CC BY
6UDC: 611.126 DOI: 10.24412/2790-1289-2022-3-1722-2733
MPHTM: 76.29.30.
THE IMPACT OF RANOLAZINE IN ADDITION TO AMIODARONE INFUSION IN THE RESTORATION OF SINUS RHYTHM IN PATIENTS WITH PAROXYSMAL ATRIAL FIBRILLATION
*1, 2, 3 I.V. Pershukov, FACC, FSCAI; 4 T.A. Batyraliev, FACC, FSCAI, FESC;
5 Z.A. Karben, FACC, FSCAI, FESC; 2 K.V. Zakamulina,
6 L.V. Shulzhenko, 3 S.V. Kuprina, 1 Zh.B. Imetova, 7 Kh.Sh. Kashikova, 7 A.O. Seidalin
1 Osh State University, Kyrgyzstan, Osh 2 Voronezh Regional Clinical Hospital №1, Russia, Voronezh 3 Invitro-Voronezh, Russia, Voronezh 4 Salymbekov University, Kyrgyzstan, Bishkek, 5 Private Sani Konukoglu Hospital, SanKo University, Turkiye, Gaziantep
6 Kuban State Medical University, Russia, Krasnodar
7 Non-state educational institution «Kazakh-Russian Medical University», Kazakhstan, Almaty
* Corresponding author: Igor V. Pershukov. E-mail: cardio.ru@gmail.com
Summary
The aim of this work was to evaluate the contribution of approved dosages of ranolazine (R) to the relief of AF paroxysms in patients receiving infusion therapy with amiodarone (A).
The present study includes 133 patients. (66±10 years, 42% of men). All included patients developed paroxysmal atrial fibrillation that lasted less than 48 hours before amiodarone infusion. All patients had no contraindications for pharmacological cardioversion. All patients received an intravenous bolus of amiodarone 5 mg/kg followed by a continuous infusion of 50 mg/h. Amiodarone infusion lasted up to 48 hours and stopped at the time of restoration of sinus rhythm. Immediately after the rhythm was restored, patients were switched to oral amiodarone at a dose of 200 mg/day.
The included patients were divided into 3 groups, the 1st group (group A, 44 patients) received only amiodarone according to the protocol, the 2nd group (group P500+A, 42 patients) received 500 mg of ranolazine orally at the time of administration of the amiodarone bolus and it continued to be taken orally every 12 hours at the same dose (500 mg), 3rd group (group P1000+A, 47 patients) received 1000 mg of ranolazine orally at the time of administration of the amiodarone bolus and it continued to be taken orally every 12 hours at the same dose (1000 mg). Patients were not randomized into groups, but subsequent analysis showed that the patients had no significant differences in their demographic and clinical characteristics. The ECG was monitored throughout the infusion, and the moment of rhythm recovery was necessarily recorded on the ECG. Three time lags were identified (the first 12 hours, i.e. before taking the 2nd dose of ranolazine, the first 24 hours, i.e. before taking the 3rd dose of ranolazine and 48 hours).
During the first 12 hours in group A, rhythm recovery occurred in 36% of patients, in the P500+A group, rhythm recovery occurred in 64% of patients (p = ,0177 between A and P500+A according to the Chi-square test), in the P1000+A group the rhythm was restored in 72% of patients (p=,0012 between A and P1000+A according to the Chi-square test). During the first 24 hours, the restoration of sinus rhythm occurred in groups A, P500+A and P1000+A in 66%, 83% (p=,1087 between A and P500+A according to Chi-square test) and 87% (p=,0305 between A and P1000+A according to the Chi-square test), respectively. After 48 hours, rhythm recovery was noted in 77%, 93% (p=,0862 between A and P500+A by Chi-square), 98% (p=,0071 between A and P1000+A by Chi-square) in groups A, P500+A and P1000+A. During the infusion of A and taking P, no significant side effects were noted.
In this study, the addition of ranolazine to amiodarone was safe and well tolerated, and was more effective than amiodarone. The combination of the maximum allowed dose of ranolazine 1000 mg every 12 hours with amiodarone infusion already in the first 12 hours of use shows the maximum efficiency - 72% restoration of sinus rhythm, which reaches 98% by 48 hours, significantly exceeding amiodarone monotherapy at all-time intervals with comparable tolerability. The use of a lower dose of ranolazine 500 mg every 12 hours with amiodarone infusion is significantly superior to amiodarone monotherapy at the beginning - in the first 12 hours and at the end - by 48 hours and can be recommended in case of individual intolerance to the maximum combination of P+A.
