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Table of Contents
ORIGINAL ARTICLE
Year : 2019  |  Volume : 30  |  Issue : 4  |  Page : 164-169

Effect of long-term administration of tadalafil on arteriosclerosis: A prospective cohort study


1 Department of Urology, Showa University Koto Toyosu Hospital, Tokyo, Japan
2 Department of Urology, Showa University Fujigaoka Hospital, Yokohama, Japan
3 Department of Urology, Yokohama Shinmidori General Hospital, Yokohama, Japan
4 Department of Urology, Showa University School of Medicine, Tokyo, Japan

Date of Submission14-Aug-2018
Date of Decision30-Jan-2019
Date of Acceptance26-Feb-2019
Date of Web Publication29-Jul-2019

Correspondence Address:
Keiichiro Hayashi
Department of Urology, Showa University Koto Toyosu Hospital, 5-1-38 Toyosu, Koto Ward, Tokyo 135-8577
Japan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/UROS.UROS_113_18

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  Abstract 


Purpose: The aim of this study is to prospectively investigate whether the long-term administration of tadalafil, which is commonly used for erectile dysfunction, could reduce arteriosclerosis. Materials and Methods: This study included 85 patients who presented to one of the three hospitals with lower urinary tract symptoms. Tadalafil was administered daily (5 mg/d), and pulse wave velocity (PWV) was measured before administration and at weeks 12, 24, 36, and 48. The International Prostate Symptom Score, Overactive Bladder Symptom Score, and Erection Hardness Score were simultaneously assessed at the same time points. Further subanalyses were performed in patients with a high risk of cardiovascular events, those aged 75 years or older, and those younger than 75 years. The Wilcoxon signed-rank test was used for statistical analysis. Results: Compared with pretreatment values, the PWV did not show any statistically significant decrease at any time point. The group at high risk of cardiovascular events showed significant improvement at weeks 24 and 36, whereas the 75 years or older group showed significant improvement at only week 24. However, the three aforementioned scores significantly improved in all patients during treatment. Conclusions: The long-term administration of tadalafil (5 mg/d) might inhibit the progression of arteriosclerosis or prevent its future development.

Keywords: Arteriosclerosis, blood, pulse wave velocity, tadalafil


How to cite this article:
Hayashi K, Sasaki H, Fukagai T, Noguchi T, Hirayama K, Ogawa Y, Igarashi A, Morita M, Ishikawa K, Ogawa Y. Effect of long-term administration of tadalafil on arteriosclerosis: A prospective cohort study. Urol Sci 2019;30:164-9

How to cite this URL:
Hayashi K, Sasaki H, Fukagai T, Noguchi T, Hirayama K, Ogawa Y, Igarashi A, Morita M, Ishikawa K, Ogawa Y. Effect of long-term administration of tadalafil on arteriosclerosis: A prospective cohort study. Urol Sci [serial online] 2019 [cited 2019 Aug 23];30:164-9. Available from: http://www.e-urol-sci.com/text.asp?2019/30/4/164/263645




