Chinese Herbal Medicine as an Adjunctive Therapy Ameliorated the Incidence of Hypotension in Patients with End-Stage Renal Disease: A Nationwide Population-Based Cohort Study

doi:10.21203/rs.3.rs-2438073/v1

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Chinese Herbal Medicine as an Adjunctive Therapy Ameliorated the Incidence of Hypotension in Patients with End-Stage Renal Disease: A Nationwide Population-Based Cohort Study

https://doi.org/10.21203/rs.3.rs-2438073/v1

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Hypotension during hemodialysis (HD) is a common complication of dialytic patients that imposes an enormous burden on the healthcare system. A few studies show that Chinese herbal medicine (CHM) treatments confer a protective effect on hypotension in HD patients, but the long-term impact remains unclear. This study investigated the adjuvant therapy of CHM in HD patients to prevent the risk of hypotension in HD patients. We extracted data from the Taiwanese National Health Insurance Registry for Catastrophic Illness Patient Database (NHI_RCIPD) from 2008 and 2018 and analyzed them using multivariate Cox proportional hazard regression models. After 1:1 frequency-matching by age, index date, HD duration, monthly income, residential area, and medical comorbidities, 3820 HD patients who were using CHM and 3820 who were not using CHM were identified as CHM users and CHM non-users, respectively. The occurrence of taking vasopressors was identified as intradialytic hypotension (IDH). The Kaplan–Meier method was used to estimate the cumulative incidence curves of vasopressors of the subjects during the follow-up period. During 12 years of follow-up, 1710 CHM users and 1927 CHM non-users were prescribed vasopressors, representing IDH incidence rates of 119.8 and 246.2 per 1000 person-years, respectively. CHM users had significantly lower IDH risk compared with CHM non-users (adjusted HR = 0.51; 95%CI = 0.48, 0.55). A markedly predominant effect was observed in those receiving CHM for more than 180 days (adjusted HR = 0.43; 95%CI = 0.39, 0.48). Lower vasopressor use and IDH risk among HD patients correlated with the use of CHM treatments. Further studies about specific CHM modalities or medications for IDH are still needed.

Health sciences/Diseases

Health sciences/Nephrology

Health sciences/Medical research

Biological sciences/Physiology

Biological sciences/Physiology/Kidney

Health sciences/Cardiology/Cardiovascular biology

End-stage renal disease

Hypotension

Vasopressor

Traditional Chinese medicine

Population-based cohort study

Chronic kidney disease (CKD) is a growing health problem in the world and is managed by life-saving renal replacement therapy^1,2. Hemodialysis (HD) is the treatment of choice for most patients to replace renal function, but it has many complications³. Hypotension during HD is common and increases morbidity and mortality⁴. It can also lead to deterioration of patients’ quality of life⁵ and is associated with vascular access thrombosis, mesenteric ischemia, cardiovascular events⁶, and decreased dialysis adequacy⁵. In a US-based cohort study of 112,013 incident HD patients, Chou et al. evaluated the association between nadir intradialytic systolic blood pressure (SBP) and death risk⁷. Patients with nadir intradialytic systolic BP below 90 had a 57% higher mortality risk at 5-year follow-up, compared with nadir intradialytic SBP of 110–120 mmHg⁸. Other researchers have found that patients with intradialytic SBP decline > 30 mm Hg had greater mortality⁷. Therefore, hypotension requires active intervention when symptoms present. Drastic measures may include stopping ultrafiltration or HD entirely, assuming the Trendelenburg position, administering BP-raising drugs, and supplemental oxygen⁹.

Midodrine is a prodrug that is widely used by clinicians to raise BP in HD patients¹⁰. It acts on the α1-adrenergic receptor of the vascular system and rapidly increases vascular tone to elevate BP. One dose is generally 2.5 to 10 mg 15–30 minutes before dialysis. In a meta-analysis including 117 patients from 10 studies, midodrine was associated with a 13.3mm Hg (95% CI 8.6, 18.0) higher nadir SBP, and more than half of previous studies reported improved intradialytic hypotension (IDH) symptoms¹¹. In a small retrospective study of 5 HD patients with poor heart function and low BP, Bergman showed that midodrine could relieve the symptoms of heart failure (HF)¹².