Key words: guidelines, atrial fibrillation, rate control, cardioversion, AF surgery, valve repair, pulmonary vein isolation, left atrial ablation.
m
Introduction. Amiodarone (A) is widely used in therapeutic hospitals without even URIC for pharmacological rhythm recovery in patients with paroxysmal atrial fibrillation (AF) lasting less than 48 hours before treatment. Known problems with amiodarone are the delayed effect of restoring sinus rhythm and the moderate efficacy of its arresting antiarrhythmic monotherapy. Ranolazine (R), registered in Europe and the CIS countries for the indication "chronic coronary syndromes", is an inhibitor of late sodium flow in cardiomyocytes - in fact, it has pronounced antiarrhythmic properties. It inhibits the relatively small but sustained late Na+ (INaL) current that follows the major rapidly inactivating INa breakdown and affects the shape and duration of the action potential (AP) in the cardiomyocyte. AP is increased in acquired or congenital proarrhythmic conditions, including hypoxia, heart failure, and long QT syndrome type 3 (LQTS3). Both clinical and experimental reports suggest that P has potential antiarrhythmic effects in INa -related arrhythmia[2]. In 2018, on the occasion of the 100th anniversary of its author Miles Vaughan Williams (1918-2016), a revision of the antiarrhythmic classification by Vaughan Williams [1] in the United States identified ranolazine as an independent antiarrhythmic in a separate 1d class [3]. Class Id effects can also contribute to multiple drug action. The combination of ranolazine and amiodarone (R+A) in the experiment and earlier in clinical practice showed significant synergy in the relief of paroxysmal atrial fibrillation [4], however, the use of ranolazine dosages approved for use has not been clinically studied in this aspect before.
The aim of this study was to evaluate the efficacy and safety of the combined use of approved doses of ranolazine (500 mg and 1000 mg) in combination with intravenous infusion of amiodarone in the treatment of paroxysmal atrial fibrillation in patients with stable hemodynamics.
Material and methods. The present study was a prospective, multicentre, non-randomized study. Since the acceptance by the ESC in August 2016 of the updated Guidelines for the management of patients with atrial fibrillation (AF) [5,6] until January 2019, we included 133 patients from the patients with paroxysmal atrial fibrillation admitted to our hospitals.
All included patients had AF paroxysms lasting less than 48 hours prior to the initiation of intravenous infusion of amiodarone (Cordarone, Sanofi), which began in the hospital. Symptomatic AF was defined as at least one symptom associated with AF, including palpitations, irregular pulse, fatigue, shortness of breath, and chest discomfort. Patients during paroxysmal AF were conscious (without syncope), had stable hemodynamics with blood pressure above 90/60 mm Hg, and a ventricular rate of 40 to 150 beats per minute, did not need pharmacological and mechanical inotropic support, prior to the onset and during therapy did not require the connection of temporary and/or permanent pacing and/or emergency electrical defibrillation. Since the use of ranolazine (registered as Ranexa or Latixa; MSD, Menarini International Operations Luxembourg S.A.) is allowed in patients diagnosed with IHD, all patients diagnosed with «Coronary Heart Disease (CHD), arrhythmic type, paroxysmal atrial fibrillation» with complaints of
dyspnea on a formal basis ranolazine could have been added and this therapy did not require consideration by the Ethics Committee.
Patients had no contraindications for prescribing oral anticoagulants according to the accepted version of the ESC Guidelines for the management of patients with atrial fibrillation (2016) [5,6]. Also, patients did not have a clinic of thyrotoxicosis or information about previous episodes of thyrotoxicosis, thus, there were no obvious contraindications for the use of amiodarone.
