Landiolol Hydrochloride for Prevention of Atrial Fibrillation after Cardiac Surgery: A Meta-Analysis SHANXIN LIU, PH.D.,* CHANG BIAN, PH.D.,† YU ZHANG, PH.D.,† YING JIAN, PH.D.,* and WENMIN LIU, M.D.* From the *Department of Cardiology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang Province, China; and †Department of Cardiology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
Background: Atrial fibrillation (AF) is the most common arrhythmic complication after cardiac surgery. Several studies have compared the efficacy of landiolol and placebo or other agents in preventing newonset AF in patients after cardiac surgery. In this study, we conducted a meta-analysis to determine whether landiolol is effective in preventing new-onset AF after cardiac surgery. Methods and Results: Five randomized controlled trials and two retrospective analyses were included in this study. The clinical outcomes of interest were the occurrence of AF after cardiac surgery and major complications. Meta-analysis was performed using RevMan 5.0.18 software, and pooled estimates of the effect were reported as risk ratios (RR) with 95% confidence intervals (CI). The results of this meta-analysis indicate that landiolol is significantly associated with a decreased risk of occurrence of AF after cardiac surgery (RR = 0.33; 95% CI: 0.23–0.48; P < 0.00001) and is not associated with an increased risk of major complications (RR = 0.79; 95% CI: 0.43–1.45; P = 0.45) compared with the control group. Conclusion: Landiolol administration in the perioperative period can reduce the occurrence of AF after cardiac surgery without increasing the risk of major complications. It can be used to prevent new-onset AF safely after cardiac surgery. (PACE 2014; 00:1–6) landiolol hydrochloride, atrial fibrillation, cardiac surgery, β1-selective blocker
Introduction Atrial fibrillation (AF) is the most common arrhythmia and continues to be so, which is associated with increased mortality and morbidity and leads to an impaired quality of life of sufferers.1 AF is also the most common arrhythmic complication after cardiac surgery and is associated with increased postoperative morbidity, such as embolism or stroke, increased intensive care unit and total hospital stays, and increased healthcare costs.2 Moreover, newonset AF after coronary artery bypass grafting has a marked adverse influence on long-term mortality.3,4 Therefore, prevention of new-onset AF after cardiac surgery is an important medical and economic issue. A β-blocker is strongly recommended by guidelines to prevent postoperative new-onset AF in patients undergoing cardiac surgery.5 However, an unexpected drop in heart Authors Shanxin Liu and Chang Bian contributed to this work equally. Address for reprints: Wenmin Liu, M.D., Department of Cardiology, the Affiliated Hospital of Hangzhou Normal University, #126 Wenzhou Road, Hangzhou, Zhejiang Province 310015, China; e-mail: [email protected] Received December 1, 2013; revised January 15, 2014; accepted February 5, 2014. doi: 10.1111/pace.12379
rate or blood pressure may be caused by an oral βblocker; therefore, this kind of drug is not utilized widely immediately after cardiac surgery.6 Landiolol hydrochloride is an ultra-short acting β1-selective blocker with a half-life of only 4 minutes. It can be given intravenously and has a weaker negative inotropic effect than other intravenous β1-blockers. Landiolol hydrochloride has been approved in Japan for the treatment of intraoperative and postoperative tachyarrhythmias.7 Several studies, including prospective randomized controlled trials (RCTs) and retrospective analyses (RAs), have evaluated the efficacy of landiolol in preventing new-onset AF in patients after cardiac surgery, including coronary artery bypass grafting and cardiac valve surgery.8–14 However, most of these studies have a relatively small sample size and the conclusions are not sufficiently dependable. Thus, we conducted a meta-analysis to determine whether landiolol is effective in preventing the new onset of AF after cardiac surgery. Methods Search Strategy and Selection Criteria Two authors independently used the standard search strategy of the Cochrane Review Group in searching Web of Science, the Cochrane Library (2013, 10 issues), PubMed (1966–2013), and
©2014, The Authors. Journal compilation ©2014 Wiley Periodicals, Inc. PACE, Vol. 00
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Clinicaltrials.gov (2013) for RCTs or other controlled studies evaluating the efficacy of landiolol in preventing new-onset AF in patients after cardiac surgery. The search terms used were as follows: (“heart surgery” or “cardiac surgery”) and “atrial fibrillation” and “landiolol.” The search was restricted to English fully published studies. We also performed manual searches for the retrieval of relevant studies from the reference lists of primary studies and review articles. The RCTs or other controlled studies included in this meta-analysis satisfy all of the following criteria: (1) comparison of the efficacies of landiolol and placebo or other agents in preventing new-onset AF in patients after cardiac surgery; (2) the purpose of landiolol administered in the perioperative period was to prevent the occurrence of AF, and the treatment of postoperative AF by landiolol was excluded; (3) new-onset AF in the follow-up period after cardiac surgery was reported. Two independent authors examined all the gathered titles and abstracts to determine whether they fulfilled the study selection criteria. The assessment of eligibility of full-text articles was conducted independently after the full-text materials were obtained. Any disagreement or uncertainty was resolved by consensus.
