We designed a prospective double blinded randomized trial comparing propafenone to amiodarone administered for a SV arrhythmia in critically ill patients with septic shock.
Primary aims
The trial should prove that propafenone is more efficient than amiodarone in cardioverting a SV arrhythmia in patients with normal to moderately reduced EF_LV at 24h from the onset. The rationale stems from the retrospective data set where the primary cardioversion rate of SV arrhythmia under propafenone was 88.9% versus 73.5% under amiodarone [44, 45]. The authors also expect faster cardioversion under propafenone and lower rates of arrhythmia recurrence in the propafenone group. Despite prejudices arising particularly from the CAST trial and case reports on dose dependent toxicity, research should prove the safety of the 1C class agent propafenone given within the summary of product characteristics [37, 39]. The retrospective study [44, 45] has shown that the ICU and 28-day mortalities of patients treated with propafenone were better than the parameters of the amiodarone patients (30.4% vs 40.4% and 39.5% vs 49.6%, respectively). The differences did not reach statistic significance however, the propafenone administration did not increase mortality as suggested by the older trials on non-ICU patients [21, 37, 38]. If proven, the physicians could avoid a widespread use of amiodarone in the critically ill. The use of amiodarone conveys side effects and multiorgan toxicity [27, 41]. Moreover, patients with a supraventricular arrhythmia treated with propafenone had an adjusted 12-months survival similar to patients medicated with the betablocker metoprolol and both groups had significantly better 12-month survival than the critically ill treated with amiodarone (Fig.1).
The cardioverted patients (rhythm control) may showcase better outcome parameters (ICU mortality, 28-day mortality, 1-year mortality) than those remaining in an acute onset arrhythmia (rate control). A rationale beyond this hypothesis is in the pilot study [44, 45] which also included patients with severe LV dysfunction and associated higher rates of recurrent SV arrhythmias. Focusing on only normal to moderate LV systolic dysfunction may minimize bias associated with arrhythmia treatment of patients with severe LV systolic dysfunction. Likewise, those patients were included in the published trials dealing with either 1C class antiarrhythmics (e.g. CAST trial,[21]) or in the trials studying rhythm vs rate control (e.g. AFFIRM, RACE or AF-CHF Trial,[3, 10, 47, 48]). The retrospective data on 234 patients in septic shock with SV arrhythmia [44, 45] showed a long-term benefit of rhythm control which was not statistically significant. Due to high success of rhythm control therapy (74.4% and 87% excluding chronic AF) the group with persisting acute onset SV arrhythmia was significantly smaller in number causing asymmetry in statistic evaluation. This may account for not signicant difference between the outcome of the cardioverted versus those remaining in the SV arrhythmias (Fig.2).
Secondary aims
The presence of a transmitral diastolic A wave and its higher velocity-time integral (VTI) at 4h post cardioversion would indicate a presence of mechanical sinus rhythm. The incidence of a small or negligible A wave or only the presence of electric sinus in the absence of its mechanical correlate could be related to the indexed left atrial end-systolic volume (LAVi) and to a recurrence of a SV arrhythmia[49, 50].
The LAVi in all patients and altered filling pressures estimated by echocardiography could be predictive of recurrent arrhythmia [12, 51].
Propafenone would be more efficient than amiodarone in patients with pulmonary hypertension and RV dysfunction without left ventricular systolic dysfunction.
Approximately 8-25% of the critically ill suffer from SV arrhythmias [4-6, 44, 45] and an echocardiography driven prediction of cardioversion has not been explored in the critically ill patients in the available literature. Hence, a complex echo assessment may contribute to the decision whether to aim for rhythm or for rate control only. An application of simple 2D echo parameters like biplanar endsystolic LAVi or just endsystolic LA size may be included in the focused critical care echocardiography performed by an intensivist on a patient with arrhythmia of unknown duration. The evaluation of the doppler parameters will depend on rhythm, heart rate, regularity of arrhythmia and peripheral pulse deficit [49, 51].
Flow chart (Fig.3, Fig.4) and study setting
Patients are randomized by the unblinded team lead by a research nurse. The planned number of included patients is 100 in each arm of the study with a total of 220 randomized patients. A dropout of 10% is anticipated. The estimated duration of the study is 4 years including follow up. The patients have been recruited since November 2017 in three university hospital ICUs. The department of Anaesthesia and Intensive Care of the General University Hospital has been performing for years as a teaching centre for critical care echocardiography and ultrasound. Together with the Coronary Care Unit of the General University Hospital both departments are integrated as a Complex Cardiovascular Centre. The department of Anaesthesia and Intensive Care of the University Hospital Kralovské Vinohrady is a mainstay of the Complex Prague Traumacentre.
