Expert Commentary

Ajay Nehra, MD, Consultant Mayo Clinic; Professor of Urology, Mayo Clinic College of Medicine, Rochester, Minnesota

Phosphodiesterase type 5 (PDE 5) inhibitors have emerged as the preferred modality for erectile dysfunction (ED) due to their efficacy, favorable tolerability and convenience. Data continues to emerge in an effort to differentiate commercially available PDE 5 inhibitors. PDE 5 inhibitors have revolutionized not only how to treat ED, but also the entire perception of sexual health and sexual medicine among both patients and physicians. The results of a non head-to-head study presented at the 5th Annual Research Meeting of the Sexual Medicine Society of North America, treatment with vardenafil HCl (Levitra®) revealed statistically and clinically significant improvements in key efficacy measures in men with severe ED who were non-responsive to treatment with sildenafil citrate (Viagra®).¹ Since the Food and Drug Administration (FDA) approval of sildenafil in March of 1998, there have been no therapeutic alternatives for patients who have either failed sildenafil or have incurred adverse events. In a second study entitled, "Alterations in Demographics and Attitudes of Erectile Dysfunction Patients since the Introduction of Oral Erectogenic Therapy," presented at this meeting, younger patients with ED are seeing their physicians at an earlier stage of their disease and possess far more knowledge about available treatment options for ED than in the recent past.²

The purpose of this Male Sexual Health Express Report is to review the previously mentioned studies. It is my hope that these data will prove beneficial in the treatment of your patients with ED.

The PROVEN (Patient RespOnse with VardENafil) Trial

According to Principal Investigator Culley C. Carson III, MD, Rhodes Distinguished Professor of Urology and Chief of Urology, University of North Carolina, Chapel Hill, North Carolina, treatment with vardenafil produced statistically and clinically significant improvements in key efficacy measures in men with severe ED who were non-responsive to treatment with sildenafil, as defined by their medical history.¹ These improvements included a four-fold increase in successful intercourse completion rates over baseline and a mean 8-point increase in the International Index of Erectile Function-Erectile Function (IIEF/EF) domain score.

In this multicenter, double-blind trial, a total of 463 men (intent-to-treat, n = 454) with moderate-to-severe ED were randomized to receive either placebo (n = 225) or vardenafil (n = 229) 10 mg as needed for four weeks, with an option to continue on 10 mg or titrate to 5 mg or 20 mg (based on mutual patient and investigator evaluation of efficacy and tolerability) after each of two consecutive 4-week intervals. All patients had to conform to rigorous inclusion criteria that identified them as sildenafil non-responders, including non-response at sildenafil 100 mg. At baseline, 90% of patients in the vardenafil treatment arm were diagnosed with moderate (11-16) or severe (6-10) ED on the EF domain score. Baseline demographic parameters (age, weight, body mass index, alcohol use) were comparable between the two treatment arms.

Dr. Carson indicated that six strict historical criteria were used to define non-responsiveness to sildenafil:

• a patient must have made at least six attempts at intercourse with sildenafil therapy AND

• reported unsuccessful intercourse in at least four of their last six attempts as defined by (at least one of the following questions being answered negatively):

Were you able to achieve at least partial erection (some enlargement of penis)?
Were you able to insert your penis into your partner's vagina?
Did your erection last long enough for you to have successful intercourse?

• reported unsuccessful intercourse at their most recent attempt at intercourse with sildenafil therapy AND

• attempted sildenafil therapy on the highest available dose (100 mg) at least once and reported unsuccessful intercourse on 100 mg at least once

• discontinued sildenafil therapy due to a lack of efficacy AND

• considered to be truly unresponsive to sildenafil in the medical opinion of the Principal Investigator.

"The determination of the definition of non-responsiveness to sildenafil was crucially important," commented Dr. Carson. "With these criteria, the investigator was assured that the patient had taken sildenafil appropriately, on multiple occasions and did not respond to sildenafil."

Dr. Carson also indicated that efficacy and tolerability of vardenafil were the two cardinal examination points. Primary endpoints included the IIEF/EF domain score, Sexual Encounter Profile—vaginal penetration achievement (SEP2), and SEP3 (ability to maintain an erection for intercourse). A secondary endpoint of the study was the Global Assessment Question (improvement of erectile function, GAQ).

