Original Research
Pharmacotherapy
Efficacy and Safety of Sildenafil by Age in Men With Erectile Dysfunction

https://doi.org/10.1016/j.jsxm.2016.02.166Get rights and content

Abstract

Introduction

Sildenafil, an oral phosphodiesterase type 5 inhibitor, has been extensively investigated for the treatment of erectile dysfunction in randomized controlled trials.

Aim

To assess the efficacy and safety of sildenafil vs placebo according to age subgroups (<65, 65–74, and ≥75 years) in 11,364 men with erectile dysfunction using pooled data from 48 randomized, double-blinded, placebo-controlled, parallel-group, flexible-dose trials.

Methods

Most trials had a 12-week treatment duration. The starting sildenafil dose was 50 mg, taken 1 hour before sexual activity, with subsequent adjustment to 100 or 25 mg based on efficacy and safety. Men taking nitrate therapy or nitric oxide donors and men with severe cardiac failure, unstable angina, or recent stroke or myocardial infarction were excluded. Efficacy analyses included all subjects with baseline and at least one postrandomization evaluation. Safety analyses included subjects who received study medication.

Main Outcome Measures

The International Index of Erectile Function and a global assessment question (“Did the treatment improve your erections?”).

Results

Mean International Index of Erectile Function scores for question 3 (frequency of penetration), question 4 (maintenance of erections after penetration), and the erectile function domain were statistically significantly improved with sildenafil vs placebo for each age subgroup; orgasmic function, intercourse satisfaction, sexual desire, and overall satisfaction domain scores also were statistically significantly improved with sildenafil vs placebo. The percentage of men reporting improved erections on the global assessment question was statistically significantly higher with sildenafil vs placebo for all age subgroups; the percentage with sildenafil tended to decrease with increasing age (<65 years, 80%; 65–74 years, 69%; ≥75 years, 59%). The most common adverse events with sildenafil were headache and flushing in each age subgroup.

Conclusion

Sildenafil is an effective and well-tolerated treatment for erectile dysfunction regardless of patient age, including men at least 75 years old.

Introduction

Erectile dysfunction (ED), defined as the inability to achieve or maintain an erection sufficient for satisfactory sexual performance,1 is a common and age-associated condition. Based on studies published in the past decade,2, 3, 4, 5, 6, 7, 8, 9, 10 the overall prevalence of ED has been estimated at 18%2 to 47%3 in the United States and 6%10 to 49%9 in international studies, with prevalence rates dependent on the age of men in the sample assessed and the method used to identify ED. Based on data from the U.S. National Health and Nutrition Examination Survey, the prevalence of ED increases from 8.2% in men 40 to 49 years old to 77.5% in those at least 75 years old.2 In addition to age, factors identified as significantly associated with ED include diabetes, obesity, smoking, cardiovascular disease, stroke, hypertension, and lower urinary tract symptoms.2, 4, 8, 11, 12, 13, 14 In men 40 to 70 years old with ED, the risk of cardiovascular disease mortality is increased 43% vs men without ED.15

Sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, was the first in-class oral medication approved by the U.S. Food and Drug Administration in 1998 for the treatment of ED based on its efficacy and safety profiles in randomized clinical trials.16 Other oral PDE5 inhibitors, including tadalafil, vardenafil, and avanafil, also have been approved for the treatment of ED.

The 15-item International Index of Erectile Function (IIEF) was developed and validated as a patient-reported outcome measurement for assessing ED in clinical trials and treatment response in men with ED.17 The six-item IIEF erectile function domain is widely accepted by regulatory agencies as a primary end point in clinical trials of ED therapies worldwide. The IIEF erectile function domain is a validated diagnostic tool that is useful for classifying ED severity and for assessing treatment response.18 More recently, estimates of minimal clinically important differences (MCIDs) in the treatment-related change in the IIEF erectile function domain score have provided additional information on treatment response for clinicians managing men with ED.19

Sildenafil has been extensively evaluated in 74 double-blinded, placebo-controlled, clinical trials, with a database of efficacy and safety data from more than 16,000 men with ED. However, published data on the treatment response to sildenafil in men with ED according to patient age are limited,20, 21, 22, 23 especially in men at least 75 years old.

Section snippets

Aims

To assess the efficacy and safety of sildenafil according to age subgroups (<65, 65–74, and ≥75 years) in men with ED using pooled data from 48 randomized, double-blinded, placebo-controlled, parallel-group, flexible-dose sildenafil trials.

Methods

Data for 74 double-blinded, placebo-controlled sildenafil clinical trials were entered in a Pfizer clinical data repository. The main determinant of study inclusion in the present analysis was study design. Overall, 48 of the 74 trials had a similar study design (ie, double-blinded, placebo-controlled, parallel-group, flexible-dose design) and were considered for the present analysis. Forty-two of these 48 studies collected IIEF data and were used for efficacy outcomes reported in this

Main Outcome Measures

The main outcome measurements for treatment efficacy were patient-reported quantitative scores for IIEF Q3, Q4, erectile function domain, orgasmic function domain, sexual desire domain, intercourse satisfaction domain, and overall satisfaction domain, and the qualitative yes-or-no response to the GAQ.

