Risk of erectile dysfunction associated with use of 5-α ...cohort entry as the date of the first...

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RESEARCH

1

open access

1Boston Collaborative Drug Surveillance Program Boston University School of Public Health Lexington MA 02421 USA2New England Research Institute Watertown MA USA3Kingston General Hospital Queenrsquos University Kingston Ontario CanadaCorrespondence to K W Hagberg khagbergbueduCite this as BMJ 2016354i4823httpdxdoiorg101136bmji4823

Accepted 15 August 2016

Risk of erectile dysfunction associated with use of 5-α reductase inhibitors for benign prostatic hyperplasia or alopecia population based studies using the Clinical Practice Research DatalinkKatrina Wilcox Hagberg1 Hozefa A Divan2 Rebecca Persson1 J Curtis Nickel3 Susan S Jick1

ABSTRACTObjeCtiveTo estimate the risk of erectile dysfunction in men who used 5-α reductase inhibitors to treat benign prostatic hyperplasia or alopeciaDesignCohort studies with nested case-control analysessettingUK Clinical Practice Research DatalinkPOPulatiOnTwo populations of men free of risk factors for erectile dysfunction and other sexual dysfunction or its treatment men aged 40 or more with benign prostatic hyperplasia who received a prescription for a 5-α reductase inhibitor (finasteride or dutasteride) or α blocker or both and men aged 18-59 with alopeciaexPOsuresIn the benign prostatic hyperplasia study exposures were classified as 5-α reductase inhibitors only 5-α reductase inhibitors+α blockers or α blockers only In the alopecia study exposures were finasteride 1 mg or no treatmentMain OutCOMe MeasuresCases were men with a diagnosis of erectile dysfunction or treatment (procedure or prescription for a phosphodiesterase type 5 inhibitor) during follow-up We calculated incidence rates and adjusted incidence rate ratios with 95 confidence intervals We also conducted nested case-control analyses to control for major confounders and calculated adjusted odds ratios with 95 confidence intervalsresultsIn the population with benign prostatic hyperplasia (n=71 849) the risk of erectile dysfunction was not

increased with use of 5-α reductase inhibitors only (incidence rate ratio 092 95 confidence interval 085 to 099 odds ratio 094 95 confidence interval 085 to 103) or 5-α reductase inhibitors+α blocker (109 099 to 121 092 080 to 106) compared with α blockers only and remained null regardless of number of prescriptions or timing of use The risk of erectile dysfunction increased with longer duration of benign prostatic hyperplasia regardless of exposure For the alopecia population (n=12 346) the risk of erectile dysfunction was not increased for users of finasteride 1 mg compared with unexposed men with alopecia (103 073 to 144 095 064 to 141)COnClusiOn5-α reductase inhibitors do not seem to significantly increase the risk of incident erectile dysfunction regardless of indication for use Risk of erectile dysfunction increased with longer duration of benign prostatic hyperplasia

IntroductionThe 5-α reductase inhibitors finasteride (5 mg) and dutasteride (05 mg) are primarily used to treat benign prostatic hyperplasia with a second indication for fin-asteride 1 mg to treat alopecia Though benign prostatic hyperplasia itself is an independent risk factor for erec-tile dysfunction1 evidence suggests that 5-α reductase inhibitors may independently increase the risk of adverse sexual side effects2-10 potentially through induction of androgen deficiency by inhibition of 5-α reductase and reduction in available 5-α dihydrotestos-terone11 Further these adverse effects may be per-sistent or irreversible even when treatment is discontinued5 9-11 In addition a recent meta-analysis of sexual adverse events from the few published clinical trials available evaluating the efficacy of finasteride 1 mg for alopecia reported that the data are limited of poor quality and insufficient for establishing the safety profile of the drug for alopecia treatment12

Changes to the labeling of finasteride were announced by the Food and Drug Administration in 2011 and 2012 to include a list of reported sexual adverse events13 Of particular concern is that many reports of sexual dysfunction were in previously healthy young men using finasteride 1 mg for alopecia9 Increasing patient activism including establishment of a research foundation for ldquopost-finasteride syndromerdquo is indicative of growing alarm and the need for aware-ness and research on long term complications of 5-α reductase inhibitor use14 Finally assessment of the safety of 5-α reductase inhibitors for benign prostatic hyperplasia and alopecia is warranted owing to the

WhAT IS AlReAdy knoWn on ThIS TopICErectile dysfunction and other sexual dysfunctions have been reported as adverse effects of 5-α reductase inhibitors in clinical trial settingsBenign prostatic hyperplasia one of the indications for use of 5-α reductase inhibitors is a risk factor for erectile dysfunction and other sexual dysfunctions

WhAT ThIS STudy AddSOur study results provide evidence that 5-α reductase inhibitors do not increase the risk of clinically meaningful incident erectile dysfunction or non-erectile dysfunction sexual dysfunction in men who are free of sexual dysfunction and major risk factors (eg prostate genital or urinary cancers surgical procedures) regardless of indication for use (benign prostatic hyperplasia or alopecia)The risk of erectile dysfunction increased with longer duration of benign prostatic hyperplasia independent of exposure which should be accounted for in the design of future studies evaluating the safety of 5-α reductase inhibitors

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large sales volume15 and prescribing of these drugs for hair loss to otherwise healthy young men We con-ducted two cohort studies with nested case-control analyses to evaluate the risk of erectile dysfunction in men who used 5-α reductase inhibitors to treat benign prostatic hyperplasia or alopecia We also estimated the rate of non-erectile dysfunction sexual dysfunctions (ejaculatory disorder psychosexual dysfunction and low libido) in these populations of 5-α reductase inhib-itor users

MethodsData sourceThis study was conducted using the UK Clinical Practice Research Datalink (CPRD) a large longitudinal popu-lation based electronic medical record database that contains data on approximately 10 million people Participating general practitioners contribute data in an anonymous format including medical diagnoses lifestyle details (eg smoking body mass index) details of hospital stays and specialist visits and deaths as well as details of all drugs prescribed including formu-lation and dosing instructions Data in the CPRD are collected prospectively and all information on diseases and prescriptions is recorded in the absence of a study hypothesis so there is no risk of recall bias Validation studies have indicated that the recorded data are of high accuracy with more than 90 of information from the manual medical records present in the general prac-titionerrsquos office recorded on the computer16 17

Patient populationsThe study period was 1 January 1992 (the year that finas-teride was first available in the UK) through 31 Decem-ber 2011 We limited the end of the study period to 31 December 2011 owing to changes in the indication for use of phosphodiesterase type 5 inhibitors (drugs indi-cated for the treatment of erectile dysfunction which were approved for the treatment of benign prostatic hyperplasia in 2012) and changes in the UK Quality and Outcomes Framework (which prompts all general prac-titioners to document whether they have asked all men with diabetes about potential erectile dysfunction)

We identified all men in the CPRD who had a pre-scription for either a 5-α reductase inhibitor (finasteride or dutasteride) or an α blocker (alfuzosin doxadosin indoramin prazosin tamsulosin and terazosin) or both plus a diagnosis of benign prostatic hyperplasia or prostatism recorded at any time prior to the first pre-scription date through three months after (to allow time for general practitioners to record diagnoses made by specialists) During the study period α blockers were the only available alternative pharmaceutical treatment for benign prostatic hyperplasia thus we chose them as an active comparator to ensure that all men included in the study population had benign prostatic hyperplasia severe enough to require treatment α blockers are also indicated for hypertension therefore to be included users were required to have a diagnosis of benign pros-tatic hyperplasia or prostatism We defined the date of cohort entry as the date of the first prescription for a 5-α

reductase inhibitor or α blocker in the patientrsquos record The study population was restricted to men who were aged 40 years or older and who had at least three years of history before the cohort entry date A three year requirement was selected to ensure that men were free from sexual dysfunction before cohort entry and were new users of a study drug These men (n=71 849) com-prised the population with benign prostatic hyperpla-sia (fig 1)

We then separately identified all men in the CPRD who had a diagnosis of alopecia (male pattern bald-ness) between 1 January 2002 (the first year finas-teride was prescribed for alopecia) and 31 December 2011 were aged 18-59 and had at least one year of history in their record before cohort entry We defined the date of cohort entry as 1 January 2002 (the start of the study period) the date of the first alopecia diag-nosis occurring after 1 January 2002 or the date of the first prescription for finasteride 1 mg where the pre-scription was recorded before the alopecia diagnosis We required only one year of history for this analysis because young men have shorter records in the CPRD and because there is less concern that patients in this age group have a history of sexual dysfunction or fin-asteride prescriptions prior to cohort entry These men (n=12 346) comprised the population with alope-cia (fig 2)

Men with prostate genital or urinary cancer prosta-tectomy or orchidectomy history of erectile dysfunction diagnosis or treatment (eg procedures or drugs used to treat erectile dysfunction) other sexual dysfunctions (eg ejaculatory disorder psychosexual dysfunction low libido) or Peyroniersquos disease before cohort entry or Klinefelterrsquos syndrome recorded at any time were

Men with a prescription of a 5 α reductaseinhibitor or an α blocker and a diagnosis of benign

prostatic hyperplasia or prostatism (n=115 443)

Eligible for benign prostatic hyperplasia studypopulation and included in cohort analysis (n=71 849)

Identied cases of erectiledysfunction (n=5814)

Controls matched to eligibleerectile dysfunctioncases (n=23 060)

Erectile dysfunction caseseligible for case-control

analysis (n=5768)

Excluded owing to cancerdiagnosis within 2 years

prior to index date (n=46)

Excluded (n=43 594) Age lt40 at cohort entry date (n=2571) lt3 years of recorded history before cohort entry date (n=25 243) Diagnosis of prostate genital or urinary cancer erectile dysfunction non-erectile dysfunction sexual dysfunction Peyroniersquos disease before cohort entry date or diagnosis of Klinefelterrsquos syndrome at any time (n=15 780)

Fig 1 | Flowchart for population with benign prostatic hyperplasia

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excluded from both the benign prostatic hyperplasia and the alopecia study populations

exposure definitionUsing the recorded prescribing details we calculated the duration of each prescription for 5-α reductase inhibitors as the quantity of pills divided by the number of pills prescribed each day For the benign prostatic hyperplasia population person days of exposure were accrued in the following categories 5-α reductase inhibitors only 5-α reductase inhibitors plus α block-ers and α blockers only as well as by timingof use cat-egorized as current (period of filled use plus 30 days) recent (days 31-90 after the end of current use) past (days 91-180 after the end of current use) and distant past use (the number of days after the end of past use) We considered men in the alopecia population to be unexposed until they received a prescription for finas-teride 1 mg Person days of finasteride 1 mg use were accrued and categorized as current (period of filled use plus 30 days) recent (days 31-90 after the end of current use) or past use (all days after the end of recent use) The censor date in both populations was the first of the following end of record death or record of prostate urinary genital pituitary or adrenal cancers prosta-tectomy orchidectomy end of study period (31 December 2011) date of being aged 60 years (for those in the alopecia population only) or date of being a case

Case identificationCases of erectile dysfunction were men with one or more of the following recorded during follow-up diag-nosis of erectile dysfunction or impotence prescription for a phosphodiesterase type 5 inhibitor (eg sildenafil tadalafil or vardenafil) where the strength and quantity prescribed was indicated for treatment of erectile

dysfunction or record of procedures for treatment of erectile dysfunction (eg penile prosthesis penile injec-tion or other operations for treatment of erectile dys-function) We defined the erectile dysfunction index datemdashthe date that the man was identified as a casemdashas the earliest date of diagnosis date of prescription for a phosphodiesterase type 5 inhibitor or date of proce-dure for erectile dysfunction

We also identified men with a diagnosis of a non-erec-tile dysfunction sexual dysfunction (ejaculatory disor-der psychosexual dysfunction or low libido) recorded during follow-up to assess the rate of these outcomes In studies on the non-erectile dysfunction sexual dysfunc-tion cohort the index date was the date that the man was given a diagnosis of ejaculatory disorder psycho-sexual dysfunction or low libido whichever came first