and only RCTs were calculated to check the robustness of the result. A scatter funnel plot of RRs of the enrolled studies on the X-axis against the standard error of log RR of each study on the Y-axis was generated to assess the presence of publication bias.16 A value of P < 0.05 was considered statistically significant. Results Included Studies and Characteristics The initial search produced 37 relevant abstracts of full-text articles, of which 11 articles were considered potentially eligible. Full-text versions of the 11 articles were obtained. After reviewing each publication, five RCTs and two RAs were included in the final analysis.8–14 Four articles were excluded; one was a review and the other three studies compared the efficacies of landiolol and placebo or other agents in the treatment of new-onset AF in patients after cardiac surgery. Information was extracted from each eligible study, as summarized in Table I. A total of 543 patients who underwent cardiac surgery were included in this analysis. These patients were divided into the group: those who received therapy with landiolol (L group, 269 patients) and those who did not receive any β-blockers (C group, 274 patients) in the perioperative period.
Data Extraction Data extraction was conducted independently by two authors who agreed on the results after comparison. The following information was extracted for each eligible study: first author, publication year, study design, number of patients included in the landiolol and control groups, dose and time of landiolol used in the landiolol group, and the occurrence of AF after cardiac surgery. Duration of follow-up and major complications were also extracted if they were reported in an eligible study.
Clinical Outcomes The occurrence of AF after cardiac surgery was analyzed. The heterogeneity among these seven studies was low (I2 = 0) so a fixedeffect model was used. Overall, prevention with landiolol was significantly associated with a decreased risk of occurrence of AF unlike in the control group (RR = 0.33; 95% CI: 0.23–0.48; P < 0.00001, Fig. 1). Five of the studies included were RCTs,9–12,14 and the analysis of these five RCTs also showed that landiolol decreased the risk of occurrence of AF significantly (I2 = 0, fixed-effect model; RR = 0.33; 95% CI: 0.22–0.51; P < 0.00001; Fig. 2). Data on major complications were recorded in four studies.9,11,13,14 All together, there was one death (mediastinitis) in landiolol groups of these four studies versus two deaths in control groups (mediastinitis and cardiac failure). Other major complications that had happened in landiolol groups of these four studies were heart failure (seven cases), renal failure (two cases), asthma (one case), low-output syndrome (one case), hypotension (one case), myocardial infarction (one case), mediastinitis (one case), cerebral infarction (one case), and seizures (one case). Analysis of the major complications of these four studies indicated that therapy with landiolol
Statistical Analysis RevMan 5.0.18 software (freeware available from The Cochrane Collaboration, http://www. ccims.net/revman/download) was used to perform the statistical analysis. Dichotomous outcomes were expressed as proportions and risk ratios (RRs) with 95% confidence intervals (CIs). The extent of heterogeneity among the included studies was assessed by the I2 -statistic. If heterogeneity among studies was low (I2 ࣘ 50%), a fixed-effect model was used to calculate summary estimates and their 95% CIs; a random-effect model was used if heterogeneity among studies was significant (50% < I2 < 70%). If the heterogeneity among studies was very significant (I2 ࣙ 70%), it could not be combined.15 Sensitivity analysis was performed by excluding other controlled studies
2
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2014
RA
RCT
Nakanishi K., 2013 (13)
Nagaoka E., 2013 (14)
CABG
CABG or cardiac valve surgery
Heart valve surgery
CABG
CABG
CABG
CABG
Surgery Category
22/23
57/48
30/30
34/34
36/34
70/70
20/35
Patients (L/C) Started after cardiopulmonary bypass. The loading dose was 1.5–2.5 µg/kg/min continued for 2 days after surgery Administered at the time of central anastomosis during CABG, started at 2 µg/kg/min and discontinued after 48 hours Immediately after surgery at 5 µg/kg/min and was continued 0–10 µg /kg/min. It was administered over a mean period of 50 hours Administered 5 µg/kg/min for 3 days, starting from the completion of central anastomosis Started at a dose of 10 µg /kg/min upon admission to the ICU and discontinued 72 hours after surgery; the dose was decreased if HR less 60 beats/min Intraoperative use of landiolol initiated at a dose of 1 µg/kg/min and titrated upward in 3–5 µg/kg/min based on HR and blood pressure responses The dosage of landiolol was restricted to 0.5–2 µg/min/kg and it was used from ICU admission until the beginning of oral drug intake
Dose and Time of Landiolol Used in the Landiolol Group
1 week after surgery
7 postoperative days
72 hours after surgery
1 week after surgery
7 postoperative days
1 week after surgery
Not mentioned
Follow-Up
1/6
5/12
6/16
5/12
4/11
7/24
2/12
Occurrence of AF (L/C)
2/0
9/8
Not mentioned
No major complications in L group; not mentioned in C group. 3/4
3/8
Not mentioned
Major Complications (L/C)
Major complications were classified as perioperative deaths, low-output syndrome, cerebral infarction, heart failure, mediastinitis, refractory arrhythmia, respiratory failure, acute renal failure (requiring dialysis), and other disorders requiring long-term management in the ICU. AF = atrial fibrillation; C = control; CABG = coronary artery bypass grafting; ICU = intensive care unit; L = landiolol; RA = retrospective analysis; RCT = randomized controlled trials.
