Traditional Chinese medicine for male sexual dysfunction and the risk of major adverse cardiovascular events: A population-based retrospective cohort study

doi:10.21203/rs.3.rs-4559949/v1

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Traditional Chinese medicine for male sexual dysfunction and the risk of major adverse cardiovascular events: A population-based retrospective cohort study

https://doi.org/10.21203/rs.3.rs-4559949/v1

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The study investigates the association between traditional Chinese medicine (TCM) use for male sexual dysfunction (SD) and the risk of major adverse cardiovascular events (MACE). Using data from Taiwan's National Health Insurance Research Database from 2001 to 2018, the study includes a random sample of 2 million individuals. Male patients aged 20–70 with newly diagnosed SD were classified as TCM users or non-TCM users. The risk of MACE was evaluated using Cox proportional hazards regression and Kaplan-Meier methods. Results show that among the 144 114 TCM users without SD and 144 114 non-TCM users without SD, TCM users exhibited a higher MACE incidence (9.93 vs. 9.08 per 1 000 person-years, adjusted hazard ratio [aHR]: 1.07). Among male patients with SD (n = 4 959) with otherwise similar baseline characteristics, the association between TCM use and an increased risk of MACE (aHR:1.23) appeared to be related to the presence of SD, particularly organic SD (aHR:1.24). In the TCM group, most MACE cases occurred in males over 40 years old. Individuals using selective serotonin reuptake inhibitors (SSRIs) and those with comorbidities such as hypertension, prostate issues, anxiety, and hyperlipidemia were more prone to MACE. The conclusion suggests that male patients with SD using TCM may encounter an increased risk of MACE. TCM practitioners should be cautious when prescribing Chinese herbal medicine (CHM) for male SD patients, considering potential cardiovascular risks.

Health sciences/Diseases/Urogenital diseases/Sexual dysfunction

Health sciences/Diseases/Cardiovascular diseases

Health sciences/Risk factors

Health sciences/Health care/Disease prevention/Preventive medicine

Erectile dysfunction (ED) and premature ejaculation (PE) are prevalent among males [1], stemming from non-organic and organic causes, including vascular, neurological, endocrine, cavernous, and drug-induced factors. Vascular causes include atherosclerosis, diabetes, hypertension, hyperlipidemia, coronary artery disease, and prostate disease, with endothelial dysfunction linked to later adverse cardiac events. Neurogenic ED can result from spinal cord injury, Parkinson's disease, dementia, multiple sclerosis, stroke, pelvic trauma, and cancer surgery. Endocrine ED examples are hyperprolactinemia and hypogonadism, while cavernous ED includes Peyronie's disease, characterized by aberrant penile curvature. Drug-induced ED arises from antipsychotics, SSRIs, and illicit drug use such as marijuana, opium, and cocaine. Psychological factors, including anxiety and depression, and unhealthy habits like smoking, alcohol use, and obesity also contribute to SD [2].

The first-line treatment for ED is oral phosphodiesterase 5 inhibitors (PDE5Is) [3]. Most studies indicate that men who experience adverse reactions to PDE5Is have underlying cardiovascular diseases, primarily due to nitrates and a drop-in blood pressure due to severe vascular stenosis [4]. PE is treated with SSRIs, which delay male ejaculation, and local anesthetics (e.g., lidocaine cream and lidocaine spray), all of which are amide local anesthetics [5]. In Asia, many men with SD seek supplementary therapy with TCM, and some may take both Western medication and CHM [6]. TCM theory relates “kidney” health to metabolism, the reproductive, nervous, and endocrine systems, attributing male SD to “kidney essence deficiency.” TCM practitioners use CHM to “tonify the kidneys” when treating SD [7, 8], though the cardiovascular risks associated with these treatments remain unclear. This study investigates the association between TCM use for male SD and the risk of MACE.