Other vasopressors, such as amezinium, etilefrine, carnitine and DDAVP, are also commonly used¹³. In general, the evidence base for these strategies is weak, with most studies being small and short in duration¹⁴. Even though these vasopressors are relatively safe and effective for acute use, a major concern is whether the patient's prognosis will be affected. Brunelli et al. performed a retrospective review of 1,046 patients and reported that midodrine was associated with high risk of death¹⁵. In a cohort study of nationwide renal data registry of all dialysis patients (n = 232,226) in Japan, patients prescribed vasopressors had higher risks of cardiovascular disease (CVD) and infection-caused deaths than did those in the control group¹⁶. Although controversy exists, the prescription of vasopressors can indicate that patients with end-stage renal disease (ESRD) are experiencing hypotension and need to be properly managed.

Taiwan has become the country with the highest prevalence of ESRD since implementation of the National Health Insurance (NHI) program in 1995. The comprehensive coverage of the NHI program provides integrated medical recording of registered participants, such as Western medicine (WM), dental medicine, and traditional Chinese medicine (TCM) services¹⁷. The NHI Research Database (NHIRD) provides an opportunity to supplement existing evidence for the use of long-established medicines in health care decision making¹⁸. TCM is commonly used by the Chinese population, with prevalence of 45.3% among patients with CKD¹⁹. There are reports of the efficacy of Chinese herbal medicine (CHM) in the treatment of HD-related complications such as hypotension, muscle cramps, and headache in Asian countries²⁰. Given the lack of previous literature results on the use of TCM in the ESRD population, we conducted a case–control study by using the NHIRD to determine the protective effects of CHM in HD patients prescribed vasopressors, determine the prescribing pattern of common CHM, and analyze its relationship with hypotension risk.

Ethical considerations

The study was conducted in accordance with the Declaration of Helsinki, we confirmed that all research was performed in accordance with relevant guidelines/regulations, and the study was approved by the Institutional Review Board of the Research Ethics Committee of China Medical University Hospital [CMUH110-REC1-038 (CR-1)], which waived the need for informed consent owing to the retrospective design and utilization of encrypted patient data.

Data source

Taiwan’s NHIRD, which contains over 99% of Taiwan resident’s registration files and original claim data, was the data source of this study. The database was first established in 1995, when the government of Taiwan launched the NHI program to improve the medical system and national health. The original claim data consist of demographic characteristics of the insured, details of inpatient and outpatient orders, medicines, and treatments. To identify patients with ESRD, we used the linked registry of the Registry for Catastrophic Illness Patient Database (RCIPD), which was derived from the NHIRD of Taiwan. The medical records were based on the International Classification of Diseases, 9th and 10th editions, Clinical Modification (ICD-9-CM and ICD-10-CM), and medicines prescribed.

Study population

Patients with newly diagnosed ESRD (ICD-9: 585, ICD-10: N18.4, N18.5, N18.6, N18.9) from the registry of catastrophic illness and with special treatment codes for HD (58001C, 58014C, 58018C, 58019C, 58020C, 58021C, 58022C, 58023C, 58024C, 58025C, 58027C, 58029C, 58030B, 69006C) from 2008 to 2018 were the study subjects of this retrospective cohort study, and the follow-up period was from 2008 to 2019. We divided the patients into two groups. Those who had received CHM for at least 30 days were defined as CHM users, and those who had not received CHM or had received it for less than 30 days were defined as CHM non-users²¹. The index date of CHM users was defined as the first prescription date of CHM after a diagnosis of ESRD, and that of the CHM non-users was a random date after the diagnosis date of ESRD. CHM non-users were matched to the case cohort by gender, age, year of the index date, HD duration, monthly income, residential area, and Charlson Comorbidity Index (CCI) to develop the control cohort. Propensity source matching with a ratio of 1:1 was applied. The exclusion criteria of this study included age under 40 years, peritoneal dialysis or kidney transplant before HD, vasopressor use before HD, vasopressor use for less than two weeks after HD, and missing data of sex or age. A flowchart illustrating the participant selection for the study is shown in Fig. 1.

Main outcome and covariates

The occurrence of taking BP-raising drugs was the main outcome in our research. Vasopressors included midodrine (C01CA17), etilefrine (C01CA01), minirin (DDAVP) (H01BA02) and urokinase (B01AD04). We utilized CCI, which is an assessment tool designed to evaluate comorbidity levels by considering both the number and severity of 19 types of diseases, to define the related comorbidities, and we further categorized the scores into 4 levels (≤ 3, 4–6, 7–9, and > 9). The covariates, including gender, age (40–64, ≥ 65), duration of HD (< 1, 1–5, and > 5), monthly income (low, medium, and high), and residential area (urban, suburban, and rural), were compared between subjects with and without CHM use.