RCT
Sakaguchi M., 2012 (12)
RCT
Fujii M., 2012 (10)
RCT
RCT
Sezai A., 2011 (9)
Sezai A., 2012 (11)
RA
Study Design
Fujiwara H., 2009 (8)
First Author, Publishing Year, (Ref.)
Information Was Extracted from Each Eligible Study
Table I.
LANDIOLOL FOR PREVENTION OF AF
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Figure 1. Overall RR and its 95% CI of occurrence of AF after cardiac surgery were pooled from seven included studies. AF = atrial fibrillation; CI = confidence interval; RR = risk ratio.
Figure 2. Sensitivity analysis was performed by excluding two retrospective analyses; overall RR and its 95% CI of occurrence of AF after cardiac surgery were pooled from five RCTs. The same results of analysis of these five RCTs indicate the robustness of the overall results. AF = atrial fibrillation; CI = confidence interval; RCTs = randomized control trials; RR = risk ratio.
Figure 3. Detailed data on major complications were reported in four studies; overall RR and its 95% CI of major complications were pooled from these four included studies. CI = confidence interval; RR = risk ratio.
in the perioperative period was not associated with an increased risk of major complications compared with control group (I2 = 0, fixed-effect model; RR = 0.79; 95% CI: 0.43–1.45; P = 0.45; Fig. 3).
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Publication Bias Assessment For the considered end point of occurrence of AF after cardiac surgery, the funnel plot of the studies with estimable RRs appeared symmetrical, indicating the absence of publication bias (Fig. 4).
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LANDIOLOL FOR PREVENTION OF AF
Figure 4. The scatter funnel plot of RRs of seven included studies on the x-axis against the standard error of log RR of each study on the y-axis. RR = risk ratio.
Discussion The overall result of this meta-analysis clearly shows that landiolol hydrochloride administration in the perioperative period significantly reduces the occurrence of AF after cardiac surgery without increasing the risk of major complications. AF is the most common arrhythmic complication after cardiac surgery, is associated with increased postoperative morbidity, and has a marked adverse influence on long-term mortality.2–4 Multiple factors have been reported to be associated with new-onset AF after cardiac surgery, such as advanced age, elevation in atrial pressure from postoperative impaired ventricular function, inflammation, oxidative stress, ischemic damage, sympathetic activation, and so on.17,18 Landiolol hydrochloride may attenuate some of these factors to reduce the occurrence of AF after cardiac surgery. Landiolol hydrochloride is an ultra-short acting β1-selective blocker that can be given intravenously to treat intraoperative and postoperative tachyarrhythmias, including AF, atrial flutter, and sinus tachycardia in Japan.7 The decreased occurrence of AF after cardiac surgery may be chiefly attributed to the antisympathetic and anti-ischemic effect resulting from the β1selective block effect of landiolol.19,20 Furthermore, landiolol and other β-blockers have also been reported to have strong anti-inflammatory
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and antioxidative effects, and they may help to reduce the occurrence of AF after cardiac surgery.9,11,21 Therefore, the reduction of AF after cardiac surgery by landiolol may be due to its antisympathetic and anti-ischemic effects in addition to its anti-inflammatory and antioxidative effects. Landiolol has also been reported to exert a more potent negative chronotropic effect but a less negative inotropic effect than other congeners.7,22–24 It is unlikely to cause hypotension, ventricular dysfunction, and aggravate hemodynamics, which may explain why landiolol used in the perioperative period does not improve the risk of major complications compared with the control group. Conclusions The results of this meta-analysis indicate that landiolol administration in the perioperative period can reduce the occurrence of AF after cardiac surgery without increasing the risk of major complications. This action of landiolol may be due to its antisympathetic and anti-ischemic effects and the reduction of the inflammation and oxidative stress. These findings show that landiolol can be used to safely prevent new-onset AF after cardiac surgery. However, this metaanalysis is limited by some factors. First, most of the studies included in this meta-analysis have small numbers of patients and the total sample
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size is not sufficient enough; second, there is disparity in administrated dose and duration of landiolol in these studies; finally, almost all of the studies used in this analysis are about coronary
artery bypass grafting. Prospective RCTs with large samples of various cardiac surgeries and unified usages of landiolol should be fulfilled to confirm these conclusions.
