The effectiveness and safety of avanafil for erectile dysfunction: a systematic review and meta-analysis.

Just Accepted by Current Medical Research & Opinion Original article The Effectiveness and Safety of Avanafil for Erectile Dysfunction: A Systematic Review and Meta-analysis Hongtao Wang, Jinqiu Yuan, Xiaolong Hu, Ke Tao, Jiaqi Liu, Dahai Hu doi: 10.1185/03007995.2014.909391 Abstract

Curr Med Res Opin Downloaded from informahealthcare.com by University of Southern California on 04/08/14 For personal use only.

Objective: To compare the efficacy and safety between different dosages of avanafil for the treatment of erectile dysfunction(ED). Methods: PubMed, Cochrane Library, EMBASE were searched to identify randomized controlled trials which compared avanafil with placebo, or compared different dosages of avanafil for ED. International Index of Erectile Function-Erectile Function domain score (IIEF-EF), Sexual Encounter Profile Question (SEP) question 2 & 3 and adverse events were considered as the study outcomes. Both pairwise meta-analysis and network meta-analysis were carried out. Results: Five studies including 2225 patients were assessed. The pairwise meta-analysis suggested that avanafil was more effective than placebo in improving IIEF-EF (Mean difference [MD]: 4.47; 95% confidence interval [CI]: 3.51 to 5.43), SEP-2 (MD: 17.41; 95%CI: 14.03 to 20.79), and SEP-3 (MD: 20.01; 95%CI: 22.98 to 37.22), with an evident dose-response relationship. The effectiveness was significantly different between 50mg and 100mg, or between 50mg and 200mg group for all outcomes. Overall, avanafil was associated with a significantly higher incidence of any adverse event (Risk Ratio [RR]:2.56; 95%CI: 1.66 to 3.94), serious adverse event (RR: 2.78; 95%CI: 1.34 to 5.76), flushing (RR: 6.06; 95%CI: 3.37 to 10.88) and headache (RR: 7.54; 95%CI: 3.52 to 16.12) when compared with placebo. No significant difference in safety was found among various dosage groups. Conclusions: Avanafil, from 50 to 200 mg, is effective and well tolerated for the treatment of ED, and an increase in dosage is associated with a significant rise of effectiveness but not with significantly more adverse events.

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1

Original article The Effectiveness and Safety of Avanafil for Erectile Dysfunction: A Systematic Review and Meta-


analysis

Hongtao Wang,1 Jinqiu Yuan, 2 Xiaolong Hu, 1 Ke Tao, 1 Jiaqi Liu, 1 Dahai Hu 1*

1. Burns Centre of PLA, Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China 2. Division of Epidemiology, School of Public Health and Primary Care, The Chinese University of Hong Kong, Hong Kong, China

Prof. Dahai Hu,

Burns Centre of PLA, Department of Burns and

Cutaneous Surgery, Xijing

Key words: Avanafil; erectile dysfunction; systematic reviews; meta-analysis

[Running head: Avanafil for Erectile Dysfunction]

2

Abstract Objective: To compare the efficacy and safety between different dosages of avanafil for the treatment


of erectile dysfunction(ED).

Methods: PubMed, Cochrane Library, EMBASE were searched to identify randomized controlled trials which compared avanafil with placebo, or compared different dosages of avanafil for ED. International Index of Erectile Function-Erectile Function domain score (IIEF-EF), Sexual Encounter Profile Question (SEP) question 2 & 3 and adverse events were considered as the study outcomes. Both pairwise metaanalysis and network meta-analysis were carried out. Results: Five studies including 2225 patients were assessed. The pairwise meta-analysis suggested that avanafil was more effective than placebo in improving IIEF-EF (Mean difference [MD]: 4.47; 95% confidence interval [CI]: 3.51 to 5.43), SEP-2 (MD: 17.41; 95%CI: 14.03 to 20.79), and SEP-3 (MD: 20.01; 95%CI: 22.98 to 37.22), with an evident dose-response relationship. The effectiveness was significantly different between 50mg and 100mg, or between 50mg and 200mg group for all outcomes. Overall, avanafil was associated with a significantly higher incidence of any adverse event (Risk Ratio [RR]:2.56; 95%CI: 1.66 to 3.94), serious adverse event (RR: 2.78; 95%CI: 1.34 to 5.76), flushing (RR: 6.06; 95%CI: 3.37 to 10.88) and headache (RR: 7.54; 95%CI: 3.52 to 16.12) when compared with placebo. No significant difference in safety was found among various dosage groups. Conclusions: Avanafil, from 50 to 200 mg, is effective and well tolerated for the treatment of ED, and an increase in dosage is associated with a significant rise of effectiveness but not with significantly more adverse events.

