Each month, questions with a common theme will be selected and answered comprehensively by one of our Steering Committee members. Previously answered questions will be archived each month for your reference. If you wish to submit a question, click here.

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This Month's Questions:

1. Question 1 (Fred E. Govier, MD):
   Why has the utility of phosphodiesterase type 5 (PDE5) inhibitor preference trials often been limited? Could you also please explain why patient preference studies are important, discuss the study recently published by Eardley and colleagues, and explain how these are relevant to clinical practice?
   
   
2. Question 2 (Robert A. Kloner, MD, PhD):
   Epidemiologic studies have shown that erectile dysfunction (ED) and cardiovascular disease (CVD) share endothelial dysfunction as a common etiologic factor. In fact, a growing body of data shows that ED may be a predictor for CVD. What is the latest clinical evidence supporting the strong link between ED and CVD?

Question 1

Why has the utility of phosphodiesterase type 5 (PDE5) inhibitor preference trials often been limited? Could you also please explain why patient preference studies are important, discuss the study recently published by Eardley and colleagues, and explain how these are relevant to clinical practice?

Response by Fred E. Govier, MD, Posted 02/28/06:

The management of erectile dysfunction (ED) can be optimized by understanding patient preferences.¹ Most patients prefer treatment with oral agents, such as PDE5 inhibitors, to more invasive alternatives.² However, most preference trials comparing PDE5 inhibitors contain design flaws that may create a bias in the data and limit use of the results.³

Recently, criteria for a well designed preference trial were published and included the following^3,4:

• Use a double-blind crossover design with equal lengths of treatment periods
• Randomize patients to different drug sequences
• Use equivalent drug dosages
• Include a washout period between treatments
• Enter only treatment-naive patients
• Use the same tools to measure baseline and end-of-treatment results
• Conduct the treatment preference assessment at the completion of both treatments
• Use intent-to-treat analysis

Eardley and investigators applied the above criteria and designed a trial comparing tadalafil with sildenafil that incorporated all of these criteria except double-blinding of the drugs. The open-label design was chosen because of the differences in half-life, duration of action, and food effects on absorption of the 2 drugs. Dosing instructions were provided to foster optimum results for each drug; men were instructed to use the package insert from each of the respective companies.⁴

Once patients completed a 4-week baseline assessment period, they were randomized to sildenafil or tadalafil for 12 weeks; the 12 weeks consisted of an 8-week dose optimization period followed by a 4-week treatment assessment period. Following a 7- to 10-day washout period, patients were crossed over to receive the other medication for 12 weeks.⁴ After completing both 12-week periods, patients continued with their preferred treatment for another 8 weeks.⁴

Both PDE5 inhibitors, as measured by the International Index of Erectile Function (IIEF) scores and Sexual Encounter Profile (SEP) diary scores, were effective treatments for ED.⁴ Tadalafil had slightly greater increases in the IIEF domain scores for orgasmic function, sexual desire, and overall satisfaction (P<.05) and in SEP diary scores for some erection, successful intercourse, and overall satisfaction (P<.05).⁴ Both drugs were well tolerated.⁴

The study found that a significantly greater number of patients preferred tadalafil (71%) to sildenafil (29%; P<.001).^4,5 Patients experienced significantly more “sexual self-confidence,” more “spontaneity,” and significantly fewer “time concerns” when taking tadalafil compared with sildenafil (P<.001).⁵ In a drug-attribute questionnaire, the most commonly cited reason for choosing tadalafil was the duration of drug effect.⁶ The short interval between drug ingestion and first erection was cited more often for preferring sildenafil over tadalafil.⁶

References

1. Hackett GI. Patient preferences in treatment of erectile dysfunction: the continuing importance of patient education. Clin Cornerstone. 2005;7:57-65.

2. Govier F, Potempa AJ, Kaufman J, Denne J, Kovalenko P, Ahuja S. A multicenter, randomized, double-blind, crossover study of patient preference for tadalafil 20 mg or sildenafil citrate 50 mg during initiation of treatment for erectile dysfunction. Clin Ther. 2003;25:2709-2723.