Matching criteria for nested case-control analysesUsing the cases of erectile dysfunction identified in the cohort analyses we conducted nested case-control analyses to control for age calendar time and risk fac-tors for erectile dysfunction We further excluded cases with a diagnosis of cancer (other than non-melanoma skin cancer) within two years before the index date because cancer and its treatment may be associated with the development of erectile dysfunction (n=46 in the population with benign prostatic hyperplasia n=1 in the alopecia population) For each eligible case we used risk set sampling to match up to four controls from the population on year of birth (within two years) gen-eral practice attended index date (the same index date as the matched case) and year the patient started in the database (within two years) Controls were required to be present in the study population on the index date (that is the index date had to fall between the candi-date controlrsquos cohort entry date and censor date) and must not have had a diagnosis of or treatment for erec-tile dysfunction before the index date or have had a diagnosis of any cancer (other than non-melanoma skin cancer) within two years prior to the index date For the benign prostatic hyperplasia case-control match 5762 erectile dysfunction cases had four matched controls each whereas one case was matched to three controls three cases were matched to two controls and one case was matched to one control For the alopecia case- control match 539 of the cases had four matched con-trols each whereas four cases were matched to three controls and three cases were matched to two controls

Covariates of interestWe assessed the presence of covariates of interest at the cohort entry date (cohort studies) and the index date (case-control analyses) Covariates of interest in this study included known or suspected risk factors for erec-tile dysfunction and non-erectile dysfunction sexual dysfunctions age calendar time body mass index (lt185 185-249 25-299 ge30 unknown) smoking status (never smoker former smoker unknown) non-erectile dysfunction sexual dysfunction (eg ejaculatory disor-ders psychosexual dysfunction low libido) Peyroniersquos disease diabetes hypertension cardiovascular

Men with alopecia (n=29 228)

Eligible for alopecia study population andincluded in cohort analysis (n=12 346)

Excluded (n=16 882) Age lt18 or ge60 years at cohort entry date (n=7820) lt1 year of recorded history before cohort entry date (n=7108) Diagnosis of prostate genital or urinary cancer erectile dysfunction non-erectile dysfunction sexual dysfunction Peyroniersquos disease before cohort entry date or diagnosis of Klinefelterrsquos syndrome at any time (n=1954)


Controls matched to eligibleerectile dysfunction

cases (n=2178)


analysis (n=547)

Excluded owing to cancerdiagnosis within 2 yearsprior to index date (n=1)

Fig 2 | Flowchart for population with alopecia

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disease atherosclerosis or coronary heart disease kid-ney failure or dialysis cancer depression alcohol mis-use and drug misuse We also identified patients who received prescriptions for β blockers which have been associated with erectile dysfunction within six months prior to the cohort entry date and index date We classi-fied each patient in the benign prostatic hyperplasia population by whether they switched between study drugs (α blockers and 5-α reductase inhibitors) during follow-up We also evaluated the duration of benign prostatic hyperplasia (lt6 months 6 months-1 year 1-2 years 2-5 years ge5 years)

statistical analysesFor the benign prostatic hyperplasia cohort analysis we calculated incidence rates of erectile dysfunction and incidence rate ratios with 95 confidence intervals for each exposure category by age calendar year and timing of use (current recent past or distant past) In the benign prostatic hyperplasia nested case-control analysis we used conditional logistic regression to cal-culate crude odds ratios and 95 confidence intervals as well as odds ratios adjusted for body mass index smoking status non-erectile dysfunction sexual dys-functions Peyroniersquos disease hypertension diabetes hyperlipidemia depression orchitis alcohol misuse switching status and duration of benign prostatic hyperplasia to estimate the risk of erectile dysfunction in users of 5-α reductase inhibitors only and 5-α reduc-tase inhibitors+α blockers compared with use of α blockers only Odds ratios approximate the incidence rate ratio through the use of risk set sampling

For the alopecia cohort analysis we calculated inci-dence rates of erectile dysfunction and incidence rate ratios with 95 confidence intervals for unexposed men and for users of finasteride 1 mg by age calendar year and timing of finasteride 1 mg use (current recent and past) In the alopecia nested case-control analysis we used conditional logistic regression to calculated crude odds ratios and 95 confidence intervals as well as odds ratios adjusted for body mass index smoking status duration of benign prostatic hyperplasia non-erectile dysfunction sexual dysfunctions hyper-tension diabetes hyperlipidemia cardiovascular dis-ease liver disease depression alcohol misuse drug misuse and receipt of a β blocker prescription within six months prior to the index date to estimate the risk of erectile dysfunction in users of finasteride 1 mg for alopecia compared with unexposed men with alopecia In both the benign prostatic hyperplasia and the alope-cia nested case-control analyses we stratified the case-control results by age group to assess effect modi-fication We also assessed the potential for misclassifi-cation of cases with erectile dysfunction in sensitivity analyses restricted to the cases with codes that sup-ported the erectile dysfunction diagnosis including the presence of multiple erectile dysfunction diagnoses or prescriptions for phosphodiesterase type 5 inhibitors surgical procedures or referrals to specialty care and their matched controls Finally we calculated incidence rates of non-erectile dysfunction sexual dysfunctions

and incidence rate ratios with 95 confidence intervals for both the benign prostatic hyperplasia population and the alopecia population We did not conduct a nested case-control study for those outcomes owing to the low number of non-erectile dysfunction sexual dys-function cases identified All statistical analyses for this study were conducted using SAS statistical software version 93 (SAS Institute Cary NC)

Patient involvementNo patients were involved in setting the research ques-tion or the outcome measures nor were they involved in developing plans for design or implementation of the study No patients were asked to advise on interpreta-tion or writing of results There are no plans to dissemi-nate the results of the research to study participants or the relevant patient community

Resultserectile dysfunction in the benign prostatic hyperplasia populationOverall 71 849 men with benign prostatic hyperplasia were eligible for inclusion at cohort entry 8977 received a prescription for 5-α reductase inhibitors only 2592 for 5-α reductase inhibitors+α blockers and 60 280 for α blockers only (table 1) At cohort entry users of 5-α reductase inhibitors only and 5-α reductase inhibitors+α blockers were older and more likely to switch between study drugs during follow-up compared with users of α blockers only Users of 5-α reductase inhibitors+α block-ers had more comorbidities compared with users of 5-α reductase inhibitors only and α blockers only

We identified 5814 cases of erectile dysfunction of whom 5022 (864) had a diagnosis of erectile dysfunc-tion or impotence and 792 (136) were identified based on prescriptions for a phosphodiesterase type 5 inhibi-tor The incidence rate of erectile dysfunction was low-est among users of 5-α reductase inhibitors only (153 per 1000 person years 95 confidence interval 143 to 165) and similar among users of 5-α reductase inhibi-tors+α blockers (192 per 1000 person years 174 to 211) and α blockers only (201 per 1000 person years 196 to 207) Compared with users of α blockers only the adjusted incidence rate ratios for users of 5-α reductase inhibitors only and 5-α reductase inhibitors+α blockers were 092 (95 confidence interval 085 to 099) and 109 (099 to 121) respectively (table 2)

In the nested case-control analysis cases of erectile dysfunction were more likely than matched controls to be overweight or obese (as measured by body mass index) or to have a diagnosis of non-erectile dysfunc-tion sexual dysfunction hypertension diabetes hyper-lipidemia depression orchitis or alcohol misuse before the index date Cases also had longer duration of benign prostatic hyperplasia compared with controls and were more likely to switch between study drugs at some time before the index date (table 3 ) There was no effect on the risk of erectile dysfunction from use of 5-α reductase inhibitors only (adjusted odds ratio 094 95 confidence interval 085 to 103) or 5-α reductase inhib-itors+α blockers (092 080 to 106) compared with α

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blockers only (table 4 ) The results remained null regardless of number of prescriptions received or timing of use To assess effect modification we stratified the estimates by switching status and duration of benign prostatic hyperplasia The risk of erectile dysfunction was higher for switchers than for non-switchers inde-pendent of exposure Risk of erectile dysfunction also increased with longer duration of benign prostatic hyperplasia independent of exposure (table 4 ) Com-pared with users of α blockers only with duration of benign prostatic hyperplasia of less than six months the risk of erectile dysfunction for men with a duration of six months to one year was 115 (95 confidence interval 101 to 132) for users of α blockers only and 120 (093 to 156) for users of 5-α reductase inhibitors only which increased to 280 (250 to 313) and 254 (213 to 303) for users of α blockers only and 5-α reductase

inhibitors only respectively with duration of benign prostatic hyperplasia for five or more years The pattern was similar for users of 5-α reductase inhibitors+α blockers Finally we assessed effect modification by diabetes status by stratifying on the presence or absence of diabetes before the index date The reference in this analysis was users of α blockers only with no dia-betes The increase in risk of erectile dysfunction was present among men with diabetes whereas the risk was null for men without diabetes regardless of exposure to α blockers only 5-α reductase inhibitors only or 5-α reductase inhibitors+α blockers (table 4)

When we stratified by age to evaluate effect modifica-tion the risk of erectile dysfunction was similar to that of the main analysis regardless of age group Among cases and controls aged 40-69 years the adjusted odds ratio was 094 (95 confidence interval 082 to 106) for

table 1 | Characteristics of benign prostatic hyperplasia population values are numbers (percentages) unless stated otherwise

Characteristics total (n=71 849)

exposure on cohort entry date

P valueα blockers only (n=60 280)

5-α reductase inhibitors only (n=8977)

5-α reductase inhibitors+α blockers (n=2592)

Age at cohort entry (years) 40-49 3588 (50) 3400 (56) 161 (18) 27 (10)

lt0001

50-59 12 288 (171) 11 057 (183) 980 (109) 251 (97) 60-69 22 228 (309) 18 883 (313) 2590 (288) 755 (291) 70-79 22 125 (308) 17 989 (298) 3224 (359) 912 (352) 80-89 10 538 (147) 8127 (135) 1829 (204) 582 (225) ge90 1082 (15) 824 (14) 193 (22) 65 (25)Year of cohort entry 1992-94 3110 (43) 1995 (33) 1068 (119) 47 (18)

lt0001 1995-99 12 213 (170) 9772 (162) 2286 (255) 155 (60) 2000-04 21 967 (306) 19 196 (318) 2356 (262) 415 (160) 2005-09 23 979 (334) 20 126 (334) 2516 (280) 1337 (516) 2010-11 10 580 (147) 9191 (153) 751 (84) 638 (246)Body mass index at cohort entry lt185 796 (11) 639 (11) 122 (14) 35 (14)

lt0001 185-249 22 395 (312) 18 571 (308) 2985 (333) 836 (323) 25-299 29 717 (414) 24 994 (415) 3631 (405) 1092 (421) ge30 13 689 (191) 11 797 (196) 1425 (159) 467 (180) Unknown 5255 (73) 4279 (71) 814 (91) 162 (63)Smoking status at cohort entry Non-smoker 29 757 (414) 24 829 (412) 3951 (440) 977 (377)

lt0001 Smoker 10 444 (145) 8874 (147) 1222 (136) 348 (134) Former smoker 26 631 (371) 22 452 (373) 3011 (335) 1168 (451) Unknown 5017 (70) 4125 (68) 793 (88) 99 (38)Comorbidities at cohort entry Lower urinary tract symptoms 43 948 (612) 37 496 (622) 4740 (528) 1712 (661) lt0001 Hypertension 25 506 (355) 21 383 (355) 3095 (345) 1028 (397) lt0001 Diabetes 7141 (99) 5963 (99) 869 (97) 309 (119) 0002 Hyperlipidemia 11 200 (156) 9494 (158) 1230 (137) 476 (184) lt0001 Cardiovascular disease 21 810 (304) 17 544 (291) 3356 (374) 910 (351) lt0001 Atherosclerosis 1431 (20) 1166 (19) 207 (23) 58 (22) 004 Metabolic syndrome 13 (00) 11 (00) 1 (00) 1 (00) Not calculated Kidney failuredialysis 4242 (59) 3399 (56) 564 (63) 279 (108) lt0001 Cancer 2922 (41) 2431 (40) 357 (40) 134 (52) 001 Depression 6926 (96) 5956 (99) 758 (84) 212 (82) lt0001 Alcohol misuse 2628 (37) 2263 (38) 270 (30) 95 (37) 0002 Drug misuse 455 (06) 389 (07) 52 (06) 14 (05) 063β blocker prescription within 6 months prior to cohort entry date 12 284 (171) 10 149 (168) 1626 (181) 509 (196) lt0001Switch between or add 5-α reductase inhibitors or α blockers during follow-updagger 15 172 (211) 11 153 (185) 2695 (300) 1324 (511) lt0001Not mutually exclusivedaggerSwitching defined as change during follow-up in prescribed study drugs (that is differed from drug prescribed at cohort entry)