References 1. Sullivan SD, Orme ME, Morais E, Mitchell SA. Interventions for the treatment of atrial fibrillation: A systematic literature review and meta-analysis. Int J Cardiol 2013; 165:229–236. 2. Mariscalco G, Klersy C, Zanobini M, Banach M, Ferrarese S, Borsani P, Cantore C, et al. Atrial fibrillation after isolated coronary surgery affects late survival. Circulation 2008; 118:1612–1618. 3. El-Chami MF, Kilgo P, Thourani V, Lattouf OM, Delurgio DB, Guyton RA, Leon AR, et al. New-onset atrial fibrillation predicts long-term mortality after coronary artery bypass graft. J Am Coll Cardiol 2010; 55:1370–1376. 4. Kaw R, Hernandez AV, Masood I, Gillinov AM, Saliba W, Blackstone EH. Short- and long-term mortality associated with new-onset atrial fibrillation after coronary artery bypass grafting: A systematic review and meta-analysis. J Thorac Cardiovasc Surg 2011; 141:1305–1312. 5. Wann LS, Curtis AB, January CT, Ellenbogen KA, Lowe JE, Estes NA 3rd, Page RL, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (updating the 2006 guideline): A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011; 123:104–123. 6. DiDomenico RJ, Massad MG. Pharmacologic strategies for prevention of atrial fibrillation after open heart surgery. Ann Thorac Surg 2005; 79:728–740. 7. Plosker GL. Landiolol: A review of its use in intraoperative and postoperative tachyarrhythmias. Drugs 2013; 73:959–977. 8. Fujiwara H, Sakurai M, Namai A, Kawamura T. Effect of low-dose landiolol, an ultrashort-acting beta-blocker, on postoperative atrial fibrillation after CABG surgery. Gen Thorac Cardiovasc Surg 2009; 57:132–137. 9. Sezai A, Minami K, Nakai T, Hata M, Yoshitake I, Wakui S, Shiono M, et al. Landiolol hydrochloride for prevention of atrial fibrillation after coronary artery bypass grafting: New evidence from the PASCAL trial. J Thorac Cardiovasc Surg 2011; 141:1478–1487. 10. Fujii M, Bessho R, Ochi M, Shimizu K, Terajima K, Takeda S. Effect of postoperative landiolol administration for atrial fibrillation after off pump coronary artery bypass surgery. J Cardiovasc Surg (Torino) 2012; 53:369–374. 11. Sezai A, Nakai T, Hata M, Yoshitake I, Shiono M, Kunimoto S, Hirayama A. Feasibility of landiolol and bisoprolol for prevention of atrial fibrillation after coronary artery bypass grafting: A pilot study. J Thorac Cardiovasc Surg 2012; 144:1241–1248. 12. Sakaguchi M, Sasaki Y, Hirai H, Hosono M, Nakahira A, Seo H, Suehiro S. Efficacy of landiolol hydrochloride for prevention of atrial fibrillation after heart valve surgery. Int Heart J 2012; 53:359– 363.
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13. Nakanishi K, Takeda S, Kim C, Kohda S, Sakamoto A. Postoperative atrial fibrillation in patients undergoing coronary artery bypass grafting or cardiac valve surgery: Intraoperative use of landiolol. J Cardiothorac Surg 2013; 8:19. 14. Nagaoka E, Arai H, Tamura K, Makita S, Miyagi N. Prevention of atrial fibrillation with ultra-low dose landiolol after off-pump coronary artery bypass grafting. Ann Thorac Cardiovasc Surg 2013 (in press [Epub ahead of print]). 15. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003; 327:557–560. 16. Sterne JA, Egger M. Funnel plots for detecting bias in meta-analysis: Guidelines on choice of axis. J Clin Epidemiol 2001; 54:1046– 1055. 17. Lo B, Fijnheer R, Nierich AP, Bruins P, Kalkman CJ. C-reactive protein is a risk indicator for atrial fibrillation after myocardial revascularization. Ann Thorac Surg 2005; 79:1530–1535. 18. Sezai A, Hata M, Niino T, Kasamaki Y, Nakai T, Hirayama A, Minami K. Study of the factors related to atrial fibrillation after coronary artery bypass grafting: A search for a marker to predict the occurrence of atrial fibrillation before surgical intervention. J Thorac Cardiovasc Surg 2009; 137:895–900. 19. Kurosawa S, Kanaya N, Niiyama Y, Nakayama M, Fujita S, Namiki A. Landiolol, esmolol and propranolol protect from ischemia/reperfusion injury in isolated guinea pig hearts. Can J Anaesth 2003; 50:489–494. 20. Kimura-Kurosawa S, Kanaya N, Kamada N, Hirata N, Nakayama M, Namiki A. Cardioprotective effect and mechanism of action of landiolol on the ischemic reperfused heart. J Anesth 2007; 21:480– 489. 21. Doo YC, Kim DM, Oh DJ, Ryu KH, Rhim CY, Lee Y. Effect of beta blockers on expression of interleukin-6 and C-reactive protein in patients with unstable angina pectoris. Am J Cardiol 2001; 88:422– 424. 22. Sasao J, Tarver SD, Kindscher JD, Taneyama C, Benson KT, Goto H. In rabbits, landiolol, a new ultra-short-acting beta-blocker, exerts a more potent negative chronotropic effect and less effect on blood pressure than esmolol. Can J Anaesth 2001; 48:985– 989. 23. Ikeshita K, Nishikawa K, Toriyama S, Yamashita T, Tani Y, Yamada T, Asada A. Landiolol has a less potent negative inotropic effect than esmolol in isolated rabbit hearts. J Anesth 2008; 22:361– 366. 24. Shibata S, Okamoto Y, Endo S, Ono K. Direct effects of esmolol and landiolol on cardiac function, coronary vasoactivity, and ventricular electrophysiology in guinea-pig hearts. J Pharmacol Sci 2012; 118:255–265.