  Introduction Top


Tadalafil is a phosphodiesterase type 5 (PDE-5) inhibitor, and it is used globally as a highly effective and safe drug for the treatment of erectile dysfunction (ED).[1] In recent years, the daily administration of tadalafil has been reported to be effective for lower urinary tract symptoms (LUTSs) associated with benign prostatic hyperplasia (BPH).[2],[3] An alpha-1 receptor blocker (α-1 blocker) is the first choice for drug treatment of prostatic hyperplasia inducing bladder outlet obstruction, but tadalafil is also a treatment option. According to the Japan clinical guideline for male LUTSs and BPH, tadalafil is as effective as an α-1 blocker.[4] PDE-5 inhibitors relieve ED or LUTS by relaxing vascular smooth muscle and increasing blood flow to the lower urinary tract tissue. PDE is distributed in pelvic organs, including the corpus spongiosum of the penis and the urethra and prostate, as well as in the lung, heart, and vascular smooth muscle. In other words, PDE is distributed throughout the body. Thus, we hypothesized that the administration of tadalafil might reduce not only systemic arteriosclerosis but also ischemia of the lower urinary tract. It is well known that atherosclerosis is one of the major causes of LUTS. An association between severity of LUTS and arteriosclerosis has been reported.[5],[6] Thus, LUTSs are severe in patients with advanced arteriosclerosis. Moreover, it has been reported that age-related impairment of the blood supply to the lower urinary tract due to atherosclerosis is important in the development of BPH.[7] Because factors contributing to LUTSs have also been associated with lifestyle diseases (e.g., heart disease, diabetes mellitus, and dyslipidemia),[8],[9] LUTSs should be treated as systemic diseases. Therefore, this study investigated whether long-term administration of tadalafil could reduce arteriosclerosis in male patients with LUTS evaluated by pulse wave velocity (PWV). PWV is known to be an indicator of arterial stiffness and a marker of atherosclerosis. Among the vascular endothelial test techniques that enable assessment of arteriosclerosis, PWV was used in this study. PWV is characterized by the following features: it can be measured in a simple, minimally invasive manner for patients; measurements are not affected by the timing of test and meals, and objective data can be obtained because measurements do not depend on the competence of examiners. Therefore, we used PWV to assess arteriosclerosis in this study.


  Materials and Methods Top


Ethics statements

This prospective study was approved by the institutional review boards of the participating hospitals. After we explained the objective of this study to patients and obtained their written consent, the study was initiated.

Study participants

Of patients who presented to Showa University Koto Toyosu Hospital, Showa University Fujigaoka Hospital, and Yokohama Shinmidori General Hospital with chief complaints of LUTSs between September 2014 and October 2017, we included 86 Japanese patients aged 50 years or older in this study.

Exclusion criteria

The following patients were excluded from this study: Those who had been or were treated for prostate or bladder cancer, patients receiving testosterone supplementation for the treatment of late-onset hypogonadism syndrome, patients who had a history of apparent cerebrovascular diseases and were suspected to have comorbid neurogenic bladder, patients who were found to have pyuria or hematuria by urinalysis, patients who could not complete the questionnaire forms by themselves, and patients with a performance status of 3 or higher. In patients with a prostate-specific antigen (PSA) level of 4 ng/mL or higher, the presence of prostate cancer was excluded by prostate biopsy or pelvic magnetic resonance imaging. Prostate size was determined using transabdominal ultrasound.

Intervention and data collection

Treatment regimen

Tadalafil (5 mg) was administered once daily after breakfast. In the patients who had already been treated with oral medications before the study period, tadalafil was added to their preexisting treatment, which was continued. Those who had not been treated were treated with tadalafil alone. Furthermore, we decided not to add new therapy for arteriosclerosis during the study period.

Outcome measures

For the primary outcome, values of PWV before administration and at weeks 12, 24, 36, and 48 were compared and analyzed. For the secondary outcomes, the International Prostate Symptom Score (IPSS), Overactive Bladder Symptom Score (OABSS), and Erection Hardness Score (EHS) were measured and analyzed. The EHS is a tool for evaluating erection hardness, and its validated Japanese version [10] was used in this study. In addition, adverse events were graded according to the Common Terminology Criteria for Adverse Events version 4.0.

Vascular endothelial function test

PWV is a technique for measuring the velocity of the pulse traveling from the heart through the arteries. By measuring the velocity of the pulse, arterial stiffness can be determined. The presence of arteriosclerosis reduces elasticity of the vascular wall; consequently, the velocity of the pulse increases. Because PWV is higher with stiffer blood vessels, it has been reported that PWV increases (higher velocity) as arterial stiffness increases (stiffer wall) in proportion to the presence of lifestyle diseases and age.[11] In other words, the value of PWV corresponds to the severity of arteriosclerosis.