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users of 5-α reductase inhibitors only and 096 (080 to 116) for users of 5-α reductase inhibitors+α blockers whereas among cases and controls aged 70 years or older the adjusted odds ratio was 089 (077 to 105) for users of 5-α reductase inhibitors only and 082 (065 to 103) for users of 5-α reductase inhibitors+α blockers The results were also not materially different from the main analysis when we conducted the sensitivity anal-ysis restricted to the erectile dysfunction cases who had additional codes that supported the erectile dysfunc-tion diagnosis (n=4960 86) and their matched con-trols (adjusted odds ratio 089 (95 confidence interval 080 to 100) for 5-α reductase inhibitors only and 085 (073 to 100) for 5-α reductase inhibitors+α blockers compared with α blockers only)

erectile dysfunction in the alopecia populationWe identified 12 346 men with alopecia who were eligi-ble for inclusion in the alopecia population of whom 463 received a prescription for finasteride 1 mg at cohort entry (n=868 of the alopecia population who used fin-asteride 1 mg at some time during follow-up) and 11 883 were unexposed at cohort entry (table 5 ) At cohort entry users of finasteride 1 mg for alopecia were younger and more likely to have depression or to have received a prescription for β blockers within the prior six months whereas unexposed men with alopecia had more diagnoses of lower urinary tract symptoms We identified 547 cases of erectile dysfunction of whom 491 (898) had a diagnosis of erectile dysfunction or impotence and 56 (102) were identified based on pre-scriptions for a phosphodiesterase type 5 inhibitor The incidence rates of erectile dysfunction were similar for users of finasteride 1 mg (101 per 1000 person years (95 confidence interval 70 to 139) and unexposed men (98 per 1000 person years 89 to 107) (table 6 ) The incidence rate ratio adjusted for age and calendar time was 113 (95 confidence interval 080 to 158) for users of finasteride 1 mg compared with unexposed men with alopecia (table 6)

In the nested case-control analysis cases of erectile dysfunction were more likely than matched controls to be overweight or obese be former smokers or have non-erectile dysfunction sexual dysfunction hyperten-sion diabetes hyperlipidemia cardiovascular disease liver disease depression and alcohol and drug misuse before the index date (table 7 ) The adjusted odds ratio for erectile dysfunction was 094 (95 confidence inter-val 064 to 140) for users of finasteride 1 mg compared with unexposed men (table 8 ) The risk of erectile dys-function increased with increasing number of finas-teride 1 mg prescriptions from 069 (95 confidence interval 033 to 140) for one prescription to 143 (071 to 290) for 10 or more prescriptions but none of the odds ratios were statistically significant The risk of erectile dysfunction was null regardless of timing of use or time since the last prescription (table 8) When we stratified by age to evaluate effect modification the risk of erec-tile dysfunction in users of finasteride 1 mg was higher in men aged 40-59 years (adjusted odds ratio 145 95 confidence interval 087 to 244) than in men aged 18-39 ta

ble

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1481

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1091

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1995

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299

21 94

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3)

9083

9610

7 (8

6 to

132

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605

165

(79

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415

9066

291

240

(22

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412

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173

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973

3316

2 (1

34

to 19

4)

Tim

ing

of u

se

Cu

rrent

2496

124 0

9920

1 (1

93

to 2

09)

421

28 42

514

8 (1

34

to 16

3)

403

20 8

4419

3 (1

75 to

213

)

Rece

nt32

713

619

240

(215

to 2

68)

4725

4718

5 (1

36

to 2

45)

527

818

0 (5

8 to

42

0)

Past

138

5752

240

(20

2 to

28

3)13

999

130

(69

to 2

23)

391

331

(67

to 9

68)

Di

stan

t pas

t17

0488

255

193

(175

to 2

13)

246

15 39

816

0 (1

40

to 18

1)11

796

138

(69

to 2

47)

Tota

l

Crud

e46

6523

1 724

201

(19

6 to

20

7)10

(ref

)72

747

369

153

(14

3 to

165

)0

76 (0

71

to 0

82)

422

22 0

0819

2 (1

74 to

211

)0

95 (0

86

to 1

05)

Ad

just

ed

10 (r

ef)

092

(0

85 to

09

9)10

9 (0

99

to 1

21)

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uste

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r age

gro

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alen

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ime

and

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ing

of u

se

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7

years (050 026 to 098) although the difference in risk by age was not statistically significant

Since men with alopecia who were prescribed finas-teride 1 mg were generally healthier and had fewer risk factors for erectile dysfunction than men with alopecia not taking finasteride 1 mg we conducted additional

analyses to determine whether the null results could be explained by differences in the baseline health status of the two groups We first restricted the analysis to cases and controls who did not have risk factors for erectile dysfunction (benign prostatic hyperplasia non-erectile dysfunction sexual dysfunction Peyroniersquos disease or

table 3 | nested case-control analysis characteristics of cases with erectile dysfunction and controls in benign prostatic hyperplasia population values are numbers (percentages) unless stated otherwise

Characteristics Cases (n=5768) Controls (n=23 060)univariate odds ratio (95 Ci)

Age at erectile dysfunction index date (years) 40-49 221 (38) 928 (40) - 50-59 1232 (214) 4730 (205) - 60-69 2557 (443) 9895 (429) - 70-79 1528 (265) 6470 (281) - 80-89 226 (39) 1015 (44) - ge90 4 (01) 22 (01) - Mean (SD) 650 (85) 654 (86)Erectile dysfunction index year 1992-95 19 (03) 71 (03) - 1995-99 396 (69) 1582 (69) - 2000-04 1854 (321) 7413 (322) - 2005-09 2447 (422) 9786 (424) - 2010-11 1052 (182) 4208 (183) -Mean (SD) length of record before erectile dysfunction index date (years) 132 (45) 132 (45) -Body mass index at erectile dysfunction index date lt185 20 (04) 215 (09) 044 (028 to 070) 185-249 1392 (241) 6561 (285) 10 (ref) 25-299 2688 (466) 9885 (429) 129 (120 to 139) ge30 1481 (257) 5163 (224) 137 (126 to 149) Unknown 187 (32) 1236 (54) 071 (060 to 084) Mean (SD) 279 (45) 274 (46)Smoking status at erectile dysfunction index date Non-smoker 2215 (384) 9568 (415) 10 (ref) Smoker 803 (139) 3424 (149) 101 (092 to 110) Former smoker 2582 (448) 9191 (399) 124 (116 to 132) Unknown 168 (29) 877 (38) 080 (067 to 095)Duration of benign prostatic dysfunction at erectile dysfunction index date lt6 months 703 (122) 4687 (203) 10 (ref) 6 months-1 year 549 (95) 3269 (142) 113 (100 to 128) 1-2 years 870 (151) 4233 (184) 142 (127 to 158) 2-5 years 1773 (307) 5842 (253) 220 (199 to 242) ge5 years 1873 (325) 5029 (218) 287 (259 to 317) Mean (SD) 42 (41) 32 (38)Comorbidities at erectile dysfunction index date Lower urinary tract symptoms 4066 (705) 16 645 (722) 092 (086 to 098) Non-erectile dysfunction sexual dysfunction 72 (13) 52 (02) 561 (392 to 803) Peyroniersquos disease 24 (04) 34 (02) 282 (167 to 476) Hypertension 2308 (400) 8486 (368) 115 (109 to 122) Diabetes 958 (166) 2374 (103) 175 (161 to 190) Hyperlipidemia 1232 (214) 4474 (194) 114 (106 to 122) Cardiovascular disease 1583 (274) 6580 (285) 094 (088 to 101) Atherosclerosis 119 (21) 537 (23) 088 (072 to 108) Metabolic syndrome 3 (01) 9 (00) 133 (036 to 493) Kidney failuredialysis 326 (57) 1447 (63) 088 (078 to 101) Cancer 201 (35) 775 (34) 104 (089 to 122) Depression 869 (151) 2854 (124) 127 (116 to 138) Alcohol misuse 296 (51) 997 (43) 120 (105 to 137) Drug misuse 50 (09) 167 (07) 120 (087 to 165) Orchitis 387 (67) 1364 (59) 115 (102 to 129)β blocker prescription within 6 months prior to index date 1043 (181) 4209 (183) 099 (092 to 107)Switching between or adding study drug 897 (156) 2750 (119) 138 (127 to 150)Non-erectile dysfunction sexual dysfunction includes ejaculatory disorders psychosexual dysfunction and low libido

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table 4 | nested case-control analysis risk of erectile dysfunction by exposure in benign prostatic hyperplasia population

exposure at index dateCases (n=5768)

Controls (n=23 060)

Crude odds ratio (95 Ci)

adjusted odds ratio (95 Ci)

Exposureα blockers only 4624 (802) 18 699 (811) 10 (ref) 10 (ref)5-α reductase inhibitors only 723 (125) 2844 (123) 103 (094 to 113) 094 (085 to 103) Finasteride 623 (108) 2455 (107) 103 (093 to 113) 093 (083 to 103) Dutasteride 100 (17) 389 (17) 105 (084 to 131) 101 (080 to 128)5-α reductase inhibitors+α blockers 421 (73) 1517 (66) 113 (101 to 127) 092 (080 to 106) Finasteride 329 (57) 1143 (50) 117 (103 to 133) 094 (081 to 110) Dutasteride 92 (16) 374 (16) 100 (079 to 126) 085 (067 to 110)No of prescriptionsα blockers only 1 prescription 1005 (174) 4688 (203) 10 (ref) 10 (ref) 2-9 prescriptions 1818 (315) 8315 (361) 103 (094 to 112) 100 (092 to 109) 10-19 prescriptions 747 (130) 2683 (116) 133 (120 to 148) 110 (098 to 123) 20-29 prescriptions 400 (69) 1180 (51) 164 (143 to 187) 121 (105 to 139) ge30 prescriptions 654 (113) 1833 (80) 179 (159 to 202) 109 (097 to 124)5-α reductase inhibitors only 1 prescription 100 (17) 465 (20) 101 (080 to 126) 096 (076 to 121) 2-9 prescriptions 348 (60) 1283 (56) 129 (113 to 148) 114 (099 to 132) 10-19 prescriptions 125 (22) 496 (22) 122 (099 to 151) 089 (072 to 112) 20-29 prescriptions 63 (11) 234 (10) 134 (101 to 180) 087 (065 to 118) ge30 prescriptions 87 (15) 366 (16) 120 (094 to 154) 071 (055 to 092)5-α reductase inhibitors+α blockers 1 prescription 41 (07) 193 (08) 101 (072 to 144) 096 (067 to 138) 2-9 prescriptions 167 (29) 735 (32) 110 (092 to 132) 089 (072 to 109) 10-19 prescriptions 85 (15) 289 (13) 146 (113 to 188) 092 (069 to 121) 20-29 prescriptions 52 (09) 114 (05) 228 (162 to 320) 127 (089 to 182) ge30 prescriptions 76 (13) 186 (08) 211 (160 to 280) 106 (079 to 143)Timing of useα blockers only Current 2480 (430) 11 015 (478) 10 (ref) 10 (ref) Recent 321 (56) 1575 (68) 091 (080 to 103) 101 (089 to 115) Past 134 (23) 639 (28) 094 (077 to 113) 107 (088 to 130) Distant past 1689 (70) 5470 (237) 139 (129 to 149) 115 (106 to 124)5-α reductase inhibitors only Current 419 (73) 1820 (79) 102 (091 to 115) 093 (082 to 105) Recent 47 (08) 175 (08) 120 (086 to 166) 113 (081 to 158) Past 13 (02) 74 (03) 078 (043 to 140) 079 (043 to 145) Distant past 244 (42) 775 (34) 142 (121 to 165) 107 (092 to 126)5-α reductase inhibitors+α blockers Current 402 (70) 1446 (63) 124 (110 to 140) 095 (082 to 110) Recent 5 (01) 32 (01) 068 (026 to 174) 061 (024 to 160) Past 3 (01) 7 (00) 198 (051 to 766) dagger Distant past 11 (02) 32 (01) 153 (077 to 304) 108 (053 to 219)Stratified by switching statusα blockers only Non-switcher 4353 (755) 17 948 (778) 10 (ref) 10 (ref) Switcher 271 (47) 751 (33) 151 (131 to 174) 126 (109 to 146)5-α reductase inhibitors only Non-switcher 456 (79) 1963 (85) 096 (086 to 108) 096 (085 to 107) Switcher 267 (46) 881 (38) 127 (110 to 146) 115 (099 to 133)5-α reductase inhibitors+α blockers Non-switcher 62 (11) 399 (17) 065 (049 to 085) 076 (057 to 100) Switcher 359 (62) 1118 (49) 134 (118 to 152) 122 (107 to 139)Stratified by duration of benign prostatic hyperplasiaα blockers only lt6 months 593 (103) 3975 (172) 10 (ref) 10 (ref) 6 months-1 year 457 (79) 2669 (116) 116 (101 to 132) 115 (101 to 132) 1-2 years 702 (122) 3466 (150) 140 (124 to 158) 139 (123 to 156) 2-5 years 1426 (247) 4706 (204) 219 (197 to 244) 216 (193 to 240) ge5 years 1446 (251) 3883 (168) 288 (256 to 321) 280 (250 to 313)

