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Vardenafil Improves Erectile Function in Men with Erectile Dysfunction and Associated Underlying Conditions, Irrespective of the Use of Concomitant Medications
244
Vardenafil Improves Erectile Function in Men with Erectile Dysfunction and Associated Underlying Conditions, Irrespective of the Use of Concomitant Medications jsm_1547
244..255
Ian Eardley, MA, MChir, FRCS (Urol), FEBU,* Jay C. Lee, MD, FRCSC,† Ridwan Shabsigh, MD,‡ John Dean, MBBS, FRCGP,§ Mario Maggi, MD,¶ Dieter Neuser, MD, PhD,** and Christiane Norenberg, Dipl. Stat** *Pyrah Department of Urology, St. James’s University Hospital, Leeds, UK; †Division of Urology, University of Calgary, Calgary, Alberta, Canada; ‡Division of Urology, Maimonides Medical Center, Columbia University, Brooklyn, NY, USA; § St. Peter’s Andrology Centre, London, UK; ¶Andrology Unit, Department of Clinical Pathophysiology, University of Florence, Florence, Italy; **Bayer Healthcare AG, Wuppertal, Germany DOI: 10.1111/j.1743-6109.2009.01547.x
ABSTRACT
Introduction. Men with erectile dysfunction (ED) are also likely to have associated underlying conditions. Aim. This retrospective analysis evaluated the efficacy and safety of vardenafil in men with ED and underlying conditions, including those taking concomitant medications. Methods. A total of 13 randomized, double-blind, placebo-controlled clinical studies were included. Vardenafil was administered at a starting dose of 10 mg, adjustable to 5 or 20 mg after 4 weeks. Efficacy analyses were performed on the intent-to-treat (ITT) population, using a last observation carried forward approach. Efficacy was assessed for subgroups of patients with diabetes, hypertension, dyslipidemia, or metabolic syndrome (as defined by International Diabetes Federation criteria). Incidence rates of treatment-emergent adverse events were analyzed overall and by subgroup for patients in the safety population. Main Outcome Measures. Primary efficacy measures were the erectile function domain of the International Index of Erectile Function (IIEF-EF), and Sexual Encounter Profile questions 2 and 3 (SEP2, SEP3). Results. In total, 4,326 patients were randomized to treatment; the ITT population included 4,143 patients, with 4,266 patients valid for safety. At 12 weeks, vardenafil therapy was associated with statistically significant improvements from baseline in IIEF-EF scores, and SEP2 and SEP3 success rates, including patients with ED and diabetes, hypertension, dyslipidemia, or metabolic syndrome. These improvements were irrespective of level of glycemic control, or use of concomitant medications for the treatment of diabetes, hypertension, or dyslipidemia. Across all subgroups, the number and type of treatment-emergent adverse events were consistent with results from previous studies of phosphodiesterase type 5 inhibitors in men with ED and underlying conditions. Conclusions. Vardenafil demonstrated favorable efficacy and tolerability in this large pool of patients with ED and underlying conditions. Importantly, the use of concomitant medications was not associated with any noteworthy changes in the efficacy or safety profile of vardenafil. Eardley I, Lee JC, Shabsigh R, Dean J, Maggi M, Neuser D, and Norenberg C. Vardenafil improves erectile function in men with erectile dysfunction and associated underlying conditions, irrespective of the use of concomitant medications. J Sex Med 2010;7:244–255. Key Words. Vardenafil; Erectile Dysfunction; Phosphodiesterase Type 5 Inhibitor; Underlying Conditions; Concomitant Medications; Retrospective Analysis
Introduction
E
rectile dysfunction (ED), the “persistent inability to achieve and/or maintain a penile erection sufficient for satisfactory sexual perfor-
J Sex Med 2010;7:244–255
mance” [1], is a common condition that increases in prevalence with age [2,3]. Organic ED shares many of the same risk factors as cardiovascular disease, including conditions such as diabetes mellitus, arterial hypertension, dyslipidemia, and the © 2009 International Society for Sexual Medicine
Vardenafil in Men with Underlying Conditions cluster of cardiovascular and metabolic factors that comprise the metabolic syndrome [4]. The link between ED, cardiovascular risk factors, and cardiovascular disease has been known since the early 1970s [5], and ED is now commonly considered a predictor of future cardiovascular disease [6,7]. ED prevalence is greater in patients with diabetes or other cardiovascular risk factors, compared with men without these risk factors [8,9]. Conversely, men with ED are also more likely to have cardiovascular risk factors [9]. In men with diabetes, ED prevalence varies from 34% to 90% [10,11], while ED prevalence in men with hypertension ranges from 26% to 68% [9,12]. Moreover, ED tends to be more severe in men with diabetes or hypertension than in men with ED without these underlying conditions [13,14]. Concurrent dyslipidemia is often seen in men with ED, and elevated levels of total and low-density lipoprotein cholesterol have been correlated with decreases in erectile function [15–17]. The use of oral phosphodiesterase type 5 (PDE-5) inhibitors, such as vardenafil, is currently recommended as first-line therapy for ED [18–20]. The efficacy and safety of vardenafil for the treatment of ED in the general population has previously been demonstrated [21–24]. Many men with ED will also be taking medications that are essential to control the short- and long-term complications of diabetes, hypertension, dyslipidemia, or any combination of the three [25]. Therefore, the current retrospective analysis sought to evaluate the efficacy and safety of vardenafil in men with ED and these associated underlying conditions, who may also be taking concomitant medications.
