Levosimendan and Atrial Fibrillation: A Meta-Analysis of Randomized Controlled Trials

Wan, Huan; Feng, Jihua; Ji, Pan; Chen, Wei; Zhang, Jianfeng

doi:10.36660/abc.20230856

Brasil

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Original Article • Arq. Bras. Cardiol. 121 (7) • July 2024 • https://doi.org/10.36660/abc.20230856i linkcopy

Levosimendan and Atrial Fibrillation: A Meta-Analysis of Randomized Controlled Trials

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Background Atrial fibrillation (AF) is a prevalent complication associated with levosimendan; however, it remains uncertain whether there are any disparities in the effects of levosimendan on non-postoperative and postoperative AF.

Objectives This study aimed to evaluate the levosimendan effect on non-postoperative and postoperative AF by conducting a meta-analysis of randomized control trials (RCTs).

Methods PubMed, Embase, Cochrane Library, and other databases were searched. Pairs of reviewers identified RCTs that compared levosimendan and placebo or other therapies, and the results reported AF events data. Random effects models were used (at a significance level of 5%).

Results Twenty-nine eligible trials comprising 6550 participants were included, eleven of which evaluated the non-postoperative AF incidence, and 18 included postoperative AF. The analysis revealed that levosimendan elevated the AF risk significantly in the non-postoperative group (OR, 1.62; 95% CI: 1.19-2.20; p=0.002) and reduced the AF incidence in the postoperative group (OR, 0.65; 95% CI: 0.44-0.96; p=0.03). AF occurrence decreased more significantly in patients who used levosimendan after cardiac surgery (OR, 0.53; 95% CI: 0.32-0.88; p=0.02) than in patients who used levosimendan before cardiac surgery (OR, 0.67; 95% CI: 0.42-1.06; p=0.09). Moreover, The AF risk was significantly elevated by levosimendan large bolus dose (bolus dose≥12 μg/kg) (OR, 1.44; 95% CI: 1.10-1.88; p=0.004) and decreased by small bolus dose of levosimendan (bolus dose<12 μg/kg) (OR, 0.64; 95% CI: 0.34-1.20; p=0.16).

Conclusion Levosimendan was linked to an increased non-postoperative AF incidence. The employment of levosimendan was effective in preventing postoperative AF.

Keywords Simendan; Atrial Fibrillation; Network Meta-Analysis

Central Illustration
: Levosimendan and Atrial fibrillation: A Meta-Analysis of Randomized Controlled Trials