Form ABI/PWV (Omron Health Co., Kyoto, Japan) was used for the measurement.

PWV was measured between both brachial arteries and both ankle arteries (brachial-ankle PWV [BaPWV]). PWV was measured separately on the right and left sides, and the mean values were used in the analysis.

Statistical analysis

For statistical analysis, the Wilcoxon signed-rank test was performed, and P < 5% was considered to indicate statistical significance. Statistical software JMP Pro14 (SAS Institute, Cary, NC, USA) was used to perform statistical analyses.


  Results Top


Of the 86 patients screened in this study, 68 were ultimately included because 6 patients discontinued the study because of adverse events and 12 discontinued at their own discretion.

Among the patients included in the analysis, the mean values were as follows: age, 72.5 ± 7.34 years; prostate volume, 34.4 ± 13.9 cc; PSA, 2.83 ± 2.61; IPSS, 12.1 ± 6.09; OABSS, 3.98 ± 2.13; quality of life index, 3.43 ± 1.51, EHS, 2.10 ± 0.78; and Sexual Health Inventory for Men (SHIM) score, 6.54 ± 5.06. Fifty-eight patients (67.4%) were treated for LUTSs before this study. Of them, 52 (60.4%) received α1-blockers, and 4 (4.75%) received 5α-reductase inhibitors [Table 1].
Table 1: Patients' background

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Compared with PWV before tadalafil administration, no statistically significant decrease in the velocity was observed at any time points [Figure 1].
Figure 1: Changes in pulse wave velocity in all patients. BaPWV: Brachial-ankle pulse wave velocity; N. S.: Not significant

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In other words, overall, tadalafil administration did not reduce arteriosclerosis. However, we assumed that this study included many patients without arteriosclerosis, in other words, those with normal vascular conditions. For subanalyses, the data were analyzed again in patients who had already developed arteriosclerosis, those aged 75 years or older, and those younger than 75 years. The patients with arteriosclerosis included in the subanalyses were at high risk of developing cardiovascular events, defined as PWV of 1800 cm/s or more.[12] As per the Japanese health-care insurance system, elderly individuals aged 65–74 years are classified as early elderly, while those aged 75 years or older are classified as late elderly, although the rationale for 75-year reference age has not been explained clearly. The results showed that PWV significantly decreased at weeks 24 and 36 [Figure 2]a. However, the PWV in another group with a value of <1800 cm/s did not show a decrease during the entire period [Figure 2]b. Furthermore, the subanalysis including only patients aged 75 years or older showed a significant decrease only at week 24 [Figure 2]c. In addition, the subanalysis including those younger than 75 years showed no decreases at any time points [Figure 2]d.
Figure 2: (a) Changes in pulse wave velocity among only the patients at a high risk of cardiovascular events. BaPWV: Brachial-ankle pulse wave velocity. (b) Changes in pulse wave velocity among only the patients at a low risk of cardiovascular events. BaPWV: Brachial-ankle pulse wave velocity. (c) Changes in pulse wave velocity among only patients aged 75 years or older. BaPWV: Brachial-ankle pulse wave velocity. (d) Changes in pulse wave velocity among only patients aged <75 years. BaPWV: Brachial-ankle pulse wave velocity

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Compared with pretreatment scores, the IPSS showed statistically significant improvement at week 12, and this improvement was maintained at weeks 24, 36, and 48 [Figure 3]a. Scores on voiding, storage, and postmicturition symptoms, which are the parameters of IPSS, were all significantly improved. Likewise, the OABSS showed statistically significant improvement at all time points [Figure 3]b. Compared with pretreatment scores, the EHS was significantly improved at all time points. In other words, erection hardness increased [Figure 4].
Figure 3: (a) Changes in the International Prostate Symptom Score. (b) Changes in the Overactive Bladder Symptom Score

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Figure 4: Changes in the Erection Hardness Score