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Background: Atrial fibrillation (AF) is the most common arrhythmic complication after cardiac surgery. Several studies have compared the efficacy of landiolol and placebo or other agents in preventing newonset AF in patients after cardiac surgery. In this study, we conducted a meta-analysis to determine whether landiolol is effective in preventing new-onset AF after cardiac surgery. Methods and Results: Five randomized controlled trials and two retrospective analyses were included in this study. The clinical outcomes of interest were the occurrence of AF after cardiac surgery and major complications. Meta-analysis was performed using RevMan 5.0.18 software, and pooled estimates of the effect were reported as risk ratios (RR) with 95% confidence intervals (CI). The results of this meta-analysis indicate that landiolol is significantly associated with a decreased risk of occurrence of AF after cardiac surgery (RR = 0.33; 95% CI: 0.23–0.48; P < 0.00001) and is not associated with an increased risk of major complications (RR = 0.79; 95% CI: 0.43–1.45; P = 0.45) compared with the control group. Conclusion: Landiolol administration in the perioperative period can reduce the occurrence of AF after cardiac surgery without increasing the risk of major complications. It can be used to prevent new-onset AF safely after cardiac surgery. (PACE 2014; 00:1–6) landiolol hydrochloride, atrial fibrillation, cardiac surgery, β1-selective blocker
Introduction Atrial fibrillation (AF) is the most common arrhythmia and continues to be so, which is associated with increased mortality and morbidity and leads to an impaired quality of life of sufferers.1 AF is also the most common arrhythmic complication after cardiac surgery and is associated with increased postoperative morbidity, such as embolism or stroke, increased intensive care unit and total hospital stays, and increased healthcare costs.2 Moreover, newonset AF after coronary artery bypass grafting has a marked adverse influence on long-term mortality.3,4 Therefore, prevention of new-onset AF after cardiac surgery is an important medical and economic issue. A β-blocker is strongly recommended by guidelines to prevent postoperative new-onset AF in patients undergoing cardiac surgery.5 However, an unexpected drop in heart Authors Shanxin Liu and Chang Bian contributed to this work equally. Address for reprints: Wenmin Liu, M.D., Department of Cardiology, the Affiliated Hospital of Hangzhou Normal University, #126 Wenzhou Road, Hangzhou, Zhejiang Province 310015, China; e-mail: [email protected] Received December 1, 2013; revised January 15, 2014; accepted February 5, 2014. doi: 10.1111/pace.12379
rate or blood pressure may be caused by an oral βblocker; therefore, this kind of drug is not utilized widely immediately after cardiac surgery.6 Landiolol hydrochloride is an ultra-short acting β1-selective blocker with a half-life of only 4 minutes. It can be given intravenously and has a weaker negative inotropic effect than other intravenous β1-blockers. Landiolol hydrochloride has been approved in Japan for the treatment of intraoperative and postoperative tachyarrhythmias.7 Several studies, including prospective randomized controlled trials (RCTs) and retrospective analyses (RAs), have evaluated the efficacy of landiolol in preventing new-onset AF in patients after cardiac surgery, including coronary artery bypass grafting and cardiac valve surgery.8–14 However, most of these studies have a relatively small sample size and the conclusions are not sufficiently dependable. Thus, we conducted a meta-analysis to determine whether landiolol is effective in preventing the new onset of AF after cardiac surgery. Methods Search Strategy and Selection Criteria Two authors independently used the standard search strategy of the Cochrane Review Group in searching Web of Science, the Cochrane Library (2013, 10 issues), PubMed (1966–2013), and
©2014, The Authors. Journal compilation ©2014 Wiley Periodicals, Inc. PACE, Vol. 00
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Clinicaltrials.gov (2013) for RCTs or other controlled studies evaluating the efficacy of landiolol in preventing new-onset AF in patients after cardiac surgery. The search terms used were as follows: (“heart surgery” or “cardiac surgery”) and “atrial fibrillation” and “landiolol.” The search was restricted to English fully published studies. We also performed manual searches for the retrieval of relevant studies from the reference lists of primary studies and review articles. The RCTs or other controlled studies included in this meta-analysis satisfy all of the following criteria: (1) comparison of the efficacies of landiolol and placebo or other agents in preventing new-onset AF in patients after cardiac surgery; (2) the purpose of landiolol administered in the perioperative period was to prevent the occurrence of AF, and the treatment of postoperative AF by landiolol was excluded; (3) new-onset AF in the follow-up period after cardiac surgery was reported. Two independent authors examined all the gathered titles and abstracts to determine whether they fulfilled the study selection criteria. The assessment of eligibility of full-text articles was conducted independently after the full-text materials were obtained. Any disagreement or uncertainty was resolved by consensus.
