Association between Body Surface Area and Prescribed Doses of Guideline-Directed Medications Among International Patients with Heart Failure and Reduced Ejection Fraction

Clinical practice guidelines advocate evidence-based heart failure (HF) medications at guideline-directed doses (GDD) for patients with HF and reduced ejection fraction (HFrEF).1 Despite standardized GDD for all patients with HFrEF, striking differences in doses of HF medications are prescribed in real-world clinical practice; differences that are not fully explained by patient intolerance or known contraindications to up-titration. Dosages are particularly low in HFrEF from Asian countries,2 which has been postulated because Asian patients have smaller body size and greater sensitivity to drugs, thus requiring reduced dosages of medications.2, 3 However, data to support this hypothesis are limited. There are currently no recommendations for dose adjustment based on body size. The combined cohort4 of HF patients with left ventricular ejection fraction ≤35% from ASIAN-HF5 and HF-ACTION6 was used to address the aims in our study. We first describe the usage patterns for HFrEF therapy in regions across Asia, United States (US), Canada, and France. Secondly, we evaluate the association of body surface area (BSA) and medication dose. Finally, we determine whether region affects the association between BSA and medication doses. Doses of HF medications [angiotensin-converting enzyme inhibitors (ACEi)/angiotensin II receptor blockers (ARB), β-blockers, diuretics] at baseline were standardized using equivalents of carvedilol for β-blockers and lisinopril for ACEi.7 Attainment of GDD (yes/no) for β-blockers was defined as ≥50 mg carvedilol and ACEi as ≥20 mg lisinopril equivalents. BSA was calculated according to the Mosteller formula [weight (kg) × height (cm)/3600]1/2. Stepwise forward regression models were used to examine the association between BSA with maximum prescribed doses (as a continuous variable) of β-blockers and ACEi, in addition to contributing factors [heart rate, systolic blood pressure (SBP), estimated glomerular filtration rate (eGFR) and other confounders]. Interaction of BSA with region (US, Canada, France, Northeast Asia, South Asia, and Southeast Asia) for the outcome of GDD was tested. Ethics approvals were obtained from institutional review committee of each participating centre, which conform to the Declaration of Helsinki. Among a combined cohort of 6683 patients with HFrEF (mean age 59 ± 13 years, 23% women), 4543 (68%) were Asian and 2140 (32%) were White or Black (non-Asian) from North America/Europe. Asians vs. non-Asians were similar in age, New York Heart Association class III/IV (36%), prevalence of coronary artery disease (51%) and chronic kidney disease (45%), but were more likely to have diabetes (42% vs. 32%, P < 0.001) and less likely to have hypertension (51% vs. 59%, P < 0.001) (online supplementary Table S1). Compared to non-Asians, Asians were less likely to be prescribed β-blockers (78% vs. 95%) and ACEi/ARBs (76% vs. 94%). Median daily carvedilol and lisinopril dose equivalents in Asians were half of those in non-Asians [12.5 (interquartile range-IQR 6.25–25) mg vs. 25 (IQR 13–50) mg and 10 (IQR 5–20) mg vs. 20 (IQR 10–40) mg, respectively]. However, furosemide daily dosages were similar (40 mg) in both sub-cohorts. There was significant variability in doses across regions (Table 1), with lowest mean doses in East Asia and South