5α-Reductase inhibitors increase acute coronary syndrome risk in patients with benign prostate hyperplasia.

5α-Reductase inhibitors increase acute

coronary syndrome risk

in patients with benign prostate hyperplasia

C.-H. Kao

Introduction

Acute coronary syndrome (ACS) includes unstable

angina, non-ST-segment elevation myocardial infarctions, and ST-segment elevation myocardial infarctions

[1]. Numerous factors may cause cardiovascular (CV) disease [2]. Males are known for higher risk of developing ACS than females. Benign prostate hyperplasia

(BPH) is the most common prostate disease in aging men, and the patients may require medication to relieve urinary symptoms. Androgens play a critical role in prostatic growth and contribute to the pathogenesis of prostate diseases [3]. Androgens are also essential in regulating

fat distribution and insulin sensitivity, and have an impact on lipid and bone metabolism [4]. With antiandrogen

effects, 5α-reductase inhibitors (5ARIs) are responsible to convert testosterone into dihydrotestosterone

(DHT) with more potent androgenic signals in tissue [5]. Finasteride and dutasteride are primary 5ARIs commonly prescribed for patients with BPH. Both agents result similar long-term effectiveness in volume reductions in prostate glands and symptoms relief [6]. However, a previous study reported that 39.2 % of first-time users of 5ARIs for the BPH treatment had experienced adverse medication effects with various CV indications [7]. Thus, it

is reasonable to evaluate the association between 5ARI

use and the ACS risk for BPH patients because comprehensive studies are scant. Using data from the National

the history of using 5ARIs between BPH patients with and without ACS to evaluate the association between the ACS risk and the use of 5ARI.

Materials and methods

We used the NHI reimbursement database, which contained claims data of 1 million randomly selected insured population for the period of 1996–2011. The identification numbers of all patients and their reimbursement data from the NHI database were encrypted to protect their privacy. The claims data provided information on the registry of medical facilities, details of inpatient orders, ambulatory cares, individual’s sociodemographic status, health care services received and all payments for outpatient visits, hospitalizations, and prescriptions.

Figure 1 shows the flow chart of identifying cases and controls for this study. Among 58156 patients with BPH (ICD-9-CM Codes 600.xx) newly diagnosed in 1996–2010, 6169 men were also diagnosed with ACS. We excluded 150 5ARIs users by the time they were diagnosed with BPH and 30 BPH patients who were less than 20 years of age. We further excluded 500 ACS cases diagnosed before 2005 and 3826 ACS cases diagnosed before the diagnosis of BPH from 2005 to 2010. The remaining 1843 ACS patients identified from 2005 to 2011 were considered as nested cases and the BPH diagnosis date as the index date. For each cases of ACS, four nested controls were randomly selected frequency matched by age (in 5 years), year of BPH diagnosis (index year), and index month. Among the controls, 42 persons were excluded because of index month not matched. Patients with a medical history of at least three claims for inpatient and outpatient visits before the index date and with diagnoses for diseases with possible association with ACS were excluded. The diseases considered to be comorbidities included hypertension (ICD-9-CM

Codes 401 to 405), diabetes (ICD-9-CM Codes 250, A181), hyperlipidemia (ICD-9-CM Code 272.2) and chronic

ischemic heart disease (ICD-9-CM Codes 414). Medication

for 2 years or longer before the index date. Medications were classified into six groups.

Ethics statement

All identification numbers of insured people in the NHRID were encrypted for privacy protection and researchers used

anonymous identification numbers to link the relevant claim information, which included the patient’s sex, date

of birth, registry of medical services, and medication prescriptions. Patient consent is not required for accessing

the NHIRD. This study was approved by the China Medical University and Hospital Research Ethics Committee

(CMU-REC-101-012). Statistical analysis

We compared the distributions of the demographic characteristics and medications between the control and ACS

groups, using the Chi-square test to examine categorical variables and t-test for continuous variables. Unconditional univariable and multivariable logistic regression

models were used to calculate odds ratio (OR) and 95 % confidence interval (CI) of ACS in association with the BPH therapy with medications of 5ARIs. The multivariable model was used to simultaneously adjust for age, hypertension, diabetes, hyperlipidemia and chronic ischemic heart

disease. In addition, the multivariable model was also used to estimate the ACS risks by the dosage of dutasteride and finasteride. We estimated the dosage associations using the daily cut-off doses of 0.01 mg for dutasteride and 0.5 mg for finasteride. We categorized medication uses into six groups: none, low dutasteride dose, high dutasteride dose, low finasteride dose, high finasteride dose, and both dutasteride and finasteride in low or high dose. All analyses were

performed using the SAS statistical package (SAS institute Inc., Cary, NC, version 9.2), and the statistical values met the significance level of 0.05.

