Focus on Phosphodiesterase Inhibitors for the Treatment of Erectile Dysfunction in Older Men

Clinical Therapeutics/Volume 33, Number 11, 2011

Focus on Phosphodiesterase Inhibitors for the Treatment of Erectile Dysfunction in Older Men Mary Lee, PharmD, FCCP Chicago College of Pharmacy, Midwestern University, Downers Grove, Illinois ABSTRACT Background: Phosphodiesterase type 5 inhibitors (PDEIs) are the drugs of choice for the medical management of erectile dysfunction independent of the etiology of the disorder. Objective: This review focuses on specific aspects of clinical use of PDEIs in older men with erectile dysfunction. Methods: An electronic search of MEDLINE was conducted for articles published between January 1990 and January 2011 using the terms erectile dysfunction and PDEIs and limited to articles in English, humans, and males aged ⱖ45 years. The search was also conducted in EMBASE using the same search criteria for literature indexed between 1990 and 2010. Results: A total of 1341 articles were identified. Of these, ⬃91 were selected for this review. Sildenafil, vardenafil, and tadalafil are considered equally effective for erectile dysfunction, but they differ in some ways. Tadalafil’s 36-hour duration of action allows for repeated sexual intercourse without the need to take additional medication in some patients, which is distinctly different from the shorter-acting sildenafil and vardenafil. Unlike tadalafil, the rate and extent of oral absorption of sildenafil and vardenafil are reduced by consumption of high-fat meals. Although headache, flushing, and rhinitis occur with all 3 PDEIs, cyanopsia is more common with sildenafil and vardenafil, and back pain is more common with tadalafil. Approximately 40% to 50% of patients who initially fail to respond to PDEIs can be salvaged with education and up-titration of dosing. PDEIs can be used in addition to antihypertensive medications in patients with wellcontrolled essential hypertension without producing clinically significant hypotension. Use of PDEIs in patients with cardiovascular disease is guided by the recommendations of the Second Princeton Consensus Conference. For the management of lower urinary tract symptoms due to benign prostatic hyperplasia, PDEIs may reduce obstructive voiding symptoms, but they do not increase urinary flow rate.

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Conclusion: PDEIs are effective for erectile dysfunction and well tolerated in older men. (Clin Ther. 2011; 33:1590 –1608) © 2011 Elsevier HS Journals, Inc. All rights reserved. Key words: erectile dysfunction, phosphodiesterase inhibitor, sildenafil, tadalafil, vardenafil.

INTRODUCTION Erectile dysfunction in adult males is common. In the landmark Massachusetts Male Aging Study, an observational survey of 1700 community-based, predominantly white males (96%) aged 40 to 69 years, 52% suffered from erectile dysfunction in the United States.1 The incidence and severity of erectile dysfunction increased with patient age. Patients who were 70 years old had a 15% incidence of complete erectile dysfunction, whereas patients who were 40 years old had a 5% incidence. Similarly, those 70 years of age had a 35% incidence of moderate erectile dysfunction, whereas those 40 years of age had a 17% incidence of the same. In the more recent Health Professionals Follow Up Study, a total of 31,742 health professionals, ranging in age from 53 to 90 years, responded to questionnaires every 2 years.2 Twenty-six percent of men aged 50 to 59 years and 40% of men aged 60 to 69 years reported having erectile dysfunction. Although not life-threatening, this disorder negatively affects a patient’s quality of life and may lead to poor self-esteem, depression, and anxiety. Phosphodiesterase inhibitors (PDEIs) are the drugs of choice for the treatment of erectile dysfunction.3,4 The objective of this review was to provide comparative data on the pharmacokinetics of sildenafil, vardenafil, and tadalafil to help guide treatment choice, drug dosage, and use in the patients with erectile dysAccepted for publication September 26, 2011. doi:10.1016/j.clinthera.2011.09.029 0149-2918/$ - see front matter © 2011 Elsevier HS Journals, Inc. All rights reserved.

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M. Lee function; review existing literature on ways to optimize response to PDEIs; manage drug– drug interactions and adverse reactions; and discuss considerations on using PDEIs in older men with cardiovascular disease, hypertension, and lower urinary tract symptoms (LUTS) secondary to benign prostatic hypertrophy.

METHODS An electronic search of MEDLINE was conducted for articles published between January 1990 and January 2011 using the terms erectile dysfunction and PDEIs and limited to articles in English, humans, and males aged ⱖ45 years. Articles were selected if they were randomized and/or controlled trials, evidence-based reviews, or national guidelines regarding treatment of erectile dysfunction with PDEIs. The search was also conducted in EMBASE using the same search criteria for literature indexed between 1990 and 2010. A total of 1341 articles were identified. Of these, ⬃91 were selected for this review.

RESULTS Definition of Erectile Dysfunction and Treatment Goals Erectile dysfunction is defined as a repeated failure to achieve or maintain an erection long enough to engage in sexual intercourse. Erectile dysfunction can negatively affect a patient’s perceived quality of life and self-esteem, and also that of his sexual partner. Thus, the goals of treatment are to improve erectile function to the satisfaction of the patient and his partner.3 Common risk factors for erectile dysfunction include: (1) vascular diseases that compromise penile arterial blood flow or decrease cavernsosal filling; (2) psychological or neurologic disorders that interfere with perception or transmission of sexual stimuli by the brain, spinal cord, and peripheral nerves; (3) primary or secondary hypogonadism that suppresses libido and leads to erectile dysfunction5; and (4) adverse effects of medications, particularly diuretic agents and antihypertensive medications, which have been associated with 45% of cases of erectile dysfunction in clinical practice6 and that can act through any of the aforementioned mechanisms to cause erectile dysfunction. For this reason, the American Urological Association treatment guidelines state that patients who present with erectile dysfunction should be evaluated first for these risk factors.3 If present, treatment of these risk

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factors should be the focus of the management plan before initiating a PDEI. By addressing the risk factors, sexual dysfunction often improves and may not worsen with time.7 In addition, lifestyle modification, which includes smoking cessation, minimizing alcohol intake, increasing physical activity, and controlling weight is recommended to minimize the risk of worsening erectile function.2,3

Efficacy of PDEIs for the Treatment of Erectile Dysfunction After correcting any underlying medical conditions that contribute to sexual dysfunction and when recommended lifestyle changes do not suffice, PDEIs are the preferred first-line agents for treatment of erectile dysfunction for several reasons.4 They can be taken by mouth, are effective in many patients independent of the cause or severity of erectile dysfunction, can be used discreetly before sexual intercourse, and have few serious adverse effects. A recent meta-analysis, which included 72, 27, and 28 placebo-controlled, randomized clinical trials of ⱕ12 weeks’ duration of sildenafil, vardenafil, and tadalafil, respectively, revealed that ondemand use of PDEIs improved erections in 67% to 89% of men compared with placebo, which improved erections in 27% to 35% of men.8 The pooled relative risk was ⬎1 (95% confidence interval [CI] did not include 1). Similar conclusions were found in a metaanalysis of 27 clinical trials of on-demand dosing of sildenafil versus placebo, in which successful intercourse was reported in 57% and 21% of patients (mean age, 55 years), respectively (weighted mean difference: 33.7 [95% CI: 29.2–38.2]).9 A subgroup analysis of men revealed that men aged ⬍65 years who were treated with sildenafil experienced successful intercourse more often compared with placebo (60% of the time vs 23%, respectively; P ⬍ 0.05) than men aged ⱖ65 years who were treated with sildenafil when compared to placebo (46% of the time vs 14%, respectively; P ⬍ 0.05). Moreover, an analysis of 13 randomized, placebo-controlled clinical trials provided similar results; the analysis included 6659 men (mean age, 55 years) using on-demand vardenafil in adjusted doses of 5 to 20 mg. Using the International Index of Erectile Function (IIEF) questionnaire, which is a standardized and reliable tool with a score range of 6 (for severe erectile dysfuntion) to 30 for normal function, the least squares mean IIEF scores for the erectile function domain (IIEF-EF) increased from 12.7 to 22.4 (P ⬍