Methods
Study Design and Inclusion Criteria A retrospective analysis of randomized, doubleblind, placebo-controlled, flexible-dose clinical trials of vardenafil of at least 12 weeks’ duration was performed. Study participants were men aged ⱖ18 years in a stable heterosexual relationship, with ED as defined by the National Institutes of Health Consensus Statement [1] for at least 6 months. For all trials, patients started on vardenafil 10 mg with the option to titrate to 20 mg or 5 mg at week 4 of the study. In total, 15 published and unpublished flexible-dose trials of vardenafil were identified and screened for inclusion.
245
Main Outcome Measures The primary measures of efficacy were the erectile function domain of the International Index of Erectile Function (IIEF-EF) questionnaire and Sexual Encounter Profile questions 2 (SEP2: “Were you able to insert your penis into your partner’s vagina?”) and 3 (SEP3: “Did your erection last long enough for you to have successful intercourse?”), reported at baseline and at least once prior to, or at, week 12 of the study. Safety The safety population included all subjects taking at least one dose of vardenafil or placebo and having at least one postbaseline measurement reported. The incidence rates of treatmentemergent adverse events were analyzed overall and by subgroup. Statistical Analysis The intent-to-treat population (ITT) was defined as subjects who took at least one dose of vardenafil or placebo and who had baseline and any postbaseline efficacy data. The primary efficacy variables were evaluated at baseline and week 12. Comparisons of treatment effect were conducted with analysis of covariance, using the last observation carried forward approach to account for missing values. A common algorithm was applied to identify patients with associated underlying conditions and to allow for valid subgroup comparisons across studies. For diabetes, the definition was based on a medical history of diabetes {all Medical Dictionary for Regulatory Activities [MedDRA] [26] Preferred Terms [PT] covered by the MedDRA HighLevel Terms: “diabetes mellitus (including subtypes)” or treatment with antidiabetic medication at baseline [Anatomical Therapeutic Chemical (ATC)] [27] code A10}. Hypertension was defined by a medical history of hypertension (all MedDRA PT covered by the MedDRA Medical Entity: “hypertension”), blood pressure measurements (systolic blood pressure [SBP] ⱖ130 mm Hg or diastolic blood pressure [DBP] ⱖ85 mm Hg at baseline) or treatment with antihypertensive drugs at baseline (ATC codes C02, C03, C07, C08, and C09). Dyslipidemia was based on treatment with lipid-lowering medication at baseline (ATC code C10). Metabolic syndrome was defined using International Diabetes Federation (IDF) criteria [28] as central obesity (body mass index [BMI] >30 kg/m2 used as a J Sex Med 2010;7:244–255
246 surrogate for central obesity) and at least two of the following four conditions: history of hyperlipidemia based upon triglyceride levels ⱖ150 mg/dL (1.7 mmol/L) at baseline or treatment with lipidlowering drugs at baseline (ATC code C10); history of high-density lipoprotein cholesterol <40 mg/dL (1.03 mmol/L) at baseline; history of hypertension (SBP ⱖ 130 mm Hg or DBP ⱖ 85 mm Hg) at baseline, treatment with antihypertensive drugs at baseline or medical history of hypertension, as above; and fasting plasma glucose levels ⱖ100 mg/dL (5.6 mmol/L) and <125 mg/dL (6.9 mmol/L) at baseline or history of diabetes, as above. Patients were excluded from the metabolic syndrome subgroup if BMI data were missing. Retrospective analyses were performed to evaluate efficacy in different patient subgroups. The following subgroups were analyzed: men with diabetes and good, moderate, poor, or very poor glycemic control (glycosylated hemoglobin [HbA1c] levels ⱕ7%, >7–ⱕ8%, >8–ⱕ10%, >10%); men with diabetes treated with insulin, oral blood glucose-lowering drugs, both