Inclusion Criteria
The study targets patients in septic shock with a new onset SV arrhythmia or known paroxysmal SV arrhythmia who show normal or mildly to moderately reduced LV systolic function according to the echocardiography examination (i.e. EF_LV >/=35%). A diagnosis of septic shock is made according to the 2016 definition[52] as sepsis with a vasopressor requirement to maintain a mean arterial pressure of 65 mm Hg or greater. The arterial lactate level should be greater than 2 mmol/L in the absence of hypovolemia or low cardiac output. The highest arterial lactate level is recorded, i.e. lactate <2.0 mmol/l at the time of randomization does not exclude a patient from the study. This might also be justified by the reported incidence of the sepsis related cardiac dysfunction which is highest 72-96h after an onset of septic shock [53]. The presence of a suspected infection is for the purpose of this study defined as a positivity of at least one inflammatory marker of the monitored CRP and PCT and a clinical decision to administer antibiotic treatment for a specified infection source.
Exclusion Criteria
The study respects all exclusion criteria for a blinded administration of propafenone or amiodarone. These are in particular severe LV systolic dysfunction (i.e. EF<35%), a history indicating more than 1st degree AV block and a high dose vasopressor therapy represented by continuous noradrenaline administration of more than 1.0 ug/kg.min. Contraindications to randomisation are known intolerance to amiodarone or propafenone, iodine allergy and an active thyroid disease other than chronic hormone substitution for benign goiter. Chronic persistant AF represents an exclusion while known chronic paroxysmal AF is not an exclusion criterion. Patients dependent on a pacemaker or after a Maze procedure are also excluded.
Interventions and research protocol
Patients in septic shock with a new onset supraventricular arrhythmia will have a haemodynamic examination provided according to the study protocol. With the onset of arrhythmia, the usual treatment is expected including preload correction, reduction of unnecessary vasopressors, ion supplementation (aiming particularly for K+ >4.0 mM and Mg2+ > 1.0 mM) and maintenance of tissue oxygen delivery. Echocardiography should also guide optimization of preload.
The complex protocol is formatted in an electronic case report form (CRF). After checking up the inclusion and exclusion criteria the CRF allocates the patients randomly using built in software (www.randomization.com) into the propafenone or amiodarone arm.
The patient´s characteristics include the illness severity scores, source of septic shock, data on mechanical ventilation and homeostasis, baseline haemodynamic data, baseline laboratory data, patient´s medications, haemodynamic data at proposed steps plus follow up data including outcome.
Haemodynamic evaluation includes ICU standard plus echocardiography. The study team involves 8 intensivists with an European Accreditation in Echocardiography (either ESC or EACTA backed) and three qualified cardiologists-intensivists.
By no means is an antiarrhythmic given out of the summary of product characteristics. Both arms will have standard treatment, there are no limits to indicate electric cardioversion as part of treatment. Electric cardioversion is indicated anytime in haemodynamic compromise and in signs of low cardiac output and/or loss of perfusion pressures due to arrhythmia. It will also be indicated should there be observed not satisfactory effect of the antiarrhythmic medication during the first 24h from the start of arrhythmia.
The propafenone arm constitutes administering a bolus of 35-70 mg of intravenous propafenone followed by a continuous infusion of 400-840 mg/24h in a black syringe. The amiodarone arm constitutes administering a bolus of 150-300 mg of intravenous amiodarone followed by a continuous infusion of 600-1800 mg/24h in a black syringe.
A 12-lead ECG is taken every 12h whilst the antiarrhythmic infusion. Besides echocardiography pre-randomization the control echocardiography is performed 1h post cardioversionand 4h post cardioversion. Echocardiography is performed also every day until cardioversion, it is also mandatory in any kind of haemodynamic instability. All the Doppler measurements are recorded at end-expiration and 3 cardiac cycles, when sinus rhythm, and 5-10, during arrhythmia, are analysed and averaged. All recordings should be acquired with an ECG (lead II), and ideally, at the speed of 100 mm/s.
