Impact of Intravenous Magnesium on Post-Cardiothoracic Surgery Atrial Fibrillation and Length of Hospital Stay: A Meta-Analysis

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1 Impact of Intravenous Magnesium on Post-Cardiothoracic Surgery Atrial Fibrillation and Length of Hospital Stay: A Meta-Analysis Nickole N. Henyan, PharmD, Effie L. Gillespie, PharmD, C. Michael White, PharmD, Jeffrey Kluger, MD, and Craig I. Coleman, PharmD Department of Pharmacy Practice, University of Connecticut and Divisions of Drug Information and Cardiology, Hartford Hospital, Hartford, Connecticut Postoperative atrial fibrillation can occur in 25% to 40% of patients undergoing cardiothoracic surgery. Although the majority of postoperative atrial fibrillation is benign, it has been associated with prolonged hospital length of stay. Magnesium prophylaxis against postoperative atrial fibrillation has been evaluated in several clinical trials; however these trials were small in size and therefore conveyed mixed or inconclusive results. In an attempt to better understand magnesium s role in this setting, we conducted a meta-analysis. A systematic literature search was conducted from January 1999 through August 2004 to identify trials of prophylactic magnesium in the setting of cardiothoracic surgery. The primary outcome measure was the incidence of postoperative atrial fibrillation. Trials were further analyzed based on cumulative doses of magnesium and perioperative time of initiation of prophylaxis, as well as length of stay. Seven randomized trials were identified. Upon meta-analysis, magnesium Postoperative atrial fibrillation (POAF) remains a common complication of cardiothoracic surgery occurring in 25% to 40% of patients [1, 2]. Although the majority of POAFs are benign and self-limiting, some cases can produce deleterious outcomes (eg, thromboembolisms and fatal ventricular arrhythmias). Postoperative atrial fibrillation is associated with an increase in both hospital length of stay (LOS) and total hospital costs [1, 2]. A recent meta-analysis identified magnesium as effective POAF prophylaxis, but did not find a reduction in LOS [3]. However, two important trials were not included in this analysis [4, 5]. As the second most abundant intracellular cation, magnesium plays a role in many of the physiologic processes in the human body. Hypomagnesemia is common in patients who undergo cardiothoracic surgery [6 8] and is associated with many cardiovascular disease states, including atrial arrhythmias. Although the role of magnesium in the pathogenesis of atrial fibrillation has not been completely determined, investigations into the utility of magnesium as an antiarrhythmic remain an area Address correspondence to Dr Coleman, University of Connecticut School of Pharmacy, Hartford Hospital, 80 Seymour St, CB 309, Hartford, CT ; ccolema@harthosp.org. was found to prevent postoperative atrial fibrillation with an odds ratio of 0.66 and 95% confidence interval of 0.51 to The incidence of postoperative atrial fibrillation was also significantly reduced in the low dose with an odds ratio of 0.36 and 95% confidence interval of 0.23 to 0.56, and in the preoperative groups with an odds ratio of 0.46 and 95% confidence interval of 0.31 to Prophylactic magnesium reduced length of stay (n 6 studies) by a weighted mean difference of 0.29 days, with a 95% confidence interval 0.54 to Prophylactic magnesium reduced cardiothoracic surgery patients risk of postoperative atrial fibrillation and length of stay. Administering lower doses and initiating prophylaxis in the preoperative period achieved the greatest reduction in postoperative atrial fibrillation. (Ann Thorac Surg 2005;80:2402 6) 2005 by The Society of Thoracic Surgeons of focus in the research community. Magnesium exerts its antiarrhythmic effects in part by inhibiting L-type calcium channels, which reduces sinus node rate firing, prolongs atrioventricular conductance, and increases atrioventricular node refractoriness [9], and inward rectifier potassium channels in the cardiac action potential. Several studies have been conducted using magnesium for POAF prophylaxis in the setting of cardiothoracic