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Adverse events

Adverse events were observed in 11 patients (12.7%). Specifically, there were 5 patients with a gastrointestinal symptom (3 with diarrhea and 2 with nausea), 3 patients with headache, 2 patients with nasal congestion, and 1 patient with cutaneous pruritus. Although the tadalafil dose was reduced to half in the 5 patients with a gastrointestinal symptom, this study was discontinued in 3 patients whose symptoms were not relieved. While the patients with headache were monitored, the symptom was poorly controlled in 2 patients, who were withdrawn from the study. Because nasal congestion might have been caused by the concomitant use of α1-blockers, they were discontinued. Nasal congestion was relieved in 1 patient, whereas no relief was observed in the other, who was withdrawn from this study. Adverse events necessitated discontinuation of this study in only 6 patients (6.97%). In these 6 patients, their symptoms were immediately relieved after discontinuation of tadalafil.


  Discussion Top


Our analysis showed that the PWV did not show a significant decrease at any time point after tadalafil treatment; however, the IPSS, OABSS, and EHS significantly improved posttreatment. The group at high risk of cardiovascular events showed significant improvement at weeks 24 and 36, whereas the 75 years or older group showed significant improvement at only week 24. Therefore, long-term tadalafil administration may inhibit arteriosclerosis and prevent its future development.

Role of phosphodiesterase type 5 inhibitors on arteriosclerosis

PDE-5 inhibitors have been used for treating ED for some time. They inhibit PDE-5 distributed in the vascular endothelium and smooth muscles of the bladder, urethra, prostate gland, and cavernous body, and they increase the concentration of cyclic guanosine monophosphate produced in response to the level of nitric oxide in tissue. Calcium ions flow from the cytosol to the extracellular space, thereby decreasing intracellular calcium levels, resulting in the relaxation of the smooth muscles. Consequently, blood flow and oxygen supply increase in tissues so that blood flow of the lower urinary tract is improved. In Europe and the United States, many randomized controlled trials (RCTs) have already demonstrated that the use of PDE-5 inhibitors clinically relieved dysuria.[3],[13],[14] Further, RCTs conducted in Asians in three countries also confirmed that the administration of tadalafil (5 mg once daily) is effective and safe for dysuria secondary to prostatic hyperplasia.[15],[16] Recent studies have reported significant improvement in subjective findings, as well as in objective findings on cystometry.[17] A meta-analysis compiling four RCTs revealed that tadalafil is effective for all patients, except those receiving two oral antihypertensive drugs or more, regardless of age, comorbidity, and the severity of dysuria.[18] Because PDE-5 is expressed in the vascular endothelium, as described above, we assumed that the long-term administration of PDE-5 inhibitors might exert positive effects on regression of arteriosclerosis in the entire body as well as improvements in the lower urinary tract.

Effect of tadalafil treatment on arteriosclerosis

Tadalafil has a duration of action of 36 h. Because it is longer than that of other PDE-5 inhibitors, we assumed that tadalafil is likely to be more effective than other PDE-5 inhibitors. In addition to the longer effect, tadalafil has greater ability than other PDE-5 inhibitors to reverse norepinephrine-induced tension and accumulate cyclic nucleotides in isolated human prostatic tissue.[19] Aversa et al. reported that the on-demand administration of tadalafil (20 mg) significantly improved flow-mediated dilation (FMD) results, which is another vascular test, at 1 month of treatment.[20] Huang et al. reported that the daily administration of tadalafil (5 mg for 6–8 weeks) improved FMD results.[21] Rosano et al. reported that the improvement in FMD results was maintained for at least 2 weeks after the discontinuation of tadalafil.[22] According to Amano et al., who administered tadalafil at a dose of 5 mg, daily to 81 patients with LUTSs, BaPWV significantly decreased at 3, 6, and 12 months of treatment, while the ankle brachial index, which enables assessment of occlusion of blood vessels in the feet, was improved at 9 months.[23] Although PWV before tadalafil administration was comparable between the patients in their study and those in our study, the patients in their study were younger than those in our study by 6.1 years. Thus, secretion of nitric oxide might have been higher in the patients in their study, because of which tadalafil might have yielded better effects. Consequently, the results of their study were better than those of our study. Moreover, Fukumoto et al. reported that in ED patients with advanced arteriosclerosis, the penile brachial index (calculated as penile systolic blood pressure/brachial systolic blood pressure) is low, which indicates advanced penile vascular disorder.[24]