3

Introduction Erectile dysfunction(ED), which is defined as the persistent inability to achieve or maintain an erection sufficient for satisfactory sexual intercourse1, is a common disorder reported to affect as many as 152 million men worldwide 2-4. Owing to the high prevalence, the total costs for the treatment of ED is huge.


The U.S National Health and Nutrition Examination Survey indicated that the annual costs of ED treatment in USA could reach $15 billion if all patients sought medical care 5. For individual patients, ED may cause serious distress and social stigma, with marked effects on their self-esteem, family relationships and quality of life 6-9. Oral phosphodiesterase type 5 inhibitors (PDE5-Is) are current first-line therapies for ED10, 11. It has been demonstrated that oral PDE5-Is are more effective than placebo for ED12. Avanafil is a highly selective PDE-5 inhibitors that has been approved for the treatment of ED in 2012 in US13, 14. In an in vitro receptor-binding study comparing the inhibitory effects of avanafil on 11 PDE isoenzymes with those of other PDE5-Is, avanafil potently inhibited PDE5 activity without significant inhibition of other PDE isoenzymes. This suggested that avanafil may be associated with less adverse events than other PDE5-Is15. So far several randomized controlled trials (RCT) have been carried out to evaluate the effectiveness and safety of avanafil for the treatment of ED16-20. These studies included various drug dosages and patients of different races, an overall evaluation of the effectiveness and safety of avanafil is lacking. In addition, the sample sizes of some trials were relatively small17, 20, and the relationship among dosage, effectiveness and safety is not clear. We therefore undertake this different dosages of avanafil for the treatment of ED.

4

Materials and Methods Data sources and searches We carried out an electronic search of Cochrane Library (Issue 5, 2013), PubMed (1966 to May 2017),


EMBASE (1984 to may 2017) with the following keywords in combination both MeSH terms and text words: “phosphodiesterase inhibitor”, “avanafil”, “Stendra”, “erectile dysfunction”, “impotence”. There was no limitation on publication status or language. MetaRigister and WHO International Clinical Trials Registry Platform were searched for ongoing studies. We also manually checked reference lists of the included studies to identify further studies.

Studies selection We included RCTs which compared different dosages of avanafil for male patients with ED. The primary outcome for this study is the change from baseline to study end in International Index of Erectile Function - Erectile Function domain score (IIEF-EF). IIEF-EF is a 30-point self-report instrument for the evaluation of male erectile function. The secondary outcomes include: I. Sexual Encounter Profile Question 2 (SEP-2. Were you able to insert your penis into your partner’s vagina?); II. Sexual Encounter Profile Question 3 (SEP-3. Did your erection last long enough for you to have successful completion of intercourse?); and III. adverse events, which include number of patients experienced any adverse event (Any AE), serious or severe adverse events (SAE), and specific adverse events. The SEP-2 and SEP-3 are measured as the change in the percentage of positive responses between the run-in and treatment periods. Trials were eligible if one of the above outcome measures was reported. The study eligibility was independently determined by two authors. Discrepancies were resolved by discussion.

5 Data extraction and quality assessment Two authors independently extracted data with a standard form predesigned for this study. The data extracted were as follows: study characteristics (authors, location, title, etc.), patient characteristics (patients number, age, body mass index, race, baseline disease severity, disease duration), intervention,


control, methodological information, outcomes (point estimates, standard error, 95% confidence interval[CI], etc.). The authors of original studies were consulted for missing information where necessary.

The methodological quality and the quality of evidence were evaluated with the Cochrane Collaboration bias appraisal tool 21 and the GRADE system22, 23, respectively. The methodological quality focuses on six domains: adequate sequence generation, adequate concealment of allocation, adequate blinding, incomplete outcome data, selective reporting and other sources of bias. Each domain of risk of bias was graded as low risk, unclear, and high risk. According to GRADE, randomized trials and observational studies were initially considered as high and low quality evidence, respectively. The quality of evidence was downgraded for the following five factors: study limitations, inconsistency of results, indirectness of evidence, imprecision and publication bias, and upgraded if there was a large magnitude of effects or plausible confounding variables, which would reduce a demonstrated effect, or dose-response gradient22, 23.