(Continued )

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orchitis) before the index date The results were similar to those of the main analysis (adjusted odds ratio 097 95 confidence interval 062 to 147) We also conducted an analysis restricted to ldquohealthyrdquo cases and controls (those with no diagnoses of hypertension diabetes hyperlipidemia cardiovascular disease liver disease or cancer prior to the index date) and found no material differences in the results (074 047 to 119)

When we conducted a sensitivity analysis restricted to cases of erectile dysfunction who had clinical codes that supported the erectile dysfunction diagnosis (n=332 61) and their matched controls the odds ratio for users of finasteride 1 mg compared with unexposed men were null (adjusted odds ratio 149 95 confi-dence interval 091 to 242) When the analysis was fur-ther restricted to the ldquohealthyrdquo cases and controls the odds ratio was similar (074 047 to 119)

non-erectile dysfunction sexual dysfunctionsIn the benign prostatic hyperplasia population we identified 232 men with a non-erectile dysfunction sex-ual dysfunction diagnosis before the censor date (n=27 ejaculatory dysfunction n=88 psychosexual dysfunc-tion n=115 low libido and n=2 with multiple diagnoses recorded on the same date) The rate of non-erectile dysfunction sexual dysfunctions was 09 per 1000 per-son years (95 confidence interval 06 to 12) for users of 5-α reductase inhibitors only 08 per 1000 person years (05 to 12) for users of 5-α reductase inhibitors+α blockers and 08 per 1000 person years (06 to 09) for users of α blockers only Compared with users of α blockers only the incidence rate ratio of non-erectile dysfunction sexual dysfunction adjusted for age calen-

dar time and timing of exposure was 135 (95 confi-dence interval 095 to 191) for users of 5-α reductase inhibitors only and 162 (079 to 272) for users of 5-α reductase inhibitors+α blockers The rates were low and not significantly different by exposure when we considered ejaculatory dysfunction psychosexual dys-function and low libido separately For ejaculatory dys-function the incidence rate was 006 per 1000 person years (95 confidence interval 001 to 017) for users of 5-α reductase inhibitors only 005 per 1000 person years (0002 to 02) for 5-α reductase inhibitors+α block-ers and 010 per 1000 person years (006 to 014) for α blockers only For psychosexual dysfunction the inci-dence rate was 03 per 1000 person years (02 to 05) for users of 5-α reductase inhibitors only 02 per 1000 per-son years (01 to 04) for 5-α reductase inhibitors+α blockers and 03 per 1000 person years (00 to 04) for α blockers only For low libido the incidence rate was 05 per 1000 person years (03 to 07) for users of 5-α reduc-tase inhibitors only 065 per 1000 person years (03 to 09) for 5-α reductase inhibitors+α blockers and 04 per 1000 person years (03 to 04) for α blockers only

In the alopecia population we identified 104 men with a diagnosis of non-erectile dysfunction sexual dysfunction before the censor date (n=40 ejaculatory dysfunction n=16 psychosexual dysfunction n=46 low libido and n=1 with multiple diagnoses recorded on the same date) The rate of non-erectile dysfunction sexual dysfunctions for users of finasteride 1 mg was 279 per 1000 person years (95 confidence interval 142 to 498) and 180 per 1000 person years (146 to 219) for unex-posed men with alopecia The incidence rate ratio of non-erectile dysfunction sexual dysfunction adjusted



Controls (n=23 060)



5-α reductase inhibitors only lt6 months 78 (14) 439 (19) 120 (093 to 155) 120 (093 to 156) 6 months-1 year 55 (10) 371 (16) 102 (076 to 137) 096 (071 to 130) 1-2 years 103 (18) 497 (22) 144 (114 to 182) 133 (105 to 168) 2-5 years 216 (37) 765 (33) 209 (174 to 327) 195 (162 to 234) ge5 years 271 (47) 772 (34) 276 (233 to 327) 254 (213 to 303)5-α reductase inhibitors+α blockers lt6 months 32 (06) 273 (12) 079 (054 to 116) 071 (049 to 105) 6 months-1 year 37 (06) 229 (10) 112 (078 to 161) 096 (066 to 139) 1-2 years 65 (11) 270 (12) 171 (129 to 228) 139 (103 to 189) 2-5 years 131 (23) 371 (16) 266 (213 to 332) 214 (168 to 273) ge5 years 156 (27) 374 (16) 329 (266 to 406) 255 (202 to 322)stratified by diabetes statusα blockers only No diabetes 3852 (668) 16 788 (728) 10 (ref) 10 (ref) Diabetes 772 (134) 1911 (83) 177 (162 to 194) 169 (153 to 186)5-α reductase inhibitors only No diabetes 616 (107) 2572 (112) 105 (095 to 116) 095 (086 to 106) Diabetes 107 (19) 272 (12) 174 (138 to 218) 142 (112 to 180)5-α reductase inhibitors+α blockers No diabetes 342 (59) 1326 (58) 114 (101 to 129) 094 (081 to 109) Diabetes 79 (14) 191 (08) 185 (141 to 241) 136 (102 to 181)Adjusted for body mass index smoking status non-erectile dysfunction sexual dysfunctions Peyroniersquos disease hypertension diabetes hyperlipidemia depression orchitis alcohol misuse switcher and duration of benign prostatic hyperplasia conditional on matching factorsdaggerToo few cases or controls

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table 6 | incidence rates (irs) and incidence rate ratios (irrs) for erectile dysfunction by exposure in analysis of alopecia cohort

variables

unexposed Finasteride 1 mg

Cases (n=511) Person yearsir1000 person years (95 Ci) irr (95 Ci)

Cases (n=36)

Person years

ir1000 person years (95 Ci) irr (95 Ci)

Age group (years) 18-29 76 14 518 52 (41 to 66) 7 1016 69 (28 to 142) 30-39 119 16 767 71 (59 to 85) 6 1386 43 (16 to 94) 40-49 134 13 286 101 (85 to 119) 11 843 130 (65 to 233) 50-59 182 7696 236 (203 to 273) 12 334 359 (185 to 627)Calendar time 2002-04 93 11 433 81 (66 to 100) 7 547 128 (51 to 264) 2005-09 263 27 625 95 (84 to 107) 19 1960 97 (58 to 151) 2010-11 155 13 209 117 (100 to 137) 10 1073 93 (45 to 171)Timing of finasteride 1 mg use Current Not applicable Not applicable Not applicable 9 1035 69 (31 to 131) Recent Not applicable Not applicable Not applicable 2 217 92 (10 to 333) Past Not applicable Not applicable Not applicable 25 2057 122 (80 to 170)Total Crude 511 52 267 98 (89 to 107) 10 (ref) 36 3580 101 (70 to 139) 103 (073 to 144) Adjusted 10 (ref) 113 (080 to 158)Adjusted for age group and calendar year

table 5 | Characteristics of population with alopecia values are numbers (percentages) unless stated otherwise



P valueFinasteride 1 mg (n=463)

unexposed (n=11 883)

Age at cohort entry (years) 18-29 5134 (412) 182 (393) 4952 (417)

lt0001 30-39 3692 (299) 166 (359) 3526 (297) 40-49 2311 (187) 81 (175) 2230 (188) 50-59 1209 (98) 34 (73) 1175 (99)Year of cohort entry 2002-04 5452 (442) 145 (313) 5307 (447)

lt0001 2005-09 4793 (388) 239 (516) 4554 (383) 2010-11 2101 (170) 79 (171) 2202 (170)Body mass index at cohort entry lt185 288 (23) 5 (11) 283 (24)

lt0001 185-249 4783 (387) 207 (447) 4576 (385) 25-299 3285 (266) 128 (277) 3157 (266) ge30 1262 (102) 28 (61) 1234 (104) Unknown 2728 (221) 95 (205) 2633 (222)Smoking status at cohort entry Non-smoker 5089 (412) 230 (497) 4859 (409)

lt0001 Smoker 3575 (290) 99 (214) 3476 (293) Former smoker 1486 (120) 80 (173) 1406 (118) Unknown 2196 (178) 54 (117) 2142 (180)Comorbidities at cohort entry Duration of alopecia (years) Not calculated lt1 9884 (801) 463 (1000) 9421 (793) 1-2 444 (36) 0 (00) 444 (37) 2-5 937 (76) 0 (00) 937 (79) ge5 1081 (88) 0 (00) 1081 (91) Benign prostatic hyperplasia 132 (11) 5 (11) 127 (11) 093 Lower urinary tract symptoms 1517 (123) 3 (83) 1514 (123) lt0001 Hypertension 368 (30) 13 (28) 355 (30) 085 Diabetes 146 (12) 2 (04) 144 (12) 011 Hyperlipidemia 276 (22) 13 (28) 263 (22) 039 Cardiovascular disease 276 (22) 5 (11) 271 (23) 007 Atherosclerosis 12 (01) 0 (00) 12 (01) Not calculated Metabolic syndrome 0 (00) 0 (00) 0 (00) Not calculated Kidney failuredialysis 42 (03) 2 (04) 40 (03) 068 Cancer 44 (04) 2 (04) 42 (04) 072 Depression 1487 (120) 75 (162) 1412 (119) 0007 Alcohol misuse 406 (33) 9 (19) 397 (33) 009 Drug misuse 245 (20) 7 (15) 238 (20) 048 β blocker prescription within 6 months prior to cohort entry date 865 (70) 54 (117) 811 (68) lt0001

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for age calendar time and timing of use was 155 (95 confidence interval 098 to 247) for users of finasteride 1 mg compared with unexposed men with alopecia The rates were low and not significantly different by expo-sure when we considered ejaculatory disorder psycho-sexual dysfunction and low libido separately For ejaculatory disorder the incidence rate was 03 per 1000 person years (00 to 14) for users of finasteride 1 mg and 08 per 1000 person years (05 to 10) for unexposed men For psychosexual dysfunction the incidence rate was 00 per 1000 person years (00 to 02)

for users of finasteride 1 mg and 03 per 1000 person years (02 to 05) for unexposed men For low libido the incidence rate was 08 per 1000 person years (02 to 23) for users of finasteride 1 mg and 08 per 1000 person years (06 to 11) for unexposed men

discussionOverall the results of our study suggest that 5-α reductase inhibitors do not increase the risk of incident erectile dysfunction regardless of indication for use (benign prostatic hyperplasia or alopecia) In a population of men

table 7 | nested case-control analysis characteristics of cases with erectile dysfunction and controls in alopecia population values are numbers (percentages) unless stated otherwise

Characteristics Cases (n=547)Controls (n=2178)

univariate odds ratio (95 Ci)