After 12 weeks, vardenafil produced statistically and clinically significant improvements in least-squares mean EF domain, SEP2, SEP3 and GAQ compared to placebo (Table 1). Patients treated with vardenafil had a 8-point increase in EF score from 9.3 at baseline to 17.6. Dr. Carson pointed out that many clinicians would consider an increase of 5 points clinically meaningful, which made the results "even more impressive".

Diary results in response to SEP2 "Could you insert your penis into your partner's vagina?" indicated a statistically significant doubling of penetration rate with vardenafil, improving from 28.5% at baseline to 62.3% after 12 weeks (P<.001). Responses to SEP3 "Does your erection last long enough for you to have successful intercourse?" revealed vardenafil quadrupled successful rates of intercourse completion, from 10.1% at baseline to 46.1% after 12 weeks (P<.001).

Vardenafil also significantly improved erectile function as assessed by the GAQ ("Has the treatment you have been taking over the last 4 weeks improved your erections?") in 61.8% of patients who were non-responders to sildenafil (P<.001).

Treatment with vardenafil was well tolerated. Compared to placebo, adverse events typical of PDE 5 inhibitors and associated with vardenafil use included headache (6.9% vs 1.8% placebo), flushing (6.9%vs 1.3% placebo), nasal congestion (5.6% vs 0.4% placebo), dyspepsia (4.8% vs 0.0% placebo), upper respiratory infections (2.6% vs 2.2% placebo) and nausea (2.2% vs 0.9% placebo).

Investigators concluded that vardenafil produced statistically and clinically significant improvements in key efficacy measures in men with severe ED and a documented history of non-response to sildenafil therapy, including a four-fold increase in successful intercourse completion rates over baseline, and brought mean EF into the mild-moderate range.

In summarizing his presentation, Dr. Carson stated the "controversial" aspects of the study. "The important issue here, as those of us who specialize in erectile dysfunction know in clinical practice, is that a patient who fails on one phosphodiesterase type 5 inhibitor may potentially respond to another. The agents may be slightly different [chemically] or perhaps it is a different point in time in the patient's life or maybe the patient has become more accustomed to phosphodiesterase type 5 inhibition. Clearly, when patients do not respond to one phosphodiesterase type 5 inhibitor, we can expect that many will respond to another," emphasized Dr. Carson.

Responding to a comment by Gregory A. Broderick MD, Professor of Urology, Residency Program Director, Mayo Clinic Jacksonville, Jacksonville, Florida, who questioned the study design of PROVEN, Dr. Carson stated, "PROVEN was neither a comparative study nor a switch study. More than anything else, PROVEN suggests that you can try another phosphodiesterase type 5 inhibitor if one fails and get clinical success with these patients."

The data suggest that vardenafil offers a safe, effective and well-tolerated option in the initial treatment of ED, as well as for those patients who were previously unresponsive to sildenafil.

Alteration in Demographics and Attitudes of Erectile Dysfunction Patients

The introduction of sildenafil in 1998 transformed the treatment and perception of ED, according to Carin V. Hopps, MD, from the Medical College of Ohio, Toledo, Ohio. Dr. Hopps presented an analysis of the impact of sildenafil on referral patterns, patient demographics, and patient treatment choice among men with ED.²

Between 1996 and 2000, patients naпve to any form of erectogenic therapy presenting to an ED clinic completed an inventory that addressed the source of referral, delay in presentation, and knowledge and acceptability of ED treatments. Comparisons were made between the data obtained from 124 patients presenting before the introduction of sildenafil and 268 patients presenting after the introduction of sildenafil.

The analysis revealed that after the introduction of sildenafil, there was a significant 10-year decrease in mean age at presentation (from 63 years to 53 years) with one year less duration of disease. There were significant reductions in the percentages of patients presenting with diabetes (from 23% to 14%) and hypertension (from 42% to 28%). All differences in the source of referral were significant, especially the percentage of patients referred from primary care physicians (increase from 48% to 62%) or by patients or their partners (increase from 10% to 22%).

The primary reason for patient delay in presentation was the same in both groups—patient embarrassment, being cited by 64% of the total patient population. The proportion of patients obtaining ED information through media increased significantly, an increase from 10% to 60% with television and an increase from 25% to 75% in print media. Clearly the result of aggressive educational and promotional efforts, significantly more patients were aware and accepting of all ED therapies (except vacuum device therapy).