6 Statistical analysis The comparative effects were initially analyzed by the standard meta-analysis method using Cochrane Collaboration review manager software (RevMan 5.2). Summary effect size was calculated as mean difference (MD), risk ratio (RR), together with their 95% CIs). A random effects model which accounts for


both within and between-study variability was employed to provide more conservative estimated effects. Heterogeneity among studies was assessed with the χ 2 test and the I2 -index statistic. Low level of heterogeneity was defined as I 2 ≤ 25 %, accompanied by P > 0.10 for the χ 2 test 21. Subgroup analysis was undertaken according to the dosage. We then pooled the data of different dosage groups with a random-effects network model within a Bayesian framework using WinBUGS24. Network meta-analysis combined both direct evidence and indirect evidence for every pair of treatments. The placebo group was considered as the reference group as it was directly connected to every dosage group in our study. A burn-in of 20,000 simulations was used for convergence, followed by 20,000 simulations for the estimation. The number of simulations was set based on our past experience and the convergence were checked before generate the final posterior summaries. More simulations were performed if convergence was not achieved. The goodness of fit for the models was determined by the Deviance Information Criterion 24 . Meta-regression analysis by adding other covariates (average age, weight, ED duration, treatment duration) to the network meta-analysis model was employed to check the assumption of similarity25, 26. Where direct and indirect estimates were combined, we applied an extension of the Bucher method to check the assumption of consistency 27. Publication bias was examined by funnel plot asymmetry and Egger’s test21.

7

Results Search results and study characteristics The literature search yielded 155 citations, of which 130 were excluded after titles and abstracts review. The full texts of 25 remaining citations were screened, and 12 studies irrelevant to avanafil, 4 non-RCTs


and 4 studies irrelevant to ED were excluded, leaving 5 studies (2225 patients) eligible for inclusion 16-20. (Figure 1) Four of the included studies were undertaken in the U.S. and one was from Korea. The Caucasians and Asians were the primary study population, which took up 76.18% (1695/2225) and 9.89% (220/2225). Three dosages of avanafil (200mg, 100mg and 50mg) were compared in included studies. (Figure 2) One study included patients with diabetes mellitus16 and another one included a male after nerve sparing radical prostatectomy20.The overall methodological quality of included studies was moderate. The randomization was adequate in two studies16,18, and all studies were double blinded. As the loss of follow up was balanced. and most of studies employed intent-to-treat analysis, the risk of bias from incomplete outcome data was low. The baseline characteristics of included studies were summarized in table 1. Effectiveness Table 2 shows the summary of the meta-analysis for effectiveness. The pairwise meta-analysis of all dosage groups suggested that avanafil was significantly more effective than placebo in improving IIEF-EF (MD: 4.47; 95%CI: 3.51 to 5.43), SEP-2 (MD: 17.41; 95%CI: 14.03 to 20.79), and SEP-3 (MD: 20.01; 95%CI: 22.98 to 37.22). The effectiveness of 200mg, 100mg and 50mg avanafil were all statistically significantly more effective than placebo as measured by IIEF-EF (MD,95%CI: 50mg 2.50, 0.92 to 4.08; 100 mg 4.34, 3.06 to 5.63; 200 mg 5.21, 3.90 to 6.51), SEP-2 (MD,95%CI: 50mg 11.10, 4.63 to 17.57; 100 mg 17.11, 12.62 to 21.59; 200 mg 20.83,16.36 to 25.31) and SEP-3 (MD,95%CI: 50mg 13.70, 6.56 to 20.84; 100 mg 19.79, 9.63 to 29.94; 200 mg 22.38, 13.91 to 30.85). As to the comparative effectiveness between

8 different dosage groups, the effectiveness of higher dosage avanafil were significantly more effective than lower dosage avanafil, except the comparison between 100mg and 200mg group, which failed to achieve statistical significance (MD, 95%CI: IIEF-EF, 0.76, -0.06 to 1.58; SEP-2, 3.74, -0.73 to 8.21; SEP-3, 2.54, -2.04 to 7.11). Of the five included studies, one study was carried out in ED patients with DM and


one study was carried out in ED patients received nerve sparing radical prostatectomy. The efficacy of these two studies was relatively inferior to other trials in all dosages groups (Data not shown). The analysis results of network meta-analysis were generally consistent with that of standard pairwise meta-analysis, though some estimates from network meta-analysis failed to achieve statistical significance. The absolute effects and test of rank by network meta-analysis demonstrated an evident dose-response gradient among various dosage groups.