Statistical analysis

The categorical data of the study participants are presented as number and percentage, and the continuous variables are presented as mean and standard deviation (SD). To compare the differences in the baseline characteristics between the two cohorts, the categorical variables were analyzed with the chi-squared test, and the Student’s t test was used to assess the continuous variables. The incidence rates of BP-raising drugs for both cohorts were calculated as the number taking BP-raising drugs divided by the total sum of the follow-up year (per 1,000 person-years). The unadjusted and adjusted hazard ratios (cHR and aHR) with corresponding 95% confidence intervals (CIs) for the risk between two cohorts were estimated by Cox proportional hazard regression model. The Kaplan–Meier method was used to estimate the cumulative incidence curves of vasopressors of the subjects during the follow-up period, and the log-rank test was used to compare the difference. All statistical analyses were performed in SAS version 9.4, and plots were plotted in the software R version 4.0. Statistical significance was set at p < 0.05.

A total of 7,640 subjects were included in the study, with 3,820 patients in each group. Table 1 lists the demographic and clinical characteristics, including gender, age, duration of HD, monthly income, residential area, and event number. These data were not significantly different between CHM users and CHM non-users. The proportions of male patients were higher than those of female patients in both cohorts. Most of the patients were aged 40 to 64 years, and the mean age of CHM users (63.4 ± 10.6) was younger than that of the non-CHM cohort (64.7 ± 12.1). As for the use of vasopressors, the CHM user group had significantly fewer subjects who received midodrine and urokinase compared to the CHM non-user group. Table 2 demonstrates the risk of vasopressor use after the division of patients with and without CHM use into three groups according to the number of days of use, including patients without use, use for 30–180 days, and use for more than 180 days. With CHM non-users as the reference group, patients prescribed CHM for 30–180 days had lower risk of vasopressor use by 0.54 folds (95%CI = 0.51, 0.58), and patients prescribed CHM for more than 180 days had lower risk of vasopressor use by 0.43 folds (95%CI = 0.39, 0.48). As Fig. 2 presents, the cumulative incidences of vasopressor use in patients taking CHM for 30–180 days and for more than 180 days were both significantly lower than those of CHM non-users.

Table 1

Demographic and clinical characteristics of HD patients with and without CHM.
Variable	Chinese Herbal medicine
	Users, N (%) N = 3,820		Non-users, N (%) N = 3,820		p value
	N	%	N	%
Gender					0.91
Female	1,790	46.9	1,785	46.7
Male	2,030	53.1	2,035	53.3
Age, y					0.93
40–64	2,078	54.4	2,074	54.3
≥ 65	1,742	45.6	1,746	45.7
Mean ± SD, y^a	63.4	10.6	64.7	12.1	< 0.001
HD duration, y					0.94
< 1	2,744	71.8	2,741	71.8
1–5	985	25.8	992	26.0
> 5	91	2.38	87	2.28
Monthly income					0.98
Low	1,146	30.0	1,149	30.1
Medium	1,971	51.6	1,975	51.7
High	703	18.4	696	18.2
Residential area					0.99
Urban	334	8.74	331	8.66
Suburban	1,536	40.2	1,540	40.3
Rural	1,950	51.1	1,949	51.0
Baseline CCI score					0.24
≤ 3	1,868	48.9	1,810	47.4
4–6	1,129	29.6	1,114	29.2
7–9	748	19.6	811	21.2
> 9	75	1.96	85	2.23
Outcome:
Midodrine	1,109	29.0	1,253	32.8	< 0.001
Etilefrine	7	0.18	8	0.21	0.80
DDAVP	401	10.5	455	11.9	0.05
Urokinase	703	18.4	830	21.7	< 0.001
Chi-squared test; ^a t-test.