Patients

In the 48 randomized, double-blinded, placebo-controlled, parallel-group, flexible-dose sildenafil trials included in the analysis, 5,237 men received placebo and 6,127 received sildenafil. The baseline demographic and clinical characteristics of the patients according to treatment and age are presented in Table 1. The mean age of the overall population was 55 years (SD = 11 years) in each treatment group, with a mean ED duration of 4.4 years. In the overall population, the prevalence rates of

Discussion

The present post hoc analysis of pooled data from 48 flexible-dose clinical trials provides valuable information on the efficacy and safety of sildenafil in men with ED according to age subgroups (ie, <65, 65–74, and ≥75 years). In each of these age subgroups, the IIEF erectile function domain score was statistically significantly improved from baseline in patients treated with sildenafil vs those receiving placebo. In 2011, Rosen et al19 published estimates of the MCIDs for the erectile

Conclusions

Sildenafil is an effective and well-tolerated treatment for ED regardless of patient age. For men at least 75 years old, sildenafil treatment is associated with statistically significant and clinically meaningful improvements in erectile function. Sexual function and sexual satisfaction can continue with aging for most sildenafil-treated men with ED.

Statement of Authorship

Category 1

  1. (a)

    Conception and Design

    • Irwin Goldstein; Li-Jung Tseng; Vera Stecher; Jed C. Kaminetsky

  2. (b)

    Acquisition of Data

    • Li-Jung Tseng; Dana Creanga

  3. (c)

    Analysis and Interpretation of Data

    • Irwin Goldstein; Li-Jung Tseng; Dana Creanga; Vera Stecher; Jed C. Kaminetsky

Category 2
  1. (a)

    Drafting the Article

    • Irwin Goldstein; Li-Jung Tseng; Vera Stecher; Jed C. Kaminetsky

  2. (b)

    Revising It for Intellectual Content

    • Irwin Goldstein; Li-Jung Tseng; Vera Stecher; Jed C. Kaminetsky

Category 3
  1. (a)

    Final Approval of the Completed Article

    • Irwin Goldstein; Li-Jung Tseng; Dana

References (27)

Cited by (36)

  • Recreational Use of Oral PDE5 Inhibitors: The Other Side of Midnight

    2022, Sexual Medicine Reviews
    Citation Excerpt :

    Besides, these drugs have been acknowledged for improving other disorders such as; pulmonary arterial hypertension, benign prostatic hyperplasia in addition to diverse therapeutic implications in different systems such as; cardiovascular, pulmonary, cutaneous, gastrointestinal, urogenital, cellular, musculoskeletal, and neurologic disorders.13–18 Generally, these drugs are usually well-tolerated, but minor adverse events may take place include; headache, flushing, nasal congestion, dyspepsia, visual disturbance, or back pain.19 However, these drugs have become used in subjects not suffering from ED for recreational use to enhance their sexual performance.

  • Could Oral Phosphodiesterase 5 Inhibitors Have a Potential Adjuvant Role in Combating COVID-19 Infection?

    2021, Sexual Medicine Reviews
    Citation Excerpt :

    Specifically, PDE5 hydrolyzes cGMP into 5′GMP by blocking cGMP hydrolysis, potentiates the effects of cGMP, resulting in decreased intracellular calcium, penile smooth muscle relaxation, and vasodilatation with increased penile blood flow.9 Currently, 4 oral PDE5 inhibitors are approved by the U.S. Food and Drug Administration (sildenafil [Viagra], vardenafil [Levitra], tadalafil [Cialis], and avanafil [Stendra]) with good efficacy and tolerable adverse effects.10,11 Sildenafil citrate was released in 1998, has a maximal plasma concentration (Tmax) at 60 min on an empty stomach, and acts for 4–6 hours.

  • Development of novel phosphodiesterase 5 inhibitors for the therapy of Alzheimer's disease

    2020, Biochemical Pharmacology
    Citation Excerpt :

    Although PDE5 inhibitors can induce vasodilatory effects when administered at high doses, the cognition enhancing properties observed in the current studies using lower doses were not related to any main effect on blood flow and glucose utilization in the brain. Interestingly, due to the FDA-approval of PDE5 inhibitors for the treatment of non-neurological conditions, their side effects have been extensively documented and consist of mild adverse effects that are generally well-tolerated by patients like headache, flushing, runny nose, stomach pain, back pain, and indigestion [138]. Nevertheless, it is acknowledged that currently available PDE5 inhibitors are characterized by suboptimal specificity, which could limit their clinical application.

  • Should We Tailor the Clinical Management of Erectile Dysfunction According to Different Ages?

    2019, Journal of Sexual Medicine
    Citation Excerpt :

    Clinically speaking, those findings suggest that a large proportion of older men are apparently reconciled to lower levels of sexual activity. Interestingly, in a large study pooling data of 11,364 patients from 48 randomized placebo-controlled trials investigating the efficacy of sildenafil, Goldstein et al15 showed that, although the treatment was effective across all age groups, the effect size in terms of IIEF improvement from baseline decreased across increasing ages. In our study, we observed that improvement in terms of sexual satisfaction for each IIEF-EF increase eventually decreased as a function of age, with older men with mild ED potentially not even perceiving any difference in terms of sexual satisfaction for further improvement in their EF.

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Conflict of Interest: Dr Goldstein is on the advisory board of and receives honorarium from Pfizer and receives research support from Endo. Dr Tseng and Dr Stecher are employees of Pfizer. Dr Creanga is a paid contractor to Pfizer in the development of this article. Dr Kaminetsky consults and speaks for and receives honorarium and research support for erectile dysfunction from Endo and Lipocine.

Funding: This study was sponsored by Pfizer Inc. Editorial and medical writing assistance was provided by Patricia B. Leinen, PhD, of Complete Healthcare Communications, Inc, and funded by Pfizer Inc.

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