Safety The adverse events caused by PDE-5 inhibitors were generally mild. Flushing and headache were the most common reported adverse events. Taking all dosage groups as whole, avanafil was associated with significantly higher incidence of any AE (RR:2.56; 95%CI 1.66 to 3.94), SAE (RR: 2.78; 95%CI: 1.34 to 5.76), flushing (RR: 6.06; 95%CI: 3.37 to 10.88) and headache (RR: 7.54; 95%CI: 3.52 to 16.12). (Figure 3). The incidences of any AE (50mg: 10.6%, 100mg: 28.7%, 200mg: 32.9%), SAE(50mg: 0.06%, 100mg: 1.0%, 200mg: 1.2%), headaches (50mg: 4.3%, 100mg: 4.6%, 200mg: 8.9%), flushing (50mg: 3.7%, 100mg: 4.9%, 200mg: 5.1%) were pooled. Subgroup analysis according to the dosage suggested no significant subgroup difference on any AE (P=0.228), flushing (P=0.514) and headache (P=0.924). No significant difference was found between various dosage groups on safety outcomes.

9 Network assumptions and publication bias There was no major heterogeneity in pairwise meta-analyses, and the meta-regressions did not identify any significant effect modifiers. The inconsistency of 36 closed loops was tested and no statistically significant inconsistency was identified.


Visual inspection suggested symmetry in the funnel plots (figures not shown) for IIEF-EF, SEP-2 and SEP-3, and this was confirmed by Egger’s test (IIEF-EF: P=0.526; SEP-2: p=0.853; SEP-3: p=0.236).

Discussion This study was based on 5 studies including 2225 patients. The principal findings are twofold as following: Firstly, oral avanafil is significantly more effective than placebo in improving IIEFEF, SEP-2 and SEP-3, and there is an evident dose-response relationship; Secondly, though oral PDE-5 inhibitors may cause more adverse events than placebo, they are generally mild and well tolerated, and an increase in dosage from 50mg to 200mg is not associated with a significant rise in adverse events.

The study results are in agreement with animal trials

28

and pharmacological studies in

healthy subjects29, 30. This meta-analysis dramatically increased the sample size when compared with individual RCTs, therefore obtained much more precise estimates. There may be a concern that our study pooled data from patients with different underlying diseases like diabetes mellitus. However, our meta-analyses were homogeneous, and an evident dose-response relationship was obtained. These factors largely increased the quality of evidence, and the above concern would not change our conclusion. In addition, we found that the improvement between 200 mg and

10 100mg was much small than the difference between 100mg and 50mg, or between 50mg and placebo. This suggested that there may be ceiling effect in 100 mg, but we believe further researches are still needed to confirm it.


Apart from the significant effectiveness, avanafil showed a favorable safety profile. For all the safety outcomes analyzed, the RR between 50mg avanafil and placebo was not statistically significant. This was primarily due to the small sample size of the 50mg group. Overall, the risks of adverse events between different dosage groups are similar. Some other adverse events like nasopharyngitis, back pain were also reported, but the incidences were low, so they were not included in the meta-analysis.

To the best of our knowledge, this study is the most comprehensive comparative study of oral avanafil for ED to date. An exhaustive and contemporaneous search strategy was undertaken to ensure all eligible clinical trials were included. In addition, we employed the relatively new approach of network meta-analysis to synthesize data, which provided tests of the rank and absolute effects for different dosage groups. Lastly, the grading system was used to evaluate the quality of the evidence, which provided a more comprehensive evidence based review for practitioners.

Limitations of this network meta-analysis primarily arise from the quality of original trials reviewed. The sequence concealment was not reported in all studies; therefore a risk of selection bias may be introduced. In addition, the estimates from network meta-analysis and standard meta-analysis for some

11 comparisons were inconsistent in the status of statistical significance. However, the inconsistency was not evident, which would not affect our conclusion. An important reason for this is that we applied a random network effects model which accounts for both within and between-study variability to provide more conservative estimated effects. Furthermore, as the primary population studies in this systematic


review was the Caucasians and Asians, the clinical effect of avanafil for ED patients of other races is still unclear. Because the study duration of most included studies were 12 weeks, the long term efficacy for avanafil is still unclear. Lastly, the related estimates for 50mg avanafil group were lacking of precision for only one study with 154 patients were involved.

