The categorization of antianginal drug in first and second line is not confirmed.

Introduction

According to the ESC guidelines [1], drugs for symptomatic relief of angina are classified as being first line (beta blockers, calcium channel blockers, short-acting nitrates) or second line (ivabradine, nicorandil, ranolazine, long-acting nitrates, trimetazidine), with the recommendation to reserve second-line medications for patients who have contraindications to first choice agents, do not tolerate them, or remain symptomatic [[1], [2], [3]].

However, such categorical approach has been recently questioned [[4], [5], [6], [7], [8], [9]]. The reasons for this criticism are multiple:

• Second line drugs have been introduced more recently and they have been approved according to more stringent protocols, with larger sample size, longer follow-up, and safety data, compared to first line drugs which were studied in the early days with less precise description of methods, smaller sample size and shorter follow-ups [4,9];

• The suggested and often-used combination of two or even three agents seems to be based on expert opinion rather than on scientific evidence [[5], [6], [7], [8], [9], [10]];

• The categorical guideline recommendations do not take into account the different pathophysiological mechanisms underlying ischemia and angina (stable atherosclerotic plaque, vasospasm on the epicardial arteries, and coronary microvascular dysfunction) [4,6];

• Patients with angina can have several co-morbidities requiring drugs with the appropriate auxiliary properties which are not considered in the guidelines [4,[8], [9], [10]].

Recently, an expert consensus proposed a new algorithm for a more personalized medical treatment of symptomatic angina, a so-called “Diamond approach” [4, Fig. 1]. The authors assumed that there was no direct comparison between first-line and second-line treatments to support the superiority of one group of drugs over the other. They referred to an old meta-analysis based only on the three antianginal drugs considered first line published by Heidenreich et al. in 1999 [4,11]. The purpose of the current systematic review is to analyze data about the more recently approved compounds which are classified as second line choice.