Chi-Jung Tai1, Mohamed El-Shazly2, Yi-Hsin Yang3, Yi-Hong Tsai4, Dezső Csupor5, Judit Hohmann6, Yang-Chang Wu7, Tzyy-Guey Tseng8, Fang-Rong Chang9, Hui-Chun Wang10. 1. Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan; Department of Family Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan; Department of Family Medicine, Pingtung Hospital, Ministry of Health and Welfare, Pingtung, 90054, Taiwan. Electronic address: taichijung@gmail.com. 2. Department of Pharmacognosy, Faculty of Pharmacy, Ain- Shams University, Organization of African Unity Street, Abassia, Cairo, 11566, Egypt; Department of Pharmaceutical Biology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, 16482, Egypt. Electronic address: elshazly444@googlemail.com. 3. School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan; National Institute of Cancer Research, National Health Research Institutes, Tainan, 704, Taiwan. Electronic address: yhyang@nhri.edu.tw. 4. Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan. Electronic address: lyph0719@hotmail.com. 5. Department of Pharmacognosy, Faculty of Pharmacy, University of Szeged, Szeged H, 6720, Hungary; Department of Clinical Pharmacy, Faculty of Pharmacy, University of Szeged, Szeged H, 6725, Hungary. Electronic address: csupor.dezso@pharmacognosy.hu. 6. Department of Pharmacognosy, Faculty of Pharmacy, University of Szeged, Szeged H, 6720, Hungary. Electronic address: hohmann@pharm.u-szeged.hu. 7. Graduate Institute of Integrated Medicine, China Medical University, Taichung, 40402, Taiwan; Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, 40402, Taiwan; Department of Biotechnology, College of Medical and Health Science, Asia University, Taichung, 41354, Taiwan. Electronic address: yachwu@gmail.com. 8. Department of Family Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan. Electronic address: tzyyguey@gmail.com. 9. Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan; Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, 80424, Taiwan; Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan. Electronic address: aaronfrc@kmu.edu.tw. 10. Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan; Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, 80424, Taiwan; Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan. Electronic address: wanghc@kmu.edu.tw.
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE: Fuzi, Aconiti Lateralis Radix Praeparata, is widely used in Traditional Chinese Medicine (TCM) for the treatment of acute heart failure (HF) for 2000 years. However, the clinical evidence of Fuzi in the treatment of chronic HF is limited, especially when used in combination with Western medications. MATERIALS AND METHODS: This population-based propensity score (PS)-matched cohort study aimed to evaluate the effectiveness of Fuzi on the chronic HF. From 4753 chronic HF patients who had used TCM herbal medicine, we performed 1:1 PS matching and selected target patients with (n = 921) and without (n = 921) Fuzi use for further analysis. The primary outcomes were all-cause mortality and composite cardiovascular (CV) outcomes. Hazard ratio (HR) was calculated by Cox proportional hazard regression and the competing risk analysis. The dose-response relationship and the association between the initiation of TCM herbal medicine and the primary outcomes were evaluated by restricted cubic spline (RCS) functions. RESULTS: There was no difference in all-cause mortality (HR, 0.99; 95% confidence interval [CI], 0.76-1.27) and composite CV outcomes (HR, 0.96; 95% CI, 0.84-1.11) between the Fuzi user and non-user groups. For CV safety issue, the result showed that Fuzi use was not associated with a higher risk of cardiac arrhythmias (HR, 1.03; 95% CI, 0.83-1.29). The dose-response relationship showed that Fuzi cumulative dose (≥150g) was associated with lower composite CV risk (HR, 0.76; 95% CI, 0.59-0.99). In addition, the RCS model showed that late initiation (≥2.5 years) of TCM herbal drugs in chronic HF patients had a higher risk of all-cause mortality (HR, 1.81; 95%CI, 1.07-3.08). CONCLUSIONS: This study is the first real-world evidence to demonstrate the effect of Fuzi combined with routine HF treatment. Importantly, the result indicated that long-term Fuzi use had a significant benefit in preventing cardiovascular events. The late initiation of TCM herbal drugs was associated with a higher risk of all-cause mortality. Further clinical trials are needed to support or undermine the assumption of using Fuzi and current Western medications to treat chronic HF.
ETHNOPHARMACOLOGICAL RELEVANCE: Fuzi, Aconiti Lateralis Radix Praeparata, is widely used in Traditional Chinese Medicine (TCM) for the treatment of acute heart failure (HF) for 2000 years. However, the clinical evidence of Fuzi in the treatment of chronic HF is limited, especially when used in combination with Western medications. MATERIALS AND METHODS: This population-based propensity score (PS)-matched cohort study aimed to evaluate the effectiveness of Fuzi on the chronic HF. From 4753 chronic HF patients who had used TCM herbal medicine, we performed 1:1 PS matching and selected target patients with (n = 921) and without (n = 921) Fuzi use for further analysis. The primary outcomes were all-cause mortality and composite cardiovascular (CV) outcomes. Hazard ratio (HR) was calculated by Cox proportional hazard regression and the competing risk analysis. The dose-response relationship and the association between the initiation of TCM herbal medicine and the primary outcomes were evaluated by restricted cubic spline (RCS) functions. RESULTS: There was no difference in all-cause mortality (HR, 0.99; 95% confidence interval [CI], 0.76-1.27) and composite CV outcomes (HR, 0.96; 95% CI, 0.84-1.11) between the Fuzi user and non-user groups. For CV safety issue, the result showed that Fuzi use was not associated with a higher risk of cardiac arrhythmias (HR, 1.03; 95% CI, 0.83-1.29). The dose-response relationship showed that Fuzi cumulative dose (≥150g) was associated with lower composite CV risk (HR, 0.76; 95% CI, 0.59-0.99). In addition, the RCS model showed that late initiation (≥2.5 years) of TCM herbal drugs in chronic HF patients had a higher risk of all-cause mortality (HR, 1.81; 95%CI, 1.07-3.08). CONCLUSIONS: This study is the first real-world evidence to demonstrate the effect of Fuzi combined with routine HF treatment. Importantly, the result indicated that long-term Fuzi use had a significant benefit in preventing cardiovascular events. The late initiation of TCM herbal drugs was associated with a higher risk of all-cause mortality. Further clinical trials are needed to support or undermine the assumption of using Fuzi and current Western medications to treat chronic HF.