ED: Efficacy and Safety of Daily Tadalafil in Men with Erectile Dysfunction Previously Unresponsive to On‐demand Tadalafil

doi:10.1111/j.1743-6109.04042.x

The Journal of Sexual Medicine

Volume 1, Issue 3, November 2004, Pages 292-300

https://doi.org/10.1111/j.1743-6109.04042.x Get rights and content

ABSTRACT

Objective

To assess the efficacy and safety of daily tadalafil, a potent selective phosphodiesterase 5 inhibitor, for the treatment of erectile dysfunction (ED) in men previously unresponsive to on‐demand tadalafil.

Materials and Methods

A total of 112 men with a mean age of 63 (range 21–79) and moderate to severe ED of various aetiologies were treated with tadalafil, taken on a daily basis at flexible daily doses of 10 and 20 mg for 12 weeks. The three primary outcomes were changes from the pretreatment and on‐demand tadalafil baseline in the erectile function domain of the International Index of Erectile Function and the proportion of yes responses to questions 2 and 3 of the Sexual Encounter Profile. Additional efficacy instruments included a Global Assessment Question administered at completion of the study.

Results

Compared with pretreatment and on‐demand tadalafil baseline, daily dosed tadalafil significantly enhanced all efficacy outcome variables. Patients receiving daily tadalafil (10 mg) experienced a significant mean improvement of 12.8 and 8.2 in the International Index of Erectile Function erectile function domain score from baseline (P < 0.001) and from on‐demand tadalafil, respectively (P < 0.001). Fifty‐eight percent of intercourse attempts (Sexual Encounter Profile question 3) were successfully completed (P < 0.001 vs. pretreatment baseline, P < 0.001 vs. on‐demand tadalafil). Improved erections at end point were reported by 69% of men compared with 42% of men with on‐demand tadalafil. Daily tadalafil was well tolerated with headache, dyspepsia, and facial flushing as the most frequent adverse events.

Conclusion

Daily tadalafil (10/20 mg) was effective and well tolerated in this study population and is an effective salvage for previous on‐demand tadalafil nonresponders.

Introduction

Community‐based epidemiological studies suggest that erectile dysfunction (ED) is a common disorder in men, affecting up to 52% of men between the ages of 40 and 70 years, and is associated with reduced quality of life [1, 2].

It is now recognized that vascular disease of the penile arteries is the most common cause of ED, accounting for up to 80% of these cases [3, 4]. The nitric oxide–cyclic guanosine‐3′5′‐monophosphate (NO‐cGMP) system is important in producing the arterial dilation and venous occlusion necessary to attain and sustain an erection. Abnormalities of this vasodilator system because of endothelial dysfunction are present in atherosclerosis and play an important role in the pathophysiology of ED [5, 6, 7]. Kaiser et al. reported that patients with ED and no significant cardiac risk factors or other clinical cardiovascular diseases have a peripheral vascular abnormality in the NO‐cGMP pathway, suggesting that ED may be the first clinical manifestation of cardiovascular disease [8].

Phosphodiesterase type 5 inhibitor drugs (PDE‐5), which inhibit the breakdown of cGMP producing vasodilation and improve endothelial cell function, are very effective in treating ED [9]. Tadalafil is a potent selective inhibitor of PDE‐5, which is rapidly absorbed with a tmax of 2 hours and a terminal half‐life of 17.5 hours. Multicenter international placebo‐controlled clinical trials have demonstrated that patients receiving 20 mg tadalafil experienced a significant mean improvement in the International Index of Erectile Function (IIEF) erectile function (EF) domain score, successful completion of 75% of intercourse attempts, and an 81% reported rate of improved erections [10]. The extended half‐life of tadalafil offers patients a prolonged period of responsiveness with the successful completion of 59.2% of intercourse attempts at 36 hours after tadalafil dosing [11].