3. Mulhall JP, Montorsi F. Evaluating preference trials of oral phosphodiesterase 5 inhibitors for erectile dysfunction. Eur Urol. 2006;49:30-37.

4. Eardley I, Mirone V, Montorsi F, et al. An open-label, multicentre, randomized, crossover study comparing sildenafil citrate and tadalafil for treating erectile dysfunction in men naïve to phosphodiesterase 5 inhibitor therapy. BJU Int. 2005;96:1323-1332.

5. Dean J, Hackett G, Gentile V, et al. Psychological and interpersonal outcomes in men receiving sildenafil citrate and tadalafil for the treatment of erectile dysfunction in an open label, crossover study. Abstract presented at: XVII World Congress of Sexology; July 10-15, 2005; Montreal, Canada. Available at: http://abstracts.co.allenpress.com/pweb/sexo2005/document/?ID=50607. Accessed January 18, 2006.

6. Dean J, Hackett G, Gentile V, et al. Drug attributes influencing the choice of sildenafil citrate and tadalafil for the treatment of erectile dysfunction in an open label, crossover study. Abstract presented at: XVII World Congress of Sexology; July 10-15, 2005; Montreal, Canada. Available at: http://abstracts.co.allenpress.com/pweb/sexo2005/document/?ID=50598. Accessed January 18, 2006.

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Question 2

Epidemiologic studies have shown that erectile dysfunction (ED) and cardiovascular disease (CVD) share endothelial dysfunction as a common etiologic factor. In fact, a growing body of data shows that ED may be a predictor for CVD. What is the latest clinical evidence supporting the strong link between ED and CVD?

Response by Robert A. Kloner, MD, PhD, Posted 03/15/06:

New information on the relationship between ED and CVD underscores the role of ED as a potentially important marker for men's vascular health. A recent study that examined the association between ED and subsequent CVD provides evidence that men with ED have a significantly greater chance (P<.001) of experiencing a cardiovascular (CV) event (angina, myocardial infarction, cerebrovascular accident, transient ischemic attack, congestive heart failure, or cardiac arrhythmia) than men without ED.¹ The study data also demonstrate that incident ED (defined as the first report of ED of any grade) may indicate the risk of later CV events as well as or better than a family history of myocardial infarction, cigarette smoking, or hyperlipidemia.¹

This evidence of the link between ED and CVD resulted from analysis of data on 9,457 men aged 55 years or older who were randomized to the placebo group of the Prostate Cancer Prevention Trial (1994 to 2003) and evaluated every 3 months for CVD and ED. At study entry, 8,063 men did not have CVD, but 3,816 (47%) of these men had some degree of ED.¹ Of the 4,247 men without ED, 2,420 (57%) reported incident ED after 5 years, a total that increased to 2,760 (65%) after 7 years.¹

Findings from this trial include

• The adjusted hazard ratio (HR) for a subsequent CV event associated with incident ED was 1.25 (1.02 to 1.53; 95% confidence interval [CI]; P=.04), and the adjusted HR associated with incident or prevalent (baseline) ED was 1.45 (1.25 to 1.69; 95% CI; P<.001)¹
  
  
• The unadjusted risk of a subsequent incident CV event was 0.015 per person-year for men without ED at study entry and 0.024 per person-year for men with ED at that point, a range associated with traditional CV risk factors¹
  
  
• The adjusted HR for subsequent angina was 1.53 (1.03 to 2.28; 95% CI; P=.04) for men with incident ED and 1.72 (1.26 to 2.33; 95% CI; P=.001) for men with incident or prevalent ED¹
  
  
• The adjusted HR for subsequent myocardial infarction was 1.29 (0.96 to 1.74; 95% CI; P=.10) for men with incident ED and 1.50 (1.20 to 1.87; 95% CI; P<.001) for men with incident or prevalent ED¹
  
  
• The adjusted HR for subsequent stroke was 1.70 (0.98 to 2.96; 95% CI; P=.06) for men with incident ED and 1.79 (1.15 to 2.80; 95% CI; P=.01) for men with incident or prevalent ED¹