and only RCTs were calculated to check the robustness of the result. A scatter funnel plot of RRs of the enrolled studies on the X-axis against the standard error of log RR of each study on the Y-axis was generated to assess the presence of publication bias.16 A value of P < 0.05 was considered statistically significant. Results Included Studies and Characteristics The initial search produced 37 relevant abstracts of full-text articles, of which 11 articles were considered potentially eligible. Full-text versions of the 11 articles were obtained. After reviewing each publication, five RCTs and two RAs were included in the final analysis.8–14 Four articles were excluded; one was a review and the other three studies compared the efficacies of landiolol and placebo or other agents in the treatment of new-onset AF in patients after cardiac surgery. Information was extracted from each eligible study, as summarized in Table I. A total of 543 patients who underwent cardiac surgery were included in this analysis. These patients were divided into the group: those who received therapy with landiolol (L group, 269 patients) and those who did not receive any β-blockers (C group, 274 patients) in the perioperative period.
Data Extraction Data extraction was conducted independently by two authors who agreed on the results after comparison. The following information was extracted for each eligible study: first author, publication year, study design, number of patients included in the landiolol and control groups, dose and time of landiolol used in the landiolol group, and the occurrence of AF after cardiac surgery. Duration of follow-up and major complications were also extracted if they were reported in an eligible study.
Clinical Outcomes The occurrence of AF after cardiac surgery was analyzed. The heterogeneity among these seven studies was low (I2 = 0) so a fixedeffect model was used. Overall, prevention with landiolol was significantly associated with a decreased risk of occurrence of AF unlike in the control group (RR = 0.33; 95% CI: 0.23–0.48; P < 0.00001, Fig. 1). Five of the studies included were RCTs,9–12,14 and the analysis of these five RCTs also showed that landiolol decreased the risk of occurrence of AF significantly (I2 = 0, fixed-effect model; RR = 0.33; 95% CI: 0.22–0.51; P < 0.00001; Fig. 2). Data on major complications were recorded in four studies.9,11,13,14 All together, there was one death (mediastinitis) in landiolol groups of these four studies versus two deaths in control groups (mediastinitis and cardiac failure). Other major complications that had happened in landiolol groups of these four studies were heart failure (seven cases), renal failure (two cases), asthma (one case), low-output syndrome (one case), hypotension (one case), myocardial infarction (one case), mediastinitis (one case), cerebral infarction (one case), and seizures (one case). Analysis of the major complications of these four studies indicated that therapy with landiolol
Statistical Analysis RevMan 5.0.18 software (freeware available from The Cochrane Collaboration, http://www. ccims.net/revman/download) was used to perform the statistical analysis. Dichotomous outcomes were expressed as proportions and risk ratios (RRs) with 95% confidence intervals (CIs). The extent of heterogeneity among the included studies was assessed by the I2 -statistic. If heterogeneity among studies was low (I2 ࣘ 50%), a fixed-effect model was used to calculate summary estimates and their 95% CIs; a random-effect model was used if heterogeneity among studies was significant (50% < I2 < 70%). If the heterogeneity among studies was very significant (I2 ࣙ 70%), it could not be combined.15 Sensitivity analysis was performed by excluding other controlled studies
2
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2014
RA
RCT
Nakanishi K., 2013 (13)
Nagaoka E., 2013 (14)
CABG
CABG or cardiac valve surgery
Heart valve surgery
CABG
CABG
CABG
CABG
Surgery Category
22/23
57/48
30/30
34/34
36/34
70/70
20/35
Patients (L/C) Started after cardiopulmonary bypass. The loading dose was 1.5–2.5 µg/kg/min continued for 2 days after surgery Administered at the time of central anastomosis during CABG, started at 2 µg/kg/min and discontinued after 48 hours Immediately after surgery at 5 µg/kg/min and was continued 0–10 µg /kg/min. It was administered over a mean period of 50 hours Administered 5 µg/kg/min for 3 days, starting from the completion of central anastomosis Started at a dose of 10 µg /kg/min upon admission to the ICU and discontinued 72 hours after surgery; the dose was decreased if HR less 60 beats/min Intraoperative use of landiolol initiated at a dose of 1 µg/kg/min and titrated upward in 3–5 µg/kg/min based on HR and blood pressure responses The dosage of landiolol was restricted to 0.5–2 µg/min/kg and it was used from ICU admission until the beginning of oral drug intake
Dose and Time of Landiolol Used in the Landiolol Group
1 week after surgery
7 postoperative days
72 hours after surgery
1 week after surgery
7 postoperative days
1 week after surgery
Not mentioned
Follow-Up
1/6
5/12
6/16
5/12
4/11
7/24
2/12
Occurrence of AF (L/C)
2/0
9/8
Not mentioned
No major complications in L group; not mentioned in C group. 3/4
3/8
Not mentioned
Major Complications (L/C)
Major complications were classified as perioperative deaths, low-output syndrome, cerebral infarction, heart failure, mediastinitis, refractory arrhythmia, respiratory failure, acute renal failure (requiring dialysis), and other disorders requiring long-term management in the ICU. AF = atrial fibrillation; C = control; CABG = coronary artery bypass grafting; ICU = intensive care unit; L = landiolol; RA = retrospective analysis; RCT = randomized controlled trials.
