Efficacy and Safety of Intravenous Calcium Pretreatment Prior to Nondihydropyridine Calcium Channel Blockers in Atrial Fibrillation or Flutter: A Comparative Synthesis

Abstract

Background:
Intravenous nondihydropyridine calcium channel blockers (CCBs), such as diltiazem and verapamil, are standard agents for acute rate control in atrial fibrillation (AF) and atrial flutter (AFL). However, their use can be limited by drug-induced hypotension. Pretreatment with intravenous calcium has been proposed to attenuate this effect without compromising rate-control efficacy, but evidence remains limited and heterogeneous.

Methods:
A systematic review was conducted according to PRISMA guidelines using a PubMed search through December 2024. Of 222 records identified, two reviewers independently screened and extracted data; nine underwent full-text review, and four met inclusion criteria. Of these four studies, only one (Az 2025) is a randomised controlled trial; the remaining three are non-randomised comparative studies: Rossi (2023, retrospective), Miyagawa (1993), and Haft (1986). Five were excluded (abstract-only, commentary, review, and single-arm cohorts). A total of approximately 616 patients were included across the four studies, comparing intravenous calcium (chloride, gluconate, or sulfate) pretreatment prior to a nondihydropyridine CCB (diltiazem or verapamil) with CCB alone. The primary endpoint was change in systolic blood pressure (SBP) and heart rate (HR) after drug administration. Timing of measurement varied—Az (2025) and Miyagawa (1993) assessed outcomes at 15 min, Rossi (2023) at 60 min, while Haft (1986) did not specify timing but measured BP via arterial line monitoring. Secondary outcomes included bradycardia, nausea, urticaria, flushing, and conversion to normal sinus rhythm (NSR) after calcium alone.

Results:
Across studies, calcium pretreatment was associated with a consistent qualitative trend toward smaller SBP reductions in all studies except Rossi et al. However, because none of the included studies reported a per-arm change in SBP as a mean ± standard deviation, a valid pooled mean difference could not be reproduced; the previously reported pooled estimate (+10 mm Hg, 95% CrI -1 to +16) is therefore not reproducible and should not be interpreted as a quantitative meta-analytic result. The change in HR was qualitatively nonsignificant across studies, and calcium did not appear to reduce rate-control efficacy, except for a modest attenuation noted in Az et al. (2025). Adverse events were rare and mild (nausea, flushing, urticaria), and several early-era patients cardioverted to NSR after calcium alone.

Conclusions:
Intravenous calcium pretreatment prior to nondihydropyridine CCBs appears to lessen CCB-induced hypotension without materially affecting rate-control efficacy. Although findings did not reach statistical significance, the direction of effect was consistent. Limitations include the small number of studies, variation in timing of BP/HR measurement, differences in calcium formulation and dosing, and significant heterogeneity. Larger randomized trials are warranted to clarify the optimal calcium dose and clinical benefit. Importantly, only one of the four included studies (Az 2025) is a randomised controlled trial; the other three are non-randomised comparative studies, and none reports per-arm SBP change as a mean ± SD suitable for pooling. The evidence base therefore does not support a reproducible pairwise meta-analysis of randomised trials, and this work is best interpreted as a narrative/comparative synthesis rather than a quantitative meta-analysis of RCTs; its directional findings should be regarded as hypothesis-generating.

Data Availability: All data analysed in this comparative synthesis are available in the published source articles cited in the Reference section. No new primary data were generated for this study.

Funding: This work received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Competing Interests: The authors declare no competing interests.

Ethics Approval: This study is a comparative synthesis of previously published, peer-reviewed data; no human or animal subjects were directly involved, and no new ethics approval was required.