Data source

This study utilized data from Taiwan's National Health Insurance Research Database (NHIRD), which includes comprehensive data on Western medicine, TCM, and nearly the entire population of Taiwan since 1995. The Health Welfare Data Center stores de-identified secondary data from NHIRD, including demographic information and health care details. NHIRD transitioned from using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes to ICD-10-CM in 2016 for its diagnostic coding system. Due to legal limits, personal data in NHIRD is encrypted, obviating the need for informed consent.

Study design and population

From 2001 to 2018, 2 million Taiwanese individuals were randomly selected from the NHIRD and divided into TCM users and non-TCM users. Exclusion criteria included index dates outside 2001–2018, ages under 20 or over 70 at the time of first TCM use, female gender, pre-existing SD or MACE, mixed non-organic and organic SD, discontinuing TCM after SD diagnosis, missing data, and patients with cancer, spinal cord injury, pelvis fracture, multiple sclerosis, Parkinson's disease, dementia, schizophrenia, or Peyronie's disease. The inclusion criteria comprised male patients newly diagnosed with SD, classified as non-organic or organic SD. The case group's index date was defined as the first instance of TCM usage, while the control group's index date, without TCM usage, was randomly selected.

Disease codes, comprising primary outcomes and baseline comorbidities, required at least two outpatient visits or one hospitalization. Comorbidities encompassed hypertension, diabetes mellitus, coronary artery disease, atherosclerosis, prostate diseases, alcohol-related illness, obesity, depression, anxiety, hyperlipidemia, chronic kidney disease, illicit drug dependence/abuse, and nicotine dependence. Medication use compared between groups included PDE5Is, amide drugs, SSRIs, and nitrates. Cases were matched with controls using a 1:1 propensity score matching method based on sex, age, comorbidities, medication use, and index year. For disease codes and drug Anatomical Therapeutic Chemical (ATC) codes, see Supplementary Table S1. Primary outcomes included MACE such as ischemic stroke, hemorrhagic stroke, acute coronary syndrome, heart failure, and malignant arrhythmia [9]. Patient tracking ceased upon the first occurrence of MACE diagnosis, withdrawal from NHIRD, death, loss of follow-up, or December 31, 2018 (Fig. 1).

Statistical analysis

Propensity scores were estimated using logistic regression, with TCM used as the dependent variable and baseline characteristics as independent variables. To ensure the quality of the matching and reduce potential confounding bias, we performed a covariate balance check on the matched data to ensure that the distribution of baseline characteristics was similar between TCM users and non-TCM users after propensity score matching. Chi-square tests examined baseline demographics, comorbidities, and medication use. Continuous variables were presented as means and standard deviations, and categorical variables as counts and percentages. Differences were assessed using unpaired t-tests and standardized mean differences (SMD), where SMD values < 0.1 indicated no significant difference [10]. Hazard ratios and 95% confidence intervals were generated using Cox proportional hazards regression, controlling for age, comorbidities, and medication use. In addition, sensitivity analysis was performed to assess the robustness of the results by varying the matching parameters and examining their impact on the estimated hazard ratio. The Kaplan-Meier method was used to estimate MACE incidence, with the cumulative incidence curve created using the R Programming Language. Statistical analyses were performed using SAS statistical software version 9.4 (SAS Institute Inc., Cary, NC, USA), with significance set at P < 0.05.

Comparison of baseline characteristics in non-TCM and TCM cohorts

Table 1 illustrates baseline demographics and comorbidities of the entire study population, consisting of 144 114 TCM users and an equal number of non-TCM users. All participants were included irrespective of SD status, with 1 921 TCM users and 3 038 non-TCM users diagnosed with SD. mean ages were similar: 41.4 ± 12.82 years for TCM users and 41.08 ± 12.81 years for non-TCM users, with follow-up times of 9.27 ± 5.21 years and 9.71 ± 5.22 years, respectively. No significant differences were observed between study groups in comorbidities and medication use (SMD < 0.1).

