|
 
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| ORIGINAL ARTICLE |
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| Year : 2018 | Volume
: 20
| Issue : 2 | Page : 104-110 |
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Medical management of patients with benign prostatic hyperplasia: A study in Indian population
Amit Kumar Shah1, Anand Srivastava1, SC Karan2
1 Department of Urology and Surgery, INHS Asvini, Mumbai, Maharashtra, India
2 Department of Urology and Renal Transplant, Columbus Hospital, Ghaziabad, Uttar Pradesh, India
| Date of Submission | 04-May-2018 |
| Date of Acceptance | 10-Aug-2018 |
| Date of Web Publication | 10-Jan-2019 |
Correspondence Address:
Lt Col Amit Kumar Shah
Department of Surgery, INHS Asvini, Colaba, Mumbai - 400 005, Maharashtra
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/jmms.jmms_22_18
Introduction: At present, the geriatric population has formed a large clientele for medical services, with an increased incidence of lifestyle diseases. Approach to lower urinary tract symptoms due to benign prostatic hyperplasia (BPH) is an upcoming challenge, especially with management showing a paradigm shift toward medical management. This study was basically designed to study the outcome of medical management of BPH on Indian population following the recommendations based on recent guidelines on medical management of BPH. Materials and Methods: With a calculated sample size of 131 based on the prevalence of BPH, a total of 170 patients were enrolled, and their complete profile with clinical examination, imaging and International Prostatic Symptom Score details were taken as per proforma and were followed up while on medical management and assessed on a cross-sectional basis at regular intervals. Results: The mean age in the study group was 64.61 years. We recorded that all patients had some formal education. These patients were prescribed α-1ablockers as monotherapy or combination therapy as per the protocol of the study. They showed improvement while on medical management with significant improvement. Adverse reactions of medical management were not significant enough to warrant discontinuation of therapy. Forty-one patients out of 170 underwent surgery for no response or worsening quality of life. This group was further analyzed which revealed that comorbid condition, prostate size, and body mass index had no association with the outcome. Conclusion: There is sufficient evidence to support the paradigm shift in the management of BPH. The present guideline is to initiate medical management with monotherapy for patients with BPH and prostate size <30 g and combination therapy for larger prostate sized >30 g. Surgery is advised for patients who do not respond to medical therapy and for the subgroup of patients with absolute indication for surgery in BPH. Keywords: 5 alpha reductase inhibitors, alpha blockers, benign prostatic hyperplasia, bladder outlet obstruction, International Prostatic Symptom Score, overactive bladder, quality of life
How to cite this article:
Shah AK, Srivastava A, Karan S C. Medical management of patients with benign prostatic hyperplasia: A study in Indian population. J Mar Med Soc 2018;20:104-10 |
| Introduction | |  |
In the present scenario, where the geriatric age group is expanding and forms a large subgroup of patient clientele, the approach to lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) is a challenge to primary care physicians and specialists. The past decade has contributed immensely to our understanding of the natural history of BPH and the patient demography. Medical management is taking a more prominent role with decreasing number of surgeries. In Asia, the studies done on BPH are available from Japan and other regions of Eastern Asia. Hence, the aim of the study was primarily to study the outcome of medical management of BPH as medical therapy forms the initial management for LUTS secondary to BPH where there are no absolute indications for surgery. This study was also designed to guide and sensitize the practicing clinicians, based on the available recommendations, for monotherapy and combination therapy based on the size of prostate on ultrasonography. Presence of changes due to bladder outlet obstruction (BOO) leading to overactive bladder (OAB) symptoms also warrants a drug trial of anticholinergic therapy before one can actually declare the failure of medical therapy. This study was basically designed to study the outcome of medical management of BPH on Indian population following the recommendations based on recent guidelines on medical management of BPH.
| Materials and Methods | | |
Sample size
The reported cumulative incidence for BPH in the male population aged 50 years or more is 15%. Autopsy studies show a histological prevalence of 8%, 50%, and 80% in the 4th, 6th, and 9th decades of life, respectively, for BPH.[1] The incidence of BPH with LUTS based on clinical diagnosis which requires intervention has been reported to be approximately 5%, in Asian population.[2] Assuming 80% power and 5% significance level (α = 0.05, β = 0.20), the minimum sample size calculated was 131.