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Clinical Therapeutics 0.0001) after 12 weeks of vardenafil; scores increased from 12 to 14.5 in the placebo group (P ⬎ 0.05).10 In patients who show an initial response to PDEIs, durable responses have been reported with continued use in open-label extension studies for 5 or 6 years.11,12 However, likely because of progressive worsening of erectile dysfunction, it is common for these patients to require increased doses of the PDEI over time. A lack of responsiveness to the PDEI is probably not due to tachyphylaxis but rather a worsening of the underlying diseases that compromise vascular flow to or innervations of cavernosal tissue.13 Among the 3 commercially available PDEIs in the United States, sildenafil, vardenafil, and tadalafil are considered to have comparable efficacy on the basis of data derived from a collection of clinical trials of a single PDEI versus placebo and the previously described meta-analyses.3,8,9 Four randomized controlled, direct-comparison studies of PDEIs have been conducted that show small but not statistically or clinically significant differences.14 –17 These studies are inconclusive because of the absence of blinding and randomization in study design. Patients who have erectile dysfunction secondary to radical prostatectomy, diabetes mellitus, or severe peripheral vascular disease have a lower response rate to PDEIs compared with patients without these comorbidities. Because of injury or compromise of the peripheral innervation to or vascular supply of the corpora cavernosa, some of these patients may fail to respond to PDEIs.18 In one double-blind, placebo-controlled clinical trial, 300 men with erectile dysfunction of 1 to 4 years’ duration due to a bilateral, nerve-sparing radical prostatectomy were randomized to receive on-demand tadalafil 20 mg for 12 weeks or placebo.19 Improved erections were reported in 62% of tadalafiltreated patients compared with 23% of controls (P ⬍ 0.001). Successful vaginal intercourse attempts were reported 41% and 19% of the time in those receiving tadalafil and placebo, respectively (P ⬍ 0.001). Patients with hypogonadism may demonstrate a lower response rate than patients with serum testosterone levels in the normal range. This finding could be due to several reasons. Symptoms of low serum testosterone levels include decreased or absent libido, and erectile dysfunction therefore results from the patient’s lack of sexual drive. Testosterone may help regulate phosphodiesterase activity in cavernosal tissue, and this physiologic action may enhance the efficacy of

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PDEIs.20 For a more detailed discussion of this topic, see the section on Ways to Enhance the Efficacy of PDEIs in Patients Who Fail to Respond to Usual Doses. Although PDEIs have comparable efficacy and safety,3,8,14 –17 a prescriber may need to individualize treatment on the basis of a patient’s preference for a particular PDEI. The guideline issued by the American College of Physicians on pharmacologic management of erectile dysfunction recognizes that the preference for a PDEI may be based on the cost of treatment, duration of drug action, the patient’s desired frequency for sexual intercourse, perceived effectiveness, or adverse-effect profile.4 In a literature analysis of 5 patient preference studies comparing tadalafil and sildenafil, 52.2% to 90.5% of patients preferred tadalafil over sildenafil for treatment of erectile dysfunction.21 It was suggested that patients might have preferred tadalafil because it allows a more flexible dosing window compared with sildenafil (0.5–24 hours vs 0.5– 4 hours, respectively). Also, absorption of tadalafil is not slowed by fatty meals compared with sildenafil.22,23 Finally, the longer duration of action of tadalafil allows repeated sexual intercourse over a 36-hour period without the need to take additional medication compared with sildenafil. PDEIs should not be used to enhance sexual performance in males who have normal erectile function. No benefit has been demonstrated.24 Also, PDEIs are contraindicated in patients who are taking nitrates by any route of administration; the drug combination can lead to hypotension, which may place some patients at risk of cardiovascular morbidity or mortality.25

Clinical Applications of Pharmacologic Differences Among Commercially Available PDEIs Sildenafil, vardenafil, and tadalafil act through the same mechanism. They competitively inhibit phosphodiesterase type 5 enzyme, which concentrates in all vascular smooth muscle cells, including those comprising the corpora cavernosa. Phosphodiesterase type 5 is responsible for degradation of cyclic guanosine monophosphate (cGMP), a vasodilatory second messenger. By inhibiting this enzyme, these medications increase the cavernosal concentration of cGMP for hours, allowing for a persistent erection. For PDEIs to be effective, cGMP must be present. Specifically, the patient must be sexually stimulated first. This action enhances release of nitric oxide from nonadrenergic–noncholin-

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M. Lee ergic neurons, which stimulate guanylyl cyclase to produce cGMP.11 Of the 3 agents, in vitro affinity studies suggest that tadalafil is the most potent inhibitor of phosphodiesterase type 5. This finding may explain differences in dosage ranges and adverse effects among these agents (Table I22,23,26 –28). PDEIs are not selective for phosphodiesterase type 5. They inhibit a number of other phosphodiesterase types, including type 6 in the retina and cones of the eye and type 11 in muscle. Variations in the inhibitory potency for these other phosphodiesterase types are thought to be responsible for differences in the adverseeffect profile among PDEIs. For example, cyanopsia occurs with a higher frequency among sildenafil users, because sildenafil is a more potent inhibitor of phosphodiesterase type 6 than vardenafil and tadalafil.23,26,27 Low back pain more often occurs with tadalafil than with sildenafil and vardenafil, possibly because tadalafil exhibits unique inhibition of phosphodiesterase type 11 (Table II).5,23,26,27,29

Clinical Applications of Pharmacokinetic Differences Among Commercially Available PDEIs Table I summarizes the chief pharmacokinetic differences and dosage ranges of on-demand sildenafil, vardenafil, and tadalafil in patients with erectile dysfunction. Sildenafil and vardenafil have similar pharmacokinetic profiles in that they have an onset of action of ⬃30 minutes, oral absorption which is slowed by fatty meals, and a short half-life of ⬃4 hours.22,26 –28 In contrast, tadalafil has a slower onset of action of 0.5 to 2 hours, oral absorption that is not affected by meals, and a long half-life of 17.5 hours.23 All 3 PDEIs undergo principally hepatic metabolism, predominantly by cytochrome P450 (CYP) 3A4 and secondarily by CYP 2C9. Sildenafil is converted to an active metabolite that contributes to 20% of its erectogenic effect. Vardenafil is converted to an active metabolite that contributes to only 7% of its erectogenic effect. Tadalafil has no active metabolites. In patients with severe hepatic insufficiency, conservative starting doses are recommended for all 3 agents. In patients with significant renal dysfunction, reduced starting doses of sildenafil and tadalafil are recommended to avoid accumulation of active metabolites or parent drug, respectively.22,23,26,27

