Tadalafil
Addition to the list
Explanation for addition:
Suggestion from clinician: “used to treat BPH”
Literature Review Question:
Is tadalafil effective in management of benign prostate hyperplasia?
Relevant medications on CLEAN Meds list
 tamsulosin
 finasteride
 sildenafil
Literature search
Utilized electronic databases: PubMed, Cochrane
Brief search strategies: (systematic review filter) AND (benign prostate hyperplasia) AND (tadalafil OR
adrenergic alpha blockers OR 5 alpha reductase inhibitors)
Wang, X., et al., Comparative effectiveness of oral drug therapies for lower urinary tract symptoms
due to benign prostatic hyperplasia: a systematic review and network meta-analysis. PLoS One,
2014. 9(9): p. e107593.
Objective
Compare the efficacy of different drug therapies for LUTS/BPH with network meta-analysis
Studies included
A total 66 RCTs covering seven different therapies with 29384 participants were included. (13 of 66
studies included Taladafil).
Results
“A-blockers (ABs) plus phosphodiesterase 5 inhibitors (PDE5-Is) ranked highest in patients’ subjective
symptom evaluation including IPSS total score, storage subscore and voiding subscore. The combination
therapy of ABs plus 5a-reductase inhibitors was the best for increasing maximum urinary flow rate
(Qmax) with a mean difference (MD) of 1.98 (95% CI, 1.12 to 2.86) as compared to placebo PDE5-Is
alone showed great effectiveness for LUTS/BPH except Qmax.”
The International Prostate Symptom Score (IPSS) is based on the answers to seven questions concerning
urinary symptoms and one question concerning quality of life. The answers are assigned points from 0 to
5. The total score can therefore range from 0 to 35 (asymptomatic to very symptomatic).
Yuan, J.Q., et al., Comparative Effectiveness and Safety of Monodrug Therapies for Lower Urinary
Tract Symptoms Associated With Benign Prostatic Hyperplasia: A Network Meta-analysis.
Medicine (Baltimore), 2015. 94(27): p. e974.
Objective
Evaluate the comparative effectiveness and safety of monodrug therapies for BPH.
Studies Included
This study included 58,548 participants from 124 trials in total.
Results
IPSS
89 trials including 48,854 participants contributed to the analysis of the IPSS.
“doxazosin and terazosin were significantly more effective than tamsulosin, alfuzosin, tadalafil,
naftopidil, dutasteride, finasteride, tolterodine and solifenacin.
The improvement in the IPSS was comparable among silodosin, tamsulosin, alfuzosin, naftopidil,
dutasteride, vardenafil, sildenafil, and tadalafil.”
Drug therapies were sorted on effectiveness with an order from large to small.
Peak Urinary Flow Rate
105 trials, including 45,955 participants, contributed to the analysis of Peak Urinary Flow (PUF).
“When compared with placebo, doxazosin, dutasteride, terazosin, alfuzosin, tamsulosin, naftopidil, and
silodosin significantly increased the PUF. Doxazosin was significantly more effective than all other drug
therapies. The effectiveness of different classes of PDE5-Is was comparable in improving PUF.”
Drug therapies were sorted on effectiveness with an order from large to small.
Adverse events
When compared with placebo, doxazosin, terazosin, silodosin, festoerodine and tadalafil were associated
with significantly higher incidence of total AE.
Guidelines
 2010 Update from: the Canadian Prostate Health Council and CUA Guidelines Committee
o “Role of Phosphodiesterase Inhibitors The phosphodiesterase (PDE) isoenzymes 4 and 5
are present in the prostate and regulate smooth muscle tone. Subsequent isoenzyme
inhibition with medications such as sildenafil and tadalafil, have shown improvement in
symptoms and quality-of-life in men with lower urinary tract symptoms.39 At the present
time however, these agents are not recommended for men with symptomatic BPH related
LUTS.”
o No reason provided
 2010 (reviewed and validity confirmed in 2014): AUA guideline for the treatment of BPH does
not list PDE5-Is as a medical management option for BPH. [4]
Should tadalafil replace sildenafil on the list of essential medications?
Research question:
Is tadalafil more effective than sildenafil in managing patients with erectile dysfunction (ED)?
CLEAN Meds agents used to treat ED
 Sildenafil
Literature search: PubMed
Brief search strategies: (erectile dysfunction[MeSH Terms]) AND inhibitors, phosphodiesterase 5[MeSH
Terms]) AND sildenafil[MeSH Terms]) AND tadalafil[MeSH Terms]
Yuan, J., et al., Comparative effectiveness and safety of oral phosphodiesterase type 5 inhibitors for
erectile dysfunction: a systematic review and network meta-analysis. Eur Urol, 2013. 63(5): p. 902-12.