In summary, we conclude that avanafil, from 50 to 200 mg, is effective and well tolerated for the treatment of ED, and increase in dosage is associated with a significant rise of the effectiveness but not with significantly more adverse events. This study has important implications . Taking both effectiveness and safety into consideration, we suggest that

should

treat ED patients with avanafil at a starting dose of 100mg, and then adjust the dosage on demand. Increasing the dosage to 200mg, the highest dosage investigated in current clinical trials is safe for ED patients.

as the sample size for analyzing low dosing avanafil was small, further large scale

studies are needed to confirm this conclusion. Future studies are also need to evaluate the effectiveness of avanafil in other ethnic groups, and patients with various disease severities. The safety of even lager dosage (>200mg) is also needed to be evaluated, which will determine if it is safe to use higher dosage avanafil to achieve even better effectiveness.

12

Transparency Declaration of funding:


This study is not funded. Publication fees are being paid for by the authors.

Declaration of financial/other relationships: The authors declare that they have no relevant financial interests. CMRO Peer Reviewers on this manuscript have no relevant financial or other relationships to disclose. Author contributions: Conception and design: J.L; Selection and screening of trials included in the analysis: J.Y, X.H, K.T; Data extraction and analysis: H.W, J.Y, X.H; Writing paper: H.W, J.Y; Manuscript revision: D.H, J.L. H.W and J.Y contributed equally and should be considered co-first authors.

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16

Figure legends

Figure 1. Flowchart of study selection

17 Figure 2. The comparision network of included studies.


The number in the middle of solid line indicated the number of studies included in the comparision.

18 Figure 3. The compartive safety of different dosages of Avanafil for erectile dysfunction.


AE: Adverse event; SAE: Seriouse adverse event; CI: Confidence interval.

19 Table 1. The characteristics of included studies Ethnicity, No of Age, year.

Caucasians

ED severity, Mild/

Treatment

Study

Country

Intervention

patients

Mean(SD)

/Asians

Moderate/Severe*

duration

Goldstein

US

Avanafil 200 mg

156

56.1

144/1

53/52/51

12 week

Avanafil 100mg

157

56.4

133/2

54/51/52

Avanafi 50 mg

154

55.5

129/1

55/48/51

Placebo

155

55.8

126/2

55/49/51

Avanafil 200mg

69

56.60(0.30)

0/69

22/28/16

Avanafil 100mg

71

55.80(8,20)

0/71

23/34/11

Placebo

68

54.90(8.90)

0/68

19/34/13

Avanafil 200mg

536

57.1 (9.9)

459/NA

142/177/217

Avanafil 100mg

171

54.2 (10.9)

147/NA

64/59/48

Avanafil 200mg

131

57.5 (8.99)

100/3

28/42/61

Avanafil 100mg

129

58.2 (9.62)

111/2

28/40/61

Placebo

130

58.2 (8.62)

103/1

29/40/61

Avanafil 200 mg

99

57.7(6.60)

76/NA

12/19/68

Avanafil 100mg

99

58.9 (5.88)

83/NA

7/17/75

Placebo

100

58.6 (5.87)

84/NA

8/22/70


2012a

16

Zhao 2012

Korea

12 week

17

Belkoff 2013

52 week

18

Goldstein 2012b

US

12 week

19

Mulhall 2012

US

US

20

12 week

20 * The severity of ED is determined by baseline IIEF-EF: no ED (EF score=26-30); mild ED (EF score=2225); mild to moderate (EF score=17-21); moderate (EF score=11-16); and severe (EF score=6-10). NA: Not available

Table 2. the effectiveness of Avanafil for the treatment of erectile dysfunction


Outcomes

Direct comparison

Network meta-analysis

GRADE

(Mean Difference, 95%CI)

(Mean Difference, 95%CI)

Avanafil all dosage vs. Placebo

4.47(3.51 to 5.43)

NA

High

Avanafil 200 mg vs. Placebo

5.21(3.90 to 6.51)

5.21 (3.63 to 6.70)

High

Avanafil 200 mg vs. 50 mg

4.10 (2.53 to 5.67)