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The reported onset of the PDEIs is based on controlled clinical trials in which stopwatches were used to determine when at least 50% of treated patients had an erection suitable for sexual intercourse. However, in routine clinical use of on-demand dosing, to maximize the percentage of patients who will respond to the first dose, it is recommended that all patients take a PDEI ⬃1 hour before sexual intercourse if taking the dose on an empty stomach. In the case of sildenafil or vardenafil, it is recommended that patients delay sexual intercourse for 2 hours after a heavy meal. When using on-demand dosing, patients should be instructed to allow adequate time for the PDEI to work; otherwise, treatment failure may result.22 Manufacturers caution that ethanol intake may reduce the efficacy of PDEIs; however, this situation is not related to a pharmacokinetic interaction.23,26,27 Instead, ethanol may cause sedation and decrease central perception of sexual stimuli. As a result, ethanol may compromise the efficacy of PDEIs.30 Studies have reported that the erectogenic effects of sildenafil may last long after its anticipated duration. For example, in one preliminary uncontrolled study of 40 patients (mean [SD] age: 54 [6] years), treated initially with sildenafil 100 mg, 97% and 74% reported having successful intercourse 1 hour and 12 hours after dosing, respectively.31 Several of the treated patients voluntarily reduced the dose of sildenafil to 50 mg because of flushing. More recently, a randomized, double-blind, crossover study of sildenafil 100 mg and placebo evaluated improvements in erectile function at 8 and 12 hours after dosing. A total of 174 patients (mean age, 53 [11] years) received sildenafil and 177 patients (mean age, 53 [9] years) received placebo. The patients’ responses were assessed using the validated Sexual Encounter Profile questionnaire, specifically question 3: “Did your erection last long enough for you to have successful intercourse?” After the first 4 weeks of the study, the mean per-patient proportion of successful intercourse attempts was 76% for sildenafil and 50% for placebo (odds ratio: 3.2; P ⬍ 0.0001) 8 hours after dosing; findings were 79% for sildenafil and 52% for placebo (odds ratio: 3.5; P ⬍ 0.0001) 12 hours after dosing.32 Similarly, it is well established that the erectogenic effect of tadalafil lasts 36 hours, exceeding its plasma half-life. This finding was demonstrated in a key multicenter, double-blind, placebocontrolled clinical trial of almost 350 men (mean age, 57 years) with erectile dysfunction who were random-

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Property Onset, h Serum half-life, h Duration, h Effect of high-fat meal on drug absorption

Effect of ethanol on drug absorption Principal route of elimination

Hepatic conversion to an active metabolite

Initial drug dosing recommendations, dosage range

Initial drug dose in the elderly (patients ⱖ65 years of age) Initial drug dosing recommendations in patients with hepatic failure

Initial drug dosing recommendations in patients with creatinine clearance ⬍30 mL/min Initial drug dosing recommendations in patients taking potent CYP 3A4 inhibitors

Sildenafil 0.5 3.82 (0.84), 100 mg 3.67 (0.69), 50 mg 4–6 Reduces maximum serum concentration by 29% and delays time to achieve maximum serum concentration by 1 hour None Hepatic, primarily through CYP 3A4

Vardenafil*

Tadalafil

0.5 4.18 (1.27), 10 mg 3.94 (1.31), 20 mg

0.5–2 17.5, 20 mg

4–6 Reduces maximum concentration by 18% and delays time to achieve maximum serum concentration by 1 hour28 None Hepatic, primarily through CYP 3A4

36 None

None Hepatic, primarily through CYP 3A4; 60%–65% is hepatically metabolized and 35% is renally excreted No

Yes. Active metabolite accounts for 20% of its erectogenic effect. 80% of active metabolite is excreted in the feces and 20% is excreted renally 50 mg 1 hour before coitus (ondemand regimen), 25–100 mg

10-mg film, coated tablet 1 hour before coitus (on-demand regimen), 5–20 mg

10 mg before coitus (on-demand regimen), 5–20 mg; OR 2.5–5 mg daily

25 mg

5 mg

Mild–moderate impairment, 25 mg Severe impairment, 25 mg

Mild impairment, 5 mg Moderate impairment, 5 mg Severe impairment, not evaluated

10 mg before coitus (on-demand regimen) or 2.5 mg daily Mild–moderate impairment, 10 mg Severe impairment, not recommended

25

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25 mg if patient is taking cimetidine, erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir, or saquinavir

Yes, but active metabolite accounts for only 7% of its effect, and 90% of the metabolite is excreted in the feces

5 2.5 mg every 72 hours if patient is taking ritonavir; 2.5 mg every 24 hours if patient is taking indinavir, ketoconazole 400 mg daily, or itraconazole 400 mg daily; 5 mg every 24 hours if patient is taking ketoconazole 400 mg daily, itraconazole 200 mg daily, or erythromycin

5 mg every 72 hours 10 mg every 72 hours if patient is taking itraconazole 200 mg daily or erythromycin

CYP ⫽ cytochrome P450. *A new addition formulation of vardenaful is dispersable table that dissolves on the tongue. it must be taken on an empty stomach and without any liquid. The usual dose is 10 mg and onset of action is 1.5 hours.

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Table II. Comparison of common adverse effects of phosphodiesterase inhibitors, as expressed as a percentage of treated patients.29 Adverse Effect

Sildenafil26

Headache Dyspepsia Flushing Abnormal vision Rhinitis Back pain

16 7 10 3 4 0

ized to receive tadalafil 20 mg or placebo; 327 patients completed the study.33 At 24 hours after dosing, the percentage of successful intercourse attempts with tadalafil and placebo were 52.9% and 29.1%, respectively (P ⬍ 0.001). At 36 hours after dosing, the percentage of successful intercourse attempts with tadalafil and placebo were 59.2% and 28.3%, respectively (P ⬍ 0.001). These efficacy rates were lower than those observed in other trials,8,9,31 possibly because of the unnatural study design which required that patients attempt sexual intercourse at designated times.33

Once-Daily Versus On-Demand Dosing Regimens of PDEIs The rationale for once-daily dosing of PDEIs is that such regimens may: (1) increase the smooth muscle content of cavernosal tissue to improve vascular flow and minimize hypoxia34; or (2) improve endothelial cell function in cavernosal tissue to enhance release of nitric oxide or other vasodilatory substances.35–37 Because a penile erection requires good vascular flow to the corpora cavernosa and release of nitric oxide from endothelial cells, daily use of PDEIs could help prevent erectile function or slow its progression. Early consideration of once-daily regimens of PDEIs was suggested in patients who had undergone radical nerve-sparing prostatectomy, in whom postoperative neuropraxia results in an inability of patients to achieve spontaneous or nocturnal erections for up to 24 months. Neuropraxia is associated with cavernosal hypoxia, which may lead to fibrosis, venous leak, and permanent erectile dysfunction.38 Thus, the daily use of PDEIs might shorten the period of neuropraxia and be useful for penile rehabilitation in that patients would have a faster recovery of normal erectile function after their surgery. In one randomized, placebo-controlled study