"The introduction of sildenafil has had a huge impact upon patient presentation and referral patterns as well as on knowledge and acceptance of erectile dysfunction therapies", advised Dr. Hopps.

Responding to a question concerning the implications of the study, Dr. Hopps cited the importance of patient and physician education. "Now, patients more readily inquire about treatment options; and their physicians are more willing to speak to them about these issues. All of these things have increased awareness of the need to discuss erectile function in general," replied Dr. Hopps.

Personal Observation from Culley C. Carson III, MD, President, Sexual Medicine Society of North America³

The Sexual Medicine Society of North America is committed to furthering the study of sexual medicine and providing this area of investigation and treatment as an established, respected subspecialty in both the research and the clinical medical sciences. The past two decades have witnessed giant leaps in the basic science understanding of central nervous system control of sexual function, neurotransmitters associated with erectile function, and the introduction of the first truly effective safe oral treatment for erectile dysfunction. Now through basic science and clinical investigation as well as pharmacological developments, we can now understand the anatomy, physiology and pathology of sexual medicine both for men and women. These developments are resulting in improved care for all our patients with sexual dysfunction.

Scientific investigation, pharmacologic development, and clinical practice will continue the strides made over the past two decades. In this 5th Annual Research Meeting of the Sexual Medicine Society of North America, the contributions of investigators, presenters and participants are key to maintaining the momentum of this new and important subspecialty of medicine. The associated seminars designed to reach both urology residents for the understanding of surgical treatment of erectile dysfunction and family practice physicians in furthering the identification and management of men and women with sexual dysfunction will increase the interest in and understanding of sexual medical problems.

I must express my appreciation to all those who have attended the 5th Annual Research Meeting and hope that you will continue to be active participants in the Sexual Medicine Society of North America and in the specialty of sexual medicine.

Information on membership in the Sexual Medicine Society of North America can be obtained from the Sexual Medicine Society of North America, 1111 N. Plaza Drive Suite 550, Schaumburg, IL 60173. Phone: 847-517-7225; Fax: 847-517-7229.

References

1. Carson CC, Hatzichristou D, Carrier, Lording D, Young J, Murdoch M for the Vardenafil Study Group. Vardenafil exhibits efficacy in men with erectile dysfunction unresponsive to prior sildenafil therapy: results of a phase III clinical trial-Patient RespOnse with VardENafil in sildenafil non-responders (PROVEN). Int J Impot Res. 2003; 15(suppl 5):S175. Abstract 31.
2. Hopps CV, Ghaly S, Parker M, Guhring P, Mulhall JP. Alteration in demographics and attitudes of erectile dysfunction patients since the introduction of oral erectogenic therapy. Int J Impot Res. 2003; 15(suppl 5):S171. Abstract 22.
3. Carson CC. Message from the SMS President. Int J Impot Res. 2003; 15(suppl 5):S2.

Disclosure

Male Sexual Health Express Report™ is a product of Millennium Medical Communications, Inc. ("MMC, Inc."), an independent, third-party organization providing educational information concerning current medical data and opinions presented at worldwide medical meetings. The Male Sexual Health Express Report™ is published in accordance with the Guidance for Industry: Industry Supported Scientific and Educational Activities, 62 Fed. Reg. 64,093, 64,096-99 (1997) adopted by the U.S. Department of Health and Human Services Food and Drug Administration. Pursuant to the foregoing standards, MMC, Inc. is solely responsible for selecting the topics discussed herein. This Male Sexual Health Express Report™ may contain data on products, product uses, indications, and dosages which are not approved for use in the USA, Canada, and the European Union and no endorsement is hereby made or intended by coverage of any unapproved use. The content of this report is intended for educational purposes only, and merely conveys scientific data presented at medical meetings. Approved product labeling should always be consulted for prescribing information. The Male Sexual Health Express Report™ is an independent and non-promotional report intended to provide accurate scientific and medical information for educational purposes. MMC, Inc. is not responsible for errors or omissions in reports. The production of this report was supported by a wholly unrestricted educational grant from GlaxoSmithKline and Bayer Pharmaceuticals Corporation. GlaxoSmithKline and Bayer Pharmaceuticals Corporation maintain no control, direct or indirect, over the content, substance, or distribution of this report.

© 2003 Millennium Medical Communications, Inc.