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Cost-Effectiveness of Rate- and Rhythm-Control Drugs for Treating Atrial Fibrillation in Korea

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Original Article Yonsei Med J 2019 Dec;60(12):1157-1163 https://doi.org/10.3349/ymj.2019.60.12.1157 pISSN: 0513-5796 · eISSN: 1976-2437 Cost-Effectiveness of Rate- and Rhythm-Control Drugs for Treating Atrial Fibrillation in Korea Min Kim1*, Woojin Kim2*, Changsoo Kim2,3, and Boyoung Joung1 1Division of Cardiology, Department of Internal Medicine, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul; 2Department of Preventive Medicine, Yonsei University College of Medicine, Seoul; 3Institute of Human Complexity and Systems Science, Yonsei University, Seoul, Korea. Purpose: Although the economic and mortality burden of atrial fibrillation (AF) is substantial, it remains unclear which treat- ment strategies for rate and rhythm control are most cost-effective. Consequently, economic factors can play an adjunctive role in guiding treatment selection. Materials and Methods: We built a Markov chain Monte Carlo model using the Korean Health Insurance Review & Assessment Service database. Drugs for rate control and rhythm control in AF were analyzed. Cost-effective therapies were selected using a cost-effectiveness ratio, calculated by net cost and quality-adjusted life years (QALY). Results: In the National Health Insurance Service data, 268149 patients with prevalent AF (age ≥18 years) were identified between January 1, 2013 and December 31, 2015. Among them, 212459 and 55690 patients were taking drugs for rate and rhythm control, respectively. Atenolol cost $714/QALY. Among the rate-control medications, the cost of propranolol was lowest at $487/QALY, while that of carvedilol was highest at $1363/QALY. Among the rhythm-control medications, the cost of pilsicainide was lowest at $638/QALY, while that of amiodarone was highest at $986/QALY. Flecainide and propafenone cost $834 and $830/QALY, respec- tively. The cost-effectiveness threshold of all drugs was lower than $30000/QALY. Compared with atenolol, the rate-control drugs propranolol, betaxolol, bevantolol, bisoprolol, diltiazem, and verapamil, as well as the rhythm-control drugs sotalol, pilsicainide, flecainide, propafenone, and dronedarone, showed better incremental cost-effectiveness ratios. Conclusion: Propranolol and pilsicainide appear to be cost-effective in patients with AF in Korea assuming that drug usage or compliance is the same. Key Words: ‌Atrial fibrillation, drugs, cost effectiveness, QALY INTRODUCTION causes substantial morbidity.1-4 AF affects millions of patients and increases one’s risk of heart failure,5,6 stroke,7,8 and death.2,5 Atrial fibrillation (AF), the most common cardiac dysrhythmia, The prevalence of AF increases with advancing age, and the older adult population is increasing worldwide.9-14 The preva- Received: July 12, 2019 Revised: October 13, 2019 Accepted: October 28, 2019 lence of AF in Korea was 1.53% in 2015 and was reported as like- Co-corresponding authors: Changsoo Kim, MD, PhD, Department of Preventive ly to increase to 5.81% by 2060.15 Given these findings, an in- Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea. creasing economic burden of AF on the health care system is Tel: 82-2-2228-1860, Fax: 82-2-392-8133, E-mail: [email protected] and anticipated, and it is important to estimate the cost and effec- Boyoung Joung, MD, PhD, Division of Cardiology, Department of Internal Medicine, tiveness of different therapeutic options.10,16 Severance Cardiovascular Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea. Several studies recently compared the economic practicality Tel: 82-2-2228-8460, Fax: 82-2-393-2041, E-mail: [email protected] of non-vitamin K antagonist oral anticoagulants to adjusted- 17-20 *Min Kim and Woojin Kim contributed equally to this work. dose warfarin for the prevention of stroke in AF. It is known •The authors have no potential conflicts of interest to disclose. that rate-control and rhythm-control drugs do not show signif- © Copyright: Yonsei University College of Medicine 2019 icant differences in mortality rates.21,22 In a previous study in This is an Open Access article distributed under the terms of the Creative Com- Korea, a rhythm-study strategy also showed no benefit on car- mons Attribution Non-Commercial License (https://creativecommons.org/licenses/ 23 by-nc/4.0) which permits unrestricted non-commercial use, distribution, and repro- diovascular mortality, compared with a rate-control strategy. duction in any medium, provided the original work is properly cited. Meanwhile, economic studies comparing AF rate control ver- www.eymj.org 1157 Cost-Effectiveness of Drugs for Atrial Fibrillation sus rhythm control have revealed that rate control reduces costs, ceptor antagonists (atenolol, betaxolol, bevantolol, bisoprolol, compared with rhythm control, which included electrical car- carvedilol, propranolol), diltiazem, and verapamil, while the dioversion in Western individuals: The study involved 4060 rhythm-control drugs included flecainide, propafenone, pilsi- patient across 213 sites in Canada and the United States, with cainide, amiodarone, sotalol, and dronedarone (Table 1). mean survival, resource use (hospital days, pacemaker proce- AF was diagnosed using ICD-10 codes I48 (AF and atrial flut- dures, cardioversions, percutaneous transluminal coronary an- ter), I48.0 (AF), and I48.1 (atrial flutter). Moreover, patients were gioplasties, coronary artery bypass graft procedures, valve surgery defined as having AF only when it was a discharge diagnosis or procedures, ablation, and short-stay and emergency department confirmed more than twice in the outpatient department to en- visits), costs, and cost-effectiveness compared as outcome in- sure diagnostic accuracy. The AF diagnosis was previously val- dicators between rate-control and rhythm-control groups. idated in the NHIS database with a positive predictive value of Rate-control drugs included digoxin, atenolol, metoprolol, pro- 94.1%. A validation study was performed in 628 randomly se- pranolol, diltiazem, and verapamil, and rhythm-control drugs lected patients with the ICD-10 code I48 at two separate institu- included flecainide, propafenone, quinidine, disopyramide, tions. The patients’ electrocardiograms (ECGs) were reviewed moricizine, amiodarone, sotalol, and dofetilide. Rate-control by two physicians. Patients were defined as AF if documented costs were $5077 less per person than those for rhythm con- by ECG.16,25,26 trol.24 However, the cost-effectiveness of treating AF with rate- control and rhythm-control strategies has not been examined Decision model in Korea. The costs of drugs and hospitalization in Korea are We developed a Markov chain Monte Carlo model to evaluate different from those in Western countries. Moreover, recently, the cost-effectiveness of the rate- and rhythm-control drugs. hospitalization for AF has increased by 420% from 767 to 3986 Health states modeled included healthy AF, congestive heart per 1 million Korean populations from 2006 to 2015 and hos- failure (CHF), MI, ischemic stroke, transient ischemic attack pitalization for AF control has increased compared with hos- (TIA), intracranial hemorrhage (ICH), gastrointestinal bleed- pitalization for ischemic stroke and myocardial infarction ing (GI), and death. Cases of “fatal” CHF, MI, ischemic stroke, (MI).16 Based on these results, cost-effectiveness analysis may TIA, ICH, and GI bleeding were defined as transition to death. play a substantial role in treatment selection. Therefore, we sought to compare the projected quality-adjusted survival and Table 1. Drugs Used to Treat Atrial Fibrillation in the Rate- and Rhythm- costs of different rate-control and rhythm-control drugs in Ko- Control Groups among Patients Newly Diagnosed with Atrial Fibrillation rean patients