Study design [Figure 1] | Figure 1: The study design based on American Urological Association guidelines where monotherapy with α-1a antagonist is recommended for prostate size <30 g and serum prostate-specific antigen value <1.5 ng/ml, while combination therapy with α-1a antagonist and 5 alpha reductase inhibitor is recommended for prostate size >30 g and serum prostate-specific antigen value >1.5 ng/ml
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The study design was duly approved by the institute's Ethical Committee. In this study [Figure 1], all patients undergoing treatment for BPH during the study period (April 2014–April 2016) were included in the study. Patients with diabetes mellitus, neurogenic bladder (due to any cause), and patients of any malignancy were excluded. In total, 221 patients were enrolled with the diagnosis of BPH, of these, 21 patients were lost to follow-up, 13 patients were later detected to have carcinoma prostate on biopsy consequent to rising prostate-specific antigen (PSA), 9 patients desired to change their α1A blocker tamsulosin/alfuzosin to silodosin, and eight patients got themselves operated at other hospitals during the study period. Hence, these patients (51) were excluded from this study. The remaining 170 patients comprised the study population.
The details were taken as per proforma based on demography details, clinical profile, International Prostatic Symptom Score (IPSS) with quality of life (QoL) score, serum PSA, ultrasonography (USG) findings, and satisfaction outcome. The treatment was started as per the study design with monotherapy (only α1A antagonist) for patients with IPSS >8, prostate size <30 g, and serum PSA <1.5 ng/ml. Patients with IPSS prostate size >30 g and serum PSA >1.5 ng/ml were placed on combination therapy (α1A antagonist with 5 alpha reductase inhibitors [ARIs]) [Figure 1]. These patients were regularly followed up while on treatment and assessed with clinical parameters, USG, uroflowmetry, and IPSS on a cross-sectional basis. The statistical analysis was done using SPSS software SPSS for Windows, Version 16.0 (SPSS Inc, Released 2007, Chicago). The tests which were applied were cross tabulation, Pearson's Chi-square test, mean standard deviation and analysis of variance, and Levene's test for equality of variances. P < 0.05 was considered statistically significant.
| Results | | |
In the study group [Figure 2], the mean age was 64.61 years (range 42–91 years). A majority of patients (110) belonged to the age group of 61–80 years (64.70%) followed by the age group of 40–60 years (48) or 28.24%. The least number of patients was seen in the age group of >80 years (12) or 7.06%. The minimum age of presentation was 42 years and maximum age was 91 years. All patients in the study group had some formal education which helped us in getting IPSS score sheet filled with better precision, and use of multilingual questionnaire added to this advantage. A total of 105 patients (61.76%) were in Grade I obesity. Only five patients were in Grade II obesity and the remaining sixty patients were within their ideal body weight. Most of the patients (109) in the study group had no comorbid condition. The commonest comorbid condition was hypertension with 45 patients (26.47%). We did not include patients with diabetes in our study group because of variability of bladder physiology in such patients. The other comorbid conditions may not have a direct correlation with BPH, but hypertension and ischemic heart disease may be part of metabolic syndrome, which may influence the development and progression of LUTS. | Figure 2: Primarily, 221 patients enrolled. The allocation done was nonrandomized and nonblinded because of the study design. However, 51 patients got excluded due to various reasons: The remaining 170 patients comprised the study population
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All patients had a benign feel of prostate on digital rectal examination (DRE). Their mean serum PSA on enrollment was 1.64 ng/ml. The patients were put on α-1a blockers as monotherapy or combination therapy as per the protocol of the study. The mean IPSS score and QoL score on enrollment in our study were 19.02 (range 10–24) and 4.51 (range 3–6), respectively. All patients on medical management showed gradual but significant improvement at 3 and 6 months [Table 1]. While on follow-up, one patient was operated at 3 months and 26 patients were operated at 6 months. The deterioration in both IPSS and QoL scores was found to be significant for the patients opting for surgical management. A total of 169 patients were further continued on