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Vardenafil27 4 1 1 ⬍2 3 2

Tadalafil23 11–15 4–10 2–3 ⬍1 2–3 3–6

in men who underwent nerve-sparing radical prostatectomy, 51 patients with a mean age of 55 (6) years received sildenafil 50 mg or 100 mg daily at nighttime and 25 patients with a mean age of 56 (6) years received placebo. After ⬃36 weeks, all patients discontinued treatment for an 8-week period. At the end of the study, 27% of sildenafil-treated patients versus 4% of those receiving placebo had erections suitable for sexual intercourse as evaluated using the IIEF (Fisher exact test, P ⫽ 0.0156). Although this study had a small sample size and a low rate of erectile function recovery after nerve-sparing radical prostatectomy, the results suggest that a daily regimen of sildenafil might be helpful for penile rehabilitation.39 In a subsequent follow-up report of a subset of this patient sample, 17 men (mean age, 55 years) received daily sildenafil 50 mg, 18 men (mean age, 55 years) received daily sildenafil 100 mg, and 19 men (mean age, 46 years) received placebo for 36 weeks.40 Nocturnal penile tumescence and rigidity were assessed during and 8 weeks after the last treatment dose. At the end of the treatment trial, 24% of patients taking sildenafil 50 mg, 33% of patients taking sildenafil 100 mg, and 5% of patients taking placebo responded. Although this study was limited by its small sample size and did not use a validated instrument to assess erectile function, the results suggest that daily use of sildenafil after prostatectomy might help restore penile function. Although conclusive evidence of the efficacy of postprostatectomy penile rehabilitation with PDEIs and the best regimen (ie, on-demand vs once daily) is lacking, the suggested benefit spurred studies of low-dose daily PDI regimens for erectile dysfunction unrelated to prostatectomy.41– 44 Among the commercially available PDEIs, tadalafil is the only one approved by the US Food and Drug Administration (FDA) for once-daily

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Clinical Therapeutics dosing in patients with erectile dysfunction independent of etiology.23 The manufacturer recommends that the patient start with 2.5 mg daily and that the dose be increased to 5 mg daily if necessary. The daily dosing regimen uses a lower dose than that used when tadalafil is used on-demand (ie, dosing range of 10 –20 mg).23,45 Once-daily regimens of sildenafil have been examined in patients with erectile dysfunction due to various causes. In one open-label study, sildenafil 50 mg at bedtime for 1 year was compared with on-demand sildenafil in patients with erectile dysfunction. Patients reported that erectile function improved; however, this was not based on using a standardized instrument to measure response.37 In another placebo-controlled, double-blind, multicenter clinical trial, vardenafil 10 mg plus placebo daily for 12 weeks and 24 weeks were compared with an on-demand regimen of vardenafil 10 mg for 24 weeks.46 A total of 198 patients with mild to moderate erectile dysfunction completed the study. The mean patient age in all 3 groups ranged from 53.5 to 55.6 years. No difference in IIEF-EF scores among the groups was demonstrated; the least squares mean differences in IIEF-EF from baseline to the end of the study were 2.02, 2.29, and 2.63 for vardenafil 10 mg daily for 12 weeks, vardenafil 10 mg daily for 24 weeks, and vardenafil 10 mg on-demand, respectively (P ⬎ 0.05). The onset of the clinical effects of daily low-dose tadalafil occurs within a few days of treatment. In a randomized, double-blind, placebo-controlled clinical trial, 121 patients were randomized to receive tadalafil 2.5 mg daily, 118 patients to tadalafil 5 mg daily, and 133 patients to placebo.47 The mean age of all study patients was 58.9 years, and all patients had a minimum 1-year history of erectile dysfunction. A greater percentage of patients who received tadalafil 5 mg daily achieved successful intercourse by day 2 compared with placebo (38.9% vs 28.0%; P ⬍ 0.025). A greater percentage of patients who received tadalafil 2.5 mg daily achieved successful intercourse by day 3 compared with placebo (35.5% vs 27.2%; P ⬍ 0.025). Thus, within a few days of starting once-daily tadalafil, patients can expect to experience improvement in sexual function. Once-daily dosing of tadalafil 5 mg has been documented to exert a durable clinical response with up to 2 continuous years of use. In an open-label extension trial of 208 patients after 1 year and 139 patients after 2 years, ⬎92% of patients reported improved quality

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of erections and an ability to engage in successful vaginal intercourse.44 Although this study was not a controlled clinical trial, sample size was small, and results were based on self-reported patient information, these results are consistent with that of on-demand regimens of PDEIs. In another open-label, noncomparison study of patients with erectile dysfunction due to any etiology and of different levels of severity, 234 patients with a mean age of 56.1 (11.4) years received treatment for 1 year and 238 patients with a mean age of 59.3 (10.6) years received treatment for 2 years.45 At the end of 1 year, 88.9% of patients completed the study. The mean IIEF-EF score improved from 13.7 (6.4) to 24.1 (6.7) at the end of the first year (when the score for patients with normal erectile function is ⱖ26). At the end of 2 years, 58.4% of patients had completed the study. The mean IIEF-EF improved from 14 (6.2) to 24.8 (6.1). The once-daily tadalafil regimen was well tolerated, and no severe adverse effects were observed. In summary, a daily low-dose regimen of a PDEI is attractive because the low dose may potentially be associated with fewer adverse effects. It is important to note that a review of the literature revealed no wellcontrolled comparison trials of daily dosing versus ondemand regimens.48 The onset of action is within 2 or 3 days. The clinical benefit persists as long as the patient continues treatment. Because the clinical effects of PDEIs are dose related, it is likely that some patients with severe erectile dysfunction may not respond to typical daily low-dose regimens.

Comparative Adverse Reaction Profile Among PDEIs PDEIs are well tolerated. The most common adverse effects are mild to moderate in severity and include headache, dyspepsia, and flushing (Table II23,26,27,29). These adverse effects are dose related. Therefore, lowering the dose may ameliorate the adverse effect. Rarely do these adverse effects require discontinuation of treatment. The PDEIs antagonize a variety of phosphodiesterase enzymes, each of which has been associated with various adverse effects.11 As previously mentioned, type 5 phosphodiesterase is found in all vascular tissue.11,49 Therefore, concern for clinically symptomatic hypotension, particularly in patients taking antihypertensive agents or those with poorly controlled hypertension, has been associated with use of phosphodiesterase type 5 inhibitors. Usual doses of sildenafil in

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M. Lee healthy young men produced a reversible mean decrease of systolic blood pressure (SBP) and diastolic blood pressure (DBP) of 8.5 and 5.5 mm Hg, respectively.26 Usual doses of vardenafil in healthy subjects produced a similar mean decrease of SBP and DBP of 7 and 8 mm Hg, respectively.27 Finally, usual doses of tadalafil in healthy subjects produced a mean decrease of supine SBP and DBP of 1.6 and 0.8 mm Hg, respectively.23 In a randomized study of 224 men with erectile dysfunction and well-controlled essential hypertension treated with ␤-adrenergic antagonists, angiotensin-converting enzyme inhibitors, or calcium channel antagonist antihypertensive agents, the patients had no decrease in blood pressure when concomitant sildenafil 25 to 100 mg was used.50 However, PDEIs should not be used until a cardiovascular assessment has been completed in patients with poorly controlled hypertension or unstable blood pressure.25 Likewise, patients who are at risk of significant clinical consequences if hypotension occurs should not be treated with PDEIs, including patients with unstable angina, New York Heart Association class IV congestive heart failure, or uncontrolled cardiac arrythmias.25 Sildenafil and vardenafil, and to a lesser extent tadalafil, inhibit in vitro phosphodiesterase type 6 isozyme, which in vivo is concentrated in the rods and cones of the eye. Cyanopsia and increased sensitivity to light, which are usually dose related, are associated with inhibition of this enzyme. Thus, cyanopsia is most common with sildenafil, less common with vardenafil, and rarely occurs with tadalafil. Cyanopsia is usually mild, does not require discontinuation of treatment, is associated with high PDEI doses, and rapidly resolves when the PDEI is discontinued.11,51,52 Nonarteritic anterior ischemic optic neuropathy (NAION) presents as a sudden, usually unilateral, painless, irreversible loss of vision, which can lead to permanent blindness. It most commonly occurs in patients who are aged ⬎50 years with ⱖ1 cardiovascular risk factor (ie, hypertension, diabetes mellitus, cigarette smoking, nocturnal hypotension, hyperlipidemia). The annual incidence is estimated to be 2.3 to 10.2 cases per 100,000 people aged ⱖ50 years.53 NAION is believed to be due to ischemia of the optic nerve head.29,51 PDEIs have been linked with the development of NAION. The proposed mechanisms for this adverse effect include a PDEI-induced decrease in blood pressure in combination with nocturnal hypotension, re-