Table 2

IRs and crude and adjusted HRs with 95% CIs of vasopressors between HD patients with and without CHM treatment.
Variable	Event	Person-Years	IR	Crude	Adjusted^#
Variable	n = 3637	Person-Years	1,000 person-years	HR (95% CI)	HR (95% CI)
CHM non-users	1,927	7,826	246.2	1 (Reference)	1 (Reference)
CHM users
30–180 days	1,258	9,682	129.9	0.57 (0.53, 0.61)***	0.54 (0.51,0.58)***
> 180 days	452	4,593	98.4	0.45 (0.41, 0.50)***	0.43 (0.39,0.48)***
Adjusted for gender, age, HD duration, monthly income, residential area, and baseline CCI score
Abbreviation: CHM, Chinese Herbal Medicine; CI, Confidence Interval; HR, Hazard Ratio; IR, Incidence Rate;
*** < 0.001

As Table 3 shows, after adjustments for gender, age, HD duration, monthly income, residential area, and baseline CCI score, CHM users had a lower risk of vasopressor use (adjusted HR = 0.51; 95%CI = 0.48, 0.55) than controls. The risk of vasopressor use for patients aged more than 65 years was 1.61 times that of those aged 40–64 (95%CI = 1.51, 1.73). In addition, the hazard ratio of vasopressor use of subjects with HD duration of less than 1 year was higher (adjusted HR = 1.51; 95%CI = 1.39, 1.64) than those with HD durations of 1 to 5 years. Compared with patients with high monthly income, those with low monthly income had a higher risk of vasopressor use (adjusted HR = 1.18; 95%CI = 1.07, 1.30). As for CCI scored, the risk of vasopressor use for subjects with scores of 4 to 6 (adjusted HR = 1.24; 95%CI = 1.14, 1.34), those with scores of 7 to 9 (adjusted HR = 1.45; 95%CI = 1.33, 1.58), and those with CCI scores of more than 9 (adjusted HR = 2.31; 95%CI = 1.87, 2.84) were higher than those of subjects with CCI scores of less than 3.

Table 3

IRs and crude and adjusted HRs with 95% CIs of vasopressors between HD patients with and without CHM treatment.
	Event	PY	Rate ^†	Crude HR (95% CI)	Adjusted^# HR (95% CI)
CHM
No	1,927	7,826	246.2	1.00	1.00
Yes	1,710	14,275	119.8	0.53 (0.50, 0.57)***	0.51 (0.48, 0.55)***
Age, y
40–64	1,831	14,162	129.3	1.00	1.00
> 65	1,806	7940	227.5	1.63 (1.52, 1.74)***	1.61 (1.51, 1.73)***
Gender
Female	1,798	10,595	169.7	1.08 (1.01, 1.15)*	1.06 (0.99, 1.13)
Male	1,839	11,507	159.8	1.00	1.00
HD duration, y
< 1	2,826	15,510	182.2	1.49 (1.38, 1.62)***	1.51 (1.39, 1.64)***
1–5	763	6,221	122.7	1.00	1.00
> 5	48	371	129.3	0.93 (0.70, 1.25)	1.01 (0.75, 1.35)
Monthly income
Low	1,126	6,074	185.4	1.20 (1.09, 1.32)***	1.18 (1.07, 1.30)**
Medium	1,858	11,638	159.7	1.06 (0.97, 1.16)	1.04 (0.95, 1.13)
High	653	4,391	148.7	1.00	1.00
Residential area
Urban	323	1,761	183.4	1.11 (0.99, 1.25)	1.05 (0.93, 1.18)
Suburban	1,470	8,835	166.4	1.03 (0.96, 1.11)	1.02 (0.95, 1.09)
Rural	1,844	11,506	160.3	1.00	1.00
Baseline CCI score
< 3	1,732	12,487	138.7	1.00	1.00
4–6	1,063	5,925	179.4	1.23 (1.14, 1.33)***	1.24 (1.14, 1.34)***
7–9	748	3,428	218.2	1.42 (1.31, 1.55)***	1.45 (1.33, 1.58)***
> 9	94	262	358.6	2.22 (1.81, 2.74)***	2.31 (1.87, 2.84)***
CI, confidence interval; HR, hazard ratio; PY, person-years;
^† Incidence rate per 1,000 person-years;
^# Multivariable analysis including gender, age, HD duration, monthly income, residential area, and baseline CCI score
p < 0.01, * < 0.001.