medical management from the first assessment at 3 months. On further assessment at 6 months, 143 (84.11%) patients were satisfied on oral medications. All patients on imaging had normal upper tracts while on regular treatment. There was mean reduction in prostate size from mean 50.02 g on enrollment to 46.27 g at 12 months and to 43.75 g at 24 months, which was statistically not significant (P = 0.97). In our study, 45 patients were started on α-1a blockers as monotherapy, while the remaining 125 patients (75.53%) were placed on combination therapy as per the protocol of the study. At 3 months, 102 (60%) patients reported no adverse effects, while 23 patients reported giddiness, 23 more patients reported retrograde ejaculation, and 12 patients reporting rhinitis on α-1a blocker therapy. Twenty-two patients reported erectile dysfunction (ED)/loss of libido on combination therapy with dutasteride. A total of 169 patients were further continued on medical management at this time and we added anticholinergic (tablet tolterodine 4 mg) in 33 patients for symptoms pertaining to an OAB. On further assessment at 6 months, 125 patients (87.41%) reported no significant adverse effects on oral medications. Out of the remaining 18 patients, 10 patients reported adverse effects pertaining to anticholinergics in the form of dry mouth and constipation. The remaining eight patients reported giddiness, ED, and retrograde ejaculation. At 12 months of continued medical management of 143 patients, 140 patients (97.9%) reported no significant adverse effects on oral medications. Out of the remaining three patients, two patients reported adverse effects pertaining to anticholinergics in the form of dry mouth. The remaining one patient reported retrograde ejaculation and rhinitis. | Table 1: Negative outcome (surgery) compared in relation to comorbid condition (nonsignificant)
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In our study group, 33 patients were prescribed anticholinergics at 3 months of follow-up for OAB/storage symptoms. Additional ten patients were also prescribed tolterodine 4 mg at 6 months. Twenty-eight patients out of these 43 (65%) reported symptomatic relief on 12 weeks' therapy with anticholinergics. None of these patients developed acute urinary retention (AUR) or had rise in postvoid residue (PVR).
Comprehensive data analysis
As we concluded our study in April 2016, due to various subgroups of patients completing a set of particular time period ranging from 6 months to 24 months, a comprehensive analysis was also carried out so as to have an applicable conclusion.
International Prostate Symptom Score and quality of life [Table 2] | Table 2: Comprehensive analysis of International Prostate Symptom Score and quality of life score with analysis of variance analysis for comparable groups
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Mean IPSS score at 24 months staggered to 11.75, while mean score on enrollment was 19.02. The range was from 9 to 16. There was a significant reduction in IPSS score in the patients while on medical management, with P = 0.000 which was highly statistically significant. Similarly, mean QoL on enrollment was 4.51 which reduced to 2 at 18 months and was staggered at 3.12 at 24 months in eight patients.
Comprehensive assessment of patients who underwent surgery
In this study, of the total 170 patients who were followed up and treated, 41 (1 + 26 + 13 + 1) patients underwent surgery at 3, 6, 12, and 18 months. Of them, one underwent surgery at 3 months because of persistently raised PVR. One of the patients out of 26, who underwent surgery at 6 months, requested for surgical treatment as he would not be available for a regular follow-up. The remaining 39 patients reported no improvement/deterioration on medical management with a poor QoL.
Surgery and comorbid condition
There were a total of 109 patients who had no comorbid disease, out of which 28 patients underwent surgery [Table 1]. In the remaining group of 61 patients, 11 patients underwent surgery for a poor QoL. The statistical analysis between these two unequal cohorts revealed no significance.
Outcome and body mass index
A total of 105 patients were in mildly obese category (body mass index [BMI]: 25–30 kg/m2) [Table 3]. The remaining 60 and 5 patients were in the category of ideal body weight (IBW) (BMI <25 kg/m2) and Grade II obesity (BMI: 30–39 kg/m2). None of the patients were morbidly obese. The statistical analysis of this group showed no statistical significance for BMI with patients' outcome on medical management of BPH or correlation between BMI and patients who underwent surgery.