types of drug, or no antidiabetic drugs at all; men with hypertension treated with angiotensin-converting enzyme (ACE) inhibitors (monotherapy), beta blockers (monotherapy), angiotensin II receptor antagonists (ARB) (monotherapy), ACE inhibitors and beta blockers (combination therapy), ACE inhibitors and thiazide or thiazide-like diuretics (combination therapy), ARB and beta blockers (combination therapy), ARB and diuretics (combination therapy), calcium channel blockers (both mono- and combination therapy), other antihypertensive drugs or no antihypertensive drugs at all; men with dyslipidemia treated with statins (monotherapy), statins plus other lipid-lowering drugs (combination therapy), other lipid-lowering drugs (not including statins), or no lipid-lowering drugs at all; and men with metabolic syndrome. Results
Clinical Trials Of the 15 randomized, double-blind, placebocontrolled, flexible dose clinical trials of vardenafil for the treatment of ED in men with underlying conditions, 13 satisfied the inclusion criteria: study numbers 10473 [29], 10621 [30], 10769 [21], 10898 [31], 10940 [32], 11139 [33], 11334 [34], 11382, 12146, 12165 [25], 100519 [35], 100539 [36], and 100540 [37]. Patients with hypertension, dyslipidemia, and metabolic syndrome were found J Sex Med 2010;7:244–255
Eardley et al. in all trials. Patients with diabetes were present in all trials except 10473 and 100539, and glycemic control data were based on eight trials (10621, 10769, 10898, 10940, 11139, 12165, 100519, and 100540). The selected trials were conducted in Europe, United States, Latin America and AsiaPacific, and most were individually published between 2004 and 2008 (Table 1).
Study Population In total, 4,266 patients were valid for safety (vardenafil, N = 2,347; placebo, N = 1,919), and the ITT population comprised 4,143 men (vardenafil, N = 2,289; placebo, N = 1,854). The baseline characteristics of each individual trial are presented in Table 1. For the ITT population, least squares (LS) mean baseline IIEF-EF scores were 12.7 and 13.0 for men taking vardenafil or placebo, respectively, indicating moderate-to-severe ED; SEP2 scores were 45.0% (vardenafil) and 48.0% (placebo); and SEP3 scores were 15.0% (vardenafil) and 16.4% (placebo). A total of 1,011 patients had diabetes (vardenafil, N = 537; placebo, N = 474), 3,481 patients had hypertension (vardenafil, N = 1910; placebo, N = 1571), 1,055 patients had dyslipidemia (vardenafil, N = 567; placebo, N = 488), and 495 patients had metabolic syndrome (vardenafil, N = 283; placebo, N = 212). Treatment groups were well matched in terms of age, race, BMI, and prior use of PDE-5 inhibitors. Efficacy For the overall ITT population, vardenafil treatment resulted in statistically significant improvements from baseline in erectile function (IIEF-EF), rates of successful penetration (SEP2), and rates of successful intercourse (SEP3), when compared with placebo. After 12 weeks of vardenafil treatment, LS mean IIEF-EF scores increased from 12.7 at baseline to 22.4; LS mean SEP2 success rates increased from 45.0% to 78.5%; and LS mean SEP3 success rates increased from 15.0% to 64.8% (all P < 0.0001). In placebo-treated patients, corresponding LS mean IIEF-EF scores increased from 13.0 to 14.5; LS mean SEP2 success rates increased from 48.0% to 49.5%; and LS mean SEP3 success rates increased from 16.4% to 30.8%. In men with ED and diabetes, a significant improvement from baseline was observed in LS mean IIEF-EF scores, and SEP2 and SEP3 success rates at week 12 following treatment with vardenafil compared with placebo treatment. After 12 weeks of vardenafil treatment, LS mean IIEF-EF scores increased from 11.3 at baseline to 19.8; LS
588
121
254
151
343
385
225
10940 [32]
11139 [33]
11334 [34]
11382
12146
12165 [25]
100519 [35]
Canada, United States
Germany
Canada, United States
Belgium, France, Germany, Italy, Netherlands, South Africa, Spain United States