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sulting in decreased blood flow to the optic nerve.54 Inhibition of phosphodiesterase type 6 is probably not the cause of NAION.55 Risk factors for PDEI-induced NAION include a number of common concomitant disorders in males ⱖ60 years of age, including diabetes mellitus, hypertension, glaucoma, and a history of NAION in 1 eye.52 Among the cases reported to date, the majority of patients had a “disc at risk,”51,54 which refers to the optic nerve (or “disc”) being squeezed through a narrow scleral canal. Compression of the capillaries to the optic nerve head may result in ischemia and NAION. The estimated incidence of NAION among sildenafil users is 2.8 cases per 100,000 patientyears of use.56 The onset was variable after the start of treatment, with some cases reported after the patient took a single PDEI dose, while in other cases, several months elapsed after the start of PDEI use before NAION was first reported.54 A common presentation of NAION is that the patient awakens the morning after having taken a PDEI dose and has no vision in 1 eye. Patients with risk factors for NAION should use PDEIs with caution. In addition, if a patient has experienced NAION in 1 eye, he is considered to be at high risk for PDEI-induced NAION in the other eye and should therefore avoid using any PDEI. No effective treatment for NAION has been identified, although aspirin has been tried.57 In the event that a patient is suspected of having NAION, the PDEI should be discontinued, and the patient should not restart use of a PDEI in the future. PDEIs have been linked with the development of sudden, unilateral, sudden sensorineural hearing loss. The pathophysiologic mechanism is not understood at this time, although it has been postulated that PDEIs may interfere with the nitric oxide/cGMP pathway in the inner ear. Of the first 25 cases reported to the FDA, hearing loss occurred within a day of taking the PDEI in 88% of patients. Approximately one third of patients had vertigo in addition to hearing loss.58 The hearing loss appeared to be dose related and was temporary in 20% of patients.59,60 At this point, a cause– effect relationship has not been established, and these cases of sudden sensorineural hearing loss may be idiopathic.59 Tadalafil inhibits phosphodiesterase type 11 isozyme, which concentrates in skeletal muscle.29 Inhibition of this enzyme has been linked with low back pain and muscle pain. However, the pathophysiologic cause of this adverse effect must still be

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Clinical Therapeutics elucidated. Low back pain is reversible on discontinuation of the drug. It usually is of mild to moderate severity and therefore does not require discontinuation of tadalafil.

Ways to Enhance the Efficacy of PDEIs in Patients Who Fail to Respond to Usual Doses The overall efficacy of phosphodiesterase type 5 inhibitors for erectile dysfunction is ⬍100%; specifically, the weighted mean percentage of successful vaginal intercourse attempts is 68% to 69%.4 The initial lack of responsiveness is often due to improper use. It has been shown that 40% to 50% of initial failures can be salvaged with improved education and counseling on proper PDEI use.61,62 Table III18,62 includes common patient education tips. In addition, dosing studies reveal that the vast majority of patients require up-titration from a lower starting dose of PDEIs. In a double-blind, multicenter, placebo-controlled, dose-escalation study, 315 pa-

tients with erectile dysfunction were randomized to receive sildenafil or placebo for 26 weeks.63 Dose titration was performed to achieve the best balance of clinical efficacy and tolerable adverse effects. Of the 159 patients who received sildenafil, patients started with 25 mg, and the dose was increased to 50 or 100 mg to achieve clinical effect; 156 patients received placebo. Clinical efficacy was measured using the patient selfreported IIEF questionnaire. At the end of the study period, 26% of patients received sildenafil 25 mg, 32% received 50 mg, and 42% received 100 mg. Seventynine percent of sildenafil-treated patients reported significant improvements in their ability to achieve and maintain erections compared with 23% of those receiving placebo (P ⬍ 0.0001). In another multicenter, flexible-dose, open-label study, 1109 patients with erectile dysfunction received sildenafil for 8 weeks. Dose titration to achieve successful intercourse resulted in 2% of patients maintained using the 25-mg dose, 45% with the 50-mg dose, and 53% with the

Table III. Instructions for patients who are using phosphodiesterase inhibitors (PDEIs) for erectile dysfunction.18,62 1. If taking the medication on an as-needed basis, take the dose on an empty stomach or after a low-fat meal 60 minutes before sexual intercourse. 2. Avoid taking the PDEI dose with alcohol. Alcohol can make you drowsy and that can interfere with sexual function. 3. Engage in foreplay before coitus. 4. Take your medication as prescribed. 5. To improve overall sexual function, maintain a heart-healthy lifestyle: no smoking; maintain an ideal weight; ensure that medical treatment for hypertension, hyperlipidemia, and diabetes mellitus is optimized; engage in regular exercise; and avoid excessive alcohol intake. 6. If the first dose does not work, do not take another dose on the same day. 7. Take no more than 1 dose per day. 8. Do not worry if the first few doses do not work well. It is common for patients to require a trial period of 7 or 8 doses before optimal effects are observed. 9. After 7 or 8 doses, if you are dissatisfied with the effect, see your physician. A dosage increase may be considered. 10. If you experience headache, dizziness, or flushing, these adverse effects are usual and expected. They do not require discontinuation of treatment. If bothersome, your physician may decrease your dosage, and this usually addresses the problem. 11. Before you begin taking any other medications, please check with your physician to ensure that there are no drug interactions, which may interfere with the PDEI’s effect or may cause serious problems. 12. Do not use any nitrate-containing medications while taking a PDEI. This includes topical, inhaled, oral, or parenteral nitrates. If you are hospitalized or go to an emergency department, be sure to let the physician know that you are taking a PDEI.