Electric cardioversion is allowed anytime when urgently indicated and even when arrhythmia persists while on the antiarrhythmic medication. If electrically cardioverted in addition to administered pharmacotherapy, then echocardiography is performed 1h post cardioversion and 4h post cardioversion.
If cardioverted later than until 24h then echocardiographies are performed at 1h and 4h after cardioversion, the times of cardioversion and arrhythmia relapses are always recorded.
Primary outcome measures
- The efficacy in restoration of sinus rhythm assessed as the proportion of patients who are in sinus rhythm 24 hours after the beginning of the infusion of the study drug and remain in sinus rhythm until discharge from ICU. Primary outcome will be assessed in all randomised patients (i.e. intention to treat analysis).
- A-priori defined subgroup analysis: Primary outcome will be analysed in the following subgroups of patients:
- with and without indexed left atrial endsystolic volume (LAVi) higher than >40 ml/m2.
- with and without pulmonary hypertension (defined as PAPs >40 mmHg) associated with moderate to severe RV dysfunction (dilated RV with TAPSE <15 mm)
Secondary outcome measures
- The cumulative proportion of patients receiving rescue treatment for arrhythmia defined as direct current cardioversion or an alternative antiarrhythmic drug during the first 24 hours (cross-over from one arm to the other resulting in unblinding of the study, e.g. from amiodarone to propafenone due to a persisting arrhythmia or from propafenone to amiodarone due to a decrease in LV systolic function).
- The cumulative proportion of patients receiving rescue treatment for arrhythmia defined as direct current cardioversion, cross-over to the alternative study drug or other antiarrhythmic drug during ICU stay.
- Mortality at discharge from ICU, at 28 days and at 1 year.
- Vasopressor-free days at day 28.
Safety issues and patient´s monitoring
TTE is performed at the onset of the arrhythmia and daily until cardioversion, also at 1h and at 4h after cardioversion. TTE is also acquired in any kind of haemodynamic instability (i.e. change in vasopressor support). This is important to avoid administering a potentialy cardiodepressant propafenone in a patient developing septic cardiomyopathy. 12 hourly 12-lead ECG for monitoring of conduction times (PQ, QRS, QTc) is performed while the patient is on the antiarrhythmic infusion. In case of an AV block of the first degree or extension of the conduction times (QRS or QTc) the slowing or temporary ceasing of the medication in relation to heart rate is mandatory. Adjustment of the infusion rate or eventual termination of an antiarrhythmic medication does not exclude the patient from the study. Ceasing of medication after reaching sinus rhythm does not exclude the patient either. If an infusion is interrupted and restarted then the number of infusion hours are counted up as a sum of infusion hours.
In case of a progression of septic cardiomyopathy and a decrease of contractility (decrease of EFLV to <35%) or a progression of mitral regurgitation with a risk of low cardiac output the study drug is unblinded and propafenone discontinued. Further treatment is decided by the clinician. If the study is unblinded due to haemodynamic instability, the second drug after study arm cross-over is administered without an initial bolus.
Anytime the patient becomes haemodynamically unstable or has another reason (as per discretion of the treating clinician) to benefit from electric cardioversion (DCC), then DCC is delivered without delay.
Should there be a concern at any point in time about the safety of the drug, the treating clinicians are encouraged to unblind the treatment drug without delay, and alter the treatment accordingly. The course of the trial is regularly reported to the hospital Ethical Board which acts as the research supervising body. The minimum frequency of the report is once per year throughout the duration of the trial which is proposed from 2018 till 2021.
Statistics and power analysis
The logistic regression and time-to-event (Cox) regression with and without adjustment for baseline patients´ characteristics will be applied in the statistic analysis. The multivariate analysis will include the patients´ baseline parameters which would be correlated with an analysed outcome parameter and will be inhomogenously distributed within the study groups regardless of the randomisation. The required number of patients is based on the power analysis and data from the pilot retrospective study [44, 45].
The entry parameters for the sample size analysis were estimated by the probabilities of cardioversion of 75% for the amiodarone group and 90% for the propafenone group within 24h from the onset of arrhythmia, randomisation ratio 1:1, p=0.05 and power 0.8. To achieve a statistically significant difference under these conditions 100 patients need to be included into each group, altogether 200 patients into the trial. Assuming 10% drop out the authors plan to randomize 220 patients.