surgery. These studies used relatively small sample sizes, various dosing regimens, and conveyed mixed results. Therefore we conducted a meta-analysis of relevant and more recent trials to determine magnesium s effect on POAF. We also analyzed the data from similar dosing regimens to determine effects on POAF. We evaluated LOS data from trials that included it as an endpoint. Material and Methods A MEDLINE search was performed using the medical subject headings (MeSH, including all subheadings) and the following keywords: atrial fibrillation, magnesium, and surgery from 1999 through August Results were limited to human studies and English language. Additional studies were identified from references cited in 2005 by The Society of Thoracic Surgeons /05/$30.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg REVIEW HENYAN ET AL 2005;80: MAGNESIUM AND ATRIAL FIBRILLATION 2403 Fig 1. Magnesium s effect on postoperative atrial fibrillation (POAF). (CI confidence interval; OR odds ratio.) identified studies and review articles. Studies were included if they were randomized controlled trials versus placebo or routine treatment; if they examined the prevention of POAF and supraventricular arrhythmias after coronary artery bypass graft or valvular surgery, or after both grafting and surgery; if they had a well described protocol; and if they adequately provided data on treatment efficacy. For studies that had greater than one experimental arm, the results of any magnesium groups were included in the meta-analysis, provided the study also had a control arm [10 12]. We did not include trials that supplemented magnesium solely by cardioplegia solution [13]. Three reviewers (NNH, ELG, CMW) evaluated the data on the number of patients included, type of intervention, POAF incidence, and LOS. The outcome measures evaluated in this meta-analysis were the incidence of POAF and LOS. One trial reported the incidence of postoperative atrial tachyarrhythmias [12]. Because 90.4 % of the atrial tachyarrhythmias in this study were atrial fibrillations, we used the incidence of postoperative atrial tachyarrhythmias for incidence of POAF. Trials were further analyzed based on cumulative dose of magnesium (low dose: 10 grams, or moderate to high dose: 10 grams) and perioperative time of initiation of prophylaxis (preoperative or intraoperative or postoperative). The occurrence rates of POAF were treated as dichotomous variables and were reported as odds ratios (ORs). LOS was treated as a continuous variable and the weighted mean difference was calculated as a difference between mean values of LOS in treatment and control groups. Pooled ORs and weighted mean differences with 95% confidence intervals (CIs) and statistical heterogeneity Table 1. Summary of Trials Study (y) n Total Dose Mg (gm) When Mg was Initiated Study Groups POAF Mg POAF Ctrl Description of Mg Protocol Bert (2001) Intraoperative Mg vs PI 24/63 23/60 2 g postoperative CPB, 2gonarrival to ICU, 2 gm QD 4 days (POD 1 4) Bert (2001-BB) Intraoperative Mg P vs P 13/69 13/71 Same mg as previous entry; propranolol 1 mg IV Q6hon arrival to ICU, then converted (usually by POD 1) to propranolol 10 mg po QID thru POD 4 Forlani (2002) Preoperative Mg vs PI 8/54 19/ g QD 6 days (through POD 5), starting preoperative CPB Hazelrigg (2004) (avg) Preoperative Mg vs PI 32/105 41/97 80 mg/kg (IBW) preoperative CPB, followed by continuous infusion 8 mg/kg/hr (IBW) over 48 hours Kaplan (2003) Preoperative Mg vs PI 15/100 16/100 3 gm infused over 2 hours, 12 hours preoperative; postoperative CPB, and QD on POD 0, 1, 2, 3 Solomon (2000) Intraoperative Mg P vs P 19/85 16/82 2 g mg postoperative CPB, followed by 16 g infusion over next 24 hr 20 mg propranolol po/ng Q6h (starting within 24 h of surgery) Toramon (2001) Preoperative Mg vs PI 2/100 21/ g 1 day before surgery, 1.5 g postoperative CPB, 1.5 g QD for 4 days after surgery Treggiari-Venzi (2000) Postoperative Mg vs PI 11/47 14/51 4 g/24 h continuous infusion for 72 h (starting within 1hofarrival to ICU) CPB cardiopulmonary bypass; IBW ideal body weight; ICU intensive care unit; P propranolol; PI placebo; po by mouth; POD postoperative day(s).