As shown as Table 4, subjects who took CHM had a lower risk of using different types of BP-raising drugs such as midodrine (adjusted HR = 0.52; 95%CI = 0.48, 0.57), DDAVP (adjusted HR = 0.50; 95%CI = 0.44, 0.57) or urokinase (adjusted HR = 0.50; 95%CI = 0.45, 0.55) than those who did not. Furthermore, among female or male patients, the risk of outcome was lower in CHM users than in CHM non-users (female: adjusted HR = 0.52; 95%CI = 0.47, 0.57; male: adjusted HR = 0.50; 95%CI = 0.46, 0.55). In both age groups, the CHM cohort had lower hazard ratios than those of the controls (40–64: adjusted HR = 0.52; 95%CI = 0.47, 0.57; > 65: adjusted HR = 0.48; 95%CI = 0.44, 0.53). Moreover, the risk of vasopressor use was lower in CHM users than in CHM non-users for all CCI score ranges.

Table 4

Incidence rates, hazard ratios, and confidence intervals of vasopressors for HD patients with and without CHM treatment stratified by sex, age, and CCI score.
Variables	CHM users (n = 3,820)			CHM non-users (n = 3,820)			Crude HR (95% CI)	Adjusted^# HR(95% CI)
Variables	Events	Person-years	IR^†	Events	Person-years	IR^†
Total	1,710	14,275	119.8	1,927	7,826	246.2	0.53 (0.50,0.57)***	0.51 (0.48, 0.55)***
Midodrine	1,109		77.7	1253		160.1	0.54 (0.50, 0.59)***	0.52 (0.48, 0.57)***
Etilefrine	7		0.49	8		1.02	0.54 (0.19, 1.49)	0.50 (0.18, 1.38)
DDAVP	401		28.1	455		58.1	0.52 (0.45, 0.60)***	0.50 (0.44, 0.57)***
Urokinase	703		49.3	830		106.1	0.52 (0.47, 0.57)***	0.50 (0.45, 0.55)***
Gender
Female	839	6,847	122.5	959	3,749	255.8	0.53 (0.49, 0.59)***	0.52 (0.47, 0.57)***
Male	871	7,429	117.2	968	4,078	237.4	0.53 (0.49, 0.58)***	0.50 (0.46, 0.55)***
Age
40–64	841	8,910	94.4	990	5,252	188.5	0.54 (0.49, 0.59)***	0.52 (0.47, 0.57)***
> 65	869	5,365	162.0	937	2,575	363.9	0.49 (0.45, 0.54)***	0.48 (0.44, 0.53)***
CCI score
< 3	808	7,969	101.4	924	4,518	204.5	0.54 (0.49, 0.59)***	0.52 (0.47, 0.57)***
4–6	508	3,880	130.9	555	2,045	271.3	0.53 (0.47, 0.59)***	0.50 (0.44, 0.56)***
7–9	347	2,241	154.9	401	1,187	337.9	0.50 (0.43, 0.58)***	0.50 (0.43, 0.58)***
> 9	47	186	252.7	47	76	617.2	0.47 (0.31, 0.73)***	0.46 (0.29, 0.73)***
^† IR per 1,000 person-years; Crude HR represented relative hazard ratio; adjusted HR^# represented adjusted hazard ratio: mutually adjusted for gender, age, HD duration, monthly income, residential area, and baseline CCI score in Cox proportional hazard regression. ∗∗∗ < 0.001.

Table 5 presents the top 10 common single herbs and formulas prescribed for HD patients with CHM. Compared with patients without prescriptions for these herbs and formulas, the risks of BP-raising drugs were all lower. For single herbs, according to the number of users, the first three were Rx. et Rz. Rhei (Da Huang), Rx. Astragali (Huang Qi) and Rx. Salviae miltiorrhizae (Dan Shen), and the hazard ratios of outcomes were 0.40, 0.43 and 0.41, separately. As for formulas, the most common prescription was for Ji Sheng Shen Qi Wan (JSSQW); the second, Ma Zi Ren Wan (MZRW); and the third, Liu Wei Di Huang Wan (LWDHW). The risks of outcomes were 0.42, 0.44 and 0.40, respectively.