Results

Table 1 shows the distributions of the demographic characteristics and medications between the control and ACS

occupation and urbanization of living residents. Four-fifths of the study population was older than 65 years with a mean age of 73 years old, and more than half of them were in jobs of labor or business and lived in areas with higher urbanization levels. Comorbidities were more prevalent in the ACS group than in controls. Compared with controls, ACS cases were less likely taking dutasteride (0.87 versus 1.01 %) but more likely taking finasteride (2.28 versus 1.45 %).

Table 2 shows the adjusted ORs of ACS in associations with 5ARIs medications compared with non users. Among BPH patients on the six medication scenarios, those who had the medication of both finasteride and dutasteride were at a higher risk of ACS with an adjusted OR of 3.47 (95 % CI 1.05–11.5). The crude OR showed a significant link with ACS for those who had taken finasteride and low; this association became moderate after adjustment for covariates. There were no other significant relationships between

the ACS risk and other types of single medication, regardless of high dose or low dose.

Discussion

Although age-adjusted CV death rates have declined in

developed countries in recent decades, the rates of CV diseases

and mortalities have substantially increased in low- and middle-income countries, with nearly 80 % of the burden

occurring in these countries [8]. The CV disease prevalence is also in increasing trend in Taiwan. In the present study for the relationship between ACS risk and BPH medications, we found that 5ARIs were not the common drugs used in Taiwan. Our case and control groups were similar in distributions of age, occupation and urbanization. The known CV

risk factors are male gender, smoking, hypertension, hyperlipidemia, and diabetes [9]. In the Framingham Heart Study,

even residents with high–normal blood pressure (defined as a systolic blood pressure of 130–139 mmHg and/or a diastolic blood pressure of 85–89 mmHg) are at two-fold higher

risk of CV diseases compared to persons with normal blood pressure. Patients with diabetes are 2–8 times more likely

to experience future CV events than age and ethnically matched persons without diabetes. In another case control study, smoking and dyslipidemia are the two strongest risk factors, followed by a history of diabetes, hypertension and/ or psychosocial disorders [10].

Our case and control groups were similar in distributions of age, occupation and urbanization. But, the ACS group in this study tended to have higher proportion of hypertension, diabetes mellitus, hyperlipidemia and chronic ischemic heart disease (Table 1). Souverein et al. [7] showed that nearly 40 % of BPH patients have a history of CV disorders. This study enrolled 9173 patients with BPH. Among

these, 73 % had hypertension, 28 % diabetes, 33 % hyperlipidemia, and 35 % chronic ischemic heart disease.

The Taiwan National Health Insurance data have been used in several CV studies to assess disease prevalence and costs. The claims data are considered sufficiently reliable for tracking the health care quality [11]. The use of ICD-9 codes for identifying CV diseases and associated risk factors has been shown to be accurate with good predictive

values for most CV events [12].

Serum testosterone undergoing 5α-reduction can be converted into DHT, which may affect the prostate in men [13, 14]. Type 2 5ARI, existing primarily in the prostate, is inhibited by finasteride and the serum DHT level can be reduced by approximately 70 % [15, 16]. Testosterone levels may affect metabolism and CV risk. Whether the exogenous testosterone use or testosterone insufficiency lead to adverse CV effect is controversial. A recent cohort study found that the testosterone therapy were at a higher risk of myocardial infarction, stroke and death in men with a low testosterone level who underwent coronary angiography. [17]. Another recent study also revealed that testosterone therapy could increase near two-fold higher risk of myocardial infarction for older men, and more than three-fold higher risk for younger men with pre-existing heart disease [18]. However, two meta-analyses failed to conclude a significant

exogenous testosterone users [19, 20]. Studies have associated lower testosterone and higher E2 levels with increased

risks of CVD and CV mortality and an increased inflammatory risk for the prostate [21, 22]. However, a recent study

reported hypogonadism could reduce near a half of new CV

events [23]. Hypogonadism, along with the increased cardiovascular risk, could be also associated with an increased

inflammatory risk in the prostate [24]. Hypogonadism in men has an important role in pathogenic mechanism for the promotion of BPH and cancer [25]. Studies have associated hypogonadism with increased inflammatory infiltrates score in prostatectomy specimens in patient with metabolic syndrome [26, 27]. A previous study showed that the longterm administration of finasteride was not associated with