Asia vs. other regions. Among Asians, only 14% achieved GDD for β-blockers, 22% for ACEi compared to 37% and 40%, respectively, in non-Asians. In general, Asians had lower BSA compared to non-Asians (1.74 ± 0.22 vs. 2.11 ± 0.29 m2) (Table 1). BSA was strongly related to medication dose [β-coefficients per unit increment = 21.51 (standard error-SE 0.909) for β-blockers;14.43 (SE 0.89) for ACEi; P < 0.001], as well as odds of attaining GDD [odds ratio per unit increase in BSA = 9.74, 95% confidence interval (CI) 7.89–12.02 for β-blockers and 4.64, 95% CI 3.78–5.70 for ACEi; P < 0.001]. These associations persisted even after multivariable adjustment. In the multivariable models, geographic region showed strong associations with doses of β-blockers and ACEi, independent of BSA, SBP, heart rate, eGFR, and co-morbidities. Furthermore, region modified the association of BSA with β-blocker (Pinteraction < 0.001) and with ACEi doses (Pinteraction = 0.008). When stratified by region (Figure 1), BSA was positively associated with β-blocker dose in the US, South Asia and Southeast Asia (all P ≤ 0.035), but only in the US (β-coefficient 7.41, SE 2.2, P < 0.001) for ACEi dose. Within each region, dosages were influenced by other factors, e.g. SBP, eGFR and β-blocker dose for ACEi dose (all P ≤ 0.001) (Figure 1). Higher doses of β-blockers and ACEi showed an inverse graded correlation with crude 1-year mortality (all P < 0.001). Despite the widely held perception that Asian patients need lower dosages of medications, studies comparing dosage patterns of HF medications in Asians vs. non-Asians are scarce.2, 8, 9 In our analysis, we found larger body size was associated with maximum prescribed dosage; however, geographic region was a strong modifier of that association. Notably, while healthcare providers might be less inclined to titrate β-blocker and ACEi doses in various regions based on BSA of patients, our findings suggest that differences in patients' risk factor profiles (SBP, heart rate, eGFR) and regional practice, rather than body size per se, may influence HF dosage patterns. Other factors may contribute to lower doses in Asians. Emerging studies suggest that persistent cough is a common side-effect associated with ACEi among Asian ethnicities,3 with incidence of ACEi-induced persistent cough occurring in one-third of patients in a multi-ethnic Asian cohort (particularly Chinese).3 Genetic differences could partly explain the variation in dosing patterns of ACEi observed across the regions and multi-ethnicities.10, 11 For β-blockers, low doses of carvedilol are commonly prescribed in Japan,2 following findings of lower doses being tested in the Japanese randomized, placebo-controlled double-blind MUCHA trial.9 Enhanced enrolment of patients from different regions in ongoing trials/registries will therefore be necessary to better understand the true optimal dosing benefits of HF medications in real-world populations. Limitations to our study include selection bias inherent in combining an observational registry with a clinical trial population (as a benchmark for best practices). There was incomplete categorization of ARB and mineralocorticoid receptor antagonist dosages, hence its exclusion from the analysis. As such, conclusions between medication dosages and patient outcomes cannot be made. In summary, we found significant regional variation in HF medication dosages among HFrEF patients, with lower doses being prescribed in Asia. While