Age at index date (years) 18-29 83 (152) 332 (152) - 30-39 125 (229) 501 (230) - 40-49 145 (265) 578 (265) - 50-59 194 (355) 767 (352) - Mean (SD) 430 (110) 429 (110)Index year 2002-04 100 (183) 396 (182) - 2005-09 282 (516) 1123 (516) - 2010-11 165 (302) 659 (303) -Mean (SD) length of record before index date (years) 131 (50) 131 (60) -Body mass index lt185 5 (09) 43 (20) 054 (021 to 139) 185-249 161 (294) 763 (350) 10 (ref) 25-299 194 (355) 735 (338) 127 (101 to 161) ge30 116 (212) 304 (140) 183 (139 to 241) Unknown 71 (130) 333 (153) 098 (072 to 133) Mean (SD) 271 (49) 261 (47)Smoking status Non-smoker 209 (382) 913 (419) 10 (ref) Smoker 179 (327) 678 (311) 116 (092 to 145) Former smoker 135 (247) 424 (195) 142 (111 to 181) Unknown 24 (44) 163 (75) 060 (037 to 096)Comorbidities at index date Benign prostatic hyperplasia 21 (38) 59 (27) 147 (087 to 248) No benign prostatic hyperplasia 526 (962) 2119 (973) 10 (ref) Duration of benign prostatic hyperplasia lt5 years 9 (17) 36 (17) 103 (048 to 218) ge5 years 12 (22) 23 (11) 216 (105 to 445) Lower urinary tract symptoms 144 (263) 352 (166) 182 (146 to 228) Orchitis 38 (70) 109 (50) 143 (097 to 211) Non-erectile dysfunction sexual dysfunction 19 (35) 13 (06) 617 (299 to 1273) Peyroniersquos disease 4 (07) 0 (00) dagger Hypertension 77 (141) 194 (89) 175 (130 to 237) Diabetes 54 (99) 48 (22) 474 (318 to 706) Hyperlipidemia 60 (110) 146 (67) 177 (128 to 246) Cardiovascular disease 45 (82) 113 (52) 164 (114 to 236) Atherosclerosis 5 (09) 8 (04) 257 (081 to 817) Metabolic syndrome 0 (00) 0 (00) dagger Kidney failuredialysis 8 (15) 22 (10) 149 (065 to 343) Cancer 6 (11) 12 (06) 200 (075 to 533) Liver disease 7 (13) 6 (03) 466 (157 to 1389) Depression 182 (333) 414 (190) 218 (176 to 270) Alcohol misuse 46 (84) 119 (55) 161 (112 to 230) Drug misuse 21 (38) 50 (23) 171 (102 to 288)β blocker prescription within 6 months prior to index date 49 (90) 84 (39) 255 (175 to 373)Non-erectile dysfunction sexual dysfunction includes ejaculatory disorders psychosexual dysfunction and low libidodaggerToo few cases or controls to calculate

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age 40 years and older with treated benign prostatic hyperplasia there was no increase in risk of incident erec-tile dysfunction with use of 5-α reductase inhibitors (fin-asteride or dutasteride) alone or in combination with α blockers compared with use of α blockers only In addi-tion among men aged 18-59 with alopecia there was no material increase in the risk of incident erectile dysfunc-tion in men prescribed finasteride 1 mg compared with unexposed men with alopecia Finally the rates of non-erectile dysfunction sexual dysfunctions were low regardless of indication for 5-α reductase inhibitor use The risk of erectile dysfunction increased with longer duration of benign prostatic hyperplasia independent of exposure This finding is noteworthy because UK pre-scribing guidelines during much of the study period rec-ommended that α blockers be first line treatment for benign prostatic hyperplasia followed by a switch to or addition of 5-α reductase inhibitors when treatment with α blockers was not effective or when benign prostatic hyperplasia had progressed Therefore users of 5-α reductase inhibitors were likely to have benign prostatic hyperplasia for a longer duration resulting in a higher risk for erectile dysfunction The absence of increased risk of erectile dysfunction in users of 5-α reductase inhibitors with benign prostatic hyperplasia as well as in users with alopecia provides strong evidence against the hypothesis that 5-α reductase inhibitors independently increase the risk of erectile dysfunction

Comparison with other studiesResults from clinical trials evaluating the efficacy of 5-α reductase inhibitors for the treatment of benign pros-

tatic hyperplasia or prevention of prostate cancer sug-gest that these drugs increase the risk of erectile dysfunction whereas our results were null The relative risk of erectile dysfunction with use of 5-α reductase inhibitors in clinical trials for prevention of prostate cancer varied from 110 to 152 3 compared with placebo and the changes in sexual function associated with 5-α reductase inhibitors were typically noted within the first year of treatment and became comparable with placebo by study termination Evidence from clinical trials evaluating the efficacy of finasteride only α block-ers only and combination treatment for benign pros-tatic hyperplasia have also suggested that use of 5-α reductase inhibitors alone or in combination with α blockers increases the risk of erectile dysfunction com-pared with placebo The risks based on published results range from 08 to 15 for finasteride only com-pared with α blockers only whereas the risks of combi-nation treatment range from 14 to 18 compared with α blockers only18-21 Our results yielded no differences in the risk of erectile dysfunction by type of 5-α reductase inhibitor (finasteride or dutasteride) which is consis-tent with results of a clinical trial that compared the efficacy and safety of finasteride with dutasteride22 A post-marketing surveillance study (n=14 772) conducted in the UK in 1992-94 shortly after finasteride was first marketed found that impotenceejaculation was reported in 21 of patients prescribed finasteride sim-ilar to the rate of erectile dysfunction in our benign prostatic hyperplasia study population23

The results of published studies evaluating the effi-cacy of finasteride 1 mg to treat alopecia have been inconsistent6-9 24-27 whereas our results were null An increase of sexual side effects has been reported in clin-ical trials evaluating the efficacy of finasteride 1 mg for treatment of alopecia with approximately 4 of men treated with finasteride reporting sexual side effects compared with approximately 2 of men treated with placebo6-9 A systematic review of six clinical trials that reported on the safety of finasteride 1 mg or 5 mg for treatment of alopecia compared with placebo found an increased risk of patient reported erectile dysfunction (relative risk 222 95 confidence interval 103 to 478)24 In contrast three small trials conducted in clin-ical settings with short term follow-up reported no sig-nificant difference in erectile dysfunction adverse events25-27

The clinical trials evaluating 5-α reductase inhibitors for the treatment of benign prostatic hyperplasia and alopecia have also identified non-erectile dysfunction sexual dysfunctions as adverse effects of 5-α reductase inhibitor use A systematic review of available random-ized clinical trials reported that ejaculatory dysfunction was more common among users of 5-α reductase inhib-itors for treatment of benign prostatic hyperplasia com-pared with users of placebo (odds ratio 273 Plt0001) in trials comparing α blockers and 5-α reductase inhibi-tors whereas in trials comparing 5-α reductase inhibitors with α blockers the prevalence of ejaculatory dysfunction was similar for users of both drugs (odds ratio 07 P=042)28 Another review of data from clinical

table 8 | nested case-control analysis risk of erectile dysfunction by exposure in alopecia population values are numbers (percentages) unless stated otherwise


Controls (n=2178)



Exposure None 511 (934) 2021 (928) 10 (ref) 10 (ref) Finasteride 1 mg 36 (66) 157 (72) 091 (062 to 133) 094 (064 to 140)No of prescriptions None 511 (934) 2021 (928) 10 (ref) 10 (ref) Finasteride 1 mg 1 prescription 10 (18) 53 (24) 075 (038 to 148) 069 (033 to 140) 2-9 prescriptions 15 (27) 67 (31) 089 (050 to 157) 092 (051 to 167) ge10 prescriptions 11 (20) 37 (17) 118 (060 to 235) 143 (071 to 290)Timing of use None 511 (934) 2021 (928) 10 (ref) 10 (ref) Finasteride 1 mg Current 9 (17) 51 (23) 069 (034 to 143) 078 (037 to 166) Recent 2 (04) 8 (04) dagger dagger Past 25 (46) 98 (45) 101 (064 to 160) 099 (062 to 159)Time since last prescription None 511 (934) 2021 (928) 10 (ref) 10 (ref) Finasteride 1 mg lt1 year 18 (33) 79 (36) 091 (054 to 154) 101 (058 to 175) 1-5 years 17 (31) 60 (28) 113 (065 to 195) 105 (060 to 186) ge5 years 1 (02) 18 (08) dagger daggerAdjusted for body mass index smoking status duration of benign prostatic hyperplasia non-erectile dysfunction sexual dysfunctions hypertension diabetes hyperlipidemia cardiovascular disease liver disease depression alcohol misuse drug misuse and receipt of a β blocker prescription within six months prior to index date conditional on matching factorsdaggerToo few cases or controls to calculate

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trials found that low libido was reported as an adverse event for 2-5 of patients treated with 5-α reductase inhibitors compared with 1-3 of the placebo group10 A small cross sectional study of men attending an outpa-tient clinic for sexual dysfunction (n=48 patients using 5-α reductase inhibitors) reported a higher prevalence of low libido among users of 5-α reductase inhibitors compared with men who did not use 5-α reductase inhibitors however there were no significant differ-ences in the prevalence of premature ejaculation or ejaculatory volume29 In comparison in our study there was no evidence of a substantial increase in risk of non-erectile dysfunction sexual dysfunctions and the rates were less than three events per 1000 person years regardless of indication for use lower than those reported in clinical trials In the UK Clinical Practice Research Datalink (CPRD) codes used to identify non-erectile dysfunction outcomes (ejaculatory disor-der psychosexual dysfunction and low libido) are nei-ther specific nor used regularly consistently or correctly (because of the close relation with diagnosis of erectile dysfunction) by general practitioners Thus it is likely that we missed cases of non-erectile dysfunc-tion sexual dysfunctions and therefore the rates reported here are underestimates Our results for non-erectile dysfunction sexual dysfunctions should be interpreted cautiously in light of the data limitations for these outcomes as well as the small number of exposed cases of non-erectile dysfunction sexual dysfunction identified (n=58 exposed non-erectile dysfunction cases in the benign prostatic hyperplasia population and n=10 exposed non-erectile dysfunction cases in the alopecia population)

Unlike the published clinical trials men in both our benign prostatic hyperplasia study population and our alopecia study population were free from diagnoses of and treatments for erectile dysfunction prior to cohort entry In addition patients with a history of other strong risk factors for erectile dysfunction prior to cohort entry such as prostate genital or urinary cancer or a history of prostatectomy or orchiectomy were excluded from the study population or censored on subsequent diagno-sis of these major erectile dysfunction and non-erectile dysfunction sexual dysfunction risk factors after cohort entry Importantly to be identified as a case of erectile dysfunction in our study men were required either to have a diagnosis or to have received treatment (pharma-ceutical or procedural) for erectile dysfunction recorded by the general practitioner in their electronic medical record before the censoring date whereas all of the clin-ical trials used questionnaires completed by partici-pants to assess changes in sexual function Thus a major strength of our study is that it captured clinically meaningful erectile dysfunction diagnoses that came to the general practitionerrsquos attention In our study users of 5-α reductase inhibitors particularly in combination with α blockers were generally less healthy than users of α blockers only Men with benign prostatic hyperpla-sia who have multiple medical problems may have less sex or may less often bring up concerns about sexual function to their doctor whereas the doctors may be

more concerned with treating the other conditions than about the sexual health of their patients that is users of 5-α reductase inhibitors may be less likely to have their erectile dysfunction diagnosed (detection bias) If this were the case then the true incidence of erectile dysfunction among users of 5-α reductase inhibitors alone or in combination might be higher than we detected in our study