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M. Lee 100-mg dose.64 The erectogenic effect of PDEIs is dose related, with higher doses producing a greater response than lower doses. For example, with sildenafil, premarketing clinical trials using 25, 50, and 100 mg produced efficacy rates of 10%, 30%, and 60%, respectively.62 Thus, patients should be instructed to follow up with their physician if the initial dose does not appear to improve their erectile dysfunction. Up-titration of the PDEI dose is likely necessary. For patients with erectile dysfunction who fail to respond to maximum daily doses of the phosphodiesterase type 5 inhibitors, additional agents have been combined with the PDEI, including vacuum erection devices65 and intracavernosal alprostadil.66 However, published trials included small sample sizes, were poorly controlled, and often did not use standardized assessment tools for efficacy. Therefore, these trials do not document that combination therapy is better than monotherapy with the PDEI, vacuum erection device, or other erectogenic agent. In addition, the combination of testosterone supplementation and PDEI has been used in patients who fail to respond to PDEIs alone. The rationale for combining testosterone supplementation with a PDEI is that testosterone is essential for proper functioning of the nitric oxide/cGMP pathway. Phosphodiesterase type 5 is an androgen-dependent enzyme.67 Studies have shown that patients with hypogonadism may have a lower response rate to PDEIs than eugonadal patients,68 –70 and the response rate to PDEIs can be optimized with testosterone supplementation. However, because the evidence of a clinical benefit of combined PDEIs and testosterone is considered equivocal4 and the potential adverse effects of testosterone supplementation including mood swings, polycythemia, and gynecomustia can be worrisome, hormone replacement should be reserved for those patients who have failed to respond to maximum tolerated doses of PDEIs and who also have documented hypogonadism, as evidenced by low serum testosterone levels and the presence of decreased libido.4,67 Testosterone supplementation should be dosed judiciously to increase serum testosterone only to the normal range because supraphysiologic levels have not been shown to be any more effective in relieving signs and symptoms of hypogonadism than physiologic levels.71 Two other strategies have been reported in patients who fail to respond to PDEIs; however, they have produced inconsistent results and are not recommended at this time: high doses of PDEIs that exceed the usual

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maximum dose and switching from one PDEI to another. Sildenafil in doses up to 200 mg, a dose that is twice the FDA-recommended maximum dose, has been reported in one uncontrolled study of 54 patients with a mean age of 59.6 (11.2) years to correct chronic erectile dysfunction in 24% of patients who failed to respond to sildenafil 100 mg.72 However, patients treated with the higher dose of sildenafil experienced a higher frequency of more severe adverse effects, including headache, facial flushing, dyspepsia, nasal congestion, dizziness, and visual disturbances, which necessitated discontinuation of treatment in 31% of treated patients. In a prospective, uncontrolled study of 59 patients (median age: 64 years) who failed to respond to sildenafil 100 mg, switching to vardenafil improved erectile function in 12% of patients.73 Statistical analysis was not performed due to the small sample size. Because the study design was not blinded and did not include a crossover study design, these results are inconclusive.

Considerations When a Patient is Taking Both Antihypertensive Agents and PDEIs The presence of hypertension and erectile dysfunction is common in males ⬎50 years of age. When PDEIs are prescribed in this group of patients, several questions arise: (1) what is the effect of usual doses of PDEIs on SBP and DBP; (2) is a particular PDEI preferred in patients with hypertension; and (3) does concurrent use of a PDEI and antihypertensive agents exert an additive or synergistic blood pressure–lowering effect? Phosphodiesterase type 5 enzyme is localized to vascular tissue. Therefore, PDEIs cause peripheral vascular vasodilation, which manifests in part as headache, flushing, and decreased blood pressure. Usual doses of PDEIs produce small decreases in SBP and DBP.74 In 8 healthy young men and 24 middle-aged men, oral sildenafil 100 mg decreased SBP and DBP by 10 and 7 mm Hg, respectively, which then returned to baseline values ⬃6 to 8 hours after the sildenafil dose. Oral sildenafil 200 mg produced a similar effect on blood pressure that was not significantly different from the 100-mg dose (P ⬎ 0.05).75 The transient and small decrease in blood pressure may have contributed to headache, flushing, and dizziness but not to any other cardiovascular consequences. Usual doses of vardenafil decrease blood pressure to the same magnitude as sildenafil,76 whereas usual doses of tadalafil lower SBP

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Clinical Therapeutics by 0.3 to 4.6 mm Hg.77 Head-to-head comparison studies have not assessed the relative safety of one PDEI over another; therefore, at this time it is not possible to recommend any one of the PDEIs as safer than another in patients in whom a decrease in blood pressure might produce undue consequences. Multiple studies have been conducted to assess the safety of PDEIs when taken with ⱖ1 antihypertensive agent.49,78 In one literature review of 35 double-blind, placebo-controlled, randomized clinical trials, 8000 patients who took sildenafil for erectile dysfunction were stratified into 2 patient groups: patients who received 1, 2, or 3 antihypertensive agents and patients who received no antihypertensive agents.79 The mean age of patients in both groups was the same (54 [12] years). The study results showed a small additive decrease in blood pressure when patients took a PDEI with ⱖ1 antihypertensive agent; however, no difference in clinically evident hypotension-related adverse effects was observed between the 2 groups. Similar outcomes were observed in Phase III studies of single oral dose tadalafil 10 mg versus placebo in male and female patients with mild or moderate hypertension, taking at least 2 antihypertensive agents, which included angiotensin-converting enzyme inhibitors, metoprolol, bendrofluazide, amlodipine, or an angiotensin II receptor antagonist. In this study, patient ages were not specified. No statistically significant difference (P ⬎ 0.05) in hypotension-related adverse effects was observed between the 2 groups.78 Moreover, in another doubleblind study of 354 patients who were randomized to receive placebo or vardenafil 5 to 20 mg daily for 3 months, no significant decrease in SBP and DBP (P ⬎ 0.05) was reported in any of the patients.80 Patients in the placebo group were receiving a mean of 1.4 antihypertensive agents per day, whereas the vardenafiltreated patients were receiving a mean of 1.5 antihypertensive agents per day. All of these studies show that in patients with stable blood pressure and who are receiving antihypertensive treatment, the concomitant use of a PDEI produces no clinically significant decrease in blood pressure. For a full discussion of the interaction of PDEIs and ␣-adrenergic antagonists, refer to the section in the following text regarding patients with benign prostatic hyperplasia and erectile dysfunction. The Second Princeton Consensus Panel considers patients with well-controlled essential hypertension to be at low risk of cardiovascular consequences when a

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PDEI is started.25 With such patients, physicians can prescribe PDEIs without taking any precautions, provided that the patient’s blood pressure is at least 90/60 mm Hg before the start of the PDEI. However, patients with unstable essential hypertension, left ventricular heart failure, New York Heart Association class III or IV, obstructive hypertrophic cardiomyopathy, or moderate to severe valvular heart disease are considered at high risk of cardiovascular consequences if the patient engages in sexual activity. Therefore, PDEIs are contraindicated.25

Considerations When a Patient Has Erectile Dysfunction and Concomitant Heart Disease Erectile dysfunction and arteriosclerosis share a common pathophysiologic mechanism. Both disorders are caused by vascular endothelial cell dysfunction, which results in impaired release of nitric oxide, decreased production of cGMP, and inadequate vasodilation.7,81,82 Erectile dysfunction may be the first presenting sign of arteriosclerosis. It has been hypothesized that penile arteries, which are smaller in diameter than coronary or carotid arteries, occlude faster than larger-sized vessels.83 In the Prostate Cancer Prevention Trial, ⬎9000 patients aged ⱖ55 years who were randomized to receive placebo were evaluated for erectile dysfunction and cardiovascular disease every 3 months.81 A hazard ratio of 1.45 (95% CI: 1.25–1.69; P ⬍ 0.001) for subsequent cardiovascular events was calculated for patients with incident or prevalent erectile dysfunction. This finding suggests that a patient who presents with erectile dysfunction is more likely to develop cardiovascular disease than a patient who does not have erectile dysfunction. This study had several limitations: medications that could cause erectile dysfunction and which could have contributed to outcomes were not assessed and the presence of erectile dysfunction was self-reported by patients. Similar findings were reported in a longitudinal population study of ⬃1250 men, of whom 8.7% had severely reduced penile rigidity.84 In this subgroup, the hazard ratio for developing adverse cardiovascular events was 2.6 (95% CI: 1.3–5.2). PDEIs can be safely used for the treatment of erectile dysfunction in selected patients with cardiovascular disease (Table IV25). According to the Second Princeton Consensus Panel, the following patients are at low risk of cardiovascular consequences when PDEIs are prescribed: patients with mild, stable ischemic heart