3 2404 REVIEW HENYAN ET AL Ann Thorac Surg MAGNESIUM AND ATRIAL FIBRILLATION 2005;80: Fig 2. Magnesium s dose on postoperative atrial fibrillation (low dose). (CI confidence interval; OR odds ratio.) scores among studies were calculated using the Review Manager (Oxford, England: The Cochrane Collaboration, 2002) with a fixed effects model (fixed effects model uses the Mantel-Haenzel method for dichotomous data). A p value 0.05 was considered statistically significant. Results Thirteen trials were identified [4, 5, 10 20], with seven [4, 5, 10 12, 14, 15] satisfying the inclusion criteria (n 1,234). Three trials were excluded because they did not include a control or standard of care group [16 18]. One trial was excluded because magnesium supplementation was given solely in cardioplegia solution [13]. One trial was excluded because it supplemented magnesiumbased intraoperative ionized levels [19]. One trial was excluded because they expressed data as numbers of events instead of numbers of patients experiencing events [20]. The majority of the studies in this analysis (6 of 7) enrolled patients undergoing coronary artery bypass grafting for the first time. One study [12] also included patients undergoing first time valvular or combination coronary artery bypass grafting with valvular surgery, or both. All surgeries were conducted using a cardiothoracic pump (ie, on-pump) with the exception of one study that included both on-pump and off-pump surgeries [14]. Male patients comprised the majority (79%) of the study population. The majority of the studies (6 of 7) excluded patients with abnormal renal function or end-stage renal disease requiring hemodialysis [4, 5, 10 12, 15]. Patients with a history of arrhythmias or concurrent use of antiarrhythmic medications, or both, were excluded from all of the trials included in this meta-analysis. Four studies did not exclude patients with left ventricular systolic dysfunction [4, 10, 14, 15]. Beta blockers were held prior to initiation of the study protocol in three trials [11, 14, 15]. All trials used intravenous magnesium sulfate as their form of magnesium supplementation. All trials used continuous electrocardiographic or Holter monitoring to detect arrhythmias. With the exception of one trial with a 1-month follow-up period [11], all of the remaining trials followed patients through the end of hospital stay or through postoperative days 3, 4, or 5. Postoperative Atrial Fibrillation The use of magnesium significantly reduced POAF with the following odds ratio (OR, 0.66; 95% CI 0.51 to 0.87) (Fig 1). There was significant statistical heterogeneity between the trials (p 0.02). The dosage of magnesium ranged from totals of 6.5 g [5] to 18 g [4, 14] and varied with respect to perioperative loading time and duration of magnesium administration (Table 1). Among the trials that utilized lower dosages of magnesium [5, 11, 15] (n 506; mean cumulative dose, 8.2 g; dosage range, 6.5 to 9 g), the incidence of POAF was significantly reduced (OR, 0.36; 95% CI 0.23 to 0.56) (Fig 2). In the trials that used a moderate to high dose of magnesium [4, 10, 12, 14] (n 728; mean cumulative dose, 15 g; dosage range, 12 to 18 g) the incidence of POAF was not significantly reduced (OR, 0.99; 95% CI, 0.70 to 1.42) (Fig 3). Among the trials that initiated prophylaxis during the intraoperative [4, 12] or postoperative [10] periods, or both (n 528), the incidence of POAF was not reduced (OR, 1.01; 95% CI, 0.68 to 1.51) (Fig 4). Among trials that initiated therapy in the preoperative setting [5, 11, 14, 15] (n 706), the incidence of POAF was significantly reduced (OR, 0.46; 95% CI, 0.31 to 0.67) (Fig 5). There was significant statistical heterogeneity among the low dose (p 0.02) and preoperative (p 0.01) groups, whereas the moderate and high dose groups (p 0.98) and intraoperative and postoperative groups (p 0.94) were comprised of homogeneous pools of data. Length of Stay Six [4, 5, 11, 12, 14, 15] of the included trials provided data (expressed as mean standard deviation) on hospital Fig 3. Magnesium s dose on postoperative atrial fibrillation (moderate-high dose). (CI confidence interval; OR odds ratio.)