Patients had no contraindications for the use of ranolazine, such as: body weight less than 60 kg; pregnancy; lactation period (breastfeeding); hypersensitivity to ranolazine; syndrome of congenital prolongation of the QT interval in a personal or family history; chronic kidney disease (CKD) 4-5 stage (severe with CC <30 ml/min); hepatic insufficiency of moderate (7-9 points according to Child-Pugh classification) or severe (more than 9 points according to Child-Pugh classification) degree; insufficiency of the CYP2D6 isoenzyme; within the previous 24 hours a) CYP3A4 inhibitors (itraconazole, ketoconazole, posaconazole, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone, diltiazem, fluconazole, erythromycin) or b) CYP3A4 inducers (rifampicin, phenytoin, phenobarbital, carbamazepine , St. John's wort (Hypericum perforatum)), or c) P-glycoprotein inhibitors (verapamil, cyclosporine), or d) class IA antiarrhythmics (quinidine) or class III (dofetilide, sotalol) other than amiodarone.
The exclusion criteria were cardiogenic shock, acute coronary syndrome, pulmonary embolism, atrial flutter, symptomatic bradycardia, a history of sick sinus node syndrome or stage II-III atrioventricular block, severe valvular heart disease, hypertrophic cardiomyopathy with LV outflow tract obstruction, QTc interval greater than 440 ms, implanted pacemaker, thyroid dysfunction, endstage renal disease, electrolyte imbalance. Also, previous electrical cardioversion for previous AF paroxysms was a non-inclusion criterion.
All patients received an intravenous bolus of amiodarone 5 mg/kg followed by a continuous infusion of 50 mg/h. Amiodarone infusion lasted up to 48 hours and stopped at the time of restoration of sinus rhythm. The moment of rhythm recovery was necessarily recorded on the ECG. Immediately after the rhythm was restored, patients were switched to oral amiodarone at a dose of 200 mg/day.
The included patients were divided into 3 groups: the 1st group (group A, 44 patients, 19 men) received only amiodarone according to the protocol, the 2nd group (group P500+A, 42 patients, 17 of them men) received 500 mg of ranolazine orally and continued to be taken orally every 12 hours at the same dose of 500 mg, 3rd group (P1000+A group, 47 patients, 20 of them men) received 1000 mg of ranolazine orally at the time of administration of the amiodarone bolus and continued to be taken orally every 12 hours at the same dose of 1000 mg.
Patients were not randomized into groups, but subsequent analysis showed that the patients had no significant differences in their demographic and clinical characteristics. 3 time intervals were allocated to identify time lags (up to 12 hours, i.e. before taking the 2nd dose of ranolazine; up to
24 hours, i.e. before taking the 3rd dose of ranolazine; and up to 48 hours).
Patients remained under continuous electrocardiogram (ECG) monitoring throughout the 48-hour study period. Heart rate control with oral beta-blockers (excluding sotalol) was permitted at the discretion of the treating physician. Amiodarone was discontinued if any of the following were observed: QTc greater than 550 ms; heart rate less than 40 beats per minute or symptomatic bradycardia, systolic blood pressure less than 80 mmHg unresponsive to intravenous fluids, or intolerable side effects. High blood pressure was corrected orally with ACE inhibitors (enalapril, ramipril, zofenopril), dihydropyridine selective slow calcium channel blockers with a predominant effect on the vessels (lercanidipine) without adverse tachycardia, loop diuretics (furosemide, torasemide) and potassium-sparing diuretics -aldosterone antagonists (spironolactone, eplerenone).
All patients at admission and later underwent general clinical and biochemical blood tests, electrolyte balance was analyzed, transthoracic echocardiography (TTE) and ultrasound duplex scanning (UDS) of the extracranial parts of the brachiocephalic arteries (BCA) were also performed. The primary efficacy endpoint was the proportion of patients who returned to sinus rhythm (SR) 48 hours after exposure to study treatment. The secondary endpoints were the proportion of SR recovery in 12 h and in 24 h. Considering the significant effect of left atrial (LA) size on SR recovery with amiodarone or other drugs [7, 8], and also taking into account the experimentally documented synergistic effect of amiodarone and ranolazine, suppressing AF, in the setting of atrial enlargement [9], during the analysis in subgroups, the rate of conversion and the time to recovery of SR were
assessed depending on the size of the LA, determined by transthoracic echocardiography. Safety was continuously assessed throughout the study period by monitoring blood pressure, vital signs, 12-lead ECG, and possible adverse reactions.
Proarrhythmic events were defined as new onset sustained ventricular tachycardia (VT), ventricular fibrillation (VF), or torsades de pointes (TdP) VT.
Statistical analysis. Statistical analysis was performed using Statistica 12.0 (StatSoft Inc.).