RCT
Sakaguchi M., 2012 (12)
RCT
Fujii M., 2012 (10)
RCT
RCT
Sezai A., 2011 (9)
Sezai A., 2012 (11)
RA
Study Design
Fujiwara H., 2009 (8)
First Author, Publishing Year, (Ref.)
Information Was Extracted from Each Eligible Study
Table I.
LANDIOLOL FOR PREVENTION OF AF
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Figure 1. Overall RR and its 95% CI of occurrence of AF after cardiac surgery were pooled from seven included studies. AF = atrial fibrillation; CI = confidence interval; RR = risk ratio.
Figure 2. Sensitivity analysis was performed by excluding two retrospective analyses; overall RR and its 95% CI of occurrence of AF after cardiac surgery were pooled from five RCTs. The same results of analysis of these five RCTs indicate the robustness of the overall results. AF = atrial fibrillation; CI = confidence interval; RCTs = randomized control trials; RR = risk ratio.
Figure 3. Detailed data on major complications were reported in four studies; overall RR and its 95% CI of major complications were pooled from these four included studies. CI = confidence interval; RR = risk ratio.
in the perioperative period was not associated with an increased risk of major complications compared with control group (I2 = 0, fixed-effect model; RR = 0.79; 95% CI: 0.43–1.45; P = 0.45; Fig. 3).
4
Publication Bias Assessment For the considered end point of occurrence of AF after cardiac surgery, the funnel plot of the studies with estimable RRs appeared symmetrical, indicating the absence of publication bias (Fig. 4).
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LANDIOLOL FOR PREVENTION OF AF
Figure 4. The scatter funnel plot of RRs of seven included studies on the x-axis against the standard error of log RR of each study on the y-axis. RR = risk ratio.
Discussion The overall result of this meta-analysis clearly shows that landiolol hydrochloride administration in the perioperative period significantly reduces the occurrence of AF after cardiac surgery without increasing the risk of major complications. AF is the most common arrhythmic complication after cardiac surgery, is associated with increased postoperative morbidity, and has a marked adverse influence on long-term mortality.2–4 Multiple factors have been reported to be associated with new-onset AF after cardiac surgery, such as advanced age, elevation in atrial pressure from postoperative impaired ventricular function, inflammation, oxidative stress, ischemic damage, sympathetic activation, and so on.17,18 Landiolol hydrochloride may attenuate some of these factors to reduce the occurrence of AF after cardiac surgery. Landiolol hydrochloride is an ultra-short acting β1-selective blocker that can be given intravenously to treat intraoperative and postoperative tachyarrhythmias, including AF, atrial flutter, and sinus tachycardia in Japan.7 The decreased occurrence of AF after cardiac surgery may be chiefly attributed to the antisympathetic and anti-ischemic effect resulting from the β1selective block effect of landiolol.19,20 Furthermore, landiolol and other β-blockers have also been reported to have strong anti-inflammatory
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and antioxidative effects, and they may help to reduce the occurrence of AF after cardiac surgery.9,11,21 Therefore, the reduction of AF after cardiac surgery by landiolol may be due to its antisympathetic and anti-ischemic effects in addition to its anti-inflammatory and antioxidative effects. Landiolol has also been reported to exert a more potent negative chronotropic effect but a less negative inotropic effect than other congeners.7,22–24 It is unlikely to cause hypotension, ventricular dysfunction, and aggravate hemodynamics, which may explain why landiolol used in the perioperative period does not improve the risk of major complications compared with the control group. Conclusions The results of this meta-analysis indicate that landiolol administration in the perioperative period can reduce the occurrence of AF after cardiac surgery without increasing the risk of major complications. This action of landiolol may be due to its antisympathetic and anti-ischemic effects and the reduction of the inflammation and oxidative stress. These findings show that landiolol can be used to safely prevent new-onset AF after cardiac surgery. However, this metaanalysis is limited by some factors. First, most of the studies included in this meta-analysis have small numbers of patients and the total sample
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size is not sufficient enough; second, there is disparity in administrated dose and duration of landiolol in these studies; finally, almost all of the studies used in this analysis are about coronary
artery bypass grafting. Prospective RCTs with large samples of various cardiac surgeries and unified usages of landiolol should be fulfilled to confirm these conclusions.