These findings support the results of earlier studies that linked ED with subsequent CVD. Previous clinical trials showed that ED may be one of the first signs of oxidative stress and endothelial dysfunction, occurring before overt CVD develops.^2-5 Prior studies also showed that damage to penile blood vessels precedes the onset of systemic vascular disease, including coronary artery disease (CAD), stroke, and complications from
diabetes.⁶

At the other end of the CVD treatment spectrum, when disease is established, research into diagnosing and treating ED in older (ages 40 to 82) men with chronic, stable CAD confirms the shared risk factors.⁷ In this study, 75% of the participants were diagnosed as also having ED, as measured by scores from the Sexual Health Inventory for Men (SHIM) questionnaire.⁷ In addition to considering the effects of medications to treat CVD and lifestyle changes to reduce the risks, the study reviews the safety of treating ED with phosphodiesterase type 5 (PDE5) inhibitors, which affect the smooth muscle cells of the CV system and the vasculature of the corpus cavernosum.⁷

As the population ages, more than 600,000 new cases of ED are estimated to occur annually in the United States among men aged 40 to 69 years.⁸ Data from the Prospect Cancer Prevention Trial study suggest that older men with ED have about a 2-fold greater risk of CVD than those without ED.¹ Because a growing number of men with ED are seeking therapy¹ — including treatment with PDE5 inhibitors, which improve endothelial dysfunction significantly⁶ — physicians have more opportunities to conduct screenings that may lead to the early detection of CV risk factors.¹

In American men, 50% of deaths due to coronary heart disease are in those who have no history of the disease.^1,9 Recognizing ED as a possible indicator of future CVD may be an important first step in identifying men at risk and initiating interventions.^1,9-11

 References

1. Thompson IM, Tangen CM, Goodman PJ, Probstfield JL, Moinpour CM, Coltman CA. Erectile dysfunction and subsequent cardiovascular disease. JAMA. 2005;294:2996-3002.

2. Kaiser DR, Billups K, Mason C, Wetterling R, Lundberg JL, Bank AJ. Impaired brachial artery endothelium-dependent and -independent vasodilation in men with erectile dysfunction and no other clinical cardiovascular disease. J Am Coll Cardiol. 2004;43:179-184.

3. Bocchio M, Desideri G, Scarpelli P, et al. Endothelial cell activation in men with erectile dysfunction without cardiovascular risk factors and overt vascular damage. J Urol. 2004;171:1601-1604.

4. Gazzaruso C, Giordanetti S, De Amici E, et al. Relationship between erectile dysfunction and silent myocardial ischemia in apparently uncomplicated type 2 diabetic patients. Circulation. 2004;110:22-26.

5. Billups KL. Endothelial dysfunction as a common link between erectile dysfunction and cardiovascular disease. Curr Sex Health Rep. 2004;1:137-141.

6. Kirby M, Jackson G, Simonsen U. Endothelial dysfunction links erectile dysfunction to heart disease. Int J Clin Pract. 2005;2:225-229.

7. Kloner RA, Mullin SH, Shook T, et al. Erectile dysfunction in the cardiac patient: how common and should we treat? J Urol. 2003;170:S46-S50.

8. Johannes CB, Arujo AB, Feldman HA, Derby CA, Kleinman KP, McKinlay JB. Incidence of erectile dysfunction in men 40 to 69 years old: longitudinal results from the Massachusetts Male Aging Study. J Urol. 2000;163:460-463.

9. American Heart Association. Heart disease and stroke statistics: 2004 update. Dallas, Tex: American Heart Association; 2003.

10. Yusuf S, Hawken S, Ounpuu S, et al, for the INTERHEART Study Investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004;364:937-952.

11. Rosengren A, Hawken S, Ounpuu S, et al, for the INTERHEART investigators. Association of psychosocial risk factors with risk of acute myocardial infarction in
    11 119 cases and 13 648 controls from 52 countries (the INTERHEART study): case-control study. Lancet. 2004;364:953-962.

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