Possible explanations for nonsignificant pulse wave velocity decrease after tadalafil treatment

PWV did not significantly decrease in any patient in our study. There are two possible reasons for this finding. One reason is that our study included many patients without arteriosclerosis. In other words, because there were many patients with normal vascular conditions, no significant decrease in PWV might have been observed. The other reason includes the inherent limitations associated with PWV measurements. Although FMD is considered to reflect changes in small blood vessels, PWV is a parameter for determining improvement in relatively large blood vessels. There is a report of a study using FMD in which early regression of arteriosclerosis was achieved.[20] Even if arteriosclerosis and the endothelium of microvessels are improved, such subtle changes are difficult to detect by means of PWV.

In our subanalyses, patients at a high risk of cardiovascular events showed significant decreases in PWV at weeks 24 and 36 compared with that before treatment. Although no significant decrease was observed at week 48, the difference in PWV between before treatment and at week 48 was small. With further accumulation of cases, the difference may increase. Even in healthy people, PWV increases with age.[25] The measurements of PWV at week 48 might have increased because of the effects of aging. After week 48, PWV did not worsen even at 1 year after the start of this study. Although these results did not reveal regression of arteriosclerosis, the progression of vascular lesions might have been inhibited. Tadalafil was suggested to be effective for reducing arteriosclerosis in patients at a high risk of cardiovascular events.

Furthermore, in patients aged 75 years or older, improvement was observed at only week 24. Because PWV values increase with age in healthy individuals, most patients aged 75 years or older had a high PWV value before tadalafil administration and hence might have shown a significant improvement.

Limitations and strengths

In this regard, PWV did not decrease in patients aged <75 years. As for the limitation of this study, we cannot exclude the possibility that patients at a high risk of arteriosclerosis might have improved their lifestyles at their own discretion or been treated for lifestyle diseases, such as hypertension, dyslipidemia, and diabetes mellitus, during the study period.

This study revealed improvement in the IPSS and OABSS. Improved blood flow in the bladder and prostate tissue improved bladder function, which might have contributed to relief of overactive bladder (OAB) symptoms. In addition, the afferent inhibitory effect of tadalafil might have been associated with the improved scores. A recent study revealed the efficacy of tadalafil for OAB.[26]

We did not use the SHIM. Because we enrolled many elderly patients, there were many patients who engaged in few sexual activities. In this condition, it seemed difficult to accurately assess patients' sexual function. Thus, we used the EHS, a measure of erectile function. The EHS is considered useful for diagnosing ED and assessing treatment effects.[27] It has also been reported that the EHS enables assessment of erectile function at levels at which neither the International Index of Erectile Function nor SHIM can detect.[28] Tsujimura et al. reported that high PWV and a low EHS are related.[29] In our study, because the EHS was significantly improved at all time points, it seemed that patients noticed regression of arteriosclerosis.


  Conclusions Top


The long-term administration of tadalafil (5 mg daily) reduced arteriosclerosis or inhibited its progression and relieved dysuria and improved erectile function. In particular, the drug was revealed to be more effective in patients at a high risk of cardiovascular events and those aged 75 years or older. Hence, tadalafil may have the potential to be used as an anti-aging medicine, although further studies with longer observation periods are needed to confirm its effectiveness and safety.

Acknowledgments

We thank all patients, nurses, medical assistants, and clinical technologists in our hospitals.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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