Efficacy and safety of 1C class antiarrhythmic agent (propafenone) for supraventricular arrhythmias in septic shock compared to amiodarone: protocol of a prospective randomised double-blind study

Martin Balik, Petr Waldauf, Michal Maly, Vojtech Matousek, Tomas Brozek, Jan Rulisek, Michal Porizka, Robert Sachl, Michal Otahal, Petr Brestovansky, Eva Svobodova, Marek Flaksa, Zdenek Stach, Jaroslav Pazout, Frantisek Duska, Ondrej Smid, Martin Stritesky, Martin Balik, Petr Waldauf, Michal Maly, Vojtech Matousek, Tomas Brozek, Jan Rulisek, Michal Porizka, Robert Sachl, Michal Otahal, Petr Brestovansky, Eva Svobodova, Marek Flaksa, Zdenek Stach, Jaroslav Pazout, Frantisek Duska, Ondrej Smid, Martin Stritesky

Abstract

Introduction: Supraventricular arrhythmias contribute to haemodynamic compromise in septic shock. A retrospective study generated the hypothesis that propafenone could be more effective than amiodarone in achieving and maintaining sinus rhythm (SR). Certain echocardiographic parameters may predict a successful cardioversion and help in the decision on rhythm or rate control strategy.

Methods and analysis: The trial includes septic shock patients with new-onset arrhythmia, but without severe impairment of the left ventricular ejection fraction. After baseline echocardiography, the patient is randomised to receive a bolus and maintenance dose of either amiodarone or propafenone. The primary outcome is the proportion of patients that have achieved rhythm control at 24 hours after the start of the infusion. The secondary outcomes are the percentages of patients that needed rescue treatments (DC cardioversion or unblinding and crossover of the antiarrhythmics), the recurrence of arrhythmias, intensive care unit mortality, 28-day and 1-year mortality. In the posthoc analysis, we separately assess subgroups of patients with pulmonary hypertension and right ventricular dysfunction. In the exploratory part of the study, we assess whether the presence of a transmitral diastolic A wave and its higher velocity-time integral is predictive for the sustainability of mechanical SR and whether the indexed left atrial endsystolic volume is predictive of recurrent arrhythmia. Considering that the restoration of SR within 24 hours occurred in 74% of the amiodarone-treated patients and in 89% of the patients treated with propafenone, we plan to include 200 patients to have an 80% chance to demonstrate the superiority of propafenone at p=0.05.

Ethics and dissemination: The trial is recruiting patients according to its second protocol version approved by the University Hospital Ethical Board on the 6 October 2017 (No. 1691/16S-IV). The results will be disseminated through peer reviewed publications and conference presentations.

Trial registration number: NCT03029169.

Keywords: amiodarone; intensive care; propafenone; septic shock; supraventricular arrhythmia.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Univariate analysis showing long-term survival of the propafenone patients similar to the metoprolol group and higher than in the amiodarone medicated patients in septic shock (HR1.76 (1.06 to 2.3), p=0.024). Copied from the author’s pilot retrospective study.
Figure 2
Figure 2
Multivariate analysis showing insignificant 12-month benefit in cardioverting septic shock patients to sinus rhythm (HR 0.67, p=0.113). Copied from the author’s pilot retrospective study.
Figure 3
Figure 3
Flowchart of the study.
Figure 4
Figure 4
SPIRIT table for the schedule of enrolment, interventions and assessments.