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Table IV. According to the Second Princeton Consensus Panel, stratification of patients into groups based on their risk for serious cardiovascular consequences if phosphodiesterase inhibitors (PDEIs) are used.25 Risk Category Low

Intermediate

High

Types of Patients in Each Category

Use of PDEIs

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Patient is asymptomatic of cardiovascular disease and has ⬍3 cardiovascular Safe to prescribe risk factors (excluding gender) or Patient has well-controlled hypertension, mild and stable angina, experienced myocardial infarction at least 6–8 weeks earlier, has mild valvular heart disease, or has left ventricular heart failure, New York Heart Association class I Patient is asymptomatic but has at least 3 risk factors for coronary artery Refer the patient to a cardiologist for cardiovascular disease (excluding gender) testing. Patient should be reclassified into low- or high-risk group (ie, sexual activity may cause significant cardiovascular consequences) or Patient has moderate, stable angina or Patient has a history of myocardial infarction that occurred ⬎2 weeks and ⬍6 weeks ago or Patient has left ventricular heart failure, New York Heart Association class II Patients have moderate or severe cardiovascular symptoms related to PDEIs are contraindicated until the patient’s cardiac unstable or refractory angina, or uncontrolled hypertension disease has been treated and stabilized, and the cardiologist determines that sexual activity will not place the patient at risk of serious cardiovascular consequences or Patient suffered a myocardial infarction in the last 2 weeks or Patient has congestive heart failure, New York Heart Association class III or IV or Patient has obstructive hypertrophic cardiomyopathy or Patient has moderate or severe valvular heart disease

Clinical Therapeutics disease and patients who experienced an uncomplicated myocardial infarction at least 6 to 8 weeks earlier and who have no anginal symptoms. In such patients, PDEIs may cause small decreases in SBP and DBP but do not cause reflex tachycardia, severe orthostatic hypotension, myocardial ischemia or infarction, or any other cardiovascular consequences. This conclusion is based on use of PDEIs in 13,000 patients in premarketing clinical trials and ⬎30,000 patients in postmarketing surveillance studies.74 Potential drug interactions between PDEIs and cardiovascular agents may be clinically significant.25 Therefore, the medication profile of such patients should be carefully scrutinized before starting a PDEI so that appropriate steps can be taken to minimize interactions.77 The most important drug interaction is that of PDEIs and nitrates, which can lead to significant hypotension.25 In one pharmacodynamic study of 150 men who received tadalafil 20 mg or placebo daily for 7 consecutive days, nitroglycerin 0.4 mg sublingual was repeatedly administered on day 7. 85 SBP ⬍ 85 mm Hg developed in 41% of tadalafil-treated patients versus 32% of those receiving placebo (P ⬍ 0.02). DBP ⬍ 45 mm Hg developed in 15% of tadalafil-treated patients versus 8% of those receiving placebo. When taken by any route of administration, nitrates are an absolute contraindication to PDEI use.23,26,27 If a patient who has recently taken a PDEI develops angina, the patient should be treated with a nonnitrate alternative; options include ␤-blockers and calcium channel blockers. If sildenafil or vardenafil was taken and a nitrate must be given, it is recommended to wait 24 hours before doing so. Likewise, if tadalafil was taken and a nitrate needs to be given, it is recommended to wait 48 hours before administration.49 If a patient does experience a PDEI–nitrate interaction, most likely the patient will present with severe hypotension. In this case, the patient should be put in a Trendelenberg position, administered intravenous fluids, and started on a peripheral vasoconstrictor, if necessary. Other drug interactions of significance are listed in Table V.23,26,27

Considerations When a Patient Has Both LUTs and Erectile Dysfunction The incidence of both benign prostatic hyperplasia and erectile dysfunction increase with patient age ⬎50 years. Patients with moderate to severely symptomatic benign prostatic hyperplasia develop urinary urgency

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or urinary incontinence, which can contribute to decreased libido and secondarily to erectile dysfunction. Treatment of benign prostatic hyperplasia could potentially relieve erectile dysfunction. In addition, PDEIs can cause smooth muscle relaxation in penile arterial vasculature and cavernosal tissue, as well as cause prostatic smooth muscle relaxation, which may lead to symptomatic improvement in voiding symptoms.86,87 This possible outcome is the basis for examination of PDEIs alone or a combination of PDEI plus postsynaptic ␣-adrenergic antagonists (eg, tamsulosin) to treat patients who suffer from both conditions. When PDEI monotherapy has been studied in men with both erectile dysfunction and LUTS thought to be secondary to benign prostatic hyperplasia, it has been shown to significantly reduce a patient’s perception of LUTS but not to improve peak urinary flow rate, an objective measure of disease. In a double-blind, placebocontrolled study, 369 patients with a history of erectile dysfunction for 6 years and a history of benign prostatic hyperplasia for 5 years were randomized to 12 weeks of sildenafil or placebo.88 In the sildenafil group, the mean patient age was 60 (8.7) years. Patients took sildenafil 50 mg at bedtime or 50 mg on-demand at least once a week; the dose was increased to 100 mg after 2 weeks. Patients could decrease their sildenafil dose to 50 mg if they experienced adverse effects. In the placebo group, the mean patient age was 60 (8.5) years. The severity of erectile dysfunction and LUTS were assessed using the IIEF and the International Prostate Symptom Score (IPSS), both standardized and validated tools. As previously mention, IIEF score ranges from 6 (sever erectile dysfunction) to 30 (normal function). The IPSS score ranges from 0 (no voiding symptoms) to 35 (severe voiding symptoms). At baseline, patients had moderate to severe erectile dysfunction (IIEF score, ⱕ25) and LUTS (IPSS score, ⱖ12). At the end of the study period, sildenafil-treated patients had greater improvements in the least squares mean IIEF scores compared with those receiving placebo (9.17 vs 1.93; P ⬍ 0.0001) and also had improved IPSS scores compared with placebo (⫺6.32 vs ⫺1.93; P ⬍ 0.0001). Neither sildenafil nor placebo increased urinary flow rates. Limitations of this study included the small sample size, short treatment period, fixed dose of sildenafil used, and that LUTS was attributed to benign prostatic hyperplasia but prostate size was not measured at study baseline.