bone mineral density, lipoprotein concentrations, or overall health status [28]. Finasteride has been used successfully in many men for the treatment of BPH [29] and male pattern baldness [30]. Dutasteride inhibits type 1 5α-reductase (located in the skin, gut, liver, and other tissues) and type 2 5α-reductase, causing a 95 % decrease in serum DHT levels [31]. Finasteride or dutasteride administration can lead to a marked decrease in DHT levels and a 25 % reduction in prostate volume; the urinary symptoms in men

with BPH are thus improved [32]. Testosterone deficiency

Table 2 Adjusted odds ratios and 95 % confidence intervals of ACS by medication type

a _{Adjusted for age, hypertension, diabetes, hyperlipidemia and chronic ischemic heart disease}

* p < 0.05, *** p < 0.001 Medication ACS group

N Event % Crude OR (95 % CI) Adjusted ORa _{(95 % CI)}

None 8923 1779 19.9 1 (Reference) 1 (Reference)

Dutasteride and low 23 5 21.7 1.12 (0.41, 3.01) 1.07 (0.39, 2.99) Dutasteride and high 67 11 16.4 0.79 (0.41, 1.51) 0.73 (0.38, 1.44) Finasteride and low 140 40 28.6 1.61 (1.11, 2.33)* 1.30 (0.89, 1.92) Finasteride and high 8 2 25.0 1.34 (0.27-6.64) 0.98 (0.19, 5.13)

Both dutasteride and finasteride, low or high 12 6 50.0 4.02 (1.29, 12.5)*** 3.47 (1.05, 11.5)***

was associated with an increased risk of osteoporosis and fractures [33]. Amory et al. [34] found that the profound suppression of circulating serum DHT by finasteride and

dutasteride in 1 year did not adversely affect bones, serum lipoproteins, or hemoglobin.

A previous case study found that for treating androgenic

alopecia, 1 mg finasteride could increase HDL- and LDLcholesterol, but significantly decrease glycated hemoglobin

(HbA1c) and moderately decrease insulin resistance [35]. Souverein et al. [36] found no evidence of an association between the use of finasteride and hospitalization for ischemic heart disease. Clinically, combination therapy with alpha blockers and 5ARI is more effective in treating BPH [37]. However, the “Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)”

study showed that doxazosin, an α-1-adrenoceptor blocker, was associated with greater risk of cardiovascular accidents than chlorthalidone [38]. An in vitro study found that doxazosin could induce the apoptosis of cardiomyocytes [39].

However, a recent meta-analysis did not find the evidence of a significant association between dutasteride therapy and adverse cardiovascular events [40].

Our study showed that most of BPH patients had been

prescribed for only one single drug, finasteride or dutasteride, while a small portion of patients took both finasteride

and dutasteride. There was no significant ACS risk for those who took only one medicine, while those who took both medicines were at a high risk. The odds ratio shown separately for a single drug medication is more informative, because of larger sizes of users. On the other hand, the result derived from using both dutasteride and finasteride is less informative, because of small sample size. This finding indicates that the high ACS risk for taking two drugs deserves a further study using a large data set to confirm the association.

Study limitations

The strengths of this study are the use of population-based insurance claims data instead of self-reported drug uses. However, certain limitations should be mentioned. First, detailed information on smoking, alcohol consumption, body mass index, and family health was unavailable for

this study. These factors were not controlled for in the data analysis. Besides, the NHIRD did not include coronary angiographic data. However, it is unlikely that these factors would have affected the prescription of 5ARIs. Second, a nested case–control study might be less efficient than a cohort design. The quality of results derived from this study may not be as good as that from randomized trials. Despite our study design being meticulous, bias might remain if unmeasured or unknown confounders were present. Third, we were unable to verify the diagnosis of diseases and the use of 5ARIs recorded in the claims data for the reason of privacy. Furthermore, no data before 1996 were available. However, the data of the prescribed 5ARIs, diagnoses of ACS and the BPH were reliable.

Conclusion

This population-based nested case control study shows that patients taking both finasteride and dutastteride for the treatment of BPH could increase ACS risk. The potential underlying mechanisms for this association have not been investigated or identified in this observation study. Further large population-based studies, large-scale randomized clinical trials, and well-designed basic research to confirm these findings are needed before definite conclusions can be drawn.