The efficacy of PDE‐5 inhibitor drugs appears related to the extent and severity of ED, with significantly reduced efficacy demonstrated in patients with diabetic ED, severe vasculogenic ED, and post‐radical prostatectomy ED. Several authors have reported their experience with salvage treatment for PDE‐5 inhibitor nonresponders using patient reeducation to ensure correct drug usage and optimize response, testosterone replacement in men with androgen deficiency, high dose sildenafil, intracavernous injection therapy, and combination therapy with sildenafil and intracavernous injection therapy or intraurethral alprostadil [12, 13, 14, 15, 16, 17].

There have been several anecdotal reports that administration of PDE‐5 inhibitors on consecutive days is associated with an improved erectile response. A study was designed to assess the efficacy and tolerability of flexible dose daily tadalafil in patients unresponsive to on‐demand tadalafil.

Section snippets

Study Design

This study was conducted at the Australian Centre for Sexual Health. The study was an open‐label flexible dose evaluation of the efficacy and safety of daily tadalafil in men who had previously failed to respond to on‐demand 20 mg tadalafil and comprised 3 phases: (i) an initial 4‐week on‐demand 20 mg tadalafil phase; (ii) a 4‐week treatment‐free period; and (iii) a 12‐week daily tadalafil treatment period (Figure 1).

Inclusion Criteria

Eligible patients were men 18 years of age or older in a stable heterosexual

Patient Population and Demographics

One hundred and twelve men with a mean age of 63.0 (range 21–79) were enrolled. The aetiology of ED was psychogenic in 5 patients (4.5%), organic in 92 patients (82.1%), and mixed psychogenic/organic in 15 patients (13.4%). The mean duration of ED from first symptom was 26.6 months. Fifty‐two men (46.4%) had diabetes mellitus; 63 (56.3%) had hypertension; 70 (61.6%) had hyperlipidemia, and 48 (42.9%) smoked cigarettes (Table 1). Sildenafil had previously been used by 104 men (92.9%), 96 of

Discussion

PDE‐5 inhibitor drugs have reduced efficacy in patients with diabetic ED, comorbid hypertension, severe vasculogenic ED, and post‐radical prostatectomy ED. Saenz de Tejada et al. reported that diabetic patients receiving daily 20 mg tadalafil had a mean IIEF EF domain score of 18.9 compared with 23.9 in unselected men with ED [18]. Intercourse was successfully completed by diabetic men treated with 20 mg tadalafil on only 57% of attempts (Sexual Encounter Profile question 3) compared with 75%

Conclusions

Treatment with daily tadalafil significantly improved all treatment outcomes in men previously unresponsive to on‐demand tadalafil. Sexual intercourse was successfully completed on 58% of attempts. Daily tadalafil was well tolerated and had a similar side‐effect profile to on‐demand tadalafil.

Conflict of Interest. Dr. McMahon is a paid consultant and/or investigator and/or member of speakers panel for Pfizer, Bayer, GlaxoSmithKline, Eli Lilly, Icos Corp., American Medical Systems, and Johnson &