4 Ann Thorac Surg REVIEW HENYAN ET AL 2005;80: MAGNESIUM AND ATRIAL FIBRILLATION 2405 Fig 4. Time of initiation of prophylaxis (intraopertive and postoperative initiation). (CI confidence interval; OR odds ratio; POAF postoperative atrial fibrillation.) LOS (n 1,136). Prophylactic intravenous magnesium reduced LOS by approximately one third of a day (weighted mean difference, 0.29; 95% CI, 0.54 to 0.05) (Fig 6), with little statistical heterogeneity between the trials (p 0.46). Adverse Effects Six of the included trials reported data on adverse effects [4, 5, 10, 11, 14, 15]. The majority of studies (5 of 6) did not find significant differences in adverse effects between the magnesium and control groups (ie, hypotension, bradycardia). Solomon and colleagues [4] reported a significant increase in the number of patients experiencing hypotension in the combination therapy group (magnesium and propranolol) than in the propranolol group alone; however hypotension was defined as systolic blood pressure 120 mm Hg. Comment Our meta-analysis illustrates that prophylactic intravenous magnesium significantly decreases the incidence of POAF and LOS in patients undergoing cardiothoracic surgery. A previous meta-analysis by Shiga and colleagues [3] found a 29% reduction in POAF (relative risk, 0.71; 95% CI 0.55 to 0.93) but no change in LOS (weighted mean difference, 0.28; 95% CI, 0.70 to 1.27). To minimize the effect of changes in patient demographics, surgical technique, and the adoption of beta-blockers as standard of care in POAF prophylaxis, we limited this metaanalysis to studies published from 1999 to In addition, we analyzed the impact of different doses and administration times as secondary analyses. We showed a reduction in LOS by approximately one third of a day. Because POAF has been shown to increase LOS by 2 days [1], and magnesium can decrease the incidence of POAF by half, these results are pharmacologically plausible. The ability to reduce hospital LOS provides more compelling evidence of tangible benefit for clinicians than simply reducing POAF, because POAF may be self-limited in many patients. Reducing LOS generally lowers hospital costs, but these studies did not evaluate this endpoint. This is the first meta-analysis to evaluate the impact of magnesium dose and the time of initiation of therapy to efficacy. Regimens utilizing lower doses of magnesium showed a significant reduction in POAF, whereas those that used moderate to high doses did not. Furthermore, initiating magnesium during the preoperative period was associated with a significant reduction in POAF, whereas initiation of magnesium prophylaxis during the intraoperative and postoperative time periods was not. There was statistical homogeneity among the data sets in the moderate and high dose groups and the intraoperative and postoperative groups, but the intra-group similarities did not exceed the similarities found among all the trials included in this meta-analysis. In addition, the three studies that comprised the low-dose group also comprised preoperative strategies. These results may be explained by effects on intracellular magnesium concentrations. Intracellular magnesium levels are significantly lower in cardiac surgery patients compared with healthy volunteers, despite both groups having serum levels within the normal range. With repletion, tissue magnesium recovery lags behind serum recovery by at least 24 hours in response to 24 hours of continuous intravenous magnesium supplementation [8]. Taken together, it is possible that lower doses of intravenous magnesium administered over a longer period of time may be optimal to correct intracellular deficiencies without precipitating intracellular or serum hypermagnesemia. This is consistent with the results of clinical trials in which appreciable doses of magnesium were administered intraoperatively into cardioplegia solution. Cardioplegia magnesium administration was not a successful strategy for reducing POAF [13, Fig 5. Time of initiation of prophylaxis (preoperative initiation). (CI confidence interval; OR odds ratio; POAF postoperative atrial fibrillation.)