References

    1. Arrigo M, Bettex D, Rudiger A. Management of atrial fibrillation in critically ill patients. Crit Care Res Pract 2014;2014:1–10. 10.1155/2014/840615
    1. Kuipers S, Klein Klouwenberg PMC, Cremer OL. Incidence, risk factors and outcomes of new-onset atrial fibrillation in patients with sepsis: a systematic review. Crit Care 2014;18 10.1186/s13054-014-0688-5
    1. Klein Klouwenberg PMC, Frencken JF, Kuipers S, et al. . Incidence, predictors, and outcomes of new-onset atrial fibrillation in critically ill patients with sepsis. A cohort study. Am J Respir Crit Care Med 2017;195:205–11. 10.1164/rccm.201603-0618OC
    1. Balik M, Kolnikova I, Maly M, et al. . Propafenone for supraventricular arrhythmias in septic shock—Comparison to amiodarone and metoprolol. J Crit Care 2017;41:16–23. 10.1016/j.jcrc.2017.04.027
    1. Balik M, Maly M, Brozek T, et al. . Propafenone for supraventricular arrhythmias in septic shock-Comparison to amiodarone and metoprolol. The authors reply. J Crit Care 2018;45:247–8. 10.1016/j.jcrc.2017.04.027
    1. Balik M, Matousek V, Maly M, et al. . Management of arrhythmia in sepsis and septic shock. Anaesthesiol Intensive Ther 2017;49:419–29. 10.5603/AIT.a2017.0061
    1. Balik M. New-onset atrial fibrillation in critically ill patients - Implications for rhythm rather than rate control therapy? Int J Cardiol 2018;266:147–8. 10.1016/j.ijcard.2018.04.078
    1. Liu WC, Lin WY, Lin CS, et al. . Prognostic impact of restored sinus rhythm in patients with sepsis and new-onset atrial fibrillation. Crit Care 2016;20 10.1186/s13054-016-1548-2
    1. Arrigo M, Jaeger N, Seifert B, et al. . Disappointing success of electrical cardioversion for new-onset atrial fibrillation in Cardiosurgical ICU patients. Crit Care Med 2015;43:2354–9. 10.1097/CCM.0000000000001257
    1. Walkey AJ, Evans SR, Winter MR, et al. . Practice patterns and outcomes of treatments for atrial fibrillation during sepsis: a Propensity-Matched cohort study. Chest 2016;149:74–83. 10.1378/chest.15-0959
    1. Morelli A, Donati A, Ertmer C, Rehberg S, et al. . Microvascular effects of heart rate control with esmolol in patients with septic shock: a pilot study. Crit Care Med 2013;41:2162–8. 10.1097/CCM.0b013e31828a678d
    1. Morelli A, Ertmer C, Westphal M, Rehberg S, et al. . Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock: a randomized clinical trial. JAMA 2013;310:1683–91. 10.1001/jama.2013.278477
    1. Balik M, Rulisek J, Leden P, Zakharchenko M, et al. . Concomitant use of beta-1 adrenoreceptor blocker and norepinephrine in patients with septic shock. Wien Klin Wochenschr 2012;124:552–6. 10.1007/s00508-012-0209-y
    1. Balik M, Rulisek J, Leden P, Zakharchenko M, et al. . Concomitant use of beta-1 adrenoreceptor blocker and norepinephrine in patients with septic shock. reply to a letter to the authors. Wien Klin Wochenschr 2014;126:246–7. 10.1007/s00508-013-0487-z
    1. McLean AS, Taccone FS, Vieillard-Baron A. Beta-Blockers in septic shock to optimize hemodynamics? no. Intensive Care Med 2016;42:1610–2. 10.1007/s00134-016-4407-3
    1. Kirchhof P, Ammentorp B, Darius H, et al. . Management of atrial fibrillation in seven European countries after the publication of the 2010 ESC Guidelines on atrial fibrillation: primary results of the PREvention oF thromboemolic events--European Registry in Atrial Fibrillation (PREFER in AF). Europace 2014;16:6–14. 10.1093/europace/eut263
    1. Sleeswijk ME, Van Noord T, Tulleken JE, Ligtenberg JJ, et al. . Clinical review: treatment of new-onset atrial fibrillation in medical intensive care patients: a clinical framework. Crit Care 2007;11 10.1186/cc6136
    1. Arrigo M, Jaeger N, Seifert B, Spahn DR, et al. . Disappointing success of electrical cardioversion for new-onset atrial fibrillation in Cardiosurgical ICU patients. Crit Care Med 2015;43:2354–9. 10.1097/CCM.0000000000001257
    1. Allen LaPointe NM, Dai D, Thomas L, et al. . Antiarrhythmic drug use in patients <65 years with atrial fibrillation and without structural heart disease. Am J Cardiol 2015;115:316–22. 10.1016/j.amjcard.2014.11.005
    1. Gwag HB, Chun KJ, Hwang JK, et al. . Which antiarrhythmic drug to choose after electrical cardioversion: a study on non-valvular atrial fibrillation patients. PLoS One 2018;13:e0197352 10.1371/journal.pone.0197352
    1. Kirchhof P, Benussi S, Kotecha D, et al. . 2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016;37:2893–962. 10.1093/eurheartj/ehw210
    1. Hofmann A, Nawara C, Ofluoglu S, Holzmannhofer J, et al. . Incidence and predictability of amiodarone-induced thyrotoxicosis and hypothyroidism. Wien Klin Wochenschr 2008;120:493–8. 10.1007/s00508-008-1017-2
    1. Rätz Bravo AE, Drewe J, Schlienger RG, et al. . Hepatotoxicity during rapid intravenous loading with amiodarone: description of three cases and review of the literature. Crit Care Med 2005;33:128–34. 10.1097/01.CCM.0000151048.72393.44