Hazard ratios and 95% CI for MACE among overall patients

Table 2 demonstrates that after adjusting for age, gender, comorbidities, and drug usage, the incidence rates of MACE were 9.93 and 9.08 per 1,000 person-years in TCM and non-TCM groups, respectively, across the entire study population, regardless of their SD status. The TCM group exhibited a higher risk of MACE compared to the non-TCM group (aHR: 1.07, 95% CI: 1.04–1.09, P < 0.001), along with a 1.24-fold increased risk of ischemic stroke (aHR: 1.24, 95% CI: 1.2–1.28, P < 0.001). Conversely, hemorrhagic stroke (aHR: 0.80, 95% CI: 0.76–0.85, P < 0.001), acute coronary syndrome (aHR: 0.93, 95% CI: 0.88–0.98, P < 0.01), and malignant arrhythmia (aHR: 0.91, 95% CI: 0.83–0.99, P < 0.05) had a lower risk in the TCM group compared to the non-TCM group. The risk of heart failure did not significantly differ between the two groups (aHR: 0.95, 95% CI: 0.91–1.00).

Stratification analysis of MACE associated with TCM use

Table 3 shows that TCM users had significantly higher risk of MACE in age groups 40–49 (aHR: 1.06, 95% CI: 1.01–1.12, P < 0.05), 50–59 (aHR: 1.09, 95% CI: 1.04–1.13, P < 0.001), and 60–69 (aHR: 1.09, 95% CI: 1.04–1.14, P < 0.001). Patients with hypertension (aHR: 1.14, 95% CI: 1.07–1.22, P < 0.001), prostate disease (aHR: 1.1, 95% CI: 1.01–1.2, P < 0.05), anxiety (aHR: 1.12, 95% CI: 1–1.24, P < 0.05), and hyperlipidemia (aHR: 1.23, 95% CI: 1.12–1.35, P < 0.001) exhibited a heightened risk of MACE in the TCM group. Conversely, there was a reduced incidence of alcohol-related illness (aHR: 0.87, 95% CI: 0.77–1, P < 0.05), chronic kidney disease (aHR: 0.84, 95% CI: 0.72–0.98, P < 0.05), and nitrates (aHR: 0.93, 95% CI: 0.88–0.99, P < 0.05) among TCM users. No significant associations were found between illicit drug dependence/abuse, nicotine dependence, and TCM use. TCM users concurrently taking SSRIs showed a significantly higher risk of MACE (aHR: 1.24, 95% CI: 1.02–1.5, P < 0.05). No association was observed between TCM use and PDE5Is or amides. Table 4 presents the incidence rates and hazard ratios of MACE in patients with different types of SD. In the overall cohort without SD, the risk of MACE in the TCM group was 1.06 times that of the non-TCM group. Among 4959 male patients newly diagnosed with SD, the risk of MACE in the TCM group was 1.23 times higher than the non-TCM group (aHR: 1.23, 95% CI: 1.05–1.43, P < 0.01), with those with organic SD exhibiting greater risk than those with non-organic SD (aHR: 1.24, 95% CI: 1.06–1.43, P < 0.01).

Impact of cumulative duration and dose of TCM on the risk of MACE

Table 5 shows hazard ratios and 95% CI for MACE in related to cumulative TCM use. After adjusting for age, comorbidities, and medication use, the risk of MACE varies with TCM duration. Patients using TCM for less than 28 days faced a 1.35-fold increased risk, while those using it for 91–180 days had a 0.86-fold decreased risk. Longer durations further reduced risks: 0.71-fold for 181-360 days and 0.52-fold for over 360 days. For herbal dose, risks varied: 1.48-fold increase with < 180 g, 1.17-fold increase with 180–360 g, and 0.82-fold decrease with > 360 g. Higher doses and durations corresponded to a reduced risk of MACE in TCM users. Figure 2 illustrates TCM users' higher cumulative MACE and ischemic stroke incidence over 10 years (Figure 2A–B), but lower hemorrhagic stroke incidence (Figure 2C, P < 0.001). Incidences of acute coronary heart disease, heart failure, and malignant arrhythmia showed no significant differences (Figure 2D–F).

