EFFICACY AND SAFETY OF SINUS RHYTHM RESTORATION WITH AMIODARONE AND PROPAFENONE IN OUTPATIENTS , ECONOMIC ASPECTS ( BASED ON DATA OF N . A . SEMASHKO NORTHERN MEDICAL CLINICAL CENTER )

T.A. Istomina1, E.V. Serdechnaya2*, L.A. Kulminskaya1, B.A. Tatarskiy3, E.V. Kazakevich1, V.L. Lipskiy2, S.I. Martyushov2 1 N.A. Semashko Northern Medical Clinical Center. Federal Medical and Biological Agency. Troitskiy prosp. 115, Arkhangelsk, 163000 Russia 2 Northern State Medical University. Troitskiy prosp. 51, Arkhangelsk, 163000 Russia 3 V.A. Almazov Federal Centre of Heart, Blood and Endocrinology. Akkuratova ul. 2, St.-Petersburg, 197341 Russia


Author information:
Tatiana A. Istomina
Aim of the study -to evaluate efficacy and safety of cardioversion with amiodarone and propafenone in outpatients with recurrent AF and to compare economic efficiency of out-patient and in-patient cardioversion.The protocol of the study was approved by Ethics Committee.All patients signed informed consent for participation in the study.
Статистический анализ проводился с использованием приложения МS Exсel 2003 и пакета прикладных статистических программ SPSS 11.5.Качественные признаки amiodarone or propafenone in hospital (without appearance of proarrhythmic effects or conductance disturbances, BP lowering, converting of atrial fibrillation in atrial flutter, allergic reactions).Outpatient cardioversion was performed as early as possible after beginning of AF paroxysm; BP, HR and ECG were monitored.Patients, treated with propafenone, needed to stay in outpatient department 3-4-hours; those, treated with amiodarone, were examined daily: ECG, BP level and HR were controlled.When AF persisted more than 48 hours, patients received transesophageal echocardiography (TEE) and anticoagulating preparation with warfarin with international normalized ratio (INR) being maintained within the range of 2-3.Each patient received clear written instructions for drug use.If arrhythmia persisted despite therapy with the whole loading AADs dose, hospitalization was recommended.Telephone contact with the patients was available.Outpatient examinations, ECG, and BP level and HR control were performed daily.
Proarrhythmic effects, hypotension and allergic reactions were registered in order to evaluate safety of outpatient and inpatient cardioversion.
The "cost-effectiveness" ratio (CER), showing the cost of one unit of effect, was calculated for economic analysis [7].Treatment costs included direct costs of staying in hospital (bed-days) and cardiologist's examinations, costs of drugs and diagnostics.Percentage of patients with successful cardiversion within a subgroup was accepted as an effectiveness criterion.
МS Exсel 2003 and SPSS 11.5 were used for statistical analysis.Qualitative characteristics are presented as absolute frequencies and percentages.Quantitative characteristics are presented as arithmetic average±standard deviation.Mann-Whitney test, χ 2 Pearson criterion, and Fisher's two-tailed exact test were used for intergroup distinctions significance estimation.Critical level of significance (p) was 0.05.

Results
Retrospective analysis showed that one year before the beginning of the study 70.6% of patients received preventive AAT due to AF; 19.8% of them did not take drugs, and treatment was efficient in 22.7% of patients.Amiodarone (39%) and β-blockers (44.1%) treatment prevailed.
Sinus rhythm restoration after cardioversion was achieved in 187 (94%) of 199 patients included into the study.Table 1 presents clinic characteristics of the patients.
The majority of relapses within the first month of the follow-up period occurred in patients who received amiodarone (35.6% of cases) and combined therapy (40% of cases).The majority of relapses within 3 months and within 6 months of the follow-up period developed in patients who received sotalol (31.3% and 39% of cases, respectively) and combined therapy -42.9%.Equal amount of relapses occurred with sotalol (43.2%), amiodarone (44.1%), and propafenone (41.2%), and 27.8% of relapses developed with β-blockers by the twelfth month of the follow-up period.We did not find significant distinctions in relapse rate depending on AAT.

Cardioversion in case of AF recurrence.
A total of 116 patients had recurrent AF.Three hundred forty one relapses of AF was registered during the follow up.Two hundred thirty five cardioversions were performed (168 were performed on an outpatient basis and 67 -in hospital).In 106 cases conversion was spontaneous.
Outpatient cardioversion required the mean dose of amiodarone 713.75±84.62mg, and the mean dose of propafenone 450.0±27.00mg (Table 2).The mean time interval between AF paroxysm beginning and taking amiodarone was 1155.0±434.17minutes (from 19 hours to 3 days), in case of propafenone -50.00±17.50minutes (from 50 minutes to 3 hours).The mean time of conversion to sinus rhythm with amiodarone was 18.9±3.57hours, with propafenone -4.3±0.59hours.Amiodarone was effective in 96.1% of the cases, propafenone -in 98.4%.
One hundred twenty nine of 341 AF relapses were terminated with peroral forms of amiodarone or propafenone.