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Does Treatment of Erectile Dysfunction With PDE 5 Inhibitor Tadalafil Improve Quality of Life in Male Patients With Compensated Chronic Liver Disease? A Prospective Pilot Study
2022, Journal of Clinical and Experimental Hepatology
Erectile dysfunction (ED) is common in patients with compensated cirrhosis but its impact on the quality of life (QOL) is usually overlooked. This study aimed at determining the frequency of ED in male patients with compensated chronic liver disease (CLD), assessing their QOL and the response to treatment with tadalafil. A secondary aim was to assess the effect of the tadalafil therapy on liver fibrosis, if any.
Consecutive patients with compensated CLD and advanced liver fibrosis were screened at the baseline with the International Index of Erectile Function-5 (IIEF-5), QOL questionnaire (WHOQOL-BREF), liver stiffness measurements (LSM) made with Fibroscan™ (Echosens, France), and fibrosis index based on 4 factors (FIB-4) scores. Patients with ED meeting eligibility criteria were prescribed PDE5 inhibitor tadalafil 20 mg on alternate days. During the follow-up, IIEF-5, LSM, and FIB-4 were monitored after 3 and 6 months while the WHOQOL-BREF questionnaire was administered at the baseline and at 6 months.
Among 89 patients with CLD and advanced liver fibrosis, ED was present in 43 (48%) and tadalafil was prescribed to 34 patients (38%) meeting exclusion and inclusion criteria. At 3 months follow-up, the mean IIEF 5 score increased from 15.57 ± 4 to 20.78 ± 3.6, (P = 0.0001) and the improvement persisted at 6 months (IIEF-5 score 21.87 ± 2.2; P = 0.12). The physical, social relationships, and environment domains in the WHOQOL-BREF questionnaire showed significant improvement at six months (P < 0.05) but not the psychological domain (P = ns). From a baseline value of 12.69 ± 3.1 kPa, the mean LSM decreased to 11.37 ± 3.9 kPa, (P = 0.02) after 3 months on tadalafil. After 6 months, the LSM further decreased from 11 ± 0.9 to 8.2 ± 3.2 kPa (P = 0.034). FIB-4 values showed a decline from the baseline at 3 months, from 1.52 ± 0.58 to 1.32 ± 0.55, P < 0.05 and at 6 months, from 1.25 ± 0.53 to 0.97 ± 0.36, P > 0.05. The CAP values did not show any significant change. There was an insignificant decline in the SGOT and SGPT levels (P > 0.05) with no significant change in CTP or MELD scores.
In the short term, tadalafil improves ED and QOL in patients with CLD and advanced liver fibrosis. It may also reduce liver fibrosis in them. Further studies that include liver histology are needed to confirm this preliminary observation of a possible antifibrotic effect.
Effects of phosphodiesterase 5 inhibition on cardiovascular function in resistant hypertension: A systematic review
2022, Life Sciences
Approximately 12–18% of hypertensive patients are diagnosed with resistant hypertension (RH). The risk of having worse cardiovascular outcomes is twice higher in those patients. The low effectiveness of conventional antihypertensive drugs in RH emphasizes the need to evaluate complementary drug therapies to achieve blood pressure (BP) control. Previous studies have demonstrated that phosphodiesterase 5 (PDE-5) inhibitors improve hemodynamics and reduce BP on essential hypertension. So, the authors aimed to summarize current clinical trials-based evidence published concerning the use of PDE-5 inhibitors on BP, cardiovascular function, and hemodynamics of patients with RH. We searched MEDLINE, EMBASE, LILACS, ClinicalTrials.gov, and WHO International Clinical Trials Registry databases on May 15th, 2020 using pre-defined search terms. Two independent reviewers assessed and extracted data from clinical trials that evaluated the effect of PDE-5 inhibitors on BP. We have included five articles in this systematic review. Four of them developed a single-day protocol, while one has developed a 14-day study. The main findings indicate that PDE-5 inhibitors ameliorate BP, vascular hemodynamics, and diastolic function parameters. Some data demonstrated improvement of endothelial function, but it was not a consensus. The side effects seemed to be limited and well-tolerated. In brief, our systematic review highlights the potential of PDE-5 inhibitors as a therapeutic alternative in addition to the multiple-drug regime for RH. Larger studies are still needed to determine whether the beneficial effects of PDE-5 inhibitors on RH would be maintained with chronic administration.