Surgery and prostate size, postvoid residue, and uroflowmetry variables
We compared the patients who underwent surgery (41) to other variables on USG (prostate size and PVR) and on uroflowmetry (Qmax and Qav). We found that prostate size was not significantly related to final outcomes for the patients who underwent surgery. However, PVR, Qmax, and Qav were significantly different between the two groups. There was a significant difference in the two unequal cohorts of patients who underwent surgery (41) and patients who were successfully managed on medical management (129) [Table 4]. The cohorts were not equal in size, so equal variances were not assumed for the two groups, and hence, the results shown were applicable in our cohorts of patients undergoing surgery (41) and those on medical management (129). | Table 4: Group statistics between negative outcome (surgery) and on successful medical management
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| Discussion | | |
The incidence of LUTS due to BPH is rare before 40 years of age, but, approximately 50% of men develop LUTS at 50 years of age. There is a gradual rise in the incidence of BPH from the 6th to 9th decades of life and may reach to 80% by 80 years of age. Approximately three-fourths of symptomatic men >50 years of age require medical management for BPH, and 20%–30% out of them may require surgical intervention before reaching 80 years of age.
The aim of treatment for BPH is to improve or relieve LUTS that results from BOO and/or due to neurophysiological changes of bladder neck and urinary bladder. Terazosin used as a nonselective alpha-adrenergic antagonist demonstrated the effectiveness in relieving LUTS in the Hytrin Community Assessment Trial.[3] Tamsulosin being more selective alpha-adrenergic antagonist provided relatively rapid symptomatic and urinary flow improvement.[4] The Proscar Long-Term Efficacy and Safety Study (PLESS) trial done for use of 5 ARI (finasteride) in BPH is still the largest trial conducted.[5] The Veterans Administration Cooperative Trial used alpha adrenergic antagonists and 5-ARIs as a combination therapy in a randomized, double-blind, placebo-controlled study.[6] On similar treatment protocol, the Prospective European Doxazosin and Combination Therapy trial investigated the use of doxazosin, finasteride, and the combination of the two in comparison with placebo for treating BPH.[7] The Medical Treatment of Prostatic Symptoms (MTOPS) trial was later designed to compare the results and included more selective alpha-adrenergic agents missing in the previous trials.[8],[9] In addition to the primary outcomes of disease progression and clinical improvement, the trial also studied the changes in American Urological Association (AUA)-IPSS score and improvement in urinary flow rates. The incidence of surgical therapy for BPH, change in PSA, and volume of the gland were other parameters analyzed in the trial. The MTOPS trial was concluded in the year 2017 and their results showed that all the three treatment groups showed a risk reduction of clinical progression and findings were significant as against the placebo arm. The three treatment groups showed significant relief in LUTS as against the placebo arm. Urinary flow rates also have shown to be significantly improved compared with placebo in the three treatment groups. Recent guidelines have been now based on the conclusions of MTOPS trial that combination therapy is both safe and the most effective therapy for patients with LUTS due to BPH.[9] The recently concluded Combination of Avodart and Tamsulosin trial[10] compared treatment with the 5-ARI dutasteride, the uroselective alpha-blocking medication tamsulosin, and the combination of two. The published results show no significant difference in the change of volume of the gland between the 5 ARI group and in the combination group. It reiterates the results of the MTOPS trial that combination therapy carries significant benefit in the management of BPH, though we did not report any significant reduction in size of the prostate on a follow-up of 12 months.[10],[11] Alpha blockers are currently recommended for the treatment of symptomatic and bothersome LUTS due to BPH. Although previous generation α-1 adrenergic receptor antagonists such as doxazosin and terazosin are all equally effective as compared to the present-generation more uroselective α-1a and α-1d adrenergic receptor antagonists such as tamsulosin, alfuzosin, and silodosin, they are preferred in the treatment of BPH and LUTS, as they vary in their side effect profiles.[11],[12] The most common side effect of α-1 adrenergic antagonist is giddiness. EDs mostly in the form of retrograde ejaculations may occur, which is related to relaxation of bladder neck and possibly from interactions at muscular level of the vas deferens.[13] Alfuzosin and tamsulosin being specific uroselective drugs allow physicians to use at the recommended dose without any dose titration at the commencement of therapy. The adverse effects of medical therapy should be balanced along with the patient's age and prostate size while choosing the first-line mode of medical therapy. The older male population may benefit from medications that are more uroselective and reduce the cardiovascular events associated with their administration, whereas younger patients may desire drugs that cause less EDs and ejaculatory dysfunctions. Tamsulosin and alfuzosin being uroselective can be safely used in the older and younger populations, respectively, for the desired results.[13]