Indices/Показатели
The total cost of outpatient treatment made up 143 724.25 rubles, of which the cost of examinations by cardiologist -82 080.0 rubles (57.1%), of diagnostics -54 720.0 rubles (38.1%), and the cost of drugs -6 924.25 rubles (4.8%).The mean cost of outpatient cardioversion per one patient amounted to 1 247.91 rubles with amiodarone and to 1 271.12 rubles with propafenone, at that the cost of examinations by cardiologist was 57.7% and 56.6% respectively.

Discussion
Our study showed that inpatient treatment with amiodarone per os started one day later (p=0.029)than respective outpatient treatment, and inpatient cardioversion with propafenone -4.5 hours later (p=0.002).Frequency of side effects did not exceed that in similar studies [5,6].One hundred fourteen hospitalizations were avoided due to outpatient cardioversion.Treatment expenses for 15 patients in hospital are comparable to those for outpatient treatment of 114 patients.At that the cost of outpatient treatment per one patient is five times less than that of treatment per one patient in hospital.
In our study majority of AF relapses were terminated on an outpatient basis (71.5%).Treatment with amiodarone on an outpatient basis was started by patients themselves significantly earlier, on average 19.
Larger total dose of amiodarone was needed to restore sinus rhythm in hospital compared with outpatient treatment: 960.0±254.4mg and 713.7±84.6 mg respectively (p=0.345).The mean doses of propafenone were equal: 45.0±116.2mg and 450.0±27.0mg respectively (p=0.729).In the Italian study, propafenone was used in bigger dosage in hospital (555±81 mg).
Efficiency of outpatient treatment with propafenone was 98.4%, with amiodarone -96.1%, which is in line with the results of the Italian study [5], in which efficiency of propafenone was 94%.Inpatient cardioversion with propafenone restored sinus rhythm in 80% of the patients, and with amiodarone -in 70% of the patients.No proarrhythmic or extracardial side effects followed cardioversion.So, outpatient cardioversion with propafenone or oral amiodarone in patients with recurrent AF allows to safely restore sinus rhythm within the first five hours with propafenone and within the first day with amiodarone in 98.4% and 96.1% of the patients respectively.Safety of propafenone in patients with heart organic diseases was proved in a placebo-controlled study [8], moreover spontaneous sinus rhythm restoration was quite rare in patients with ischemic heart disease (IHD_, which confirms necessity of drug cardioversion.Efficiency of propafenone was 78% with no significant differences between patients with and without arterial hypertension and IHD [8].SATE study showed [9], that according to daily ECG monitoring results, frequency of side effects in case of cardioversion with propafenone 450-600 mg did not distinguish significantly compared with that in case of treatment with placebo.
Outpatient cardioversion allows to start treatment earlier.In case of outpatient cardioversion with amiodarone lesser doses are needed, which lowers the risk of thyroid dysfunction in patients with frequent relapses of arrhythmia.First cardioversion with amiodarone or propafenone must be performed in hospital in order to reveal patients with proarrhythmic and extracardial side effects.
High cost of inpatient cardioversion is determined by necessity of bed-day payment (45.2% of expenses).In our study 114 hospitalizations were avoided due to outpatient cardioversion, which decreased treatment cost.
Treatment expenses for 15 patients in hospital are comparable to those for 114 ambulant ones (92 870.5 and 143 724.2 rubles respectively), at that treatment of one ambulant patient is five times cheaper than that of one patient in hospital.The "cost-effectiveness" rate of outpatient cardioversion (~1300 rubles%) was less than that of inpatient cardioversion both with amiodarone and propafenone.
Outpatient cardioversion with propafenone and amiodarone is not only effective and safe, but also economically feasible.
The "pill-in-the-pocket" strategy of sinus rhythm restoration [5] helps to significantly reduce monthly rate of hospitalizations compared with hospital cardioversion (1.6 and 15.0 respectively, p<0.001).Frequency of hos-
pitalizations into emergency unit was also lower (4.9 and 45.6 respectively, p<0.001).Some AF paroxysms were terminated spontaneously.The rate of spontaneous conversion was 30,1% before inclusion into the study, 69.8% -in the group of outpatient cardioversion and 30.2% -in the group of inpatient cardioversion.This is explained by the fact, that our study mostly included patients with AF episode duration up to 7 days (73.9%), which is likely to recover to sinus rhythm spontaneously [8].

Conclusion
Thus, efficacy of outpatient cardioversion with amiodarone made up 96.1%, with propafenone -98.4%, and efficacy of cardioversion in hospital made up 70% and 80%, respectively.Outpatient cardioversion with AADs had no severe side effects.The "cost/effectiveness" rate of outpatient cardioversion was less both with propafenone and amiodarone.That is why outpatient cardioversion with propafenone and amiodarone is not only effective and safe, but also economically feasible.

Table 2 .
Comparison 2 hours after onset of