Daily Oral L-Arginine Plus Tadalafil in Diabetic Patients with Erectile Dysfunction: A Double-Blinded, Randomized, Controlled Clinical Trial
2019, Journal of Sexual Medicine
Erectile dysfunction is a common condition among diabetic men. Many treatments are now available with variable responses.
This study aimed to evaluate the effect of daily oral l-arginine plus tadalafil in diabetic patients with mild to moderate erectile dysfunction.
A double-blinded, randomized, controlled clinical trial was conducted with 108 diabetic male patients. Each patient was assessed by medical and sexual histories, International Index of Erectile Function 5-item questionnaires, pharmaco-penile duplex ultrasonography, and serum testosterone level.
Improvement in International Index of Erectile Function 5-item, serum testosterone level and pharmaco-penile duplex ultrasonography.
Erectile functions were significantly improved in all patients after treatment as compared with baseline and placebo (P < .001). Patients who received both drugs showed significant improvement compared to those treated with single drugs, as assessed by International Index of Erectile Function scores and total testosterone (P < .001). Pharmaco-penile ultrasound duplex results showed non-significant differences among patients treated with both drugs and those with each drug alone.
Daily use of l-arginine with tadalafil significantly increased the International Index of Erectile Function scores and total testosterone levels as compared to each drug alone in diabetic patients with erectile dysfunction. No differences were found based on pharmaco-penile duplex findings.
El Taieb M, Hegazy E, Ibrahim A. Daily Oral l-Arginine Plus Tadalafil in Diabetic Patients with Erectile Dysfunction: A Double-Blinded, Randomized, Controlled Clinical Trial. J Sex Med 2019; 19:1390–1397.
British Society for Sexual Medicine Guidelines on the Management of Erectile Dysfunction in Men—2017
2018, Journal of Sexual Medicine
This is an update of the 2008 British Society for Sexual Medicine (BSSM) guidelines.
To provide up-to-date guidance for U.K. (and international) health care professionals managing male sexual dysfunction.
Source information was obtained from peer-reviewed articles, meetings, and presentations. A search of Embase, MEDLINE, and Cochrane Reviews was performed, covering the search terms “hypogonadism,” “eugonadal or hypogonadism or hypogonadal or gonadal,” and “low or lower testosterone,” starting from 2009 with a cut-off date of September 2017.
We offer evidence-based statements and recommendations for clinicians.
Expert guidance for health care professionals managing male sexual dysfunction is included.
Current U.K. management has been largely influenced by non-evidence guidance from National Health Service departments, largely based on providing access to care limited by resources. The 2008 BSSM guidelines to date have been widely quoted in U.K. policy decision making.
There is now overwhelming evidence that erectile dysfunction is strongly associated with cardiovascular disease, such that newly presenting patients should be thoroughly evaluated for cardiovascular and endocrine risk factors, which should be managed accordingly. Measurement of fasting serum glucose, lipid profile, and morning total testosterone should be considered mandatory in all newly presenting patients. Patients attending their primary care physician with chronic cardiovascular disease should be asked about erectile problems. There can no longer be an excuse for avoiding discussions about sexual activity due to embarrassment.
Hackett G, Kirby M, Wylie K, et al. British Society for Sexual Medicine Guidelines on the Management of Erectile Dysfunction in Men—2017. J Sex Med 2018;15:430–457.
Continuous use of PDE5 inhibitors in the treatment of erectile dysfunction: New insights and opportunities
2018, Revista Internacional de Andrologia
Actualmente existe un debate acerca del uso continuado de los inhibidores de la fosfodiesterasa 5 en el tratamiento de la disfunción eréctil. Varios estudios apoyan el beneficio que, incluso a bajas dosis, esta estrategia terapéutica tiene sobre la función eréctil –incluso en pacientes considerados difíciles de tratar–, y sobre la espontaneidad y naturalidad de las relaciones sexuales. También ha demostrado además ser bien tolerados y seguros. Más allá de la inhibición de la fosfodiesterasa 5, el efecto sobre la función eréctil parece basarse en la mejora de la función endotelial y de la oxigenación del área vascular peneana resultado del incremento del número de erecciones, restando así importancia a la farmacocinética. Aunque la evidencia es limitada, este nuevo escenario abre nuevas oportunidades en el tratamiento de pacientes para los que el tratamiento a demanda no es efectivo o apropiado, y podría favorecer la espontaneidad de la vida sexual.