Testosterone and dihydrotestosterone are major contributors in development of BPH. That makes use of available 5-ARIs (finasteride and dutasteride) logical, as they block the synthesis of DHT from testosterone, and hence help in arresting the growth of prostate gland.[14] There are other multiple factors which contribute towards LUTS in cases of BPH and remain to be discovered. These are currently being studied and likely involve the interaction between the prostatic and cells of bladder neck to various endocrine and neural pathways.[15],[16] For patients on 5 ARIs, the values of total PSA show a reducing trend by about 50%, without affecting the free PSA percentage. For patients on 5 ARIs of more than 6 months' duration, the present guidelines recommend the doubling of total PSA values when done as prostate cancer screening.[17]
Recently introduced dutasteride has low rate of adverse events, mainly being ED, altered libido, gynecomastia, and ejaculatory disorders.[18] Both in the PLESS and MTOPS trials,[5],[9] the results demonstrate that for preventing disease progression, combination therapy is superior to either drug alone. A similar association was recorded in our study where majority on combination therapy showed improvement in LUTS and QoL and only <5% of patients reported ED or loss of libido. Reduction in prostate size was not significant in our study group at the end of 12 months and 24 months (P = 0.097). A higher serum PSA concentration is associated with BPH disease progression (>1.6 ng/ml), in men without prostate cancer, and treatment with 5 ARI therapy shows significant benefit.[4] Lower PSA concentration (<1.3 ng/ml) is associated with higher treatment success during treatment with antimuscarinic drugs.[4] Presently, there is no true consensus or guideline for the use of anticholinergics in the management of BPH-related irritative bladder symptoms. However, recent evidences show that addition of an anticholinergic to ongoing medical therapy with alpha-blocker provides a significant improvement in irritative part of LUTS.[16],[19] In this study, we used tablet tolterodine for duration of 3 months and 65% of the patients reported significant relief in the storage symptoms.
The Guideline Panel formed by the AUA in 1989 recommended a formal assessment of the patients' symptoms, using any scoring system, preferring the AUA Symptom Index/IPSS. A DRE is recommended to be done by urologists for the assessment of size and consistency. A baseline imaging and serum creatinine completes the initial profile. Patients with mild symptoms (with a score of 0–7) are assigned to watchful waiting; those with moderate (8–19) or severe (20–35) symptoms would undergo further testing or treatment, or both. Mebust et al.[20] showed that patients with a serum creatinine level >1.5% had a 25% incidence of postoperative complications versus 17% in those who had a normal creatinine level. Diokno et al. had reported annual incidence rates of 2.6% and 3.3% for undergoing prostatectomy while on medical management at 1 and 2 years, respectively, in their study.[19]
Medical management should be initiated first for patients with bothersome LUTS due to BPH, until there are absolute indications for surgery which are AUR, recurrent infection, recurrent hematuria, and azotemia.[21] Persistently raised PVR has been an indication for surgery in various studies, but Bruskewitz et al.[22] have brought out in their study that there are extreme variability in calculating PVR in the same patient at various time intervals considering other clinical scenarios.
| Conclusion | | |
During the latter part of the 20th century, transurethral resection of the prostate and prostatectomy were the only available therapies for BPH. These procedures had their own problems and results were not consistent, even at large-volume centers. Medical therapy hence got a start and presumptive acceptance at various centers.[15],[23] The success and persistence with medical therapy has been supported with current studies on complex neurological association of bladder neck with prostate and BOO. Recent guidelines state to use monotherapy with α-blocker therapy in patients with small prostates (<30 g), whereas combination therapy with α-blocker therapy and 5 ARI in patients with larger prostates (>30 g). Patients who perceive a lack of improvement in their LUTS, or have deterioration in QoL, or have significant adverse effects while on medical management are considered to have failed with medical management and surgical intervention is recommended for such patients.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]
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