Table 5

Ten most common herbs and formulas prescribed for HD patients with CHM.
Herbal formula	Frequency	Number of person-days	Average daily dose (g)	Average duration for prescription (Days)	Crude HR (95% CI)	Adjusted HR^# (95% CI)
Single herb (Latin)
Da Huang (Rx. et Rz. Rhei)	15,357	126,654	0.8	8.2	0.42 (0.38, 0.46)***	0.40 (0.36, 0.44)***
Huang Qi (Rx. Astragali)	9,783	85,486	1.8	8.7	0.44 (0.40, 0.48)***	0.43 (0.39, 0.47)***
Dan Shen (Rx. Salviae Miltiorrhizae)	8,842	75,293	1.4	8.5	0.41 (0.38, 0.46)***	0.41 (0.36, 0.44)***
Dang Gui (Rx. Angelicae Sinensis)	5,222	43,562	1.4	8.3	0.46 (0.41, 0.51)***	0.44 (0.39, 0.49)***
Fu Ling (Poria)	5,518	42,201	1.7	7.6	0.42 (0.38, 0.47)***	0.41 (0.37, 0.46)***
Hou Po (Cx. Magnoliae)	5,528	41,873	1.6	7.6	0.41 (0.37, 0.46)***	0.40 (0.35, 0.44)***
Du Zhong (Cx. Eucommiae)	4,813	40,386	1.4	8.4	0.42 (0.37, 0.47)***	0.40 (0.35, 0.45)***
Mai Men Dong (Rx. Ophiopogonis)	5,307	39,610	1.4	7.5	0.43 (0.39, 0.48)***	0.41 (0.37, 0.45)***
Huang Qin (Rx. Scutellariae)	5,355	38,527	1.7	7.2	0.43 (0.39, 0.48)***	0.42 (0.38, 0.47)***
Jie Geng (Rx. Platycodi)	6,008	37,401	1.4	6.2	0.41 (0.37, 0.45)***	0.39 (0.35, 0.43)***
Formula
Ji Sheng Shen Qi Wan	10,940	97,026	8.9	8.9	0.44 (0.40, 0.48)***	0.42 (0.38, 0.47)***
Ma Zi Ren Wan	7,462	59,575	4.0	8.0	0.47 (0.42, 0.53)***	0.44 (0.40, 0.50)***
Liu Wei Di Huang Wan	6,073	47,864	5.9	7.9	0.42 (0.38, 0.47)***	0.40 (0.36, 0.45)***
Zhi Gan Cao Tang	5,952	47,339	4.3	8.0	0.46 (0.42, 0.52)***	0.44 (0.40, 0.49)***
Zhen Wu Tang	5,525	46,284	7.3	8.4	0.45 (0.41, 0.51)***	0.44 (0.39, 0.49)***
Tian Wang Bu Xin Dan	4,939	39,338	4.3	8.0	0.43 (0.39, 0.49)***	0.42 (0.37, 0.47)***
Gui Pi Tang	3,948	35,206	5.8	8.9	0.44 (0.39, 0.50)***	0.43 (0.38, 0.48)***
Sheng Mai San	4,479	33,671	4.7	7.5	0.50 (0.45, 0.56)***	0.48 (0.43, 0.53)***
Xiang Sha Liu Jun Zi Tang	4,322	31,593	4.9	7.3	0.42 (0.38, 0.48)***	0.40 (0.36, 0.45)***
Ping Wei San	4,766	31,442	4.5	6.6	0.44 (0.40, 0.49)***	0.43 (0.38, 0.47)***
Crude HR represents relative hazard ratio; adjusted HR^# represents adjusted hazard ratio: mutually adjusted for gender, age, HD duration, monthly income, residential area, and baseline CCI score in Cox proportional hazard regression. ∗∗∗ < 0.001.

In this study, we compared the administration of vasopressors in HD patients between CHM users and non-users. The main findings are as follows: (1) CHM users had a lower risk of using vasopressors, even though those with age > 65, female sex, dialysis duration < 1 year, low monthly income and baseline CCI score > 3 had a higher risk of using vasopressors. (2) CHM users who took CHM for 30–180 days and > 180 days had a lower risk of vasopressor use compared to CHM non-users. The protective effect was greater in those taking CHM for more than 180 days. (3) The most commonly used CHM formula and single herb in HD patients with hypotension were JSSQW and Rx. et Rz. Rhei. To our knowledge, large-scale studies evaluating CHM therapy for IDH are lacking. Considering the poor prognosis of IDH, there is a call for validation of the effect of this traditional and complementary strategy. From this nationwide population-based retrospective cohort study, we identified the beneficial role of CHM in reducing hypotension risk in patients with ESRD.