The age range of 20 to 70 was chosen to focus on adults most susceptible to SD and ensure generalizability, excluding those under 20 due to lower SD prevalence and those over 70 due to increased comorbidities and polypharmacy, which could confound the result. Patients with mixed SD were also excluded to clearly define non-organic or organic SD and investigate specific TCM and cardiovascular associations.

This groundbreaking study explores whether TCM heightens the risk of MACE in SD patients. Initially, the risk of MACE rises with short-term TCM use (< 28 days, < 360 grams) but diminishes with continued use. Possible explanations include the body's adaptation and tolerance to the herbs, dosage adjustments, or discontinuation due to side effects. Furthermore, the bidirectional regulatory effects of TCM should be considered regarding cumulative dose and duration [11]. Common kidney-tonifying herbs for male SD, such as Epimedium Leaf (Yin-Yang-Huo, EPIMEDII FOLIUM) [12], Eucommia Bark (Du-Zhong, EUCOMMIAE CORTEX) [13], Morinda Root (Ba-Ji-Tian, MORINDAE OFFICINALIS RADIX) [14], and Desert-living Cistanche (Rou-Cong-Rong, CISTANCHIS HERBA) may temporarily affect blood pressure and vasoconstriction [15], potentially increasing the risk of ischemic stroke but not hemorrhagic stroke, as observed in this study. Similarly, Ginseng Root (Ren-Shen, GINSENG RADIX ET RHIZOME), when used as an aphrodisiac, may elevate blood pressure and cause palpitations; however, long-term use can alleviate hypertension [16, 17]. Nevertheless, prolonged usage of these herbs has shown cardiovascular and neuroprotective benefits, leading to reduced cardiovascular risk [18–21].

The influence of testosterone-like TCM on cardiovascular risk is another aspect to consider. Although the effect of testosterone replacement therapy on cardiovascular disease remains uncertain [22], some TCM herbs like Ginseng Root, Epimedium Leaf, Morinda Root, and Desert-living Cistanche are believed to have androgen-like properties, potentially boosting testosterone levels [14, 16, 23]. However, these herbs could elevate blood pressure, increasing cardiovascular risk [24]. This aligns with our finding that hypertensive patients face a higher risk of MACE when using TCM. Recent research also indicates a potential increase in intracranial bleeding and the risk of MACE associated with SSRIs [25, 26], contrary to previous beliefs about their cardioprotective benefits [27]. Table 3 illustrates a significant increase in the risk of MACE among patients using both TCM and SSRIs compared to those not using TCM (aHR: 1.24). Further investigation is needed to determine if TCM interacts with SSRIs, affecting blood pressure, heart rate, or coagulation function. In addition, patients in the TCM group might use Western medicine alongside or switch to TCM due to unsatisfactory results with Western treatment, potentially indicating more severe cardiovascular conditions and a higher initial risk of MACE.

This study has several strengths aimed at minimizing potential biases. A disparity in cardiovascular risk was observed between the non-TCM and TCM groups among the 2 million samples examined. For instance, Table 2 reveals that the TCM group had a 1.07 times higher risk of MACE than the non-TCM group, regardless of whether they had a SD diagnosis. Table 4 further shows that individuals without confirmed SD had a 1.06-fold increased risk of MACE when using TCM compared to non-TCM users. For those with SD, the TCM group had a 1.23 times higher risk of MACEs than the non-TCM group, particularly among those with organic SD (aHR: 1.24). These findings indicate an elevated cardiovascular risk in the TCM group. To address information bias, previous research indicates that NHIRD is highly accurate in identifying ischemic stroke, making it a valuable resource for cardiovascular disease research [28, 29]. Given that Taiwanese individuals tend to be cautious about discussing SD, a diagnosis should carry high diagnostic validity. To avoid research design bias, we carefully matched the cohorts to balance their demographics and conducted stratified analyses, ensuring no significant differences between groups and affirming our conclusions' robustness. We also applied strict criteria to exclude neurological or major psychiatric disorders related to SD and unmeasured confounders, such as pelvic surgery, prostate disease, cancer [30, 31], multiple sclerosis, spinal cord injury, schizophrenia [32], dementia, and Peyronie's disease, ensuring a rigorous screening process consistent with real-world epidemiological analyses.