References 1. Sullivan SD, Orme ME, Morais E, Mitchell SA. Interventions for the treatment of atrial fibrillation: A systematic literature review and meta-analysis. Int J Cardiol 2013; 165:229–236. 2. Mariscalco G, Klersy C, Zanobini M, Banach M, Ferrarese S, Borsani P, Cantore C, et al. Atrial fibrillation after isolated coronary surgery affects late survival. Circulation 2008; 118:1612–1618. 3. El-Chami MF, Kilgo P, Thourani V, Lattouf OM, Delurgio DB, Guyton RA, Leon AR, et al. New-onset atrial fibrillation predicts long-term mortality after coronary artery bypass graft. J Am Coll Cardiol 2010; 55:1370–1376. 4. Kaw R, Hernandez AV, Masood I, Gillinov AM, Saliba W, Blackstone EH. Short- and long-term mortality associated with new-onset atrial fibrillation after coronary artery bypass grafting: A systematic review and meta-analysis. J Thorac Cardiovasc Surg 2011; 141:1305–1312. 5. Wann LS, Curtis AB, January CT, Ellenbogen KA, Lowe JE, Estes NA 3rd, Page RL, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (updating the 2006 guideline): A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011; 123:104–123. 6. DiDomenico RJ, Massad MG. Pharmacologic strategies for prevention of atrial fibrillation after open heart surgery. Ann Thorac Surg 2005; 79:728–740. 7. Plosker GL. Landiolol: A review of its use in intraoperative and postoperative tachyarrhythmias. Drugs 2013; 73:959–977. 8. Fujiwara H, Sakurai M, Namai A, Kawamura T. Effect of low-dose landiolol, an ultrashort-acting beta-blocker, on postoperative atrial fibrillation after CABG surgery. Gen Thorac Cardiovasc Surg 2009; 57:132–137. 9. Sezai A, Minami K, Nakai T, Hata M, Yoshitake I, Wakui S, Shiono M, et al. Landiolol hydrochloride for prevention of atrial fibrillation after coronary artery bypass grafting: New evidence from the PASCAL trial. J Thorac Cardiovasc Surg 2011; 141:1478–1487. 10. Fujii M, Bessho R, Ochi M, Shimizu K, Terajima K, Takeda S. Effect of postoperative landiolol administration for atrial fibrillation after off pump coronary artery bypass surgery. J Cardiovasc Surg (Torino) 2012; 53:369–374. 11. Sezai A, Nakai T, Hata M, Yoshitake I, Shiono M, Kunimoto S, Hirayama A. Feasibility of landiolol and bisoprolol for prevention of atrial fibrillation after coronary artery bypass grafting: A pilot study. J Thorac Cardiovasc Surg 2012; 144:1241–1248. 12. Sakaguchi M, Sasaki Y, Hirai H, Hosono M, Nakahira A, Seo H, Suehiro S. Efficacy of landiolol hydrochloride for prevention of atrial fibrillation after heart valve surgery. Int Heart J 2012; 53:359– 363.
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13. Nakanishi K, Takeda S, Kim C, Kohda S, Sakamoto A. Postoperative atrial fibrillation in patients undergoing coronary artery bypass grafting or cardiac valve surgery: Intraoperative use of landiolol. J Cardiothorac Surg 2013; 8:19. 14. Nagaoka E, Arai H, Tamura K, Makita S, Miyagi N. Prevention of atrial fibrillation with ultra-low dose landiolol after off-pump coronary artery bypass grafting. Ann Thorac Cardiovasc Surg 2013 (in press [Epub ahead of print]). 15. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003; 327:557–560. 16. Sterne JA, Egger M. Funnel plots for detecting bias in meta-analysis: Guidelines on choice of axis. J Clin Epidemiol 2001; 54:1046– 1055. 17. Lo B, Fijnheer R, Nierich AP, Bruins P, Kalkman CJ. C-reactive protein is a risk indicator for atrial fibrillation after myocardial revascularization. Ann Thorac Surg 2005; 79:1530–1535. 18. Sezai A, Hata M, Niino T, Kasamaki Y, Nakai T, Hirayama A, Minami K. Study of the factors related to atrial fibrillation after coronary artery bypass grafting: A search for a marker to predict the occurrence of atrial fibrillation before surgical intervention. J Thorac Cardiovasc Surg 2009; 137:895–900. 19. Kurosawa S, Kanaya N, Niiyama Y, Nakayama M, Fujita S, Namiki A. Landiolol, esmolol and propranolol protect from ischemia/reperfusion injury in isolated guinea pig hearts. Can J Anaesth 2003; 50:489–494. 20. Kimura-Kurosawa S, Kanaya N, Kamada N, Hirata N, Nakayama M, Namiki A. Cardioprotective effect and mechanism of action of landiolol on the ischemic reperfused heart. J Anesth 2007; 21:480– 489. 21. Doo YC, Kim DM, Oh DJ, Ryu KH, Rhim CY, Lee Y. Effect of beta blockers on expression of interleukin-6 and C-reactive protein in patients with unstable angina pectoris. Am J Cardiol 2001; 88:422– 424. 22. Sasao J, Tarver SD, Kindscher JD, Taneyama C, Benson KT, Goto H. In rabbits, landiolol, a new ultra-short-acting beta-blocker, exerts a more potent negative chronotropic effect and less effect on blood pressure than esmolol. Can J Anaesth 2001; 48:985– 989. 23. Ikeshita K, Nishikawa K, Toriyama S, Yamashita T, Tani Y, Yamada T, Asada A. Landiolol has a less potent negative inotropic effect than esmolol in isolated rabbit hearts. J Anesth 2008; 22:361– 366. 24. Shibata S, Okamoto Y, Endo S, Ono K. Direct effects of esmolol and landiolol on cardiac function, coronary vasoactivity, and ventricular electrophysiology in guinea-pig hearts. J Pharmacol Sci 2012; 118:255–265.
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