body size was related to HF medication dosages, geographic region modified this association and remained a strong independent predictor of prescribed doses. Greater understanding of the regional differences in dosage patterns and their association with patient outcomes is needed. We thank all investigators and participants of HF-ACTION and ASIAN-HF for their contribution. The ASIAN-HF study is supported by grants from Boston Scientific Investigator Sponsored Research Program, National Medical Research Council of Singapore, A*STAR Biomedical Research Council ATTRaCT program, and Bayer. The HF-ACTION trial was supported by grants from the National Heart, Lung and Blood Institute (USA) (NCT00047437). Conflict of interest: A.S. is supported by the Alberta Innovates Health Solution Fellowship and has received research and personal support from Takeda, Boehringer Ingelheim, BMS/Pfizer, Merck, Akcea Pharmaceutical, and Roche Diagnostics. A.M.R. has received research support from Boston Scientific, Bayer, AstraZeneca, Medtronic, Roche Diagnostics, Abbott Laboratories, Thermo Fisher, Critical Diagnostics; and has consulted for Bayer, Novartis, Merck, AstraZeneca, Roche Diagnostics. C.S.P.L. is supported by a Clinician Scientist Award from the National Medical Research Council Singapore; has received research support from Boston Scientific, Medtronic, and Vifor Pharma; and has consulted for Bayer, Novartis, Takeda, Merck, AstraZeneca, Janssen Research & Development, LLC and Menarini; has served on the Clinical Endpoint Committee for DC Devices. The other authors have nothing to disclose. China: Fuwai Hospital: Shu Zhang (Country PI), Xiaohan Fan, Keping Chen. Ruijin Hospital, Shanghai Jiaotong University: Liqun Wu, Yucai Xie, Qi Jin, Tianyou Ling. The First Affiliated Hospital with Nanjing Medical University: Xinli Li, Fang Zhou, Yanli Zhou, Dongjie Xu, Haifeng Zhang. Zhongshan Hospital Fudan University: Yangang Su, Xueying Chen, Shengmei Qin, Jingfeng Wang, Xue Gong, Zhaodi Wu. Hong Kong: The Chinese University of Hong Kong: Cheuk Man Yu (Country PI). India: CARE Hospital: Calambur Narasimhan (Country PI), B.K.S. Sastry, Arun Gopi, K. Raghu, C. Sridevi, Daljeet Kaur. Care Institute of Medical Sciences: Ajay Naik, Keyur Parikh, Anish Chandarana, Urmil Shah, Milan Chag, Hemang Baxi, Satya Gupta, Jyoti Bhatia, Vaishali Khakhkhar, Vineet Sankhla, Tejas Patel, Vipul Kapoor. Hero Dayanand Medical College Heart Institute: Gurpreet Singh Wander, Rohit Tandon. Medanta-The Medicity: Vijay Chopra, Manoj Kumar, Hatinder Jeet Singh Sethi, Rashmi Verma, Sanjay Mittal. Sir Ganga Ram Hospital: Jitendra Sawhney, Manish Kr. Sharma. Westfort Hi-Tech Hospital Ltd: Mohanan Padinhare Purayil. Indonesia: Rumah Sakit Jantung dan Pembuluh Darah Harapan Kita: Bambang Budi Siswanto (Country PI). RS Dr Hasan Sadikin: Pintoko Tedjokusumo, Erwan Martanto, Erwinanto. RS Khusus Jantung Binawaluya: Muhammad Munawar, Jimmy Agung Pambudi. RS Siloam Karawaci: Antonia Lukito, Ingrid Pardede, Alvin Thengker, Vito Damay, Siska Suridanda Danny, Rarsari Surarso. Japan: Nippon Medical School: Wataru Shimizu (Country PI), National Cerebral and Cardiovascular Center: Takashi Noda, Ikutaro Nakajima, Mitsuru Wada, Kohei Ishibashi. Kinki University Hospital Cardiovascular Center: Takashi Kurita, Ryoubun Yasuoka. Nippon Medical School Hospital: Kuniya Asai, Kohji Murai, Yoshiaki Kubota, Yuki Izumi. Toho University Omori Medical Center: Takanori Ikeda, Shinji Hisatake, Takayuki Kabuki, Shunsuke