Alopecia and prostate enlargementbenign prostatic hyperplasia are both related to the conversion of testos-terone to dihydrotestosterone which is stimulated by increased activity of the enzyme 5-α reductase10 Owing to underlying biochemistry men who have benign pros-tatic hyperplasia or alopecia may be at an increased risk of erectile dysfunction compared with men without either condition regardless of treatment Our study was designed to control for confounding by indication In the benign prostatic hyperplasia study we used an active comparator (α blockers only) rather than non-exposed to control for confounding by severity and duration of benign prostatic hyperplasia whereas men in our alopecia study population were required to have a recorded diagnosis of alopecia The number of patients in our benign prostatic hyperplasia study pop-ulation identified as a case of erectile dysfunction (8) was similar to the proportion of patients who self reported having erectile dysfunction in clinical trials (0 to 16)2 3 19-21 whereas the rates of erectile dysfunc-tion among men with alopecia in our study were similar to those reported among men in general30 31 Also erec-tile dysfunction has not been reported as a common side effect of the α blockers evaluated in our study32 Approximately 46 of the patients who used α blockers only in our benign prostatic hyperplasia population were prescribed tamsulosin followed by alfuzosin (12) and doxazosin (11) in our study the risk of erectile dysfunction did not differ by type of α blocker prescribed (data not shown) We do not believe that the null results found in our study were due to use of com-parison groups who had an increased baseline risk for erectile dysfunction

strengths and limitations of this studyStrengths of our population based study included the use of CPRD a large validated longitudinal primary care database known for high accuracy of diagnoses and completeness of drug prescribing data We found known risk factors to be independently associated with risk for erectile dysfunction (eg increased body mass index hypertension hyperlipidemia diabetes) provid-ing confidence in the quality of the data and its ability to detect associations between benign prostatic hyper-plasia treatments and risk of erectile dysfunction As all information on diseases and drug exposures is recorded in the absence of a study hypothesis there is no risk of recall bias The mean length of follow-up was greater than four years We further controlled our analyses for a range of potential confounders including non-erectile dysfunction sexual dysfunction hypertension diabe-tes body mass index smoking status depression and duration of benign prostatic hyperplasia By excluding

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men who had insufficient history in their medical record before cohort entry we reduced the risk of includ-ing men who had used the study drugs before cohort entry as well as reduced the risk of including men with prevalent rather than incident erectile dysfunction

A major strength of our study is that it relied on doc-tor recorded diagnoses rather than patient reported changes in sexual function to identify cases Finally the population of men prescribed 5-α reductase inhibi-tors and α blockers for benign prostatic hyperplasia (n=71 849) and the population of men with alopecia (n=12 346 of which 868 received prescriptions for finas-teride 1 mg during follow-up) described in our study are robust and are the largest populations of ldquoreal worldrdquo users of these drugs evaluated to date This allowed us to study the effects of these drugs as prescribed in rou-tine clinical practice This is not possible in clinical trials given their smaller size and highly selected study populations

There are some limitations to consider Drug informa-tion in the CPRD covers written not dispensed prescrip-tions therefore we cannot be sure that patients used all prescribed drugs However the relative risks did not change among those with repeat (ge2) prescriptions suggesting that this did not affect the results During our study period phosphodiesterase type 5 inhibitors were available in the UK for prescriptions through pri-vate sources therefore we may have missed some cases of erectile dysfunction where these drugs were pre-scribed outside of the general practitionerrsquos office This is unlikely to be differential by exposure category and thus may have biased the true estimates toward the null Objective measures of the severity of benign pros-tatic hyperplasia are not captured in the CPRD data thus we were unable to assess the impact of severity on the results We were able to identify codes relating to lower urinary tract symptoms however these codes are symptom based are not specific to benign prostatic hyperplasia and might be related to other urological and medical conditions Severe lower urinary tract symptoms are known to be associated with erectile dys-function but in our study such symptoms did not con-found the relation between exposure and outcome in either the benign prostatic hyperplasia population or the alopecia population Although the populations of men evaluated in these studies were robust in some of the analyses the numbers of exposed cases were small particularly for non-erectile dysfunction sexual dys-functions (n=36 exposed erectile dysfunction cases in the alopecia population n=58 exposed non-erectile dysfunction sexual dysfunction cases in the benign prostatic hyperplasia population and n=10 exposed in the alopecia population) thus the results for these analyses should be interpreted with caution However it is important to note that the CPRD is one of the few observational data sources in the world where these numbers of erectile dysfunction and non-erectile dys-function sexual dysfunction cases could be identified and evaluated Our study results suggest that the dura-tion of benign prostatic hyperplasia is a strong indepen-dent risk factor for erectile dysfunction therefore

studies evaluating the incidence of erectile dysfunction after use of 5-α reductase inhibitors or α blockers should be interpreted cautiously and with consider-ation to the duration of benign prostatic hyperplasia

Conclusions and policy implicationsThe results of our study provide evidence that 5-α reductase inhibitors do not increase the risk of clini-cally meaningful incident erectile dysfunction in men who are free of sexual dysfunction and major risk fac-tors (eg prostate genital or urinary cancers surgical procedures) regardless of indication for use (benign prostatic hyperplasia or alopecia) The risk of erectile dysfunction increases with longer duration of benign prostatic hyperplasia which should be accounted for in the design of future studies evaluating the safety of 5-α reductase inhibitors Since benign prostatic hyperpla-sia and alopecia are common conditions in men and 5-α reductase inhibitors are primary drug treatments for these conditions the results of this study provide reas-surance that these drugs are not associated with a mate-rially important increased risk of clinically meaningful erectile dysfunction in every day clinical practiceContributors KWH participated in the study conception and design identified the study population and reviewed the cases cleaned the data and conducted the statistical analysis participated in the interpretation of results and drafted and revised the paper She is a guarantor HAD participated in the interpretation of the results and revised the paper RP participated in identification of the study population and cases cleaned the data and conducted the statistical analysis participated in the interpretation of results and revised the paper JCN participated in the study conception interpretation of the results and revised the paper SSJ participated in the study conception and design interpretation of the results and revised the paper She is a guarantor All authors had access to the data (including statistical reports and tables) in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis All authors reviewed and approved the final version of the paper for publicationFunding This study was funded by a grant (5R21DK100820-02) from the United States National Institutes of HealthNational Institute of Diabetes and Digestive and Kidney Diseases All authors had independence from the funding sourceCompeting interests All authors have completed the ICMJE uniform disclosure form at wwwicmjeorgcoi_disclosurepdf (available on request from the corresponding author) and declare that all authors have support from an United States National Institutes of HealthNational Institute of Diabetes and Digestive and Kidney Diseases grant (5R21DK100820-02) for the submitted work KWH HAD RP and SSJ have no relationships that might have an interest in the submitted work in the previous three years JCN had a financial relationship with GlaxoSmithKline three years ago consulting on a non-related patent lawsuit and has a current non-financial relationship with GlaxoSmithKline for access to REDUCE trial data for research outside of the submitted work their spouses partners or children have no financial relationships that may be relevant to the submitted work and none of the authors have non-financial interests that may be relevant to the submitted workEthical approval The protocols for this study were reviewed and approved by the independent scientific advisory committee of the CPRD (protocol Nos 15_132R and 15_223R)Data sharing No additional data availableTransparency The guarantors (KWH and SSJ) affirm that the manuscript is an honest accurate and transparent account of the study being reported that no important aspects of the study have been omitted and that any discrepancies from the study as planned have been explainedThis is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 30) license which permits others to distribute remix adapt build upon this work non-commercially and license their derivative works on different terms provided the original work is properly cited and the use is non-commercial See httpcreativecommonsorglicensesby-nc30

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No commercial reuse See rights and reprints httpwwwbmjcompermissions Subscribe httpwwwbmjcomsubscribe

1 Glina S Glina FPA Pathogenic mechanisms linking benign prostatic hyperplasia lower urinary tract symptoms and erectile dysfunction Ther Adv Urol 20135211-8 doi1011771756287213488236

2 Thompson IM Goodman PJ Tangen CM et al The influence of finasteride on the development of prostate cancer N Engl J Med 2003349215-24 doi101056NEJMoa030660

3 Andriole GL Bostwick DG Brawley OW et al REDUCE Study Group Effect of dutasteride on the risk of prostate cancer N Engl J Med 20103621192-202 doi101056NEJMoa0908127

4 Rittmaster RS Fleshner NE Thompson IM Pharmacological approaches to reducing the risk of prostate cancer Eur Urol 2009551064-73 doi101016jeururo200901037

5 Thompson IM Tangen CM Goodman PJ Lucia MS Klein EA Chemoprevention of prostate cancer J Urol 2009182499-507 discussion 508 doi101016jjuro200904015

6 Kaufman KD Olsen EA Whiting D et al Finasteride Male Pattern Hair Loss Study Group Finasteride in the treatment of men with androgenetic alopecia J Am Acad Dermatol 199839578-89 doi101016S0190-9622(98)70007-6

7 Leyden J Dunlap F Miller B et al Finasteride in the treatment of men with frontal male pattern hair loss J Am Acad Dermatol 199940930-7 doi101016S0190-9622(99)70081-2

8 Rosen RC Riley A Wagner G Osterloh IH Kirkpatrick J Mishra A The international index of erectile function (IIEF) a multidimensional scale for assessment of erectile dysfunction Urology 199749822-30 doi101016S0090-4295(97)00238-0

9 Irwig MS Kolukula S Persistent sexual side effects of finasteride for male pattern hair loss J Sex Med 201181747-53 doi101111j1743- 6109201102255x

10 Traish AM Hassani J Guay AT Zitzmann M Hansen ML Adverse side effects of 5α-reductase inhibitors therapy persistent diminished libido and erectile dysfunction and depression in a subset of patients J Sex Med 20118872-84 doi101111j1743- 61092010 02157x

11 Irwig MS Persistent sexual side effects of finasteride could they be permanent J Sex Med 201292927-32 doi101111 j1743-6109201202846x

12 Belknap SM Aslam I Kiguradze T et al Adverse event reporting in clinical trials of finasteride for androgenic alopecia JAMA Dermatol 2015151600-6 doi101001jamadermatol201536

13 US Food and Drug Administration Questions and answers finasteride label changes Silver Spring MD US Food and Drug Administration [cited 2012 December 3] wwwfdagovDrugsDrugSafetyInformationbyDrugClassucm299754htm

14 The Post-Finasteride Syndrome Foundation Welcome to the Post-Finasteride Syndrome Foundation [Internet] Somerset NJ the Post-Finasteride Syndrome Foundation [cited 2012 December 3] wwwpfsfoundationorg

15 MMampM Online Pharma Report 2011 httpmediammm-onlinecomdocuments23pharma_report_5720pdf [cited 2012 Dec 3]

16 Jick SS Kaye JA Vasilakis-Scaramozza C et al Validity of the general practice research database Pharmacotherapy 200323686-9 doi101592phco23568632205

17 Herrett E Thomas SL Schoonen WM Smeeth L Hall AJ Validation and validity of diagnoses in the General Practice Research Database a systematic review Br J Clin Pharmacol 2010694-14 doi101111j1365-2125200903537x

18 Wu XJ Zhi Y Zheng J et al Dutasteride on benign prostatic hyperplasia a meta-analysis on randomized clinical trials in 6460 patients Urology 201483539-43 doi101016jurology201310007

19 Lepor H Williford WO Barry MJ et al Veterans Affairs Cooperative Studies Benign Prostatic Hyperplasia Study Group The efficacy of terazosin finasteride or both in benign prostatic hyperplasia N Engl J Med 1996335533-40 doi101056NEJM199608223350801

20 Kirby RS Roehrborn C Boyle P et al Prospective European Doxazosin and Combination Therapy Study Investigators Efficacy and tolerability of doxazosin and finasteride alone or in combination in treatment of symptomatic benign prostatic hyperplasia the Prospective European Doxazosin and Combination Therapy (PREDICT) trial Urology 200361119-26 doi101016S0090-4295(02)02114-3

21 McConnell JD Roehrborn CG Bautista OM et al Medical Therapy of Prostatic Symptoms (MTOPS) Research Group The long-term effect of doxazosin finasteride and combination therapy on the clinical progression of benign prostatic hyperplasia N Engl J Med 20033492387-98 doi101056NEJMoa030656

22 Nickel JC Gilling P Tammela TL Morrill B Wilson TH Rittmaster RS Comparison of dutasteride and finasteride for treating benign prostatic hyperplasia the Enlarged Prostate International Comparator Study (EPICS) BJU Int 2011108388-94 doi101111j1464-410X201110195x

23 Wilton L Pearce G Edet E Freemantle S Stephens MDB Mann RD The safety of finasteride used in benign prostatic hypertrophy a non-interventional observational cohort study in 14772 patients Br J Urol 199678379-84 doi101046j1464-410X199600091x

24 Mella JM Perret MC Manzotti M Catalano HN Guyatt G Efficacy and safety of finasteride therapy for androgenetic alopecia a systematic review Arch Dermatol 20101461141-50 doi101001archdermatol2010256

25 Tosti A Pazzaglia M Soli M et al Evaluation of sexual function with an international index of erectile function in subjects taking finasteride for androgenetic alopecia Arch Dermatol 2004140857-8 doi101001archderm1407857