3.10 (-0.60 to 6.80)

Low


0.76 (-0.06 to 1.58)

0.85 (-0.64 to 2.39)

High


4.34(3.06 to 5.63)

4.36 (2.76 to 5.82)

High


2.90 (1.33 to 4.47)

1.85 (-1.51 to 5.05)

Low


2.50(0.92 to 4.08)

2.51 (-0.38 to 5.40)

Moderate


17.41(14.03 to 20.79)

NA

High


20.83(16.36 to 25.31)

20.68 (15.24 to 25.93)

High


11.60 (5.13 to 18.07)

9.47 (-0.28 to 19.12)

Low


3.74 (-0.73 to 8.21)

3.79 (-1.50 to 9.10)

High

IIEF-EF

SEP-2

21 Avanafil 100 mg vs. Placebo

17.11(12.62 to 21.59)

16.89 (11.48 to 22.10)

High


9.00 (2.55 to 15.45)

6.69 (-4.07 to 17.29)

Low


11.10(4.63 to 17.57)

11.21 (3.02 to 19.17)

Moderate


20.01(22.98 to 37.22)

NA


22.38(13.91 to 30.85)

22.75 (16.48 to 28.87)

High


16.40 (9.26 to 23.54)

11.16 (-2.64 to 24.84)

Low


2.54 (-2.04 to 7.11)

2.50 (-3.66 to 8.61)

High


19.79(9.63 to 29.94)

20.25 (14.01 to 26.32)

High


15.60 (8.48 to 22.72)

10.66 (-5.17 to 26.41)

Low


13.70(6.56 to 20.84)

13.59 (3.65 to 23.58)

Moderate


SEP-3

IIEF-EF: International Index of Erectile Function - Erectile Function domain (range:1-30); SEP-2: the change in the percentage of sexual attempts in which the men were able to insert the penis into the partner’s vagina between the run-in and treatment periods; SEP-3: the change in the percentage of sexual attempts in which men were able to maintain an erection of sufficient duration to have successful intercourse between the run-in and treatment periods; NA: Not available

Avanafil for erectile dysfunction.

Avanafil for male erectile dysfunction: a systematic review and meta-analysis.

Acupuncture for Erectile Dysfunction: A Systematic Review.

Erectile dysfunction in hemodialysis: A systematic review.

Avanafil for erectile dysfunction in elderly and younger adults: differential pharmacology and clinical utility.

Diagnostic markers for hyperemesis gravidarum: a systematic review and metaanalysis.

Male sexual dysfunction and ankylosing spondylitis: a systematic review and metaanalysis.

A review of the efficacy and safety of mirodenafil in the management of erectile dysfunction.

Mirodenafil for the treatment of erectile dysfunction: a systematic review of the literature.

Innovative trends and perspectives for erectile dysfunction treatment: A systematic review.

Postprostatectomy Erectile Dysfunction: A Review.

The incidence of erectile dysfunction after pelvic fracture urethral injury: A systematic review and meta-analysis.

The effect of statins on erectile dysfunction: a systematic review and meta-analysis.

The role of statins in erectile dysfunction: a systematic review and meta-analysis.

The Effectiveness and Safety of Acupuncture for Patients with Chronic Urticaria: A Systematic Review.

A Randomized, Placebo-Controlled, Double-Blind, Multi-Center Therapeutic Confirmatory Study to Evaluate the Safety and Efficacy of Avanafil in Korean Patients with Erectile Dysfunction.

A comparison of the available phosphodiesterase-5 inhibitors in the treatment of erectile dysfunction: a focus on avanafil.

Direct comparison of tadalafil with sildenafil for the treatment of erectile dysfunction: a systematic review and meta-analysis.

Effectiveness and safety of methylphenidate and atomoxetine for attention deficit hyperactivity disorder: a systematic review.

Effectiveness and safety of moxibustion for primary insomnia: a systematic review and meta-analysis.

Erectile dysfunction in patients with chronic viral hepatitis: a systematic review of the literature.

A systematic review of the psychosocial outcomes associated with erectile dysfunction: does the impact of erectile dysfunction extend beyond a man's inability to have sex?

Effectiveness and Safety of Manufactured Chinese Herbal Formula for Knee Osteoarthritis: Insights from a Systematic Review.

Effectiveness and safety of Wuling capsule for post stroke depression: a systematic review.