Hypotension is one of the most common complications of HD due to the older age of dialysis patients and the increasing prevalence of comorbidities such as diabetes mellitus and heart failure (HF)²². Prevalence of the chronic form of hypotension, especially for long-term dialyzed patients, is estimated to occur in 3–5% of treated individuals²³. As for the occurrence in the first year of dialysis, it is mostly because the dry weight or the antihypertensive drugs are still being adjusted⁹. According to the Kidney Disease Outcomes Quality Initiative and European Best Practice Guidelines, IDH is defined as a decline in SBP ≥ 20 mm Hg or a decrease in mean arterial pressure by 10 mm Hg, and it is associated with clinical events such as abdominal pain, nausea, vomiting, muscle cramps, dizziness, fatigue, and restlessness²⁴. There is no consensus definition of IDH; however, current definitions based on symptoms and/or interventions are clinically relevant⁹. Vasopressors are usually administered to prevent and control hypotension episodes during HD²⁵. This is why our study used vasopressors to correlate the incidence of hypotension in HD patients.

Previous research reported that ESRD patients with comorbidities such as diabetes mellitus, CVD, poor nutritional status, hypoalbuminaemia, female sex, and age > 65 years had higher risk of IDH. IDH is an independent risk factor for all-cause mortality⁹. CCI is a valid tool for assessing comorbidity and predicting survival in patients with ESRD²⁶. Consistent with a previous study⁹, our results showed that HD patients who were over 65 years old and with a higher CCI index level had higher risks of IDH. Midodrine is the most commonly used vasopressor, and the more it is used, the higher the number of IDH episodes in dialysis patients²⁵. In our study, 30.9% of HD patients used midodrine, and its prescription rate was higher in CHM non-users than in CHM users. This result shows that CHM users are less likely to need to use vasopressors. Further analysis found that those who took CHM for a longer period of time were more likely to reduce the risk of hypotension, and the results tended to be consistent after adjustments for variation. In addition, CHM users had less use of other BP-raising drugs than did CHM non-users.

In the past, due to concerns about aristolochic acid and heavy metal pollution in herbal medicines, the value of CHM for CKD patients was underestimated in Taiwan^27,28. Today, the Ministry of Health and Welfare has banned the import of aristolochic acid-containing medicinal materials, requires TCM pharmaceutical companies to implement the Good Manufacturing Practice (GMP) system to check the quality of CHM products, and regularly checks the heavy metal content and impurities in such products²⁹. Since the NHIRD provides real-world data to support the effect of CHM in CKD, such as slowing the deterioration of renal function³⁰, improving long-term survival¹⁹, and lowering mortality rates³¹, the public’s confidence in TCM has only gradually recovered. The key point is whether to use syndrome differentiation (Zheng in Chinese) based on TCM theory for prescriptions. A previous study by Hsieh et al. found that occasional use of non-prescribed CHM was associated with the risk of CKD in Taiwan³². Compared to CHM non-users, the benefits of Zheng-based CHM prescription in decreasing the 60% risk of ESRD was supported by another retrospective cohort study¹⁹. However, the research on CHM in HD patients is still limited.

From the perspective of TCM, most patients with IDH have a syndrome of Yang deficiency³³. Especially, a deficiency of Yang-qi in Heart and Kidney may explain why clinical doctors choose those herbs as IDH treatments. For example, a recent review²⁰ noted that Shenfu decoction, Sheng Mai San (SMS), ginseng and Rx. Astragali are usually used for IDH to invigorate the Heart- and Kidney-qi. In our study, JSSQW, LWDHW, and Zhen Wu Tang (ZWT) were the most commonly prescribed formulas and could exert the function of activating Kidney Yang to alleviate edema. Previous investigators³⁴ have demonstrated that JSSQW has a nephroprotective effect, as it can lower the levels of uremic toxins and hydroxyl radicals to ameliorate renal damage in a subtotal nephrectomy rat model, as well as significantly reducing interstitial fibrosis and inflammation. JSSQW is also a derivative of LWDHW, which is a fundamental formula to tonify the Kidney and is frequently prescribed for patients with CKD³¹. ZWT has been demonstrated to have a protective effect against renal fibrosis by alleviating oxidative stress³⁵. Three frequently used single herbs, namely, Rx. Astragali, Rx. Salviae miltiorrhizae, and Rx. Angelicae sinensis, were found to reduce the administration of vasopressors in IDH patients. The possible mechanisms involved in reno-protective effects include affecting the VEGF up-regulation to strengthen the density of renal microvasculature³⁶, improving renal microcirculation³⁷, or restoring renal and hepatic erythropoietin production³⁸. It seems that, regardless of the stage of CKD or dialysis-related complications, the direction of TCM in nourishing Kidney-qi is consistent. Certain commonly prescribed inotropic CHMs for nourishing the Heart, such as Zhi Gan Cao Tang (ZGCT), Gui Pi Tang (GPT), and SMS, have been shown to confer benefits to cardiac function^39,40, thus contributing to the reduction of IDH risk. Accordingly, this might be the possible reason that CHM with a BP-raising effect can replace WM.