26 Tosti A Piraccini BM Soli M Evaluation of sexual function in subjects taking finasteride for the treatment of androgenetic alopecia J Eur Acad Dermatol Venereol 200115418-21 doi101046j1468-3083200100315x

27 Narasimhalu CRV Randomized questionnaire based case-control research study on evaluation of sexual function in Indian patients taking oral finasteride for androgenetic alopecia Dermatol Ther (Heidelb) 20155231-4 doi101007s13555-015-0084-3

28 Gacci M Ficarra V Sebastianelli A et al Impact of medical treatments for male lower urinary tract symptoms due to benign prostatic hyperplasia on ejaculatory function a systematic review and meta-analysis J Sex Med 2014111554-66 doi101111jsm12525

29 Corona G Rastrelli G Maseroli E et al Inhibitors of 5α-reductase-related side effects in patients seeking medical care for sexual dysfunction J Endocrinol Invest 201235915-20

30 Kubin M Wagner G Fugl-Meyer AR Epidemiology of erectile dysfunction Int J Impot Res 20031563-71 doi101038sjijir3900949

31 Medical Surveillance Monthly Report (MSMR) Erectile dysfunction among male active component service members US Armed Forces 2004-2013 Sept 20142113-16 wwwncbinlmnihgovpubmed25267600

32 Van Asseldonk B Barkin J Elterman DS Medical therapy for benign prostatic hyperplasia a review Can J Urol 201522(Suppl 1)7-17

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large sales volume15 and prescribing of these drugs for hair loss to otherwise healthy young men We con-ducted two cohort studies with nested case-control analyses to evaluate the risk of erectile dysfunction in men who used 5-α reductase inhibitors to treat benign prostatic hyperplasia or alopecia We also estimated the rate of non-erectile dysfunction sexual dysfunctions (ejaculatory disorder psychosexual dysfunction and low libido) in these populations of 5-α reductase inhib-itor users

MethodsData sourceThis study was conducted using the UK Clinical Practice Research Datalink (CPRD) a large longitudinal popu-lation based electronic medical record database that contains data on approximately 10 million people Participating general practitioners contribute data in an anonymous format including medical diagnoses lifestyle details (eg smoking body mass index) details of hospital stays and specialist visits and deaths as well as details of all drugs prescribed including formu-lation and dosing instructions Data in the CPRD are collected prospectively and all information on diseases and prescriptions is recorded in the absence of a study hypothesis so there is no risk of recall bias Validation studies have indicated that the recorded data are of high accuracy with more than 90 of information from the manual medical records present in the general prac-titionerrsquos office recorded on the computer16 17

Patient populationsThe study period was 1 January 1992 (the year that finas-teride was first available in the UK) through 31 Decem-ber 2011 We limited the end of the study period to 31 December 2011 owing to changes in the indication for use of phosphodiesterase type 5 inhibitors (drugs indi-cated for the treatment of erectile dysfunction which were approved for the treatment of benign prostatic hyperplasia in 2012) and changes in the UK Quality and Outcomes Framework (which prompts all general prac-titioners to document whether they have asked all men with diabetes about potential erectile dysfunction)

We identified all men in the CPRD who had a pre-scription for either a 5-α reductase inhibitor (finasteride or dutasteride) or an α blocker (alfuzosin doxadosin indoramin prazosin tamsulosin and terazosin) or both plus a diagnosis of benign prostatic hyperplasia or prostatism recorded at any time prior to the first pre-scription date through three months after (to allow time for general practitioners to record diagnoses made by specialists) During the study period α blockers were the only available alternative pharmaceutical treatment for benign prostatic hyperplasia thus we chose them as an active comparator to ensure that all men included in the study population had benign prostatic hyperplasia severe enough to require treatment α blockers are also indicated for hypertension therefore to be included users were required to have a diagnosis of benign pros-tatic hyperplasia or prostatism We defined the date of cohort entry as the date of the first prescription for a 5-α

reductase inhibitor or α blocker in the patientrsquos record The study population was restricted to men who were aged 40 years or older and who had at least three years of history before the cohort entry date A three year requirement was selected to ensure that men were free from sexual dysfunction before cohort entry and were new users of a study drug These men (n=71 849) com-prised the population with benign prostatic hyperpla-sia (fig 1)

We then separately identified all men in the CPRD who had a diagnosis of alopecia (male pattern bald-ness) between 1 January 2002 (the first year finas-teride was prescribed for alopecia) and 31 December 2011 were aged 18-59 and had at least one year of history in their record before cohort entry We defined the date of cohort entry as 1 January 2002 (the start of the study period) the date of the first alopecia diag-nosis occurring after 1 January 2002 or the date of the first prescription for finasteride 1 mg where the pre-scription was recorded before the alopecia diagnosis We required only one year of history for this analysis because young men have shorter records in the CPRD and because there is less concern that patients in this age group have a history of sexual dysfunction or fin-asteride prescriptions prior to cohort entry These men (n=12 346) comprised the population with alope-cia (fig 2)

Men with prostate genital or urinary cancer prosta-tectomy or orchidectomy history of erectile dysfunction diagnosis or treatment (eg procedures or drugs used to treat erectile dysfunction) other sexual dysfunctions (eg ejaculatory disorder psychosexual dysfunction low libido) or Peyroniersquos disease before cohort entry or Klinefelterrsquos syndrome recorded at any time were

Men with a prescription of a 5 α reductaseinhibitor or an α blocker and a diagnosis of benign

prostatic hyperplasia or prostatism (n=115 443)

Eligible for benign prostatic hyperplasia studypopulation and included in cohort analysis (n=71 849)


Controls matched to eligibleerectile dysfunctioncases (n=23 060)


analysis (n=5768)

Excluded owing to cancerdiagnosis within 2 years

prior to index date (n=46)

Excluded (n=43 594) Age lt40 at cohort entry date (n=2571) lt3 years of recorded history before cohort entry date (n=25 243) Diagnosis of prostate genital or urinary cancer erectile dysfunction non-erectile dysfunction sexual dysfunction Peyroniersquos disease before cohort entry date or diagnosis of Klinefelterrsquos syndrome at any time (n=15 780)

Fig 1 | Flowchart for population with benign prostatic hyperplasia

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cases (n=2178)


analysis (n=547)



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1995

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605

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415

9066

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(22

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412

402

173

(15

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197

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2702

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20

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785

198

(18

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917

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167

(14

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187

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011

317

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(178

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20

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183

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113

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Rece

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713

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68)

4725

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5 (1

36

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45)

527

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8 to

42

0)

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138

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(20

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999

130

(69

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23)

391

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(67

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68)

Di

stan

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0488

255

193

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13)

246

15 39

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796

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(69

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(19

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747

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153

(14

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)0

76 (0

71

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82)

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22 0

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Controls (n=23 060)




(Continued )

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Controls (n=23 060)




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Cases (n=36)

Person years













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Controls (n=2178)




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ble

2 | i

ncid

ence

rate

s (ir

) and

inci

denc

e ra

te ra

tios (

irr)

for e

rect

ile d

ysfu

nctio

n by

exp

osur

e in

coho

rt w

ith b

enig

n pr

osta

tic h

yper

plas

ia

varia

bles

α bl

ocke

rs o

nly

5-α

redu

ctas

e in

hibi

tors

onl

y5-α

redu

ctas

e in

hibi

tors+α

blo

cker

sCa

ses

(n=4

665)

Pers

on

year

sir

100

0 pe

rson

ye

ars

(95

Ci)

irr

(9

5 C

i)Ca

ses

(n=7

27)

Pers

on

year

sir

100

0 pe

rson

ye

ars

(95

Ci)

irr

(9

5 C

i)Ca

ses

(n=4

22)

Pers

on

year

sir

100

0 pe

rson

ye

ars

(95

Ci)

irr

(95

Ci)

Age

grou

p (y

ears

)

40-5

912

9245

713

283

(26

7 to

29

8)11

142

2426

3 (2

16 to

316

)64

1481

432

(22

2 to

55

2)

60-7

932

1114

3 000

225

(217

to 2

32)

570

29 67

319

2 (1

77 to

20

9)33

513

920

241

(216

to 2

68)

ge8

016

243

012

38

(32

to 4

4)

4613

472

34

(25

to 4

6)

2366

063

5 (2

2 to

52

)Ca

lend

ar ti

me

19

92-9

59

1596

56

(26

to 10

7)

1091

211

0 (5

2 to

20

2)0

500

0 (0

0 to

72

7)

1995

-99

299

21 94

013

6 (1

21

to 15

3)

9083

9610

7 (8

6 to

132

)10

605

165

(79

to 3

04)

20

00-0

415

9066

291

240

(22

8 to

25

2)21

412

402

173

(15

0 to

197

)63

2702

233

(179

to 2

98)

20

05-0

919

3397

785

198

(18

9 to

20

7)29

917

941

167

(14

8 to

187

)23

011

317

203

(178

to 2

31)

20

10-1

183

444

113

189

(176

to 2

02)

114

7718

148

(12

2 to

177

)11

973

3316

2 (1

34

to 19

4)

Tim

ing

of u

se

Cu

rrent

2496

124 0

9920

1 (1

93

to 2

09)

421

28 42

514

8 (1

34

to 16

3)

403

20 8

4419

3 (1

75 to

213

)

Rece

nt32

713

619

240

(215

to 2

68)

4725

4718

5 (1

36

to 2

45)

527

818

0 (5

8 to

42

0)

Past

138

5752

240

(20

2 to

28

3)13

999

130

(69

to 2

23)

391

331

(67

to 9

68)

Di

stan

t pas

t17

0488

255

193

(175

to 2

13)

246

15 39

816

0 (1

40

to 18

1)11

796

138

(69

to 2

47)

Tota

l

Crud

e46

6523

1 724

201

(19

6 to

20

7)10

(ref

)72

747

369

153

(14

3 to

165

)0

76 (0

71

to 0

82)

422

22 0

0819

2 (1

74 to

211

)0

95 (0

86

to 1

05)

Ad

just

ed

10 (r

ef)

092

(0

85 to

09

9)10

9 (0

99

to 1

21)

Adj

uste

d fo

r age

gro

up c

alen

dar t

ime

and

tim

ing

of u

se

on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

7







on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

8



Controls (n=23 060)




(Continued )

on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

9








Controls (n=23 060)




on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

10


variables



Cases (n=36)

Person years













on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

11








on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

12








Controls (n=2178)




on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

13






on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

14






on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from

RESEARCH


































on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

4









on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

5











lt0001





on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

6




ble

2 | i

ncid

ence

rate

s (ir

) and

inci

denc

e ra

te ra

tios (

irr)

for e

rect

ile d

ysfu

nctio

n by

exp

osur

e in

coho

rt w

ith b

enig

n pr

osta

tic h

yper

plas

ia

varia

bles

α bl

ocke

rs o

nly

5-α

redu

ctas

e in

hibi

tors

onl

y5-α

redu

ctas

e in

hibi

tors+α

blo

cker

sCa

ses

(n=4

665)

Pers

on

year

sir

100

0 pe

rson

ye

ars

(95

Ci)

irr

(9

5 C

i)Ca

ses

(n=7

27)

Pers

on

year

sir

100

0 pe

rson

ye

ars

(95

Ci)

irr

(9

5 C

i)Ca

ses

(n=4

22)

Pers

on

year

sir

100

0 pe

rson

ye

ars

(95

Ci)

irr

(95

Ci)

Age

grou

p (y

ears

)

40-5

912

9245

713

283

(26

7 to

29

8)11

142

2426

3 (2

16 to

316

)64

1481

432

(22

2 to

55

2)

60-7

932

1114

3 000

225

(217

to 2

32)

570

29 67

319

2 (1

77 to

20

9)33

513

920

241

(216

to 2

68)

ge8

016

243

012

38

(32

to 4

4)

4613

472

34

(25

to 4

6)

2366

063

5 (2

2 to

52

)Ca

lend

ar ti

me

19

92-9

59

1596

56

(26

to 10

7)

1091

211

0 (5

2 to

20

2)0

500

0 (0

0 to

72

7)

1995

-99

299

21 94

013

6 (1

21

to 15

3)