Continuous variables are presented as mean + standard deviation (SD) and compared using unpaired and paired t-tests. Categorical variables are presented as absolute values and percentages and compared using a Chi-square test. All P values were based on two-tailed tests and were considered significant at less than 0.05.
Results. Patient demographic and clinical data are presented in Table 1. No significant differences in scores were found between groups.
Considering the high risk of thromboembolic complications (cardioembolic stroke) according to the current ESC Guidelines for the management of patients with atrial fibrillation [5, 6], according to the calculated CHA2DS2-VASc Score index, all patients received oral anticoagulants - factor Xa inhibitors. The choice of the anticoagulant dose was carried out according to the current instructions for the drug.
Instrumental indicators and characteristics of this paroxysm of arrhythmia are shown in Table 2. According to these indicators, there were also no intergroup differences. All groups were well balanced in terms of demographic, clinical and TTE characteristics.
Table 1. Patient demographic and clinical data.
Index Group A Group P500+A Group P1000+A
Number of patients, n 44 42 47
Age 66±10 67±11 65±9
Male gender (%) 19 (43%) 17 (40%) 20 (43%)
Arterial hypertension (%) 33 (75%) 35 (83%) 38 (81%)
Vascular atherosclerosis (%) 31 (70%) 30 (71%) 32 (68%)
Type 2 diabetes (%) 18(41%) 17 (40%) 21 (45%)
Heart failure (II-IV by NYHA) (%) 22 (50%) 24 (57%) 23 (49%)
Previous MI (%) 0 0 0
History of stroke (%) 0 0 0
CHA2DS2-VASC Score 2,9±0,7 3,1±0,6 3,0±0,7
HAS-BLED Score 1,2±0,4 1,3±0,4 1,3±0,4
CKD 3 stage 18(41%) 19 (45%) 20 (43%)
Index Group A Group P500+A Group P1000+A
Number of patients, n 44 42 47
Number of previous paroxysms of AF
0-3 27 (61%) 28 (67%) 30 (63%)
More than 3 17 (39%) 14 (33%) 17 (37%)
Duration of AF paroxysm before 18±5 16±6 17±7
therapy, hours
LA size, cm 4,6±0,5 4,5±0,5 4,9±0,6
reduced LV ejection fraction (less than 50%) (%) 9 (20%) 8 (19%) 10 (21%)
Table 2. Instrumental indicators and characteristics of this paroxysm of arrhythmia.
m
Efficacy and safety of the combination of ranolazine and amiodarone in the relief of AF. During the first 12 hours in group A, rhythm recovery occurred in 36% of patients, in the P500+A group, rhythm recovery occurred in 64% of patients (p=,0177 between A and P500+A according to the Chi-square test), in the P1000+A group the rhythm was restored in 72% of patients (p=,0012 between A and P1000+A according to the Chi-square test).
During the first 24 hours, the restoration of sinus rhythm occurred in groups A, P500+A and P1000+A in 66%, 83%
(p=,1087 between A and P500+A according to Chi-square test) and 87% (p=,0305 between A and P1000+A according to the Chi-square test), respectively.
The primary endpoint, namely, rhythm recovery at 48 hours, was achieved in 77%, 93% (p=,0862 between A and P500+A Chi-squared), 98% (p=,0071 between A and P1000 +A by Chi-square test) in groups A, P500+A and P1000+A. During the infusion of A and taking P, no significant side effects were noted. The frequency of SR recovery by groups is shown in Figure 1.
Figure 1. Sinus rhythm recovery rates by group at 12, 24, and 48 hours.
The median size of the LA was derived for all included patients and amounted to 4.7 cm. an increase in LA size greater than the median, the frequency of reaching the primary endpoint (CP at 48 hours) was significantly higher in both groups of the P + A combination compared to the monotherapy group A.
During therapy, one patient in group P1000+A developed hot flashes and mild dyspnea, and one patient in group A complained of acute low back pain. Amiodarone infusion was temporarily discontinued and restarted 6 hours later without further complications, and both patients recovered passed without complications. Transient hypotension (systolic blood pressure (SBP) less than 85 mm Hg) was observed in 19%, 22% and 25% of patients, respectively, in groups A, P500+A and P1000+A; the decrease in SBP was completely reversible with intravenous saline. Three patients in the P1000+A group reported dizziness or nausea, which were presumed to be side effects of ranolazine; these effects gradually disappeared. There were no cases of ventricular fibrillation, polymorphic VT, or torsades de pointes VT.
Discussion. This study shows that the combination of P and A is safe and more effective than A alone for the treatment of recent onset AF. Patients treated with combination therapy had significantly higher rates of SR recovery and faster recovery compared to patients treated with A monotherapy. Subgroup analysis showed that combination treatment was more effective in patients with LA enlargement as measured by echocardiography, while A alone was as effective as combination treatment in patients with smaller LA. Thus, the present results
confirm and develop the preliminary findings of earlier studies [4, 10], and they provide confirmation of the pronounced synergistic clinical effect of amiodarone and ranolazine for the treatment of AF.
The combination of the maximum allowed dose of ranolazine 1000 mg every 12 hours with amiodarone infusion already in the first 12 hours of use shows the maximum efficiency - 72% restoration of sinus rhythm, which reaches 98% by 48 hours, significantly exceeding amiodarone monotherapy at all-time intervals with comparable tolerability. The use of a lower dose of ranolazine 500 mg every 12 hours with amiodarone infusion is significantly superior to amiodarone monotherapy at the beginning - in the first 12 hours and at the end - by 48 hours and can be recommended in case of individual intolerance to the maximum combination of P+A.
A growing number of data of evidence suggests that ranolazine has remarkable antiarrhythmic properties [11, 12, 13, 14, 15]. Previously, ranolazine has been shown to be beneficial in the prevention and treatment of AF in several clinical settings, including prevention of AF after acute coronary syndrome [16, 17], prevention of postoperative AF after coronary revascularization [18], maintenance of HR in recurrent AF [19], and facilitation of electrical cardioversion of AF [20].
Further studies are required to evaluate the potential of the P+A combination to restore HR in various subgroups of patients, including those with significant atrial dilatation.
Conclusion. In this study, the addition of ranolazine to amiodarone was safe and well tolerated, and was more
effective than amiodarone for reversing recent-onset AF. These results may have clinical implications, suggesting a simple therapeutic maneuver to improve the effectiveness of amiodarone in reversing AF.
References:
1. Vaughan Williams M. Classification of antiarrhythmic drugs. In: Sandoe E., Flensted-Jensen E., Olsen K., eds. Symposium on Cardiac Arrhythmias. Elsinore, Denmark: Astra; 1970: 826 pp.
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3. Lei M., Wu L., Terrar D.A., Huang CL-H. Modernized Classification of Cardiac Antiarrhythmic Drugs. Circulation. 2018; 138:1879-1896. DOI: 10.1161/ CIRCULATIONAHA.118.035455.
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6. Kirchhof P., Benussi S., Kotecha D., et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur J Cardiothorac Surg. 2016;50(5): e1-e88. doi:10.1093/ejcts/ezw313.
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8. Kochiadakis G.E., Igoumenidis N.E., Hamilos M.E., et al. A comparative study of the efficacy and safety of procainamide versus propafenone versus amiodarone for the conversion of recent-onset atrial fibrillation. Am J Cardiol 2007; 99: 1721 - 5.
9. Frommeyer G., Milberg P., Uphaus T., et al. Antiarrhythmic effect of ranolazine in combination with class-III drugs in an experimental whole heart model of atrial fibrillation. Cardiovasc Ther 2013;31: e63 - 71.
10. Fragakis N., Koskinas K.C., Katritsis D.G., et al. Comparison of effectiveness of ranolazine plus amiodarone versus amiodarone alone for conversion of recent-onset atrial fibrillation. Am J Cardiol 2012; 110:673 - 7.
11. Antzelevitch C., Belardinelli L., Zygmunt A.C., et al. Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties. Circulation 2004;110: 904 - 10.
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13. Sicouri S., Glass A., Belardinelli L., Antzelevitch C. Antiarrhythmic effects of ranolazine in canine pulmonary vein sleeve preparations. Heart Rhythm 2008; 5: 1019 - 26.
14. Burashnikov A., Di Diego J.M., Zygmunt A.C., et al. Atriumselective sodium channel block as a strategy for suppression of atrial fibrillation: differences in sodium channel inactivation between atria and ventricles and the role of ranolazine. Circulation 2007; 116:1449 - 57.
15. Kumar K., Nearing B.D., Carvas M., et al. Ranolazine exerts potent effects on atrial electrical properties and abbreviates atrial fibrillation duration in the intact porcine heart. J Cardiovasc Electrophysiol 2009; 20: 796 - 802.
16. Scirica B.M., Morrow D.A., Hod H., et al. Effect of ranolazine, an antianginal agent with novel electrophysiological properties, on the incidence of arrhythmias in patients with non-ST-segment elevation acute coronary syndrome: results from the Metabolic Efficiency with Ranolazine for Less Ischemia in Non ST-Elevation Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) randomized controlled trial. Circulation 2007; 116: 1647 - 52.
17. Scirica B.M., Belardinelli L., Chaitman B.R., et al. Effect of ranolazine on atrial fibrillation among patients with non-ST elevation acute coronary syndromes (NSTEACS) - observations from the MERLIN - TIMI 36 Trial. Circulation 2011; 124: A13798.
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ЖУРЕК АЛДЫ ФИБРИЛЛЯЦИЯНЬЩ ПАРОКСИЗМАЛЬД1 TYPI БАР НАУ^АСТАРДА СИНУС РИТМ1Н ЦАЛПЫНА КЕЛТ1РУДЕ АМИОДАРОН ИНФУЗИЯСЫНАН БАСЦА РАНОЛАЗИННЩ ЦОСЦАН YЛЕСI
1 2 3 И.В. Першуков, 4 Т.А. Батыралиев, 5 З.А. Карбен, 2 К.В. Закамулина, 6 Л.В. Шульженко, 3 С.В. Куприна, 1 Ж.Б. Иметова, 7 Х.Ш. Кашикова,
7 А.О. Сейдалин
1 Ош мемлекеттiк университетi, Кыргызстан, Ош ц.
2 БУЗ «№1 Воронеж областыц клиникалыц ауруханасы», Ресей, Воронеж ц.
3 Инвитро-Воронеж, Ресей, Воронеж ц.
4 Salymbekov University, Кыргызстан, Бiшкек ц. 5 Private Sani Konukoglu Hospital, SanKo University, ТYркия, Газиантеп ц.
6 Кубан мемлекетпк медициналыц университетi РФ ДСМ, Ресей, Краснодар ц.
7 «Казацстан-Ресей медициналыц университета» МЕББМ, Казацстан, Алматы ц.
* Корреспондент автор: И.В. Першуков. E-mail: cardio.ru@gmail.com
Тушнд1
Б^л ж^мыстын мацсаты амиодарон (а) инфузиялыц терапиясын алатын науцастарда АФ пароксизмдерш тоцтатуга ранолазиннiн (Р) цолдануга р^цсат етiлген дозаларынын Yлесiн багалау болды.
Б^л зерттеуге 133 пациент кiрдi (66±10 жас, 4 42%). Барлыц пациенттер амиодарон инфузиясы басталганга дейн 48 сагаттан аз уацытца созылган атриальды фибрилляция пароксизмiн дамытты. Барлыц пациенттерде фармакологиялыц кардиоверсияга царсы керсетшмдер болган жоц. Барлыц пациенттерге амиодарон болюсше 5 мг/кг масса енпзшд^ содан кейiн 50 мг/саг Yздiксiз инфузия.амиодарон инфузиясы 48 сагатца дешн созылды жэне синус восстановленияагы цалпына келген кезде тоцтады. Ритм цалпына келгеннен кейн бiрден пациенттер амиодаронды тэулiгiне 200 мг дозада ауызша цабылдауга ауыстырылды.
Енгiзiлген пациенттер 3 топца белшда, 1мен Топ (А тобы, 44 пациент) тек амиодаронды хаттама бойынша алды, 2мен топ (р500+А тобы, 42 пациент) амиодарон болусын тагайындау кезiнде 500 мг ранолазин шке цабылданды жэне ол сол дозада (500 мг)эр 12 сагат сайын ауызша цабылдауды жалгастырды, 3мен тобы (P1000+a тобы, 47 пациент) амиодарон болусын тагайындау кезшде 1000 мг ранолазин шке цабылданды жэне ол эр 12 сагат сайын бiрдей дозада (1000 мг) шке цабылдауды жалгастырды. Науцастарды топтарга рандомизациялау жYргiзiлмедi, бiрац кейiнгi талдау кезiнде пациенттердiн демографиялыц жэне клиникалыц сипаттамалары бойынша айтарлыцтай айырмашылыцтар болмаганы белгiлi болды. ЭКГ инфузиянын барлыц уацытын бацылап отырды жэне ЭКАКТЫ цалпына келтiру сэтi мiндеттi тYPде ЭКГ-га бекiтiлдi. 3 уацыт артта цалды (алгашцы 12 сагат, ягни ранолазиннiн 2 дозасын цабылдаганга дешн, алгашцы 24 сагат, ягни ранолазиннщ 3 дозасын цабылдаганга дейiн жэне 48 сагат).
А тобындагы алгашцы 12 сагат шшдемаацты цалпына келлру науцастардын 36% - у, р500 + А тобында бацты цалпына келлру науцастардын 64% - у болды (p= ,0177 А жэне Р500+А арасында Хи-квадрат критерийi бойынша), р1000 + А тобында ритац науцастардын 72% - восстанов цалпына келдi (p= ,0012 арасында А жэне Р1000 + а критерий бойынша хи-квадрат). Алгашцы 24 сагат шшде синус ритагыньщ цалпына келуi А, Р500+А жэне Р1000+а топтарында 66%, 83% (p= ,1087 А жэне Р500+а арасында хи-квадрат критерий бойынша) жэне 87% (p= ,0305 А жэне Р1000+А арасында Хи-квадрат) сэйкесшше. 48 сагаттан кейнмаацты цалпына келтiру 77%, 93%(p= ,0862 арасында А жэне Р500+А Хи-квадрат критерий бойынша), 98%(p= ,0071 арасында А жэне Р1000+а Хи-квадрат критерий бойынша) А, Р500+А жэне Р1000+топтарында байцалдыА. инфузия жэне Р цабылдау кезiнде айцын жанама эсерлер байцалмады.
Б^л зерттеуде амиодаронга ранолазин цосу цаушаз жэне жацсы тезiмдi болды жэне онын тиiмдiлiгi амиодаронга цараганда жогары болды. Амиодарон инфузиясымен эр 12 сагат сайын 1000 мг ранолазиннщ р^цсат етiлген ен жогары дозасынын комбинациясы цолданудын алгашцы 12 сагатында максималды тиiмдiлiктi керсетедi - синус восстановленияагынын 72% цалпына келу^ ол 48 сагатца дейн 98% жетедi, салыстырмалы тезiмдiлiкпен амиодарон монотерапиясынан айтарлыцтай асып тYседi. Амиодарон инфузиясымен эр 12 сагат сайын 500 мг ранолазиннщ аз дозасын цолдану амиодарон монотерапиясынан басында - алгашцы 12 сагатта жэне сонында - 48 сагатта айтарлыцтай асып тYседi жэне Р+А максималды комбина-циясына жеке тезбеушiлiк жагдайында усынылуы мYмкiн.
Клт свздер: клиникалыц рекомендация, ЖYрек алды фибрилляция, кардиоверсияныц жижгт бацылау, ЖYрек алды фибрилляция хирургиялыц емдеу, ЖYрек клапандарына хирургиялыц ота, вкпе квктамыры сагасыныц оцшаулануы, сол жац ЖYрекшенiц аблациясы.
ВКЛАД РАНОЛАЗИНА В ДОПОЛНЕНИЕ К ИНФУЗИИ АМИОДАРОНА В ВОССТАНОВЛЕНИИ СИНУСОВОГО РИТМА У ПАЦИЕНТОВ С ПАРОКСИЗМАЛЬНОЙ ФОРМОЙ ФИБРИЛЛЯЦИИ ПРЕДСЕРДИЙ
1 2 3 И.В. Першуков, 4 Т.А. Батыралиев, 5 З.А. Карбен, 2 К.В. Закамулина, 6 Л.В. Шульженко, 3 С.В. Куприна, 1 Ж.Б. Иметова, 7 Х.Ш. Кашикова,
7 А.О. Сейдалин
1 Ошский государственный университет, Кыргызстан, Ош 2 БУЗ «Воронежская областная клиническая больница №1», Россия, Воронеж 3 Инвитро-Воронеж, Россия, Воронеж 4 Salymbekov University, Кыргызстан, Бишкек 5 Private Sani Konukoglu Hospital, SanKo University, Турция, Газиантеп 6 Кубанский государственный медицинский университет МЗ РФ, Россия, Краснодар 7 НУО «Казахстанско-Российский медицинский университет», Казахстан, Алматы
* Корреспондирующий автор: И.В. Першуков. E-mail: cardio.ru@gmail.com
Аннотация
Целью настоящей работы было оценить вклад разрешенных к применению дозировок ранолазина (Р) в купирование пароксизмов ФП у больных, получающих инфузионную терапию амиодароном (А).