At present, there is debate regarding the continuous use of phosphodiesterase 5 inhibitors in the treatment of erectile dysfunction. Cumulative evidence supports the benefit, even at low doses, thatcontinuous treatment has on erectile function -even in difficult-to-treat patients-, and on the spontaneity and naturalness of sexual relationships. Safety and tolerability have also proven to be good. Beyond phosphodiesterase 5 inhibition, the effect of continuous treatment of erectile function appears to be based on improvement of endothelial function and oxygenation of the penile vascular bed as a result of the increased number of erections, hence playing down the importance of pharmacokinetics. Although evidence is still limited, this new scenario opens new paths for the treatment of erectile dysfunction patients in whom on-demand treatments are not effective or deemed appropriate, and would benefit the spontaneity of sexual life.
Useful Implications of Low-dose Long-term Use of PDE-5 Inhibitors
2016, Sexual Medicine Reviews
Phosphodiesterase type 5 (PDE-5) hydrolyzes cyclic guanylate monophosphate (cGMP) specifically to 5′ GMP, promoting successful corporeal vascular relaxation and penile erection during sexual stimulation. Oral PDE-5 inhibitors such as sildenafil, vardenafil, tadalafil, and avanafil have provided noninvasive, effective, well-tolerated treatment for erectile dysfunction (ED) patients and, at the same time, stimulated both academic and clinical interests. Lately, some oral PDE-5 inhibitors were released as low-dose preparations with the concept of potential daily administration and long-term use.
To highlight the possible potential implications of low-dose long-term use of PDE-5 inhibitors.
A systematic review was carried out until December 2015 based on a search of all concerned articles in MEDLINE, medical subjects heading (MeSH) databases, Scopus, The Cochrane Library, EMBASE, and CINAHL databases without language restriction. Key words used to assess the outcome and estimates for concerned associations were: PDE-5 inhibitors; erectile dysfunction; low-dose; long-term; sildenafil; tadalafil; vardenafil; avanafil.
Demonstrating different implications for low-dose long-term use of PDE-5 inhibitors.
Low-dose and/or long-term use of PDE-5 inhibitors was shown to put forth beneficial sound effects in different medical implications with potentials that could be extended for different utilities. These implications included sexual, urogenital, cardiovascular, pulmonary, cutaneous, gastrointestinal, and reproductive, as well as neurological disorders. However, it is evident that most potential appliances were carried out experimentally on preclinical studies with off-label indications.
Making use of and exploring low-dose and/or long-term use of several PDE-5 inhibitors for their possible implications seem to be valuable in different medical disorders. Increased knowledge of the drug characteristics, comparative treatment regimens, optimal prescribing patterns, and well-designed clinical trials are needed before these agents can be recommended for use.

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ORIGINAL RESEARCH-PHARMACOTHERAPY FOR EDED: Efficacy and Safety of Daily Tadalafil in Men with Erectile Dysfunction Previously Unresponsive to On‐demand Tadalafil

ABSTRACT

Objective

Materials and Methods

Results

Conclusion

Introduction

Section snippets

Study Design

Inclusion Criteria

Patient Population and Demographics

Discussion

Conclusions

J Urol

Lancet

Am J Hypertens

J Urol

J Urol

J Am Coll Cardiol

J Urol

Urology

J Urol

Am J Hypertens

J Urol

J Urol

Am Heart J

Am J Cardiol

J Urol

Trends Endocrinol Metab

J Urol

J Am Coll Cardiol

J Am Coll Cardiol

Sexual dysfunction in the United States: Prevalence and predictors

JAMA

Impaired neurogenic and endothelium‐mediated relaxation of penile smooth muscle from diabetic men with impotence

N Engl J Med

ORIGINAL RESEARCH-PHARMACOTHERAPY FOR ED
ED: Efficacy and Safety of Daily Tadalafil in Men with Erectile Dysfunction Previously Unresponsive to On‐demand Tadalafil