Placebo-controlled efficacy of 17 anti-anginal drugs and percutaneous coronary intervention for first-line treatment of stable angina: systematic review & meta-analysis of 5153 patients from 53 trials
Authors: Kaura A , Trickey A , Roddick A , Sesia D , Mayet J , Francis D P , Al-Lamee R 
Published: October 2024

Abstract

Background
Percutaneous coronary intervention (PCI) for stable angina is currently recommended for patients with residual symptoms despite maximal anti-anginal medication. Placebo-controlled data demonstrating efficacy of PCI has recently become available.

Purpose
We evaluated the placebo-controlled efficacy of anti-anginal agents and PCI, as monotherapies for stable angina.

Methods
We performed a systematic review and meta-analysis of placebo-controlled randomised controlled trials (RCTs) of anti-anginal agents (17 medications across 7 drug classes [beta-blocker, dihydropyridine (DHP) calcium channel blocker (CCB), non-DHP CCB, ivabradine, nicorandil, nitrates and ranolazine]), and PCI, which reported the placebo-controlled treatment effect on standardised exercise duration in patients with stable angina, who were receiving no background anti-anginal medications.
We searched MEDLINE, EMBASE, and Cochrane CENTRAL from database inception to 01 December 2023. Relevant systematic reviews and reference lists were inspected to identify publications which had not been identified in the primary searches. Two independent reviewers extracted the data and assessed the risk of bias of included studies. Intention-to-treat data were used. Meta-analyses were carried out using random-effects methods and reported using the PRISMA guidelines. The primary outcome was mean difference in total exercise time with treatment compared with placebo. A pairwise comparison of all anti-anginal medications and PCI was performed to evaluate their relative placebo-controlled efficacy on total exercise time.

Results
A total of 52 trials were eligible, evaluating 83 treatment arm comparisons of anti-anginal monotherapy (2408 patients) and placebo (2444 patients). The number of trials per medication class ranged from one (ivabradine) to 19 (non-DHP CCBs). All classes improved exercise time compared to placebo, with mean increment ranging from 22.4 seconds (95% confidence interval, 0.8 to 44.0, p=0.04) for ranolazine, to 76.5 seconds (63.2 to 89.8, p&lt;0.0001) for DHP CCBs (Figure 1). There was substantial heterogeneity in exercise time increment between drug classes (I2 98%, p&lt;0.0001). However, across all classes, there was a clear dose-response relationship (b-coefficient 24.8, 15.8 to 33.9, &lt;0.0001).
The only trial which compared PCI (151 patients) to placebo (150 patients) showed a placebo-controlled exercise duration increment of 59.5 seconds (16 to 103, P=0.001). This was comparable to the global mean effect across all anti-anginal medications (59, 39 to 79, P&lt;0.0001).

Conclusions
Each anti-anginal drug class showed a clear increase in placebo-controlled exercise time, with varying effect sizes between classes. The DHP CCB class showed the largest effect size, and ivabradine and ranolazine showed the smallest. The effect of PCI monotherapy was similar to the mean anti-anginal medication monotherapy effect.Figure 1