with AF. between January 1, 2013 and December 31, 2015 in Korea Years Total 2013 2014 2015 MATERIALS AND METHODS Rate control Overall 212459 (100) 68182 (100) 69225 (100) 75052 (100) This study examined data from the National Health Insurance Digoxin 39360 (17.2) 13235 (19.4) 13195 (19.1) 12930 (17.2) Service (NHIS) database. The NHIS is a single insurer con- Atenolol 10852 (4.2) 4242 (6.2) 3449 (5.0) 3161 (4.2) trolled by the Korean government, and the majority (97.1%) of Betaxolol 928 (0.4) 364 (0.5) 277 (0.4) 287 (0.4) Korean residents are mandatory subscribers, with the remain- Bevantolol 536 (0.2) 212 (0.3) 172 (0.2) 152 (0.2) ing 3% being medical aid subjects. The sociodemographic in- Bisoprolol 49493 (23.8) 15410 (22.6) 16253 (23.5) 17830 (23.8) formation of patients, their use of inpatient and outpatient ser- Carvedilol 38412 (18.1) 12404 (18.2) 12398 (17.9) 13610 (18.1) vices, pharmacy dispensing claims, and mortality data were Propranolol 32854 (16.5) 9998 (14.7) 10473 (15.1) 12383 (16.5) extracted. This study was approved by the Institutional Review Diltiazem 24096 (11.2) 7893 (11.6) 7802 (11.3) 8401 (11.2) Board of Yonsei University Health System (4-2019-0802), which Verapamil 4803 (2.2) 1695 (2.5) 1463 (2.1) 1645 (2.2) waived the need for informed consent. Rhythm control Overall 55690 (100) 16617 (100) 18758 (100) 20315 (100) Study population Flecainide 13914 (25.0) 4082 (24.6) 4616 (24.6) 5216 (25.7) In the Korean NHIS database, a total of 268149 patients with Propafenone 14078 (25.2) 4196 (25.2) 4792 (25.6) 5090 (25.1) prevalent AF who were aged 18 years or older were identified Pilsicainide 2890 (5.2) 1058 (6.4) 998 (5.3) 834 (4.1) between January 1, 2013 and December 31, 2015. Those with Amiodarone 21976 (39.5) 6547 (39.4) 7367 (39.3) 8062 (39.7) valvular AF, such as moderate to severe mitral valve stenosis Sotalol 1065 (1.9) 324 (1.9) 327 (1.7) 414 (2.0) and prosthetic valve disease [International Classification of Dronedarone 1767 (3.2) 410 (2.5) 658 (3.5) 699 (3.4) Disease 10th Revision (ICD)-I050, I052, I342] were excluded. Finally, this study included 212459 and 55690 patients who Values are presented as n (%).
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  • (12) Patent Application Publication (10) Pub. No.: US 2015/0202317 A1 Rau Et Al

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    US 20150202317A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0202317 A1 Rau et al. (43) Pub. Date: Jul. 23, 2015 (54) DIPEPTDE-BASED PRODRUG LINKERS Publication Classification FOR ALPHATIC AMNE-CONTAINING DRUGS (51) Int. Cl. A647/48 (2006.01) (71) Applicant: Ascendis Pharma A/S, Hellerup (DK) A638/26 (2006.01) A6M5/9 (2006.01) (72) Inventors: Harald Rau, Heidelberg (DE); Torben A 6LX3/553 (2006.01) Le?mann, Neustadt an der Weinstrasse (52) U.S. Cl. (DE) CPC ......... A61K 47/48338 (2013.01); A61 K3I/553 (2013.01); A61 K38/26 (2013.01); A61 K (21) Appl. No.: 14/674,928 47/48215 (2013.01); A61M 5/19 (2013.01) (22) Filed: Mar. 31, 2015 (57) ABSTRACT The present invention relates to a prodrug or a pharmaceuti Related U.S. Application Data cally acceptable salt thereof, comprising a drug linker conju (63) Continuation of application No. 13/574,092, filed on gate D-L, wherein D being a biologically active moiety con Oct. 15, 2012, filed as application No. PCT/EP2011/ taining an aliphatic amine group is conjugated to one or more 050821 on Jan. 21, 2011. polymeric carriers via dipeptide-containing linkers L. Such carrier-linked prodrugs achieve drug releases with therapeu (30) Foreign Application Priority Data tically useful half-lives. The invention also relates to pharma ceutical compositions comprising said prodrugs and their use Jan. 22, 2010 (EP) ................................ 10 151564.1 as medicaments. US 2015/0202317 A1 Jul. 23, 2015 DIPEPTDE-BASED PRODRUG LINKERS 0007 Alternatively, the drugs may be conjugated to a car FOR ALPHATIC AMNE-CONTAINING rier through permanent covalent bonds.