Journal of Cardiology 66 (2015) 69–72
Contents lists available at ScienceDirect
Journal of Cardiology journal homepage: www.elsevier.com/locate/jjcc
Original article
Design of a prospective observational survey on landiolol in atrial fibrillation/atrial flutter patients with chronic heart failure – AF-CHF landiolol survey Takeshi Yamashita (MD, PhD, FJCC)a, Takeshi Saitoh (BSc)b, Masaru Matsushita (BSc)b,* a b
The Cardiovascular Institute, Tokyo, Japan Post-Marketing Medical Research, Pharmacovigilance Division, Ono Pharmaceutical Co., Ltd., Osaka, Japan
A R T I C L E I N F O
A B S T R A C T
Article history: Received 25 July 2014 Received in revised form 29 August 2014 Accepted 17 September 2014 Available online 6 November 2014
Background: In Japan, intravenous digoxin was previously recommended as a standard drug for acute control of the heart rate in atrial fibrillation (AF)/atrial flutter (AFL) patients with chronic heart failure (CHF). Treatment alternatives for such cases were limited and new drugs for this purpose are needed. In November 2013, landiolol hydrochloride (Onoact1 50 for Injection, Ono Pharamaceutical, Osaka, Japan) was approved with the indication for ‘‘tachyarrhythmia (AF/AFL) in patients with cardiac dysfunction.’’ However, clinical experience with this condition is still insufficient. Therefore, it is important to conduct a surveillance of landiolol under actual clinical settings. In addition, collecting data on the mid- and longterm outcomes in patients treated with landiolol which have not been collected in clinical trials are indispensable. Methods: This prospective survey will involve patients treated with landiolol for the treatment of tachyarrhythmia (AF/AFL) in cardiac dysfunction at Japanese medical facilities from June 2014 to May 2017. The planned number of patients for analysis is approximately 500. The evaluations will be made not only to identify the adverse events and clinical effectiveness of the drug, but also to characterize the mid- and long-term outcomes of patients receiving and switching to oral-b-blockers after the discontinuation of landiolol. Results: This study was started in June 2014 (registration period 2 years, survey period 3 years) and will end in May 2017. Conclusions: This survey will clarify both the characteristics and mid- and long-term outcome of using landiolol to treat AF/AFL patients with cardiac dysfunction in clinical practice. Moreover, this survey will simultaneously provide important data that will reveal the possible gap between clinical trials and clinical practice in these patients. ß 2014 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Keywords: Atrial fibrillation b-Blocker Landiolol Heart failure Long-term outcome
Introduction Atrial fibrillation (AF) is an arrhythmia that often develops in the presence of heart failure (HF) [1,2]. The presence of AF reduces cardiac output by about 15–25% and possibly results in a deterioration of the hemodynamics in HF patients [3]. Furthermore, the excessive ventricular rate, loss of atrial contraction, and irregular ventricular filling time that is associated with AF may all cause negative clinical outcomes in patients with HF [4–10].
* Corresponding author at: 8-2, Kyutaromachi 1-Chome, Chuo-ku, Osaka-shi 541-8564, Japan. Tel.: +81 6 6263 2948; fax: +81 6 6263 2969. E-mail address: [email protected] (M. Matsushita).
Drug treatment of AF and atrial flutter (AFL) entails a rhythm control and a rate control. Rhythm control is typically achieved with the administration of Na channel blockers and K channel blockers, either alone or in combination based on the patient characteristics [2,11]. Rate control has been primarily regulated with the administration of b-blockers, Ca channel blockers, and digoxin, again either alone or in combination. Before selecting a drug for rate control it is necessary to consider the presence/ absence of other complications, such as Wolff–Parkinson–White syndrome, left ventricular dysfunction, and obstructive pulmonary disease; Ca channel blockers and b-blockers have negative inotropic actions while digoxin does not. Therefore, digoxin has conventionally been recommended the most effective drug for rate control in AF/AFL patients with cardiac dysfunction. In addition, it is recommended to follow-up digoxin treatment with low doses of
http://dx.doi.org/10.1016/j.jjcc.2014.09.008 0914-5087/ß 2014 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
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b-blockers to act as the second-line drug. However, there is currently no consensus for the proper methods for using oral b-blockers in AF/AFL patients with HF and treatment with these drugs has only been done empirically. Landiolol is a short-acting b-blocker that is rapidly metabolized to inactive forms in the blood and liver, resulting in a half-life of approximately 4 min in the human blood. In addition, it selectively binds to b1 receptors, with a b1 receptor selectivity ratio (b1/b2) as high as 251. Furthermore, landiolol rapidly reduces heart late (HR) without lowering blood pressure [12]. Based on these properties, landiolol has been reported to be useful for treating several acute disorders. A clinical study (J-Land Study) was carried out in order to evaluate the efficacy and safety of landiolol in comparison to digoxin in AF/AFL patients with a New York Heart Association class III–IV, a left ventricular ejection fraction (LVEF) of 25–50%, and a HR 120 bpm or higher [13]. On the basis of the results, in 2013, landiolol was approved for ‘‘tachyarrhythmia (AF/AFL) in patients with cardiac dysfunction’’. Therefore, in the current ‘‘AF Treatment Guidelines’’ (revised edition, 2013) landiolol is recommended as the rate control treatment drug for use in AF patients with HF (Class I, Level B) [14]. However, a sufficient evaluation of the safety and efficacy of landiolol during clinical use has not been performed. Moreover, no information about mid- and long-term outcome is available and information about switching to oral b-blockers from landiolol is also not sufficient. Under such circumstances, it is mandatory to continue collecting data on landiolol treatment in AF/AFL patients with cardiac dysfunction especially in view of the anticipated increase of these patients in our aging society. To achieve these goals, we propose the design and details of the present study in this report. Methods Patients The target patients for this study will be AF/AFL patients with cardiac dysfunction. Because this study is performed under clinical settings, no special exclusion criteria will be applied for the selection of patients. The number of patients feasible to enroll and that enables a comparison analysis with the results from the domestic clinical trials is established as 500 patients and it was obtained by using an interval estimation of population ratio. Further, the planned number of patients for this study was established as 800 patients by taking into consideration possible occurrences of patient dropout and exclusion from analysis. Patients’ informed consent will not be obtained because this study is a survey conducted under the Re-examination system in compliance with Good Post-marketing Study Practice ordinance under the Japanese Pharmaceutical Affairs Act. Research facilities In view of the purpose of this study, this study will be performed in hospitals with sufficient experience in HF treatment; the target numbers of patients for this study is 800; namely, 5–10 patients per medical institution (hospital department) in a total of 80–160 medical institutions. Design This study will be carried out continuously with the use of an electronic data capture (EDC) system; the ADDIN System (ASKLEP Inc., Tokyo, Japan) will be employed as an EDC system, with the electronic signature serving as the physician’s signature. Baseline data will be collected from the admission episodes between June
2014 and May 2016 (plan) while outcome data will be collected until 180 days after the start of treatment with landiolol. Objectives The objectives of the present study are to identify: 1) Patient characteristics that required landiolol to control the conditions with rapid AF/AFL with cardiac dysfunction. 2) Status (frequency, type, severity, etc.) of adverse drug reactions (adverse events) associated with the negative inotropic effects of landiolol. 3) Status of concomitant medication and interactions with drugs acting on the circulation, among others. 4) Landiolol dosage and its effects on heart rate and blood pressure (BP) during the treatment. 5) Dose, presence/absence of oral b-blocker after discontinuation of landiolol, and dose of oral b-blockers. 6) Death and readmission due to HF during the 180-day period after the start of treatment with landiolol.
Data collection/processing (attachments) Data will be entered with the web-based EDC system. For each patient, the following baseline data will be collected: demographic characteristics, complications, HR, BP, cardiac function, and electrocardiographic (ECG) findings. The condition of all patients will be investigated from the start of treatment with landiolol to 7 days after discontinuation of its use and will cover the following information: status of treatment with landiolol, status of switching to oral b-blockers, HR, BP, cardiac function, ECG findings, and any status related to adverse events. In addition, information on the survival of individual patients will be collected for investigation of outcome until 180 days after the start of treatment with landiolol. Confidentiality of patients The confidentiality of individual patients will be protected in this study because it is not designed to collect information about direct identifiers (name, address, telephone number, etc.). Access to the EDC system from each hospital is carefully managed by the system administrator of the system vendor. The study is performed in compliance with Good Post-marketing Study Practice, an ordinance issued by the Ministry of Health Labor and Welfare establishing the standards for implementation of post-marketing surveillance of all new drugs approved in Japan. Statistical analysis Frequency distribution, summary statistics, etc. will be calculated concerning background variables, safety endpoints, and effectiveness endpoints. For the subgroup analysis of adverse drug reactions, the incidence and 95% confidence interval (Clopper–Pearson method) will be calculated for each category. Regarding death and readmission due to HF, independent determinants will be analyzed in an explorative manner by multivariate analysis. Furthermore, we will utilize the SAS program (latest version; Carey, NC, USA) for all statistical analysis related to this study.
Results planning This study was started in June 2014 (registration period 2 years, survey period 3 years) and will end in May 2017.
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Discussion
Appendix 1. Patient data form for AF-CHF landiolol survey
This study is a post-marketing surveillance of landiolol regarding its indication ‘‘tachyarrhythmia (AF/AFL) in patients with cardiac dysfunction.’’ It is aimed at collecting information to facilitate the proper use of landiolol by analyzing the background variables of patients treated with landiolol (demographic data, disease history, reasons for discontinuation, presence/absence of re-use, etc.), clinical course (particularly HR, BP, ECG, etc.), and previously unknown/known adverse events. However, the information expected from this study is not confined to this range. Because no clinical report is available concerning the long-term outcome of AF/AFL patients with HF who require treatment with landiolol, this study is expected to provide basic data on these patients in Japan. Conditions necessitating intravenous b-blockers for HR control associated with AF/AFL patients in HF can be easily assessed clinically as a single category and stratification of these patients can be enabled. The exploration of factors determining the outcome in these patients is important. In fact, the J-Land Study is currently the only paper that has been published on switching landiolol to oral b-blockers during treatment [13]. In this study, approximately 80% of the patients began to receive oral b-blockers following the end of treatment with landiolol while bisoprolol (1.8 1.3 mg/dose) was used in about 50% of these cases and carvedilol (3.2 2.7 mg/dose) in about 30%. However, this report did not include a detailed discussion entailing the initial dose of the oral b-blockers. Although it may be explorative, and such information will provide useful information for clinical practice.
1. Background Demographic data Sex Age or date of birth (month/year) Body weight Hyperreactivity to drugs Information specific to females (pregnancy/lactation) Clinical data (medical history) Date and time of tachyarrhythmia outbreak requiring treatment with landiolol Reason for treatment with landiolol Complications and medical history (especially heart disease) Implantable pacemaker Implantable defibrillator Respirator use Assessment of cardiac function New York Heart Association (NYHA) classification Electrocardiogram (ECG) Chest X-ray Echocardiography Percutaneous arterial oxygen saturation Brain natriuretic peptide 2. Treatment with landiolol (start of treatment until 7 days after discontinuation) Route of administration Time of administration (start; discontinuation) Infusion rate at the start of treatment Presence/absence of a temporary suspension and resumption of treatment
Limitations Two significant limitations in the design of this study need to be discussed. First, it was designed as an observational study without incorporating a control group. Second, it is a study that will be accomplished under clinical settings and thus it will be unable to control all of the variables surveyed, including factors that will possibly affect the outcome. Conclusions In this report, we propose a study designed to collect and supply information that will facilitate the proper use of landiolol hydrochloride, a short-acting b1 selective blocker, in the clinical treatment of ‘‘tachyarrhythmia (AF/AFL) in patients with cardiac dysfunction’’. The study is expected to provide valuable information not only concerning patients for whom landiolol is indicated and the status of use of landiolol in these patients, but also concerning the long-term outcome of patient groups and the status of switching from landiolol to oral b-blockers. This information will be critical for assessing the clinical significance of therapeutic intervention of this disease with the use of landiolol. Funding This study is funded by Ono Pharmaceutical Co., Ltd. (Osaka, Japan). Disclosures T.Y. has received consulting fees from Ono Pharmaceutical Co., Ltd.; T.S. and M.M. are employees of Ono Pharmaceutical Co., Ltd. Acknowledgments The authors thank all investigators, site staff, and patients who will contribute to this post-marketing surveillance.
If ‘‘present’’, the date/time of suspension, reason for suspension, date/time of resumption, and infusion rate at the time of resumption Minimum and maximum infusion rate of landiolol Reason for discontinuation Presence/absence of re-treatment* (discontinuation of treatment until 7 days after discontinuation) If ‘‘present’’, the reason for re-treatment and the period of re-treatment *: ‘‘Re-treatment’’ indicates a case where treatment with landiolol is resumed within 7 days after Day 0 (the day when the therapeutic interventions with landiolol have been discontinued) 3. Clinical data (start of treatment with landiolol until 7 days after discontinuation) Heart rate (HR) and blood pressure (BP) (immediately before the start of treatment, immediately after discontinuation, 30 min after discontinuation, and 7 days after discontinuation) Presence/absence of ECG If ECG is ‘‘present’’, a description is made about the presence/absence of noteworthy changes in the ECG findings during treatment with landiolol and the presence/absence of a sinus rhythm (if sinus rhythm has been restored, the date/time of first restoration to be entered) Presence/absence of a stay in the intensive care unit or coronary care unit for left ventricular dysfunction requiring treatment with landiolol If ‘‘present’’, the duration of stay 4. Concomitant drugs/therapies (start of treatment with landiolol until 7 days after discontinuation) Treatment with oral b-blockers Presence/absence of treatment with such drugs used
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If ‘‘present,’’ brand name of the drug, reason for treatment, duration with treatment, and daily dose level HR and BP immediately before start of treatment with such drugs Treatment with other drugs Presence/absence of treatment with other drugs If ‘‘present,’’ brand name of the drug, formulation, reason for treatment, and duration with treatment Concomitant therapies Presence/absence of treatment with concomitant therapies If ‘‘present,’’ name of the therapy (electrical defibrillation, pacing, catheter ablation, etc.), frequency of the therapy, time of the therapy, and reason for treatment 5. Adverse events (immediately after start of treatment with landiolol until 48 h after discontinuation) Presence/absence of adverse events If ‘‘present,’’ the name of the event, date of outbreak, seriousness, therapeutic intervention into the event, causal relationship, other factors involved, dechallenge, rechallenge, date of outcome assessment, and outcome of the event If causal relationship is ruled out, the other responsible factor Laboratory test data related to the adverse events (test name, date, value, and criterion range at the facility) If the physician in charge of the survey becomes aware of an outbreak of a serious adverse event, he/she is required to enter the event into the survey data entry page of the electronic data capture system or to inform the Medical Representative of the event immediately 6. Regarding the outcome (30, 90, and 180 days after the start of treatment with landiolol) (1) Outcome Presence/absence of outcome check Presence/absence of discharge after the end of treatment of hospitalization-requiring heart failure episode If ‘‘present,’’ the date of discharge Presence/absence of readmission If ‘‘present,’’ the date of readmission and the reason Survival/death If ‘‘survival,’’ the date of the confirmed survival If ‘‘death,’’ the date of death, cause, and causal relationship with landiolol If outcome is unknown, the reason for why it is unknown (2) Heart function test NYHA class and date of diagnosis (3) Impression about the influence of acute stage heart rate control with landiolol on long-term heart failure events Impression about the influence of acute stage heart rate control with landiolol on long-term heart failure events ‘‘No influence,’’ ‘‘influence present,’’ ‘‘neutral’’ If ‘‘influence present,’’ specify the influence
References [1] Hamaguchi S, Yokoshiki H, Kinugawa S, Tsuchihashi-Makaya M, Yokota T, Takeshita A, Tsutsui H. Effects of atrial fibrillation on long-term outcomes in patients hospitalized for heart failure in Japan – a report from the Japanese Cardiac Registry of heart failure in Cardiology (JCARE-CARD). Circ J 2009; 73:2084–90. [2] Camm AJ, Savelieva I, Bharati S, Lindsay BD, Nattel S, Shinagawa K, Chen SA. Atrial tachycardia, flutter, and fibrillation. In: Saksena S, Camm AJ, editors. Electrophysiological disorders of the heart. Philadelphia: Elsevier ChurchillLivingstone; 2005. p. 283–363. [3] Naito M, David D, Michelson EL, Schaffenburg M, Dreifus LS. The hemodynamic consequences of cardiac arrhythmias: evaluation of the relative roles of abnormal atrioventricular sequencing, irregularity of ventricular rhythm and atrial fibrillation in a canine model. Am Heart J 1983; 106:284–91. [4] Dries DL, Exner DV, Gersh BJ, Domanski MJ, Waclawiw MA, Stevenson LW. Atrial fibrillation is associated with an increased risk for mortality and heart failure progression in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: a retrospective analysis of the SOLVD trials. J Am Coll Cardiol 1998;32:695–703. [5] Bourassa MG, Gurne´ O, Bangdiwala SI, Ghali JK, Young JB, Rousseau M, Johnstone DE, Yusuf S. Natural history and patterns of current practice in heart failure. J Am Coll Cardiol 1993;22(Suppl. A):14A–9A. [6] Carson PE, Johnson GR, Dunkman WB, Fletcher RD, Farrell L, Cohn JN. The influence of atrial fibrillation on prognosis in mild to moderate heart failure: the V-HeFT Studies. Circulation 1993;87(Suppl. VI). VI-102–10. [7] Middlekauff HR, Stevenson WG, Stevenson LW. Prognostic significance of atrial fibrillation in advanced heart failure: a study of 390 patients. Circulation 1991;84:40–8. [8] The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987;316:1429– 35. [9] Doval HC, Nul DR, Grancelli HO, Perrone SV, Bortman GR, Curiel R. Randomised trial of low-dose amiodarone in severe congestive heart failure. Lancet 1994;344:493–8. [10] Deedwania PC, Singh BN, Ellenbogen K, Fisher S, Fletcher R, Singh SN. Spontaneous conversion and maintenance of sinus rhythm by amiodarone in patients with heart failure and atrial fibrillation: observations from the Veterans Affairs Congestive Heart Failure Survival Trial of Antiarrhythmic Therapy (CHF-STAT). Circulation 1998;98:2574–9. [11] Blomstro¨m-Lundqvist C, Scheinman MM, Aliot EM, Alpert JS, Calkins H, Camm AJ, Campbell WB, Haines DE, Kuck KH, Lerman BB, Miller DD, Shaeffer CW, Stevenson WG, Tomaselli GF, Antman EM, et al. ACC/AHA/ESC guidelines for the management of patients with supraventricular arrhythmias-executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing committee to develop guidelines for the management of patients with supraventricular arrhythmias). Circulation 2003;108:1871–909. [12] Hoshi T, Sato A, Nishina H, Kakefuda Y, Wang Z, Noguchi Y, Aonuma K. Acute hemodynamic effects of landiolol, an ultra-short-acting beta-blocker, in patients with acute coronary syndrome: preliminary study. J Cardiol 2012;60:252–6. [13] Nagai R, Kinugawa K, Inoue H, Atarashi H, Seino Y, Yamashita T, Shimizu W, Aiba T, Kitakaze M, Sakamoto A, Ikeda T, Imai Y, Daimon T, Fujino K, Nagano T, et al. Urgent management of rapid heart rate in patients with atrial fibrillation/ flutter and left ventricular dysfunction – comparison of the ultra-short-acting b1-selective blocker landiolol with digoxin (J-Land Study). Circ J 2013;77: 908–916. [14] JCS Joint Working Group. Guidelines for pharmacotherapy of atrial fibrillation (JCS 2013). Circ J 2014;78:1997–2021.
Contents lists available at ScienceDirect
Journal of Cardiology journal homepage: www.elsevier.com/locate/jjcc
Original article
Design of a prospective observational survey on landiolol in atrial fibrillation/atrial flutter patients with chronic heart failure – AF-CHF landiolol survey Takeshi Yamashita (MD, PhD, FJCC)a, Takeshi Saitoh (BSc)b, Masaru Matsushita (BSc)b,* a b
The Cardiovascular Institute, Tokyo, Japan Post-Marketing Medical Research, Pharmacovigilance Division, Ono Pharmaceutical Co., Ltd., Osaka, Japan
A R T I C L E I N F O
A B S T R A C T
Article history: Received 25 July 2014 Received in revised form 29 August 2014 Accepted 17 September 2014 Available online 6 November 2014
Background: In Japan, intravenous digoxin was previously recommended as a standard drug for acute control of the heart rate in atrial fibrillation (AF)/atrial flutter (AFL) patients with chronic heart failure (CHF). Treatment alternatives for such cases were limited and new drugs for this purpose are needed. In November 2013, landiolol hydrochloride (Onoact1 50 for Injection, Ono Pharamaceutical, Osaka, Japan) was approved with the indication for ‘‘tachyarrhythmia (AF/AFL) in patients with cardiac dysfunction.’’ However, clinical experience with this condition is still insufficient. Therefore, it is important to conduct a surveillance of landiolol under actual clinical settings. In addition, collecting data on the mid- and longterm outcomes in patients treated with landiolol which have not been collected in clinical trials are indispensable. Methods: This prospective survey will involve patients treated with landiolol for the treatment of tachyarrhythmia (AF/AFL) in cardiac dysfunction at Japanese medical facilities from June 2014 to May 2017. The planned number of patients for analysis is approximately 500. The evaluations will be made not only to identify the adverse events and clinical effectiveness of the drug, but also to characterize the mid- and long-term outcomes of patients receiving and switching to oral-b-blockers after the discontinuation of landiolol. Results: This study was started in June 2014 (registration period 2 years, survey period 3 years) and will end in May 2017. Conclusions: This survey will clarify both the characteristics and mid- and long-term outcome of using landiolol to treat AF/AFL patients with cardiac dysfunction in clinical practice. Moreover, this survey will simultaneously provide important data that will reveal the possible gap between clinical trials and clinical practice in these patients. ß 2014 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Keywords: Atrial fibrillation b-Blocker Landiolol Heart failure Long-term outcome
Introduction Atrial fibrillation (AF) is an arrhythmia that often develops in the presence of heart failure (HF) [1,2]. The presence of AF reduces cardiac output by about 15–25% and possibly results in a deterioration of the hemodynamics in HF patients [3]. Furthermore, the excessive ventricular rate, loss of atrial contraction, and irregular ventricular filling time that is associated with AF may all cause negative clinical outcomes in patients with HF [4–10].
* Corresponding author at: 8-2, Kyutaromachi 1-Chome, Chuo-ku, Osaka-shi 541-8564, Japan. Tel.: +81 6 6263 2948; fax: +81 6 6263 2969. E-mail address: [email protected] (M. Matsushita).
Drug treatment of AF and atrial flutter (AFL) entails a rhythm control and a rate control. Rhythm control is typically achieved with the administration of Na channel blockers and K channel blockers, either alone or in combination based on the patient characteristics [2,11]. Rate control has been primarily regulated with the administration of b-blockers, Ca channel blockers, and digoxin, again either alone or in combination. Before selecting a drug for rate control it is necessary to consider the presence/ absence of other complications, such as Wolff–Parkinson–White syndrome, left ventricular dysfunction, and obstructive pulmonary disease; Ca channel blockers and b-blockers have negative inotropic actions while digoxin does not. Therefore, digoxin has conventionally been recommended the most effective drug for rate control in AF/AFL patients with cardiac dysfunction. In addition, it is recommended to follow-up digoxin treatment with low doses of
http://dx.doi.org/10.1016/j.jjcc.2014.09.008 0914-5087/ß 2014 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
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b-blockers to act as the second-line drug. However, there is currently no consensus for the proper methods for using oral b-blockers in AF/AFL patients with HF and treatment with these drugs has only been done empirically. Landiolol is a short-acting b-blocker that is rapidly metabolized to inactive forms in the blood and liver, resulting in a half-life of approximately 4 min in the human blood. In addition, it selectively binds to b1 receptors, with a b1 receptor selectivity ratio (b1/b2) as high as 251. Furthermore, landiolol rapidly reduces heart late (HR) without lowering blood pressure [12]. Based on these properties, landiolol has been reported to be useful for treating several acute disorders. A clinical study (J-Land Study) was carried out in order to evaluate the efficacy and safety of landiolol in comparison to digoxin in AF/AFL patients with a New York Heart Association class III–IV, a left ventricular ejection fraction (LVEF) of 25–50%, and a HR 120 bpm or higher [13]. On the basis of the results, in 2013, landiolol was approved for ‘‘tachyarrhythmia (AF/AFL) in patients with cardiac dysfunction’’. Therefore, in the current ‘‘AF Treatment Guidelines’’ (revised edition, 2013) landiolol is recommended as the rate control treatment drug for use in AF patients with HF (Class I, Level B) [14]. However, a sufficient evaluation of the safety and efficacy of landiolol during clinical use has not been performed. Moreover, no information about mid- and long-term outcome is available and information about switching to oral b-blockers from landiolol is also not sufficient. Under such circumstances, it is mandatory to continue collecting data on landiolol treatment in AF/AFL patients with cardiac dysfunction especially in view of the anticipated increase of these patients in our aging society. To achieve these goals, we propose the design and details of the present study in this report. Methods Patients The target patients for this study will be AF/AFL patients with cardiac dysfunction. Because this study is performed under clinical settings, no special exclusion criteria will be applied for the selection of patients. The number of patients feasible to enroll and that enables a comparison analysis with the results from the domestic clinical trials is established as 500 patients and it was obtained by using an interval estimation of population ratio. Further, the planned number of patients for this study was established as 800 patients by taking into consideration possible occurrences of patient dropout and exclusion from analysis. Patients’ informed consent will not be obtained because this study is a survey conducted under the Re-examination system in compliance with Good Post-marketing Study Practice ordinance under the Japanese Pharmaceutical Affairs Act. Research facilities In view of the purpose of this study, this study will be performed in hospitals with sufficient experience in HF treatment; the target numbers of patients for this study is 800; namely, 5–10 patients per medical institution (hospital department) in a total of 80–160 medical institutions. Design This study will be carried out continuously with the use of an electronic data capture (EDC) system; the ADDIN System (ASKLEP Inc., Tokyo, Japan) will be employed as an EDC system, with the electronic signature serving as the physician’s signature. Baseline data will be collected from the admission episodes between June
2014 and May 2016 (plan) while outcome data will be collected until 180 days after the start of treatment with landiolol. Objectives The objectives of the present study are to identify: 1) Patient characteristics that required landiolol to control the conditions with rapid AF/AFL with cardiac dysfunction. 2) Status (frequency, type, severity, etc.) of adverse drug reactions (adverse events) associated with the negative inotropic effects of landiolol. 3) Status of concomitant medication and interactions with drugs acting on the circulation, among others. 4) Landiolol dosage and its effects on heart rate and blood pressure (BP) during the treatment. 5) Dose, presence/absence of oral b-blocker after discontinuation of landiolol, and dose of oral b-blockers. 6) Death and readmission due to HF during the 180-day period after the start of treatment with landiolol.
Data collection/processing (attachments) Data will be entered with the web-based EDC system. For each patient, the following baseline data will be collected: demographic characteristics, complications, HR, BP, cardiac function, and electrocardiographic (ECG) findings. The condition of all patients will be investigated from the start of treatment with landiolol to 7 days after discontinuation of its use and will cover the following information: status of treatment with landiolol, status of switching to oral b-blockers, HR, BP, cardiac function, ECG findings, and any status related to adverse events. In addition, information on the survival of individual patients will be collected for investigation of outcome until 180 days after the start of treatment with landiolol. Confidentiality of patients The confidentiality of individual patients will be protected in this study because it is not designed to collect information about direct identifiers (name, address, telephone number, etc.). Access to the EDC system from each hospital is carefully managed by the system administrator of the system vendor. The study is performed in compliance with Good Post-marketing Study Practice, an ordinance issued by the Ministry of Health Labor and Welfare establishing the standards for implementation of post-marketing surveillance of all new drugs approved in Japan. Statistical analysis Frequency distribution, summary statistics, etc. will be calculated concerning background variables, safety endpoints, and effectiveness endpoints. For the subgroup analysis of adverse drug reactions, the incidence and 95% confidence interval (Clopper–Pearson method) will be calculated for each category. Regarding death and readmission due to HF, independent determinants will be analyzed in an explorative manner by multivariate analysis. Furthermore, we will utilize the SAS program (latest version; Carey, NC, USA) for all statistical analysis related to this study.
Results planning This study was started in June 2014 (registration period 2 years, survey period 3 years) and will end in May 2017.
T. Yamashita et al. / Journal of Cardiology 66 (2015) 69–72
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Discussion
Appendix 1. Patient data form for AF-CHF landiolol survey
This study is a post-marketing surveillance of landiolol regarding its indication ‘‘tachyarrhythmia (AF/AFL) in patients with cardiac dysfunction.’’ It is aimed at collecting information to facilitate the proper use of landiolol by analyzing the background variables of patients treated with landiolol (demographic data, disease history, reasons for discontinuation, presence/absence of re-use, etc.), clinical course (particularly HR, BP, ECG, etc.), and previously unknown/known adverse events. However, the information expected from this study is not confined to this range. Because no clinical report is available concerning the long-term outcome of AF/AFL patients with HF who require treatment with landiolol, this study is expected to provide basic data on these patients in Japan. Conditions necessitating intravenous b-blockers for HR control associated with AF/AFL patients in HF can be easily assessed clinically as a single category and stratification of these patients can be enabled. The exploration of factors determining the outcome in these patients is important. In fact, the J-Land Study is currently the only paper that has been published on switching landiolol to oral b-blockers during treatment [13]. In this study, approximately 80% of the patients began to receive oral b-blockers following the end of treatment with landiolol while bisoprolol (1.8 1.3 mg/dose) was used in about 50% of these cases and carvedilol (3.2 2.7 mg/dose) in about 30%. However, this report did not include a detailed discussion entailing the initial dose of the oral b-blockers. Although it may be explorative, and such information will provide useful information for clinical practice.
1. Background Demographic data Sex Age or date of birth (month/year) Body weight Hyperreactivity to drugs Information specific to females (pregnancy/lactation) Clinical data (medical history) Date and time of tachyarrhythmia outbreak requiring treatment with landiolol Reason for treatment with landiolol Complications and medical history (especially heart disease) Implantable pacemaker Implantable defibrillator Respirator use Assessment of cardiac function New York Heart Association (NYHA) classification Electrocardiogram (ECG) Chest X-ray Echocardiography Percutaneous arterial oxygen saturation Brain natriuretic peptide 2. Treatment with landiolol (start of treatment until 7 days after discontinuation) Route of administration Time of administration (start; discontinuation) Infusion rate at the start of treatment Presence/absence of a temporary suspension and resumption of treatment
Limitations Two significant limitations in the design of this study need to be discussed. First, it was designed as an observational study without incorporating a control group. Second, it is a study that will be accomplished under clinical settings and thus it will be unable to control all of the variables surveyed, including factors that will possibly affect the outcome. Conclusions In this report, we propose a study designed to collect and supply information that will facilitate the proper use of landiolol hydrochloride, a short-acting b1 selective blocker, in the clinical treatment of ‘‘tachyarrhythmia (AF/AFL) in patients with cardiac dysfunction’’. The study is expected to provide valuable information not only concerning patients for whom landiolol is indicated and the status of use of landiolol in these patients, but also concerning the long-term outcome of patient groups and the status of switching from landiolol to oral b-blockers. This information will be critical for assessing the clinical significance of therapeutic intervention of this disease with the use of landiolol. Funding This study is funded by Ono Pharmaceutical Co., Ltd. (Osaka, Japan). Disclosures T.Y. has received consulting fees from Ono Pharmaceutical Co., Ltd.; T.S. and M.M. are employees of Ono Pharmaceutical Co., Ltd. Acknowledgments The authors thank all investigators, site staff, and patients who will contribute to this post-marketing surveillance.
If ‘‘present’’, the date/time of suspension, reason for suspension, date/time of resumption, and infusion rate at the time of resumption Minimum and maximum infusion rate of landiolol Reason for discontinuation Presence/absence of re-treatment* (discontinuation of treatment until 7 days after discontinuation) If ‘‘present’’, the reason for re-treatment and the period of re-treatment *: ‘‘Re-treatment’’ indicates a case where treatment with landiolol is resumed within 7 days after Day 0 (the day when the therapeutic interventions with landiolol have been discontinued) 3. Clinical data (start of treatment with landiolol until 7 days after discontinuation) Heart rate (HR) and blood pressure (BP) (immediately before the start of treatment, immediately after discontinuation, 30 min after discontinuation, and 7 days after discontinuation) Presence/absence of ECG If ECG is ‘‘present’’, a description is made about the presence/absence of noteworthy changes in the ECG findings during treatment with landiolol and the presence/absence of a sinus rhythm (if sinus rhythm has been restored, the date/time of first restoration to be entered) Presence/absence of a stay in the intensive care unit or coronary care unit for left ventricular dysfunction requiring treatment with landiolol If ‘‘present’’, the duration of stay 4. Concomitant drugs/therapies (start of treatment with landiolol until 7 days after discontinuation) Treatment with oral b-blockers Presence/absence of treatment with such drugs used
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If ‘‘present,’’ brand name of the drug, reason for treatment, duration with treatment, and daily dose level HR and BP immediately before start of treatment with such drugs Treatment with other drugs Presence/absence of treatment with other drugs If ‘‘present,’’ brand name of the drug, formulation, reason for treatment, and duration with treatment Concomitant therapies Presence/absence of treatment with concomitant therapies If ‘‘present,’’ name of the therapy (electrical defibrillation, pacing, catheter ablation, etc.), frequency of the therapy, time of the therapy, and reason for treatment 5. Adverse events (immediately after start of treatment with landiolol until 48 h after discontinuation) Presence/absence of adverse events If ‘‘present,’’ the name of the event, date of outbreak, seriousness, therapeutic intervention into the event, causal relationship, other factors involved, dechallenge, rechallenge, date of outcome assessment, and outcome of the event If causal relationship is ruled out, the other responsible factor Laboratory test data related to the adverse events (test name, date, value, and criterion range at the facility) If the physician in charge of the survey becomes aware of an outbreak of a serious adverse event, he/she is required to enter the event into the survey data entry page of the electronic data capture system or to inform the Medical Representative of the event immediately 6. Regarding the outcome (30, 90, and 180 days after the start of treatment with landiolol) (1) Outcome Presence/absence of outcome check Presence/absence of discharge after the end of treatment of hospitalization-requiring heart failure episode If ‘‘present,’’ the date of discharge Presence/absence of readmission If ‘‘present,’’ the date of readmission and the reason Survival/death If ‘‘survival,’’ the date of the confirmed survival If ‘‘death,’’ the date of death, cause, and causal relationship with landiolol If outcome is unknown, the reason for why it is unknown (2) Heart function test NYHA class and date of diagnosis (3) Impression about the influence of acute stage heart rate control with landiolol on long-term heart failure events Impression about the influence of acute stage heart rate control with landiolol on long-term heart failure events ‘‘No influence,’’ ‘‘influence present,’’ ‘‘neutral’’ If ‘‘influence present,’’ specify the influence
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