9083

9610

7 (8

6 to

132

)10

605

165

(79

to 3

04)

20

00-0

415

9066

291

240

(22

8 to

25

2)21

412

402

173

(15

0 to

197

)63

2702

233

(179

to 2

98)

20

05-0

919

3397

785

198

(18

9 to

20

7)29

917

941

167

(14

8 to

187

)23

011

317

203

(178

to 2

31)

20

10-1

183

444

113

189

(176

to 2

02)

114

7718

148

(12

2 to

177

)11

973

3316

2 (1

34

to 19

4)

Tim

ing

of u

se

Cu

rrent

2496

124 0

9920

1 (1

93

to 2

09)

421

28 42

514

8 (1

34

to 16

3)

403

20 8

4419

3 (1

75 to

213

)

Rece

nt32

713

619

240

(215

to 2

68)

4725

4718

5 (1

36

to 2

45)

527

818

0 (5

8 to

42

0)

Past

138

5752

240

(20

2 to

28

3)13

999

130

(69

to 2

23)

391

331

(67

to 9

68)

Di

stan

t pas

t17

0488

255

193

(175

to 2

13)

246

15 39

816

0 (1

40

to 18

1)11

796

138

(69

to 2

47)

Tota

l

Crud

e46

6523

1 724

201

(19

6 to

20

7)10

(ref

)72

747

369

153

(14

3 to

165

)0

76 (0

71

to 0

82)

422

22 0

0819

2 (1

74 to

211

)0

95 (0

86

to 1

05)

Ad

just

ed

10 (r

ef)

092

(0

85 to

09

9)10

9 (0

99

to 1

21)

Adj

uste

d fo

r age

gro

up c

alen

dar t

ime

and

tim

ing

of u

se

on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

7







on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

8



Controls (n=23 060)




(Continued )

on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

9








Controls (n=23 060)




on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

10


variables



Cases (n=36)

Person years













on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

11








on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

12








Controls (n=2178)




on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

13






on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

14






on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from

RESEARCH


































on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

5











lt0001





on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

6




ble

2 | i

ncid

ence

rate

s (ir

) and

inci

denc

e ra

te ra

tios (

irr)

for e

rect

ile d

ysfu

nctio

n by

exp

osur

e in

coho

rt w

ith b

enig

n pr

osta

tic h

yper

plas

ia

varia

bles

α bl

ocke

rs o

nly

5-α

redu

ctas

e in

hibi

tors

onl

y5-α

redu

ctas

e in

hibi

tors+α

blo

cker

sCa

ses

(n=4

665)

Pers

on

year

sir

100

0 pe

rson

ye

ars

(95

Ci)

irr

(9

5 C

i)Ca

ses

(n=7

27)

Pers

on

year

sir

100

0 pe

rson

ye

ars

(95

Ci)

irr

(9

5 C

i)Ca

ses

(n=4

22)

Pers

on

year

sir

100

0 pe

rson

ye

ars

(95

Ci)

irr

(95

Ci)

Age

grou

p (y

ears

)

40-5

912

9245

713

283

(26

7 to

29

8)11

142

2426

3 (2

16 to

316

)64

1481

432

(22

2 to

55

2)

60-7

932

1114

3 000

225

(217

to 2

32)

570

29 67

319

2 (1

77 to

20

9)33

513

920

241

(216

to 2

68)

ge8

016

243

012

38

(32

to 4

4)

4613

472

34

(25

to 4

6)

2366

063

5 (2

2 to

52

)Ca

lend

ar ti

me

19

92-9

59

1596

56

(26

to 10

7)

1091

211

0 (5

2 to

20

2)0

500

0 (0

0 to

72

7)

1995

-99

299

21 94

013

6 (1

21

to 15

3)

9083

9610

7 (8

6 to

132

)10

605

165

(79

to 3

04)

20

00-0

415

9066

291

240

(22

8 to

25

2)21

412

402

173

(15

0 to

197

)63

2702

233

(179

to 2

98)

20

05-0

919

3397

785

198

(18

9 to

20

7)29

917

941

167

(14

8 to

187

)23

011

317

203

(178

to 2

31)

20

10-1

183

444

113

189

(176

to 2

02)

114

7718

148

(12

2 to

177

)11

973

3316

2 (1

34

to 19

4)

Tim

ing

of u

se

Cu

rrent

2496

124 0

9920

1 (1

93

to 2

09)

421

28 42

514

8 (1

34

to 16

3)

403

20 8

4419

3 (1

75 to

213

)

Rece

nt32

713

619

240

(215

to 2

68)

4725

4718

5 (1

36

to 2

45)

527

818

0 (5

8 to

42

0)

Past

138

5752

240

(20

2 to

28

3)13

999

130

(69

to 2

23)

391

331

(67

to 9

68)

Di

stan

t pas

t17

0488

255

193

(175

to 2

13)

246

15 39

816

0 (1

40

to 18

1)11

796

138

(69

to 2

47)

Tota

l

Crud

e46

6523

1 724

201

(19

6 to

20

7)10

(ref

)72

747

369

153

(14

3 to

165

)0

76 (0

71

to 0

82)

422

22 0

0819

2 (1

74 to

211

)0

95 (0

86

to 1

05)

Ad

just

ed

10 (r

ef)

092

(0

85 to

09

9)10

9 (0

99

to 1

21)

Adj

uste

d fo

r age

gro

up c

alen

dar t

ime

and

tim

ing

of u

se

on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

7







on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

8



Controls (n=23 060)




(Continued )

on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

9








Controls (n=23 060)




on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

10


variables



Cases (n=36)

Person years













on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

11








on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

12








Controls (n=2178)




on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

13






on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

14






on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from

RESEARCH


































on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

6




ble

2 | i

ncid

ence

rate

s (ir

) and

inci

denc

e ra

te ra

tios (

irr)

for e

rect

ile d

ysfu

nctio

n by

exp

osur

e in

coho

rt w

ith b

enig

n pr

osta

tic h

yper

plas

ia

varia

bles

α bl

ocke

rs o

nly

5-α

redu

ctas

e in

hibi

tors

onl

y5-α

redu

ctas

e in

hibi

tors+α

blo

cker

sCa

ses

(n=4

665)

Pers

on

year

sir

100

0 pe

rson

ye

ars

(95

Ci)

irr

(9

5 C

i)Ca

ses

(n=7

27)

Pers

on

year

sir

100

0 pe

rson

ye

ars

(95

Ci)

irr

(9

5 C

i)Ca

ses

(n=4

22)

Pers

on

year

sir

100

0 pe

rson

ye

ars

(95

Ci)

irr

(95

Ci)

Age

grou

p (y

ears

)

40-5

912

9245

713

283

(26

7 to

29

8)11

142

2426

3 (2

16 to

316

)64

1481

432

(22

2 to

55

2)

60-7

932

1114

3 000

225

(217

to 2

32)

570

29 67

319

2 (1

77 to

20

9)33

513

920

241

(216

to 2

68)

ge8

016

243

012

38

(32

to 4

4)

4613

472

34

(25

to 4

6)

2366

063

5 (2

2 to

52

)Ca

lend

ar ti

me

19

92-9

59

1596

56

(26

to 10

7)

1091

211

0 (5

2 to

20

2)0

500

0 (0

0 to

72

7)

1995

-99

299

21 94

013

6 (1

21

to 15

3)

9083

9610

7 (8

6 to

132

)10

605

165

(79

to 3

04)

20

00-0

415

9066

291

240

(22

8 to

25

2)21

412

402

173

(15

0 to

197

)63

2702

233

(179

to 2

98)

20

05-0

919

3397

785

198

(18

9 to

20

7)29

917

941

167

(14

8 to

187

)23

011

317

203

(178

to 2

31)

20

10-1

183

444

113

189

(176

to 2

02)

114

7718

148

(12

2 to

177

)11

973

3316

2 (1

34

to 19

4)

Tim

ing

of u

se

Cu

rrent

2496

124 0

9920

1 (1

93

to 2

09)

421

28 42

514

8 (1

34

to 16

3)

403

20 8

4419

3 (1

75 to

213

)

Rece

nt32

713

619

240

(215

to 2

68)

4725

4718

5 (1

36

to 2

45)

527

818

0 (5

8 to

42

0)

Past

138

5752

240

(20

2 to

28

3)13

999

130

(69

to 2

23)

391

331

(67

to 9

68)

Di

stan

t pas

t17

0488

255

193

(175

to 2

13)

246

15 39

816

0 (1

40

to 18

1)11

796

138

(69

to 2

47)

Tota

l

Crud

e46

6523

1 724

201

(19

6 to

20

7)10

(ref

)72

747

369

153

(14

3 to

165

)0

76 (0

71

to 0

82)

422

22 0

0819

2 (1

74 to

211

)0

95 (0

86

to 1

05)

Ad

just

ed

10 (r

ef)

092

(0

85 to

09

9)10

9 (0

99

to 1

21)

Adj

uste

d fo

r age

gro

up c

alen

dar t

ime

and

tim

ing

of u

se

on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

7







on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

8



Controls (n=23 060)




(Continued )

on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

9








Controls (n=23 060)




on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

10


variables



Cases (n=36)

Person years













on 2 Septem


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eptember 2016 D

ownloaded from


RESEARCH

11








on 2 Septem


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eptember 2016 D

ownloaded from


RESEARCH

12








Controls (n=2178)




on 2 Septem


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eptember 2016 D

ownloaded from


RESEARCH

13






on 2 Septem


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eptember 2016 D

ownloaded from


RESEARCH

14






on 2 Septem


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eptember 2016 D

ownloaded from

RESEARCH


































on 2 Septem


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eptember 2016 D

ownloaded from


RESEARCH

7







on 2 Septem


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eptember 2016 D

ownloaded from


RESEARCH

8



Controls (n=23 060)




(Continued )

on 2 Septem


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eptember 2016 D

ownloaded from


RESEARCH

9








Controls (n=23 060)




on 2 Septem


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jcom

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eptember 2016 D

ownloaded from


RESEARCH

10


variables



Cases (n=36)

Person years













on 2 Septem


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wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

11








on 2 Septem


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wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

12








Controls (n=2178)




on 2 Septem


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jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

13






on 2 Septem


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wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

14






on 2 Septem


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wbm

jcom

BM


eptember 2016 D

ownloaded from

RESEARCH


































on 2 Septem


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jcom

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eptember 2016 D

ownloaded from


RESEARCH

8



Controls (n=23 060)




(Continued )

on 2 Septem


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jcom

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eptember 2016 D

ownloaded from


RESEARCH

9








Controls (n=23 060)




on 2 Septem


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wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

10


variables



Cases (n=36)

Person years













on 2 Septem


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wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

11








on 2 Septem


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wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

12








Controls (n=2178)




on 2 Septem


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jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

13






on 2 Septem


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wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

14






on 2 Septem


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wbm

jcom

BM


eptember 2016 D

ownloaded from

RESEARCH


































on 2 Septem


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wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

9








Controls (n=23 060)




on 2 Septem


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wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

10


variables



Cases (n=36)

Person years













on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

11








on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

12








Controls (n=2178)




on 2 Septem


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wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

13






on 2 Septem


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wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

14






on 2 Septem


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wbm

jcom

BM


eptember 2016 D

ownloaded from

RESEARCH


































on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

10


variables



Cases (n=36)

Person years













on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

11








on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

12








Controls (n=2178)




on 2 Septem


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wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

13






on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

14






on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from

RESEARCH


































on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

11








on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

12








Controls (n=2178)




on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

13






on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

14






on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from

RESEARCH


































on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

12








Controls (n=2178)




on 2 Septem


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wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

13






on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

14






on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from

RESEARCH


































on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

13






on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

14






on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from

RESEARCH


































on 2 Septem


httpww

wbm

jcom

BM


eptember 2016 D

ownloaded from


RESEARCH

14






on 2 Septem


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wbm

jcom

BM


eptember 2016 D

ownloaded from

RESEARCH


































on 2 Septem


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BM


eptember 2016 D

ownloaded from

RESEARCH


































on 2 Septem


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eptember 2016 D

ownloaded from

Risk of erectile dysfunction associated with use of 5-α ...cohort entry as the date of the first...

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Transcript of Risk of erectile dysfunction associated with use of 5-α ...cohort entry as the date of the first...