    1. Singh VK, Maheshwari V. Acute Respiratory Distress Syndrome Complicated by Amiodarone Induced Pulmonary Fibrosis: Don't Let Your Guard Down. J Clin Diagn Res 2017;11:Ud01–2. 10.7860/JCDR/2017/24710.9674
    1. Hughes M, Binning A. Intravenous amiodarone in intensive care. time for a reappraisal? Intensive Care Med 2000;26:1730–9.
    1. Papiris SA, Triantafillidou C, Kolilekas L, et al. . Amiodarone: review of pulmonary effects and toxicity. Drug Saf 2010;33:539–58. 10.2165/11532320-000000000-00000
    1. Echt DS, Liebson PR, Mitchell LB, Peters RW, et al. . Mortality and morbidity in patients receiving encainide, flecainide, or placebo. the cardiac arrhythmia suppression trial. N Engl J Med 1991;324:781–8. 10.1056/NEJM199103213241201
    1. Chevalier P, Durand-Dubief A, Burri H, Cucherat M, et al. . Amiodarone versus placebo and class Ic drugs for cardioversion of recent-onset atrial fibrillation: a meta-analysis. J Am Coll Cardiol 2003;41:255–62. 10.1016/S0735-1097(02)02705-5
    1. Courand P-YN, Sibellas F, Ranc S, Mullier A, et al. . Arrhythmogenic effect of flecainide toxicity. Cardiol J 2013;20:203–5. 10.5603/CJ.2013.0035
    1. Aliot E, Capucci A, Crijns HJ, Goette A, et al. . Twenty-five years in the making: flecainide is safe and effective for the management of atrial fibrillation. Europace 2011;13:161–73. 10.1093/europace/euq382
    1. Varon J, Marik PE. Irwin RS, Rippe JM, Irwin and Rippe's intensive care medicine. 6th ed Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2008: 1855–69.
    1. Ganetsky MBE. Antiarythmic agents : Irwin RS RJ, Intensive care medicine. 6th ed Philadelphia: Wolters Kluwer/Lippincott, Williams&Wilkins, 2008: 1486–98.
    1. Stoschitzky K, Stoschitzky G, Lercher P, et al. . Propafenone shows class Ic and class II antiarrhythmic effects. Europace 2016;18:568–71. 10.1093/europace/euv195
    1. Lafuente-Lafuente C, Valembois L, Bergmann J-F, et al. . Antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation. Cochrane Database Syst Rev 2015;151 10.1002/14651858.CD005049.pub4
    1. Bonora A, Turcato G, Franchi E, et al. . Efficacy and safety in pharmacological cardioversion of recent-onset atrial fibrillation: a propensity score matching to compare amiodarone vs class Ic antiarrhythmic drugs. Intern Emerg Med 2017;12:853–9. 10.1007/s11739-016-1497-4
    1. Van Gelder IC, Hagens VE, Bosker HA, et al. . A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002;347:1834–40. 10.1056/NEJMoa021375
    1. Wyse DG, Waldo AL, DiMarco JP, et al. . A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002;347:1825–33. 10.1056/NEJMoa021328
    1. Peake SL, Delaney A, Bailey M, et al. . Goal-directed resuscitation for patients with early septic shock. N Engl J Med 2014;371:1496–506. 10.1056/NEJMoa1404380
    1. Gillinov AM, Bagiella E, Moskowitz AJ, et al. . Rate control versus rhythm control for atrial fibrillation after cardiac surgery. N Engl J Med 2016;374:1911–21. 10.1056/NEJMoa1602002
    1. Chung CS, Kovács SJ. Consequences of increasing heart rate on deceleration time, the velocity-time integral, and E/A. Am J Cardiol 2006;97:130–6. 10.1016/j.amjcard.2005.07.116
    1. Fornengo C, Antolini M, Frea S, Gallo C, et al. . Prediction of atrial fibrillation recurrence after cardioversion in patients with left-atrial dilation. Eur Heart J Cardiovasc Imaging 2015;16:335–41. 10.1093/ehjci/jeu193
    1. Nagueh SF, Appleton CP, Gillebert TC, Marino PN, et al. . Recommendations for the evaluation of left ventricular diastolic function by echocardiography. Eur J Echocardiogr 2009;10:165–93. 10.1093/ejechocard/jep007
    1. Marchese P, Bursi F, Delle Donne G, et al. . Indexed left atrial volume predicts the recurrence of non-valvular atrial fibrillation after successful cardioversion. Eur J Echocardiogr 2011;12:214–21. 10.1093/ejechocard/jeq176
    1. Poelaert J, Declerck C, Vogelaers D, et al. . Left ventricular systolic and diastolic function in septic shock. Intensive Care Med 1997;23:553–60. 10.1007/s001340050372
    1. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, et al. . The third International consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 2016;315:801–10. 10.1001/jama.2016.0287
    1. Repessé X, Charron C, Vieillard-Baron A. Evaluation of left ventricular systolic function revisited in septic shock. Crit Care 2013;17 10.1186/cc12755
    1. Levy MM, Fink MP, Marshall JC, et al. . 2001 SCCM/ESICM/ACCP/ATS/SIS international sepsis definitions conference. Crit Care Med 2003;31:1250–6. 10.1097/01.CCM.0000050454.01978.3B
    1. Sterling SA, Puskarich MA, Glass AF, et al. . The impact of the Sepsis-3 septic shock definition on previously defined septic shock patients. Crit Care Med 2017;45:1436–42. 10.1097/CCM.0000000000002512

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit