Archives of Academic Emergency Medicine. 2022; 10(1): e6 OR I G I N A L RE S E A RC H Nifekalant versus Amiodarone for Out-O f-Hospital Car- diac Arrest with Refractory Shockable Rhythms; a Post Hoc Analysis Hiraku Funakoshi1,2∗, Shotaro Aso3, Yosuke Homma1, Ryuta Onodera1, Yoshio Tahara4 1. Department of Emergency and Critical Care Medicine, Tokyobay Urayasu Ichikawa Medical Center, 3-4-32 Todaijima, Urayasu, Chiba 279-0001, Japan. 2. Department of Clinical Epidemiology and Health Economics, School of Public Health, Graduate School of Medicine, The University of Tokyo. 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8555, Japan. 3. Department of Biostatistics & Bioinformatics, Graduate School of Medicine, The University of Tokyo 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. 4. Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, 6-1 Kishibe-shimmachi, Suita, Osaka 564-8565, Japan. Received: November 2021; Accepted: November 2021; Published online: 1 January 2022 Abstract: Introduction: It is still unclear that which anti-arrhythmics are adequate for treating refractory dysrhythmia. This study aimed to compare amiodarone and nifekalant in management of out-of-hospital cardiac arrest cases with refractory shockable rhythm. Methods: This was a post hoc analysis of cases registered in a nationwide, multicentre, prospective registry that includes 288 critical care medical centres in Japan. From June 2014 to December 2017, we included all out-of-hospital cardiac arrest patients aged ≥18 years who presented with re- fractory arrhythmia (sustained ventricular fibrillation or ventricular tachycardia following delivery of at least two defibrillator shocks) and treated with nifekalant or amiodarone after arrival to hospital. Overlap weight was performed to address potential confounding factors. Results: 1,317 out-of-hospital cardiac arrest patients with refractory arrhythmia were enrolled and categorized into amiodarone (n = 1,275) and nifekalant (n = 42) groups. After overlap weight was performed, there were no significant intergroup differences in increased the rate of admission after return of spontaneous circulation [–5.9% (95%CI: –7.1 to 22.4); p = 0.57], 30-day favourable neu- rological outcome [0.1% (95%CI: –14 to 13.9); p = 0.99], and 30-day survival [–3.9% (95% CI: –19.8 to 12.0); p = 0.63]. Conclusion: This nationwide study showed that nifekalant was not associated with improved outcomes regarding admission after return of spontaneous circulation, 30-day survival, and 30-day favourable neurologi- cal outcome compared with amiodarone. Keywords: Anti-arrhythmia agents; Cardiopulmonary resuscitation; Nifekalant; Ventricular fibrillation; Ventricular flutter Cite this article as: Funakoshi H, Aso S, Homma Y, Onodera R, Tahara Y. Nifekalant versus Amiodarone for Out-Of-Hospital Cardiac Arrest with Refractory Shockable Rhythms; a Post Hoc Analysis. Arch Acad Emerg Med. 2022; 10(1): e6. https://doi.org/10.22037/aaem.v10i1.1425. 1. Introduction Approximately 12% of patients with out-of-hospital cardiac arrest (OHCA) survive until discharge from the hospital. In spite of widespread early bystander cardiopulmonary resus- citation (CPR) and automated external defibrillator (AED) ∗Corresponding Author: Hiraku Funakoshi; Department of Emergency and Critical Care Medicine, Tokyobay Urayasu Ichikawa Medical Center, 3-4-32 Todaijima, Urayasu, Chiba 279-0001, Japan. Telephone: +81- 473513101, Fax: +81-473526237, Email: hfunakoshi-tbmc@umin.org, ORCID: http://orcid.org/0000-0001-5828-6986. use, the overall survival from OHCA remains low and 20% of patients with OHCA who survive develop irreversible neuro- logical disability (1). It was previously reported that only 8% of patients were discharged from the hospital after recover- ing to a condition in which they could live without any sup- port (1). Thus, the need for a standardized approach to CPR to improve patients’ outcomes after cardiac arrest has been considered for many years. For refractory arrhythmia, which is defined as sustained ven- tricular fibrillation (VF) or pulseless ventricular tachycardia (VT) despite performing defibrillation twice, administration of anti-arrhythmics following administration of adrenaline This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem H. Funakoshi et al. 2 and defibrillation is recommended, and the guidelines rec- ommend amiodarone administration (2, 3). Although the benefits of administration of anti-arrhythmics are limited, anti-arrhythmics are key for return of spontaneous circula- tion (ROSC) in cases of refractory arrhythmia (4). Nifekalant, which was developed and approved in Japan in 1999, is a class III anti-arrhythmic agent per the Vaughan Williams classification. Although a meta-analysis suggested that nifekalant may be effective in improving short-term and long-term survival, the only study that had a low risk of bias among those included in the meta-analysis had shown no benefit from nifekalant. It had also stated that the effect of amiodarone on either of these outcomes could not be con- firmed (5). Due to this limitation, nifekalant was an alterna- tive to amiodarone for refractory arrhythmias in the Interna- tional Liaison Committee on Resuscitation (ILCOR) consen- sus and nifekalant was not mentioned in the guidelines of the American Heart Association (AHA) and European Resuscita- tion Council (ERC) (2, 3). In addition, the guidelines released by the Japan Resuscitation Council ( JRC) in 2015 recommend the use of amiodarone over nifekalant (6). A large study us- ing a Japanese nationwide in-hospital patient administrative database conducted after the publication of these guidelines compared the effectiveness of nifekalant and amiodarone and found no difference between the two anti-arrhythmics (7). However, the study did not include information on pre- hospital care, such as bystander witness, bystander CPR, and AED use, which is the most important determinant of the prognoses of patients with cardiorespiratory arrest (8-10). On the other hand, a previous study using prehospital data does not include precise information on in-hospital treatment, and the dose of amiodarone was not consistent in the study. Therefore, evaluation of the effectiveness of nifekalant in the context of data on both pre- and in-hospital care have been the remaining issue. Based on the above-mentioned points, this study aimed to compare amiodarone and nifekalant in management of out-of-hospital cardiac arrest cases with refractory shock- able rhythm in terms of patients’ admission after ROSC, 30- day favourable neurological outcome (Cerebral Performance Category 1 or 2), and 30-day survival. 2. Methods 2.1. Study design and setting This study is a post hoc analysis of cases registered in the Japanese Association for Acute Medicine out-of-hospital car- diac arrest ( JAAM-OHCA) registry, which is a nationwide, multi-centre prospective registry that includes 288 critical care medical centres in Japan. The detailed study protocol has been previously described (11). All patients with car- diorespiratory arrest in a prehospital setting who were then transported to a member institution are included in the reg- istry. To allow refusal for inclusion in the registry by patients or their family members, a special committee and each par- ticipating institution made available a document regarding opt-out consent on the website and/or a notice board in the emergency department. Therefore, the requirement for in- formed consent from patients was waived. The registry was approved by the Ethics Committee of Kyoto University (Ref- erence number is R1045), and each hospital also approved the JAAM-OHCA Registry protocol as necessary. 2.2. Emergency medical system in Japan In Japan, all patients with cardiorespiratory arrest are trans- ported by an emergency medical system (EMS) team, be- cause EMS providers are not allowed to terminate resusci- tation in the field unless there are obvious signs of death (e.g. lividity or rigor mortis) (12). EMS teams in Japan pro- vide defibrillation via an AED and protect the airway using supraglottic airway or endotracheal intubation and admin- ister adrenaline per remote instruction from a doctor. How- ever, EMS providers are not permitted to administer any anti- arrhythmics. 2.3. Participants This study included all patients in the JAAM-OHCA registry from June 2014 to December 2017. Of these patients, we in- cluded all OHCA patients aged ≥18 years in whom refractory arrhythmia was treated with nifekalant or amiodarone. We excluded patients who received both nifekalant and amio- darone. 2.4. Data gathering The JAAM-OHCA registry includes both pre- and post- hospitalization data. Prehospitalization data were obtained from the All-Japan Utstein Registry of the Fire and Disaster Management Agency (FDMA) as previously reported (12, 13). In-hospital data were collected via an Internet-based system by physicians or medical staff at each institution. The JAAM- OHCA registry committee integrated the prehospital and in- hospital data, as previously described (12). The protocol was approved by the institutional review board of each participat- ing hospital. During the study period, anonymized data were entered into the web form by the medical staff in charge of the patient and were finally confirmed by the JAAM-OHCA registry committee, which consists of specialists in emer- gency medicine and epidemiology. A committee member returned any incomplete data forms to the institution sub- mitting the form and the data form was filled out as com- pletely as possible. In-hospital data were systemically com- bined with prehospital resuscitation data obtained from the All-Japan Utstein Registry of the FDMA, by using the five key items in both datasets: prefecture, emergency call time, age, This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 3 Archives of Academic Emergency Medicine. 2022; 10(1): e6 sex, and cerebral performance category (CPC) 1 month after the OHCA (13). 2.5. Exposure and outcome measures The exposure was the administration of nifekalant or amio- darone. The responsibility for selecting the anti-arrhythmic medication was entirely entrusted to each physician or insti- tution. Although there are no specific protocols for refractory arrhythmia in the JAAM-OHCA registry, most facilities follow the guidelines published by the JRC, which comply with IL- COR, for performing CPR. The primary outcome measure of interest was admission af- ter ROSC. The secondary outcomes were 30-day survival and 30-day favourable neurological outcome. A favourable neu- rological outcome was defined as a CPC score of 1 or 2 (11). The CPC score scale accounts for five outcomes: 1, good cere- bral recovery; 2, moderate cerebral disability; 3, severe cere- bral disability; 4, coma or vegetative state; and 5, death/brain death (13). 2.6. Statistical analysis All descriptive statistics were reported as number (%) or mean ± standard deviation. For comparison of character- istic variables among cohorts, independent-sample t-tests were used for numeric variables, while chi-squared tests were used for categorical variables. Overlap weight was per- formed to address potential confounding (14, 15). A propen- sity score for nifekalant administration was estimated us- ing a multivariable logistic regression model containing age, sex, witness status, presence of a bystander who performed CPR, aetiology of cardiac arrest (cardiac or not), prehospi- tal adrenaline administration, prehospital airway manage- ment, prehospital AED use, response time, physicians, and hospital number. Based on previous studies, these variables would be relevant to treatment assignment (8-10). Overlap weight is defined as 1- propensity score for patients receiving nifekalant and propensity score for patients receiving amio- darone. By applying overlap weights for each patient, we ad- justed for the patients’ backgrounds and compared the out- comes. We used absolute standardized differences to evaluate dif- ferences in patient characteristics between the groups. We regarded an absolute standardized difference of <0.1 as an acceptable balancing of covariates between the groups (16). Although data on in-hospital treatments or interven- tions (veno-arterial extracorporeal membrane oxygenation (VA-ECMO), percutaneous coronary intervention (PCI), and targeted temperature management (TTM)) were collected, these variables were not included in the variables for the es- timation of the propensity score, because we assumed that these treatments are administered after ROSC (17). In ad- dition, we also performed a series of sensitivity analyses to examine the robustness of our inference: 1) Based on the as- sumption that the decision to use these three treatments (VA- ECMO, PCI, and TTM) is made prior to admission, we cal- culated propensity score including the three treatments and performed an analysis with overlap weight. 2) Analysis was performed excluding patients with ECMO to avoid reverse causation; because it is difficult to identify whether patients with ECMO had resumed spontaneous circulation at the time of admission or not. Stata/SE 16.0 (Stata Corp, College Sta- tion, TX, USA) was used for data analyses. The threshold for significance was set at P < 0.05. 3. Results 3.1. Baseline characteristics During the study period, 1,374 OHCA patients with refrac- tory arrhythmia were enrolled in this study. Of these pa- tients, 1,317 eligible patients were included in this analysis after excluding 57 patients who had received both nifekalant and amiodarone. These patients were categorized into amio- darone (n = 1,275) and nifekalant (n = 42) groups. Table 1 compares the baseline characteristics of studied cases be- tween nifekalant and amiodarone groups. The mean pa- tients’ age was 64.0 ± 15.4 years (20.7% female). Propen- sity score based on the variables listed in methods section are presented in figure 1. After overlap weight adjustment for treatment with nifekalant, baseline patient characteristics were well-balanced between the two groups, as shown in ta- ble 2 (p < 0.01). 3.2. Comparing outcomes In crude data, the proportions of admission after ROSC in nifekalant group were not significantly different from those in amiodarone group (64.3% vs. 56.6%, p = 0.32). The pro- portions of the favourable 30-day neurological outcome were significantly higher among patients who received nifekalant compared to patients for whom amiodarone was adminis- tered (23.8% vs. 10.4%, p < 0.01). The proportions of 30-day survival in nifekalant group were not significantly different from those in amiodarone group (31.0% vs 20.1%, p = 0.09). With overlap weight, nifekalant use was not associated with improved outcomes (Hospital admission after ROSC: risk dif- ference, –5.9% (95% CI: -26.7 to 14.8); favourable 30-day neu- rological outcome: risk difference, 0.1% (95% CI: –14 to 13.9); 30-day survival: risk difference, –3.9% (95% CI: –19.8 to 12.0) (Table 3)). 3.3. Key in-hospital treatments Table 4 shows differences in key in-hospital treatments or in- terventions between the two groups. The proportions of pa- tients who received veno-arterial extracorporeal membrane oxygenation (VA-ECMO), percutaneous coronary interven- This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem H. Funakoshi et al. 4 Table 1: Comparing the baseline characteristics of studied cases between amiodarone (n = 1,275) and nifekalant (n = 42) groups Variables Total Amiodarone Nifekalant SD P Age (year) 64.0 ± 15.4 64.1 ±15.4 60.1±16.3 0.25 0.14 Gender (female) 273 (20.7) 267 (20.9) 6 (14.3) 0.18 0.30 Witness 929 (70.5) 900 (70.6) 29 (69.0) 0.03 0.83 Bystander CPR 581 (44.1) 564 (44.2) 17 (40.5) 0.08 0.63 AED use 933 (74.4) 897 (70.4) 36 (85.7) 0.42 0.02 Prehospital adrenaline 495 (37.6) 485 (38.1) 10 (23.8) 0.31 0.06 Airway equipment use 656 (59.3) 645 (50.6) 11 (26.2) 0.24 0.26 Physician on scene 280 (21.3) 273 (21.4) 7 (16.7) 0.12 0.46 Presumed cause of CPA 1,138(86.4) 1,098(86.1) 40 (95.2) 0.32 0.09 Call to dispatch (minute) 8.5 ±3.5 8.6 ± 3.5 7.8 ± 2.4 0.24 0.15 Data are presented as mean ± standard deviation or number (%). Abbreviations: AED, automated external defibrillator; CPA, cardiopulmonary arrest; CPR, cardiopulmonary resuscitation; SD, Standardized difference. Table 2: Overlap propensity score-weighted characteristics in amiodarone (n = 1,275) and nifekalant (n = 42) groups Variables Amiodarone Nifekalant SD Age (year) 61.9 ±15.9 61.9 ± 17.5 <0.01 Female sex 9.0 9.0 <0.01 Witness 73.8 73.8 <0.01 Bystander CPR 43.8 43.8 <0.01 AED use 82.4 82.4 <0.01 Prehospital adrenaline 26.6 26.6 <0.01 Airway equipment use 48.7 48.7 <0.01 Physician on scene 9.1 9.1 <0.01 Presumed cause of CPA 91.0 91.0 <0.01 Call to dispatch (minute) 7.72 ± 2.53 7.72 ± 2.43 <0.01 Data are presented as mean ± standard deviation or number (%). Abbreviations: AED, automated external defibrillator; CPA, cardiopulmonary arrest; CPR, cardiopulmonary resuscitation; SD, standardized difference. Table 3: Comparisons of outcomes between amiodarone (n = 1,275) and nifekalant (n = 42) groups Variables Amiodarone Nifekalant RD (95% CI) Unadjusted analysis Hospital admission after ROSC 56.6 64.3 7.6 (–7.1 - 22.4) 30-day favourable neurological outcome 10.4 23.8 13.5 (0.46 - 26.5) 30-day survival 20.1 31.0 10.9 (–3.3 - 25.0) Weighted analysis Hospital admission after ROSC 62.1 56.2 –5.9 (–26.7 -14.8) 30-day favourable neurological outcome 12.8 12.8 0.1 (–14.0 - 13.9) 30-day survival 21.2 17.3 –3.9 (–19.8 -12.0) Data are presented as percentage. Abbreviations: ROSC, return of spontaneous circulation; RD: risk difference; CI: confidence interval. tion (PCI), and target temperature management (TTM) were higher in the nifekalant group. Intergroup differences in these proportions were not significant. Although the pro- portions of the patients who received VA-ECMO were well- balanced after overlap weight, the proportions of those who received the percutaneous coronary intervention and tar- geted temperature management remained different between the two groups (Table 4). In the sensitivity analysis, VA-ECMO, PCI, and TTM were well-balanced between the two groups with overlap weight using another propensity score, and nifekalant use showed no significant association with higher proportion of 30-day favorable neurological outcome [0.3% (95% CI: –14.2 to 13.6)] and 30-day survival [–4.6% (95% CI: –20.6 to 11.3)]. As with This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 5 Archives of Academic Emergency Medicine. 2022; 10(1): e6 Figure 1: The histogram of propensity score distribution in each treatment group. Table 4: Comparing the treatments and interventions after return of spontaneous circulation between amiodarone (n = 1275) and nifekalant (n = 42) groups Treatment Un-weighted Weighted Amiodarone Nifekalant SD P Amiodarone Nifekalant SD VA-ECMO 40.5 50.0 0.19 0.22 46.4 47.2 0.02 PCI 23.5 31.0 0.17 0.27 27.2 21.6 -0.13 TTM 29.1 47.6 0.38 <0.01 32.4 38.5 0.13 Data are expressed as %. PCI, Percutaneous coronary intervention; TTM, Target temperature management; VA-ECMO, veno-arterial extracorporeal membrane oxygenation. SD: standardized difference. the results of main analysis, after excluding patients with ECMO, nifekalant use showed no significant association with higher proportion of admission after ROSC [risk difference: –0.4% (95% CI: –20.6 to 13.0)]. 4. Discussion In this nationwide study, we compared the proportions of ad- mission after ROSC and 30-day outcomes between patients treated with nifekalant and those treated with amiodarone after OHCA associated with refractory arrhythmias. After ad- justing for patients’ background, including both pre-hospital and in-hospital data by overlap weight, no significant dif- ference in the proportions of admission after ROSC and 30- day favourable outcomes was found between nifekalant and amiodarone administration after arrival in hospital. This study compared the effectiveness of nifekalant with that of amiodarone by using data including detailed prehospital care data from a nationwide registry of patients with car- diorespiratory arrest. Amiodarone and nifekalant are both This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem H. Funakoshi et al. 6 classified as class III antiarrhythmic agents (potassium chan- nel blockers) in the Vaughan-Williams classification. How- ever, these two antiarrhythmic drugs have different pharma- cological characteristics (18, 19). Amiodarone is not only a potassium channel blocker but also has blocking effects on other ion channels such as sodium and calcium chan- nels and α and β receptors. As a result of these multi- channel blocking effects, amiodarone has negative inotropic and vasodilatory effects, which may in turn negatively affect the haemodynamic status for coronary artery flow and af- ter ROSC in OHCA patients. On the other hand, nifekalant is a pure potassium channel blocker that does not block sodium or calcium channels (20). In a study conducted using an animal model, nifekalant use decreased the defibrillation threshold for ventricular fibrillation (21). From these phar- macological points of view, nifekalant could have advantages over amiodarone for the treatment of refractory arrhythmia. However, clinical studies are limited. Amino et al. reported that nifekalant and amiodarone were both associated with improved 24-hour survival compared to lidocaine in OHCA patients with refractory arrhythmia (22). However, this study did not perform a direct comparison between nifekalant and amiodarone. In addition, because the dose of amiodarone was not standardized during the study period, only approx- imately 200 people received the international standard dose of 300 mg (22). In this study, only 3.2% (57/1374) of the patients received nifekalant. Because nifekalant was recommended alongside amiodarone for refractory arrhythmias until 2005, the use of nifekalant was relatively common in previous studies (7, 22). The removal of nifekalant from the recommendations in the 2015 guideline of the AHA could result in a decrease in the use of nifekalant (2). In the 2020 guideline of the AHA, the use of nifekalant for refractory arrhythmias has not been in- cluded. Thus, Japan is a rare country in which nifekalant was included as an alternative to amiodarone to treat OHCA pa- tients with refractory arrhythmia. High-quality studies with sufficient size are warranted to determine which antiarrhyth- mic drugs are effective for the treatment of refractory ar- rhythmias with greater confidence across the country. 5. Limitations There are several limitations in this study. First, as with any observational study, there was a risk of selection bias. Espe- cially in this study, the number of patients in nifekalant group was limited, which may lead to differences in patient distri- bution. As a result, comparability may be compromised. In addition, there was a risk of confounders. To overcome this limitation, we performed overlap weight, and all measured confounding factors were well balanced among each group, yet the risk of unmeasured confounder remained. Second, the power of this study was low due to the small number of patients in the nifekalant group. However, it has been pointed out that it is inappropriate to judge the appropriate- ness of a study based on its post hoc power, and the results should be interpreted with caution (25). Third, we could not adjust for treatment and intervention after ROSC and dur- ing admission. As described in the results, the proportions of patients who received target temperature management and percutaneous coronary intervention differed between the nifekalant and amiodarone groups. However, even in randomized controlled trials, statistical adjustment for fac- tors after group allocation could introduce over-adjustment bias and could inappropriately dilute the true relationship between the exposure and outcome in the study (17). There- fore, we conducted a sensitivity analysis using propensity score including the three treatments and performed an anal- ysis with overlap weight based on the assumption that the decision to use these three treatments (VA-ECMO, PCI, and TTM) is made prior to admission. The result is consistent, which may support the robustness of the results. Fourth, al- though dose and timing of anti-arrhythmics is an important factor, JAAM-OHCA registry does not include the time of ad- ministration or the dose of anti-arrhythmics. 6. Conclusion This nationwide study showed that nifekalant was not as- sociated with improved outcomes regarding admission after return of spontaneous circulation, 30-day survival, and 30- day favourable neurological outcome compared with amio- darone. 7. List of Abbreviations AED, Automated external defibrillator; AHA, American Heart Association; CPC, Cerebral performance category; CPR, Car- diopulmonary resuscitation; EMS; Emergency medical sys- tem; ERC, European Resuscitation Council; FDMA, The Fire and Disaster Management Agency; ILCOR, Interna- tional Liaison Committee on Resuscitation; JAAM-OHCA, The Japanese Association for Acute Medicine out-of-hospital cardiac arrest; JRC, Japan Resuscitation Council; OHCA, Out- of-hospital cardiorespiratory arrest; ROSC, Return of sponta- neous circulation; VF, Ventricular fibrillation; VT, Ventricular tachycardia 8. Declarations 8.1. Acknowledgments None. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 7 Archives of Academic Emergency Medicine. 2022; 10(1): e6 8.2. Author contribution HF and SA performed the quantitative analysis and drafted the manuscript, which was critically reviewed by all of the authors. HF, YH, RO and YT planned the study and analyzed and interpreted the data. All authors read and approved the final manuscript. 8.3. Funding The authors received no financial support for the research, authorship and/or publication of this article. 8.4. Conflict of Interest The authors declare that they have no competing interests. 8.5. Ethical consideration The study was conducted according to the ethical guidelines of the Declaration of Helsinki. The patients’ information was anonymized and de-identified prior to the analysis, thus the informed consent of the patient was waived. References 1. 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Journal of cardiovascular phar- macology. 2015;66(6):600-9. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem Introduction Methods Results Discussion Limitations Conclusion List of Abbreviations Declarations References