Study	Participants(n)	Study population	Mean LVEF(%)		Bolus dose	Continous infusion dose	Control	Follow-up
Study	Participants(n)	Study population	Levosimendan	Control	Bolus dose	Continous infusion dose	Control	Follow-up
Abacilar 2013¹⁹	200	CABG	2 6.30 ± 6.36	24.86 ± 1.08	None	24μg/kg	Placebo	In-hospital
Al-Shawaf 2006¹²	30	CABG, LVEF≤35%	29 ± 6	31 ±6	12μg/kg	0.1-0.2μg/kg/min for 24 hours	Milrinone	In-hospital
Altenberger 2014¹³	120	HF, LVEF≤35%	24 ±5	24 ±5	None	0.2μg/kg/min for 6h at 2-week intervals over 6 weeks	Placebo	24 weeks
Anastasiadis 2016¹⁴	32	CABG, LVEF≤40	35.7 ± 4.9	37.5 ± 3.4	None	0.1μg/kg/min for 24 hours	Placebo	In-hospital
Baysal 2014¹⁵	128	mitral valve surgery, LVEF≤45%	35.0 (20-50)	37.5 (25-50)	6μg/kg	0.1μg/kg/min for 24 hours	Standard inotropic therapy	30days
Bergh 2010²	60	ADHF, LVEF≤35%	21.2±5.8	21.8±6.1	12μg/kg	0.1-0.2μg/kg/min for 24 hours	Dobutamine	1 month
Bharathi, 2023⁴⁷	60	mitral valve surgery	-	-	None	0.1 mcg/kg/min after induction for 24 hours	Placebo	6 hours, 24 hours, and 7 days
Cholley 2017¹⁶	335	CABG or combined with valve surgery, LVEF≤40%	-	-	None	0.1μg/kg/min for 24 hours	Placebo	6 months
De Hert 2007¹⁷	30	elective cardiac surgery, LVEF≤30%	24±6	27±3	None	0.1μg/kg/min	Milrinone	In-hospital
Desai 2018¹⁸	60	OPCAB, LVEF <30%	25.17±5.49	25.5±4.42	None	0.1μg/kg/min for 24 hours	Conventional inotropes	In-hospital
Follath 2002²⁰	203	HF, LVEF <35%	-	-	24μg/kg	0.1μg/kg/min for 24 hours	Dobutamine	In-hospital
Fuhrmann 2008²¹	32	Cardiogenic shock	22(18-31)/22±9	27(20-34)/27±10	12μg/kg	0.1-0.2μg/kg/min for 24 hours	Enoximone	30 days
Gerhard Pölzl,2023³³	145	HF, LVEF≤30%	24 ± 5	24 ± 5	None	0.2 mcg/kg/min every 2 weeks, or as 24-hour infusion at a rate of 0.1 mcg/kg/min every 3 weeks	Placebo	14 and 26 weeks
Husebye 2013²²	61	HF within 48 h after a primary PCI-treated STEMI	43 (38-49)	40 (33-47)	12μg/kg	0.1μg/kg/min for 24 hours	Placebo	6 months
Juhl-Olsen 2015²³	20	AVR, LVEF> 45%	62 (55–75)	62 (58–70)	None	0.1μg/kg/min	Placebo	In-hospital
Kandasamy 2017²⁴	80	OPCABG	-	-	None	0.1μg/kg/min for 24 hours	Dobutamine	In-hospital
Lahtinen 2011³	200	Valve surgery or combined with CABG	77%>50%	73%>50%	24μg/kg	0.1μg/kg/min	Placebo	In-hospital
Levin 2008⁴⁸	137	Coronary surgery with LCOS	36.62±4.36	38.22±5.24	10μg/kg	0.1μg/kg/min for 24 hours	Dobutamine	In-hospital
Levin 2012⁴⁹	252	CABG, LVEF<25%	17.56±3.24	18.62±2.12	10μg/kg	0.1μg/kg/min for 24 hours	Placebo	In-hospital
Lilleberg 2006²⁵	22	HF	25±5	28±6	12μg/kg	0.1-0.2μg/kg/min for 24 hours	Placebo	14 days
Mebazaa 2007⁸	1320	ADHF	24±5	24±5	12μg/kg	0.1μg/kg/min for 24 hours	Dobutamine	6 months
Mehta 2017²⁶	849	Cardiac surgery, LVEF<35%	26(24–32)	27(22-31)	12μg/kg	0.1μg/kg/min for 24 hours	Placebo	30 days
Moiseyev 2002²⁷	504	Left ventricular failure	-	-	6-24μg/kg	0.1-0.4μg/kg/min	Placebo	In-hospital
Nieminen 2008²⁸	307	HF, LVEF≤30%	25±5.3	25±4.9	None	1 mg capsule once or twice daily	Placebo	180 days
Packer 2013⁷	587	ADHF	23±7	24±7	12μg/kg	0.1μg/kg/min	Placebo	In-hospital
Shah 2014 ²⁹	50	OPCABG, LVEF<30%	22.45±4.06	22.56±3.41	None	200μg/kg over 24 h	Placebo	In-hospital
Sharma 2014³⁰	40	CABG+mitral valve repair	23.55±4.87	22.55±0.92	None	200μg/kg over 24 h	Placebo	In-hospital
Tritapepe 2006³¹	24	CABG	50±7	52±5	24μg/kg	None	Placebo	In-hospital
Tritapepe 2009³²	102	CABG	41.6±10.7	44.1±9.8	24μg/kg	None	Placebo	In-hospital

Group	No. studies	Heterogeneity		Model	Meta-analysis
Group	No. studies	p	I² (%)	Model	OR(95%CI)	p
Levosimendan vs Placebo/Control
LVEF≤40%	20	<0,001	71,6	Aleatório	0,82 (0,55, 1,22)	0,33
LVEF>40%	4	0.545	0	Aleatório	1,30 (0,80, 2,13)	0,30
Time of administration
Before surgery	14	<0,001	75,3	Aleatório	0,67 (0,42, 1,06)	0,09
After surgery	4	0,870	0	Aleatório	0,53 (0,32, 0,88)	0,02
Follow-up duration
≤7 days	18	<0,001	68,5	Aleatório	0,68 (0,42,1.12)	0,14
>7 days	11	0.812	0	Aleatório	1,30 (1,07, 1,57)	0,007
Bolus dose
≥12 μg/kg	10	0.294	16.2	Aleatório	1,44 (1,10, 1,88)	0,004
<12 μg/kg	9	<0,001	72,6	Aleatório	0,64 (0,34, 1,20)	0,16

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[TFN1001] LVEF: left ventricular ejection fraction; CABG: coronary artery bypass grafting; HF: heart failure; ADHF: acutely decompensated heart failure; OPCABG: Off-pump coronary artery bypass surgery; STEMI: ST-segment elevation infarction; AVR: aortic valve replacement; LCOS: low cardiac output syndrome All studies considered values < 0.05 to indicate statistical significance.