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Table V. Cardiovascular drug interactions with phosphodiesterase inhibitors (PDEIs).23,26,27 Manifestation of Drug Interaction

Object Drug

Precipitant Drug

Nitrates, by any route of administration

PDEI

Type IA antiarrhythmic agents (quinidine and procainamide)

Vardenafil

Type III antiarrhythmic agents (sotalol and amiodarone)

Vardenafil

Prolonged QT interval, which can lead to torsade de pointes

Amlodipine

Sildenafil

Mixed ␣- and ␤-adrenergic antagonists (carvediol and labetalol)

PDEIs

Decreased systolic and diastolic blood pressure by 8 and 7 mm Hg, respectively Decreased systolic and diastolic blood pressures, which can lead to orthostatic hypotension

Decreased diastolic and systolic blood pressure Prolonged QT interval, which can lead to torsade de pointes

In a randomized, double-blind, placebo-controlled study conducted at 20 medical centers in the United States and Canada, the effect of tadalafil on bladder versus prostate function was assessed.86 Two hundred patients with LUTS for at least 6 months, which was attributed to benign prostatic hyperplasia, had a baseline IPSS score ⱖ13. Patients were randomized to tadalafil 20 mg by mouth once a day or placebo for 12 weeks. A total of 181 patients completed the study. Urodynamic testing performed at baseline and at the end of the study showed no significant effect of tadalafil on maximum detrusor pressure, bladder contractility index, or bladder capacity (P ⬎ 0.05), which suggests that tadalafil had no effect on bladder smooth muscle function. Tadalafil did not improve peak urinary flow rate. However, tadalafil decreased IPSS total

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Management Nitrates are contraindicated with PDEIs Vardenafil should not be used with type IA antiarrhythmic agents. Sildenafil and tadalafil can be safely administered with type IA antiarrhythmic agents Vardenafil should not be used with type III antiarrhythmic agents. Sildenafil and tadalafil can be safely administered with type III antiarrhythmic agents Sildenafil should be used cautiously in amlodipine-treated patients26 Patient’s blood pressure with use of a mixed ␣- and ␤-adrenergic antagonist should be stabilized and at least 90/60 mm Hg before PDEI is started. Patient should then be started on the lowest effective PDEI dose and slowly titrated up to higher doses25

score by a mean of ⫺4.2 (1.1) (P ⬍ 0.001), decreased IPSS obstructive score by a mean of ⫺2.8 (0.7) (P ⬍ 0.001), and decreased IPSS irritative score by a mean of ⫺1.4 (0.5) (P ⫽ 0.006). Although ⬃50% of tadalafiltreated patients developed mild adverse effects (eg, headache, back pain, gastroesophageal reflux), the reactions were generally mild, and only 2% of patients discontinued treatment. In another double-blind, placebo-controlled study, 1058 men with benign prostatic hyperplasia and LUTS were randomized to receive tadalafil 2.5, 5, 10, or 20 mg or placebo once a day for 12 weeks.89 The patient age in all groups ranged from 44.99 to 92.64 years. IPSS and peak urinary flow rate were assessed at baseline and at 4, 8, and at the end of 12 weeks. The improvement in IPSS least squares mean change from

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Clinical Therapeutics baseline to end point with tadalafil 5 mg was greater than with tadalafil 2.5 mg or placebo: ⫺4.9 versus ⫺3.9 or ⫺2.3, respectively. However, the improvement with tadalafil 5 mg was similar to that observed with tadalafil 10 mg and 20 mg: ⫺4.9 versus ⫺5.2 and ⫺5.2. Therefore, the authors concluded that 5 mg appeared to be the optimal dose. None of the tadalafiltreated patients or those receiving placebo had an increase in peak urinary flow rate. Although this study suggests that doses of tadalafil ⬍20 mg daily may improve LUTS, further study with longer follow-up is needed to confirm the results. The combination of a PDEI plus an ␣-adrenergic antagonist has been directly compared with an ␣-adrenergic antagonist alone for the treatment of benign prostatic hyperplasia and erectile dysfunction. In a randomized, double-blind, crossover study, 30 men, all at least 50 years of age, with both medical conditions for at least 6 months were randomized to receive tadalafil 20 mg and tamsulosin 0.4 mg, both once a day, or tamsulosin 0.4 mg once a day.90 Treatment was continued for 45 days. After a washout period, patients were switched to the alternative regimen for another 45 days. At the end of each treatment period, IPSS and IIEF scores were assessed. IPSS scores improved compared with baseline in both groups (P ⬍ 0.05); however, greater improvements were observed with combination therapy (P ⬍ 0.001). No differences in peak urinary flow rate or decreased postvoid residual urine volume were observed between treatment groups (P ⬎ 0.05). IIEF scores improved compared with baseline with the combination therapy group (P ⬍ 0.001) but not with the tamsulosin-only group (P ⬎ 0.05). Although this study suggests that a combination of tadalafil plus tamsulosin may be a good choice for management of patients with LUTS and erectile dysfunction, the results have limited application because the use of tamsulosin alone for treatment of patients who have both medical disorders is not established. In addition, this was a fixed-dose study using a short treatment trial period and a small sample size. The drug interaction of postsynaptic ␣-adrenergic antagonists and PDEIs may lead to clinical hypotension, particularly because both medications may be taken during the late evening or bedtime hours when peak plasma levels occur at about the same time. However, the drug combination has not been associated with myocardial infarction or stroke. For this reason, manufacturers recommend that before the start of

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the PDEI in a patient taking an ␣-adrenergic antagonist, blood pressure should be stabilized at normotensive levels first.23,26,27 As an added precaution, administration of the ␣-adrenergic antagonist and the PDEI may be separated by ⱖ4 hours. The patient should be started on the lowest effective dose of PDEI and then slowly titrated up to higher doses, as needed. Similarly, if a patient is already taking a PDEI and an ␣-adrenergic antagonist is to be started, the latter agent should be started at the lowest effective dose and then slowly titrated up over time, if appropriate.23,26,27,49

DISCUSSION Oral drug treatment with PDEIs is convenient, effective in the majority of treated patients, and well tolerated. In this review of 3 commercially available PDEIs in the United States, the focus was on selected pharmacologic and pharmacokinetic aspects of these agents to clinical practice. This review is not an exhaustive assessment of all published literature but rather a more concise analysis of selected literature in men ⱖ45 years of age.

CONCLUSIONS PDEIs are the drugs of first choice for medical management of erectile dysfunction. They have demonstrated comparable efficacy and have a good safety profile. To maximize the efficacy of PDEIs, patient education is key to minimize drug–food and drug– drug interactions and to ensure an adequate trial period of use. Based on some studies of PDEIs for penile rehabilitation in patients after a prostatectomy, a low-dose, once-daily regimen of tadalafil is used for erectile dysfunction. Because the erectogenic effect of PDEIs is dose related, direct comparison studies of on-demand versus once-daily dosing regimens must still be conducted to clarify the role of the latter. In patients with hypogonadism and erectile dysfunction, the effect of PDEIs may be optimized by first correcting hypogonadism with testosterone supplements. In patients with well-controlled essential hypertension who are receiving ⱖ1 antihypertensive agent, PDEIs are well tolerated; no clinically significant hypotensive adverse effects have been reported. The guidelines established by the Second Princeton Consensus Conference are widely accepted as the principles for prudent use of PDEIs in patients with cardiovascular disease. Such patients should be stratified into low-, intermediate-,

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M. Lee and high-risk categories for cardiovascular consequences if PDEIs are used, and only low-risk patients should be prescribed PDEIs by noncardiac physicians. At this time, although PDEIs have been studied for treatment of LUTS secondary to benign prostatic hyperplasia, they are not recommended.

ACKNOWLEDGMENTS Dr. Lee received no current or previous support from industry or institutions for the present or any other research or work for erectile dysfunction. The author received no editorial assistance for the preparation of this manuscript.

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Address correspondence to: Mary Lee, PharmD, BCPS, FCCP, Midwestern University, 555 31st Street, Downers Grove, IL 60515. E-mail: mleexx@ midwestern.edu

Volume 33 Number 11