5 2406 REVIEW HENYAN ET AL Ann Thorac Surg MAGNESIUM AND ATRIAL FIBRILLATION 2005;80: Fig 6. Magnesium s effect on length of stay (LOS). (CI confidence interval; SD standard deviation; WMD weighted mean difference.) 14]. Unfortunately, tissue magnesium levels were only measured in one of the trials included in this metaanalysis, with samples taken only during the intraoperative period [5]. The potential for publication bias is a concern for any meta-analysis. Publication bias results from it being easier to find studies that yielded significant or positive results, potentially leading to overrepresentation of a drug s benefit in systematic reviews. Intravenous magnesium prophylaxis reduces the incidence of POAF and reduces hospital LOS in cardiothoracic surgery. It appears that the greatest reduction in the occurrence of POAF occurs when utilizing lower dosages of magnesium and initiating prophylaxis during the preoperative period. References 1. Mathew JP, Fontes ML, Tudor IC, et al. A multicenter risk for atrial fibrillation after cardiac surgery. JAMA 2004;291: Fuster V, Ryden LE. ACC/AHA/ESC Guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and Policy Conference. American Heart Association Heart and Stroke Statistical Update. Dallas, Texas: American Heart Association, 2001 (accessed 8/7/02). 3. Shiga T, Wajima Z, Inuoue T, Ogawa R. Magnesium prophylaxis for arrhythmias after cardiac surgery: a meta-analysis of randomized controlled trials. Am J Med 2004;117: Solomon AJ, Berger AK, Trivedi KK, Hannan RL, Katz NM. The combination of propranolol and magnesium does not prevent postoperative atrial fibrillation. Ann Thorac Surg 2000;69: Hazelrigg SR, Boley TM, Cetindag IB, et al. The efficacy of supplemental magnesium in reducing atrial fibrillation after coronary artery bypass grafting. Ann Thorac Surg 2004;77: Booth JV, Phillips-Bute B, McCants CB, et al. Low serum magnesium level predicts major adverse cardiac events after coronary artery bypass graft surgery. Am Heart J 2003;145: Aglio LS, Stanford GG, Maddi R, et al. Hypomagnesemia is common following cardiac surgery. J Cardiothorac Vasc Anesth 1991;5: Haigney MCP, Silver B, Tanglao E, et al. Noninvasive measurement of tissue magnesium and correlation with cardiac levels. Circulation 1995;92: Touyz RM. Magnesium in clinical medicine. Frontiers in Bioscience 2004;9: Treggiari-Venzi MM, Waeber JL, Perneger TV, Suter PM, Adamec R, Romand JA. Intravenous amiodarone or magnesium sulphate is not cost-beneficial prophylaxis for atrial fibrillation after coronary artery bypass surgery. Br J Anaesth 2000;85: Forlani S, De Paulis R, de Notaris S, et al. Combination of sotalol and magnesium prevents atrial fibrillation after coronary artery bypass grafting. Ann Thorac Surg 2002;74: Bert AA, Reinert SE, Singh AK. A -blocker, not magnesium, is effective prophylaxis for atrial tachyarrhythmias after coronary artery bypass graft surgery. J Cardiothorac Vasc Anes 2001;15: Yeatman M, Caputo M, Narayan P, et al. Magnesiumsupplemented warm blood cardioplegia in patients undergoing coronary artery revascularization. Ann Thorac Surg 2002;73: Kaplan M, Sinan M, Icer UA, Demirtas MM. Intravenous magnesium sulfate prophylaxis for atrial fibrillation after coronary artery bypass surgery. J Thorac Cardiovasc Surg 2003;125: Toraman F, Karabulut EH, Alhan HC, Dagdelen S, Tarcan S. Magnesium infusion dramatically decreases the incidence of atrial fibrillation after coronary artery bypass grafting. Ann Thorac Surg 2001;72: Ott RA, Gutfinger DE, Alimadadian H, et al. Reduced postoperative atrial fibrillation using multidrug prophylaxis. J Card Surg 1999;14: Sparicio D, Landoni G, Cerchierini E, et al. A randomized controlled trial on high dose magnesium supplementation to prevent atrial fibrillation after off pump CABG. Minerva Anestesiol 2004;70: Geertman H, van der Starre PJA, Sie HT, Beukema WP, van Rooyen-Butijn M. Magnesium in addition to sotalol does not influence the incidence of postoperative atrial tachyarrhythmias after coronary artery bypass surgery. J Cardiothorac Vasc Anes 2004;18: Wilkes NJ, Mallett SV, Peachey T, Di Salvo C, Walesby R. Correction of ionized plasma magnesium during cardiopulmonary bypass reduces the risk of postoperative cardiac arrhythmia. Anesth Analg 2002;95: Speziale G, Ruvolo G, Fattouch K, et al. Arrhythmia prophylxis after coronary artery bypass grafting: regimens of magnesium sulfate administration. Thorac Cardiov Surg 2000;48:22 6.