Patients with such disorders might be at a higher risk of developing constipation, and this may explain the frequent prescription of MZRW, Rx. et Rz. Rhei, or Cx. Magnoliae for IDH in our study. The prevalence rate of constipation in HD is 40–53%⁴¹, and the causes are complex, include limited intake of water, potassium-containing fruits and vegetables, and fiber, as well as use of aluminum and calcium phosphorous binders or iron supplements. Constipation can lead to serious consequences, such as colonic diverticular disease and melanosis coli⁴². It can affect quality of life and place high economic burdens on families and society⁴³. In addition, constipation interferes with the daily feces excretion of 30–40 mg of potassium, which will aggravate hyperkalemia in HD patients⁴⁴. Both TCM and WM are very important in treating constipation in HD patients. However, the correlation between constipation and IDH or the use of vasopressors needs to be further confirmed.

The strengths of this study include the comprehensiveness of the nationwide database, which eliminated the possibility of recall bias in questionnaire assessments and was helpful in the planning, implementation, and assessment of healthcare work, as well as the analysis of the national health status and disease causes. The selection of the study population was rigorous in this study because the RCIPD data were extracted from the NHIRD. The RCIPD registration requires that ESRD patients receive regular HD for more than 3 months from a certified nephrologist. Therefore, the use of vasopressors in this study could correlate with the hypotension of HD patients. It is difficult to define IDH, as there is no accepted safe BP range for HD patients. In our study, the HD patients who needed to take vasopressors were identified as the group most affected by IDH. Thus, the protective effect of CHM in our study could correlate with IDH. Despite these strengths, several limitations should be noted when interpreting the results of the present study. First, it was difficult to obtain medical compliance or other clinical characteristics, including diet, smoking, alcohol consumption and physical activity, from the NHIRD. Thus, the CCI index was used to adjust for putative risk factors in our study. Second, self-paid CHM decoctions or pills, natural herbs, and folk medicine are not reimbursed by the NHI and thus were not analyzed in this study. However, this missing data could possibly have resulted in underestimation of CHM use and weakened the effect of CHM.

In conclusion, HD patients who used CHM as an adjunctive therapy had lower hypotension risk, as indicated by the lower rate of prescription of vasopressors. Among the CHMs explored, JSSQW, MZRW, LWDHW, Rx. et Rz. Rhei, Rx. Astragali and Rx. Salviae miltiorrhizae were found to be the most protective against hypotension. Further studies should be performed to evaluate the association of CHMs for IDH patients with major adverse cardiovascular events, as well as to functionally investigate other potential compounds for IDH treatment.

Contributors

M-Y Tsai were responsible for the study design, coordination, and drafting of the manuscript. Y-J Chen, C-T Liu, C-Y Chin, W-C Lee, F-J Tsai, B-C Cheng, and Y-H Chen collected data and performed analysis. Y-J Chen, C-T Liu, C-Y Chin, W-C Lee, F-J Tsai, B-C Cheng, Y-H Chen, and M-Y Tsai provided guidance and reviewed the manuscript. Y-J Chen and C-T Liu contributed equally to this work. All authors collaborated in writing the final version of the manuscript. All authors read and approved the final manuscript.

Conflicts of Interest

The authors report no conflicts of interest or financial interests associated with this work, both collectively and individually.

Data Availability Statement

The original contributions presented in the study are included in the article; further inquiries can be directed to the corresponding author.

Ethics Statement

Author Contributions

Acknowledgments

This study was supported in part by the Taiwan Ministry of Health and Welfare Clinical Trial Center (MOHW110-TDU-B-212-124004), China Medical University Hospital (DMR-111-105) and Kaohsiung Chang Gung Memorial Hospital (CMRPG8L1311). We are grateful to the Health Data Science Center of China Medical University Hospital for providing administrative, technical and funding support. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding was received for this study.

Declaration of Conflicting Interests

The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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No competing interests reported.

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Chinese Herbal Medicine as an Adjunctive Therapy Ameliorated the Incidence of Hypotension in Patients with End-Stage Renal Disease: A Nationwide Population-Based Cohort Study

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