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Tchouapi P, Anderson KE, Hein PN. “Intravenous magnesium as an adjunct to standard of care for treatment of atrial fibrillation with rapid ventricular response.” Academic Emergency Medicine. Published online April 6, 2023:acem.14734.

Study Population: 745 patients with atrial fibrillation and rapid ventricular response enrolled in 6 randomized controlled trials

Efficacy Endpoints

Rate control, conversion to normal sinus rhythm

Harm Endpoints

Adverse events (bradycardia, hypotension, flushing)

Narrative

Atrial fibrillation with rapid ventricular response (RVR) is the most encountered arrhythmia in the emergency department. Its natural course posits significant morbidity and mortality risk from complications such as stroke, thromboembolism, heart failure, and decreased quality of life. The current management of atrial fibrillation involves rate control or rhythm control. Intravenous (IV) magnesium use in the emergency department in conjunction with standard of care is proposed as a means for achieving rate control and potentiation of rhythm conversion in atrial fibrillation with RVR.

The systematic review and meta-analysis by Ramesh et al. discussed here, examined the effectiveness of IV magnesium as an adjunct to standard of care for rate control and rhythm control on atrial fibrillation in non-post operative patients.1 The systematic review includes 6 randomized controlled trials (n = 745 patients) from 1993 to 2018, with 448 in the IV magnesium group and 297 in the control group. Five trials used 4.5 to 10 grams of IV magnesium and one study used 3 grams. The “standard of care” that magnesium sulfate was adjunct to, was most commonly digoxin, although beta blockers and calcium channel blockers were used as well. The primary outcomes included rate control (achieving a heart rate <100 or <90 or a drop in heart rate more than 20%). And conversion to normal sinus rhythm (being in sinus rhythm at the endpoints of the study, ranging from 2.5 to 24 hours from initiation).1

The meta-analysis demonstrated that the use of IV magnesium for the treatment of atrial fibrillation with RVR in addition to routine care was superior to placebo in achieving rate control (Odds Ratio [OR]: 2.49, 95% CI, 1.80 to 3.45; Absolute Risk Difference [ARD]: 23%; Number-needed-to-treat [NNT]: 4) and conversion to sinus rhythm (OR: 1.75, 95% CI, 1.08 to 2.84: ARD: 7%, NNT= 14).1 The risk of flushing was significantly higher in the IV magnesium group compared to the placebo group (9% vs. 0.4%; OR: 19.79, 95% CI, 4.30 to 91.21; ARD: 8.6%; NNH: 11).1 The risk of bradycardia and hypotension was not significantly differenct between the groups. The heterogeneity among trials was relatively low for all primary outcomes analyses.1

Two other systematic reviews by Ho et. al (2006) and Onalan et al. (2007) assessed the effectiveness of IV magnesium in the as primary therapy and as an adjunct.2^, 3 Ho et al. included 10 randomized controlled trials (n = 515 patients) in their systematic review and found a reduction in ventricular response (defined as HR <100) in patients receiving IV magnesium as an adjunct to digoxin.2 When compared directly to calcium channel blockers or amiodarone, IV magnesium was less effective in reducing ventricular response. Of note, most of the included trials enrolled patients with rapid atrial fibrillation following cardiac surgery.

The systematic review by Onlan et. al included 8 trials (n = 476 patients) with only 4 of the included trials (n = 303) reported IV magnesium superiority in achieving rate control when directly compared to placebo, calcium channel blockers or beta blockers.3 In all eight trials, IV magnesium group had a higher chance to regain normal sinus rhythm when compared to controls (placebo, calcium channel blockers, and ajmaline). This systemic review reported significant heterogeneity in comorbidities, baseline pharmacological management, and baseline magnesium levels of patients included in the review.

Though both systematic reviews ultimately concluded that IV magnesium is safe and effective in rate control in atrial fibrillation with RVR, both as a single agent or as an adjunct, it is important to note that these meta-analyses included older studies, mostly published more than 15 years ago, less likely to reflect the current care. The systematic review by Ramesh et al. discussed here, included two more recent trials that were not included in the other two systematic reviews.

We did not discuss the most recent (2022) systematic review by Hoffer et al, because it additionally included two studies using only IV magnesium versus placebo. We consider this a separate question to using magnesium as an adjunctive treatment, and wished to focus on the more narrow question of magnesium as adjunct to first line agents.4 We used the systematic review and meta-analysis by Ramesh et al. published in 2021 as the primary source for this evidence-based summary given its recent publication, more stringent requirement for definition of heart rate control, and its superior methodology.

Caveats

The criteria for rate and rhythm control in the included studies varied both for heart rate goal and time to outcome measure. Treatment groups varied in magnesium dosage (ranging from 3-10 g) and infusion rates. Notably, while these studies discussed care in the RVR time period, they largely did not discuss care after achieving RVR for maintenance therapy (such as a proposed magnesium maintenance rate). Cardiac comorbidities, antiarrhythmic therapies, and additional medications were not consistently reported in the included studies. More than 90% of patients included in the meta-analysis were enrolled in two of the included trials and their findings significantly skewed the results of the analysis.

The routine care for treatment of atrial fibrillation was not standardized among trials. As many of the trials were older, digoxin was used as a common treatment for atrial fibrillation in many of the trials. Therefore, the standard of care used in the original trials may not reflect modern practices of first-line agents, particularly beta blockers or calcium channel blockers.

Experts in the field have raised concern about patient selection in studies evaluating magnesium as a rate and rhythm control agent.5 The clinicians are reminded that atrial fibrillation has numerous different underlying causes, both from different types of primary cardiac disease and from underlying systemic illness triggering a secondary atrial fibrillation as a result. As such, studies should target specific patients’ modifiers to better stratify magnesium’s utility based on underlying etiology. It is likely that certain patients such as those with underlying electrolyte abnormalities (e.g. hypomagnesemia or hypokalemia) may have more favorable responses to IV magnesium. Some patients such as those with severe heart failure or chronic kidney disease may be subject to additional harms from IV magnesium.

Lastly, it must be emphasized that in this review IV magnesium use is assessed as an adjunct to other treatments for atrial fibrillation. The evidence for efficacy of intravenous magnesium as a sole agent is lacking. Therefore, intravenous magnesium should not be used as the primary agent in treatment of atrial fibrillation with RVR, pending further studies.

The available evidence indicates a modest benefit form IV magnesium as an adjunct in management of atrial fibrillation with RVR with limited harms. However, significant heterogeneity particularly in regards to magnesium dose, infusion rate, and underlying pathologies or comorbidities threatens the validity of the results. Additionally, many of the patients in the included trials received digoxin as the first line treatment, a treatment that is rarely used in current practice. Therefore, we have assigned an NNT color recommendation of Yellow (Unclear if benefits/More data needed) to this intervention.

The original manuscript was published in Academic Emergency Medicine as part of the partnership between TheNNT.com and AEM.

Author

Pierre-Carole Tchouapi, MD; Kevin E. Anderson; Paul Narayan Hein, MD
Supervising Editors: Shahriar Zehtabchi, MD

Published/Updated

April 20, 2023