Objective
To compare the efficacy and safety of different classes of oral PDE5-Is for ED.
Studies Included
“A total of 118 trials (placebo controlled 105 and 13 active controlled trials) (31 195 individuals) were
included. There was no major difference in the results between the traditional meta-analysis and the
network meta-analysis. The included studies covered seven differrent PDE5-Is: sildenafil, tadalafil,
vardenafil, udenafil, mirodenafil, avanafil, and lodenafil.”
Outcomes measured
“The primary outcomes for this study were the Global Assessment Questionnaire question 1 (GAQ-1),
and change from baseline to study end in the International Index of Erectile Function-Erectile Function
domain score (IIEF-EF). The secondary outcomes included (1) change from baseline to study end in
Sexual Encounter Profile question 2 (SEP-2), (2) change from baseline to study end in Sexual Encounter
Profile question 3 (SEP-3), and (3) adverse events (AEs) that included the number of treatment-related
adverse events, serious or severe adverse events, patients who experienced any adverse event (AE), and
specific AEs.”
Results
Efficacy
Tadalafil was the most effective ED treatment among all PDE5-Is analyzed as measured by the
erectile function domain of the International Index of Erectile Function. “For all efficacy outcomes, the
absolute effects and the rank tests indicated that tadalafil and vardenafil were the most effective agents.
After adjusting for dosage, the conclusion remained the same. Safety analysis showed there was no major
difference among different agents.”
Tadalafil is more effective than sildenafil on IIEF EF scores, SEP-2 and SEP-3 questions.
Safety
“The safety between different classes of PDE-5 inhibitors was similar, except tadalafil caused a higher
incidence of myalgia than sildenafil (RR: 4.69; 95% CI, 1.39–14.21).”
Complete search strategies
PubMed (n=23)
(((systematic review [ti] OR meta-analysis [pt] OR meta-analysis [ti] OR systematic literature review [ti]
OR this systematic review [tw] OR pooling project [tw] OR (systematic review [tiab] AND review [pt])
OR meta synthesis [ti] OR meta synthesis [ti] OR integrative review [tw] OR integrative research review
[tw] OR rapid review [tw] OR consensus development conference [pt] OR practice guideline [pt] OR
drug class reviews [ti] OR cochrane database syst rev [ta] OR acp journal club [ta] OR health technol
assess [ta] OR evid rep technol assess summ [ta] OR jbi database system rev implement rep [ta]) OR
(clinical guideline [tw] AND management [tw]) OR ((evidence based[ti] OR evidence-based medicine
[mh] OR best practice* [ti] OR evidence synthesis [tiab]) AND (review [pt] OR diseases category[mh]
OR behavior and behavior mechanisms [mh] OR therapeutics [mh] OR evaluation studies[pt] OR
validation studies[pt] OR guideline [pt] OR pmcbook)) OR ((systematic [tw] OR systematically [tw] OR
critical [tiab] OR (study selection [tw]) OR (predetermined [tw] OR inclusion [tw] AND criteri* [tw]) OR
exclusion criteri* [tw] OR main outcome measures [tw] OR standard of care [tw] OR standards of care
[tw]) AND (survey [tiab] OR surveys [tiab] OR overview* [tw] OR review [tiab] OR reviews [tiab] OR
search* [tw] OR handsearch [tw] OR analysis [ti] OR critique [tiab] OR appraisal [tw] OR (reduction
[tw]AND (risk [mh] OR risk [tw]) AND (death OR recurrence))) AND (literature [tiab] OR articles [tiab]
OR publications [tiab] OR publication [tiab] OR bibliography [tiab] OR bibliographies [tiab] OR
published [tiab] OR pooled data [tw] OR unpublished [tw] OR citation [tw] OR citations [tw] OR
database [tiab] OR internet [tiab] OR textbooks [tiab] OR references [tw] OR scales [tw] OR papers [tw]
OR datasets [tw] OR trials [tiab] OR meta-analy* [tw] OR (clinical [tiab] AND studies [tiab]) OR
treatment outcome [mh] OR treatment outcome [tw] OR pmcbook)) NOT (letter [pt] OR newspaper
article [pt])) AND(benign prostatic hyperplasia[MeSH Terms]) AND (Tadalafil OR sildenafil OR
inhibitors, phosphodiesterase 5[MeSH Terms])) Filters: published in the last 10 years; Humans; English
Cochrane (n=91)
#1
benign prostate hyperplasia
#2
MeSH descriptor: [Prostatic Hyperplasia] explode all trees
#3
Tadalafil
#4
MeSH descriptor: [Tadalafil] explode all trees
#5
(#1 or #2) and (#3 or #4)