В настоящее исследование вошли 133 пациента (66±10 лет, 42% мужчин). У всех включенных пациентов развился пароксизм фибрилляции предсердий, который длился менее 48 часов до начала инфузии амиодарона. Все пациенты не имели противопоказаний для фармакологической кардиоверсии. Всем пациентам был введен в/в болюс амиодарона 5 мг/кг массы с последующей непрерывной инфузией 50 мг/ч. Инфузия амиодарона длилась до 48 ч и прекращалась в момент восстановления синусового ритма. Сразу после восстановления ритма пациенты переводились на прием амиодарона перорально в дозе 200 мг/сут.
Включенные пациенты были разделены на 3 группы, 1я группа (группа А, 44 пациента) получала только амиода-рон по протоколу, 2я группа (группа Р500+А, 42 пациента) в момент назначения болюса амиодарона получила перо-рально 500 мг ранолазина и он продолжал приниматься перорально каждые 12 часов в той же дозе (500 мг), 3я группа (группа Р1000+А, 47 пациентов) в момент назначения болюса амиодарона получила перорально 1000 мг ранолазина и он продолжал приниматься перорально каждые 12 часов в той же дозе (1000 мг). Рандомизации больных в группы не производилось, но при последующем анализе оказалось, что по своим демографическим и клиническим характеристикам больные не имели значимых различий. ЭКГ мониторировали все время инфузии, и момент восстановления ритма обязательно фиксировали на ЭКГ. Были выделены 3 временных лага (первые 12 часов, т.е. до приема 2й дозы ранолазина, первые 24 часа, т.е. до приема 3й дозы ранолазина и 48 часов).
За первые 12 часов в группе А восстановление ритма произошло у 36% больных, в группе Р500+А восстановление ритма случилось у 64% больных (p= ,0177 между А и Р500+А по критерию Хи-квадрат), в группе Р1000+А ритм восстановился у 72% больных (p= ,0012 между А и Р1000+А по критерию Хи-квадрат). За первые 24 часа восстановление синусового ритма произошло в группах А, Р500+А и Р1000+А в 66%, 83% (p= ,1087 между А и Р500+А по критерию Хи-квадрат) и 87% (p= ,0305 между А и Р1000+А по критерию Хи-квадрат), соответственно. Через 48 часов восстановление ритма было отмечено в 77%, 93%(p= ,0862 между А и Р500+А по критерию Хи-квадрат), 98%(p= ,0071 между А и Р1000+А по критерию Хи-квадрат) в группах А, Р500+А и Р1000+А. За время инфузии А и приема Р выраженных побочных эффектов не отмечалось.
В этом исследовании добавление ранолазина к амиодарону было безопасным и хорошо переносимым, а его эффективность была выше, чем у амиодарона. Комбинация максимально разрешенной дозы ранолазина 1000 мг каждые 12 часов с инфузией амиодарона уже в первые 12 часов применения показывает максимальную эффективность - 72% восстановления синусового ритма, которая к 48 часам достигает 98%, значительно превосходя во все временные промежутки монотерапию амиодароном при сопоставимой переносимости. Применение меньшей дозы ранолазина 500 мг каждые 12 часов с инфузией амиодарона значимо превосходит монотерапию амиодароном в начале - в первые 12 часов и в конце - к 48 часам и может быть рекомендовано в случае индивидуальной непереносимости максимальной комбинации Р+А.
Ключевые слова: клинические рекомендации, фибрилляция предсердий, контроль частоты кардиоверсия, хирургическое лечение фибрилляции предсердий, хирургические вмешательства на клапанах сердца, изоляция устьев легочных вен, аблация левого предсердия.
Отношения и деятельность: все авторы заявляют об отсутствии потенциального конфликта интересов, требующего раскрытия в данной статье.
Relationships and activities: all authors declare that there is no potential conflict of interest requiring disclosure in this article.