The disparities in risk between non-organic SD and organic SD require clarification. Organic SD is closely associated with cardiovascular disease, increasing the risk of MACE. Potential cardiovascular risks from PDE5Is, amides, SSRIs, and TCM used to treat SD are not well-explored. Our study examined if these medications raise cardiovascular risk alone or in combination. Encouragingly, we found that TCM and nitrate medications did not increase the risk of MACE (aHR: 0.93, 95% CI: 0.88–0.99, P < 0.05). Previous research has suggested that combining SSRIs with TCM may be effective in treating PE, but its safety remains uncertain [33]. Our investigation revealed that combining SSRIs with TCM significantly raised the risk of MACE (aHR: 1.24, 95% CI: 1.02–1.5, P < 0.05), highlighting the need for further investigation.

This study has several limitations. Firstly, Taiwan's National Health Insurance does not cover variables such as illegal substance dependence/abuse, nicotine dependence, and medications like PDE5Is and amide sprays, which require out-of-pocket payments. Consequently, the limited number of cases makes it challenging to accurately represent the population, and it's impossible to determine the hazards of combining TCM with these pharmaceuticals. Secondly, Taiwan's NHIRD lacks laboratory data or medical records, including the International Index of Erectile Function-5 (IIEF-5) and testosterone levels, making it difficult to ascertain the severity of SD. It's hypothesized that the severity of ED in the TCM group, dissatisfied with Western medicine treatment within 28 days, may be more profound. SD severity correlates with the vascular endothelium, increasing cardiovascular risk. Thirdly, while our analysis goes beyond previous NHIRD studies by controlling for most potential confounders, especially drug interactions, the observational nature of this study hinders understanding the direct harmful consequences of TCM use based on medical records. Explicitly inferring a causal association between individual TCM and cardiovascular risk is challenging. Therefore, we explored alternative explanations for our findings, such as endothelial dysfunction and an initial increase in blood pressure following TCM treatment. People with SD often worry about their sexual performance, leading to over-the-counter pharmaceuticals and excessive use of TCM, which are identified as potential reasons for elevated cardiovascular risk.

Our analysis of extensive Taiwanese data reveals a correlation between the use of TCM and cardiovascular risk in patients with SD. Males with SD using TCM experience a higher cardiovascular risk compared to non-TCM users. TCM practitioners in Taiwan should carefully assess cardiovascular risk when prescribing CHM to patients with SD to minimize the occurrence of early MACE. Future research should focus on exploring the relationship between sexual dysfunction and the use of TCM.

DATA AVAILABILITY

The dataset analyzed during the current study is available from the corresponding author on reasonable request.

ACKNOWLEDGMENTS

We are grateful to the Health Data Science Center at China Medical University Hospital for providing administrative and technical support.

AUTHOR CONTRIBUTIONS

WCY: Conceptualization; investigation; project administration; supervision; writing – original draft, review and editing. HJL: Data curation; formal analysis; methodology; software; visualization.

ETHICAL APPROVAL

This study received approval from the Ethics Committee of China Medical University Hospital, Taiwan (approval number CMUH109-REC2-031).

FUNDING

No funding

COMPETING INTEREST

The authors declare no competing interests.

ADDITIONAL INFORMATION

Supplementary information: Table S1: Disease and ATC codes in the study population.

The online version contains supplementary material available at https://doi.org/

Correspondence and requests for materials should be addressed to Wen-Chieh Yang

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Tables 1 to 5 are available in the Supplementary Files section.

There is NO conflict of interest to disclose.

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Traditional Chinese medicine for male sexual dysfunction and the risk of major adverse cardiovascular events: A population-based retrospective cohort study

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Abstract

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INTRODUCTION

MATERIALS AND METHODS

Data source

Study design and population

Statistical analysis

RESULTS

DISCUSSION

CONCLUSION

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References

Tables

Additional Declarations

Supplementary Files

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