Kiuchi, Tokyo Women's Medical University: Nobuhisa Hagiwara, Atsushi Suzuki, Tsuyoshi Suzuki. Korea: SeJong General Hospital: Sang-Weon Park (Country PI), Suk Keun Hong, SookJin Lee, Lim Dal Soo, Dong-Hyeok Kim. Korea University Anam Hospital: Jaemin Shim, Seong-Mi Park, Seung-Young Roh, Young Hoon Kim, Mina Kim, Jong-Il Choi. Korea University Guro Hospital: Jin Oh Na, Seung Woon Rha, Hong Seog Seo, Dong Joo Oh, Chang Gyu Park, Eung Ju Kim, Sunki Lee, Severance Hospital, Yonsei University Health System: Boyoung Joung, Jae-Sun Uhm, Moon Hyoung Lee, In-Jeong Cho, Hui-Nam Park. Chonnam National University Hospital: Hyung-Wook Park, Jeong-Gwan Cho, Namsik Yoon, KiHong Lee, Kye Hun Kim. Korea University Ansan Hospital: Seong Hwan Kim. Malaysia: Hospital Queen Elizabeth II: Houng Bang Liew (Country PI), Sahrin Saharudin, Boon Cong Beh, Yu Wei Lee, Chia How Yen, Mohd Khairi Othman, Amie-Anne Augustine, Mohd Hariz Mohd Asnawi, Roberto Angelo Mojolou, You Zhuan Tan, Aida Nurbaini Arbain, Chii Koh Wong. Institut Jantung Negara: Razali Omar, Azmee Mohd Ghazi, Surinder Kaur Khelae, David S.P. Chew, Lok Bin Yap, Azlan Hussin, Zulkeflee Muhammad, Mohd. Ghazi Azmee. University Malaya Medical Centre: Imran Zainal Abidin, Ahmad Syadi Bin Mahmood Zhudi, Nor Ashikin Md Sari, Ganiga Srinivasaiah Sridhar, Ahmad Syadi Mahmood Zuhdi. Muhammad Dzafir Ismail. Sarawak General Hospital Heart Centre: Tiong Kiam Ong, Yee Ling Cham, Ning Zan Khiew, Asri Bin Said, Alan Yean Yip Fong, Nor Hanim Mohd Amin, Keong Chua Seng, Sian Kong Tan, Kuan Leong Yew. Philippines: Manila Doctors Hospital: Eugenio Reyes (Country PI), Jones Santos, Allan Lim. Makati Medical Center: Raul Lapitan, Ryan Andal, Philippine Heart Center: Eleanor Lopez. Singapore: National Heart Centre Singapore: Carolyn S.P. Lam (Country PI), Kheng Leng David Sim, Boon Yew Tan, Choon Pin Lim, Louis L.Y. Teo, Laura L.H. Chan. National University Heart Centre: Lieng Hsi Ling, Ping Chai, Ching Chiew Raymond Wong, Kian Keong Poh, Tan Tock Seng Hospital: Poh Shuan Daniel Yeo, Evelyn M. Lee, Seet Yong Loh, Min Er Ching, Deanna Z.L. Khoo, Min Sen Yew, Wenjie Huang. Changi General Hospital-Parent: Kui Toh Gerard Leong, Jia Hao Jason See, Yaozong Benji Lim, Svenszeat Tan, Colin Yeo, Siang Chew Chai. Singapore General Hospital-Parent: Fazlur Rehman Jaufeerally, Haresh Tulsidas, Than Aung. Khoo Teck Puat Hospital: Hean Yee Ong, Lee Fong Ling, Dinna Kar Nee Soon. Taiwan: Mackay Memorial Hospital, Taipei, Taiwan: Chung-Lieh Hung (Country PI), Hung-I Yeh, Jen-Yuan Kuo, Chih-Hsuan Yen. National Taiwan University Hospital: Juey-Jen Hwang, Kuo-Liong Chien, Ta-Chen Su, Lian-Yu Lin, Jyh-Ming Juang, Yen-Hung Lin, Fu-Tien Chiang, Jiunn-Lee Lin, Yi-Lwun Ho, Chii-Ming Lee, Po-Chih Lin, Chi-Sheng Hung, Sheng-Nan Chang, Jou-Wei Lin, Chih-Neng Hsu. Taipei Veterans General Hospital: Wen-Chung Yu, Tze-Fan Chao, Shih-Hsien Sung, Kang-Ling Wang, Hsin-Bang Leu, Yenn-Jiang Lin, Shih-Lin Chang, Po-Hsun Huang, Li-Wei Lo, Cheng-Hsueh Wu. China Medical University Hospital: Hsin-Yueh Liang, Shih-Sheng Chang, Lien-Cheng Hsiao, Yu-Chen Wang, Chiung-Ray Lu, Hung-Pin Wu, Yen-Nien Lin, Ke-Wei Chen, Ping-Han Lo, Chung-Ho Hsu, Li-Chuan Hsieh. Thailand: Ramathibodi Hospital: Tachapong Ngarmukos (Country PI), Mann Chandavimol, Teerapat Yingchoncharoen, Prasart Laothavorn. Phramongkutklao Hospital:Waraporn Tiyanon. Maharaj Nakorn Chiang Mai Hospital: Wanwarang Wongcharoen, Arintaya Phrommintikul. 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