Turkey
Belgium, Denmark, Finland, France, Germany, UK
Spain
UK
Australia, Canada, France, Hong Kong, Italy, Mexico, Portugal, Spain, United States Canada, France, Italy, Spain, United States Austria, Germany, UK, Greece, France, Italy, Netherlands, Spain, Switzerland United States
Trial location
Men with ED and hypertension taking at least one antihypertensive medication Men with ED and diabetes
Men with ED and dyslipidemia on stable statin therapy Men with ED
Men with ED
Men with ED previously untreated with PDE-5 inhibitors Men with ED
Men with ED
Men with ED previously unresponsive to sildenafil therapy Men with ED
Men with ED and depression Men with ED
Men with ED as a result of traumatic spinal cord injury
Patient population
65
71
55
89
81
68
75
79
60
59
67
67
29
Aged 45–64 years, %
NI
NI
50.2
20.3
53.4
53.0
55.5
48.8
55.7
33.0
39.5
54.2
0
Mixed
NI
NI
44*
75.3
28.6
19.9
27.6
28.9
30.1
60.8
39.1
15.4
100.0
Organic
NI
NI
5.3
4.2
18.1
27.2
16.9
22.3
14.1
6.2
21.4
30.4
0
Psychogenic
0
0
78
69
63
60
45
41
67
77
60
65
79
Time since onset of ED ⱖ3 years, %
Vn Pl Vn Pl
Vn Pl Vn Pl
Vn Pl Vn Pl
12.6 Vn 13.5 Pl
13.2 13.5 13.9 14.5
12.0 Vn 12.4 Pl
15.0 15.4 13.3 13.3
9.5 Vn 9.5 Pl 15.3 Vn 15.6 Pl 13.6 Vn 13.3 Pl
9.6 Vn 10.0 Pl
12.7 13.1 12.6 13.1
11.6 Vn 12.1 Pl
Mean IIEF-EF score
Baseline
Vn Pl Vn Pl
Vn Pl Vn Pl
Vn Pl Vn Pl
Vn Pl Vn Pl
41.1 Vn 48.0 Pl
45.3 50.1 50.6 49.1
46.1 Vn 47.2 Pl
54.1 63.8 45.2 45.0
63.4 66.2 46.6 45.9
NI
30.3 Vn 33.9 Pl
40.7 42.5 38.7 43.5
35.6 Vn 41.0 Pl
Mean SEP2 success rate (%)
Vn Pl Vn Pl
Vn Pl Vn Pl
Vn Pl Vn Pl
14.1 Vn 20.1 Pl
17.8 19.6 18.5 18.2
17.4 Vn 16.0 Pl
11.0 Vn 8.8 Pl 9.5 Vn 12.4 Pl
22.5 25.1 18.9 20.9
NI
10.5 Vn 12.4 Pl
16.4 15.0 14.5 18.1
9.6 Vn 9.8 Pl
Mean SEP3 success rate (%)
*Total percentage does not equal 100% because of “no information” indicated for one patient. Missing data not shown. ED = erectile dysfunction; IIEF-EF = erectile function domain of the International Index of Erectile Function; ITT = intent-to-treat; NI = no information; PDE-5 = phosphodiesterase type 5; Pl = placebo group; SEP = Sexual Encounter Profile question; Vn = vardenafil group.
303
454
10898 [31]
100540 [37]
309
10769 [21]
354
260
10621 [30]
100539 [36]
396
ITT population (N)
ED etiology, %
Double-blind, placebo-controlled trials of flexible-dose vardenafil selected for analysis
10473 [29]
Study
Table 1
Vardenafil in Men with Underlying Conditions 247
J Sex Med 2010;7:244–255
248
Eardley et al. Placebo
Vardenafil
Baseline
n= Men with ED and diabetes
460 524
Good (HbA1c <7%)
127 160
Moderate (HbA1c >7 to <8%)
119 134
Poor (HbA1c >8 to <10%)
95 101
Very poor (HbA1c >10%)
24 24
No drugs used
28 41
Insulin and analogs + other drugs
198 214
Oral blood glucose-lowering drugs + other drugs
188 223
13.4
Both + other drugs
42 45
13.5
Level of glycemic control
14.0 19.8* 12.7 19.9* 13.8 19.7* ** 13.4 17.8* 14.5 20.8* 11.8 21.1* 14.2 19.6*
19.6*
18.6*
0
5
10
15
20
25
LS mean IIEF-EF score at week 12 LOCF
Figure 1 LS mean IIEF-EF scores in patients with ED and diabetes, stratified by level of glycemic control and type of antidiabetic medication, at baseline and following 12 weeks of treatment with vardenafil or placebo. *P < 0.0001 for vardenafil vs. placebo, **P = 0.2421 for comparison of glycemic control subgroups, 䉫P = 0.1972 for comparison of antidiabetic medication subgroups. ED = erectile dysfunction; HbA1c = glycosylated hemoglobin; IIEF-EF = erectile function domain of the International Index of Erectile Function; LOCF = last observation carried forward; LS = least squares.
mean SEP2 success rates increased from 35.2% to 67.7%; and LS mean SEP3 success rates increased from 10.8% to 52.3% (all P < 0.0001). This improvement with vardenafil was irrespective of the level of glycemic control (IIEF-EF: P = 0.2421, SEP2: P = 0.6952, SEP3: P = 0.4121 for between-group comparison of glycemic control subgroups), or use of concomitant antidiabetic medications (IIEF-EF: P = 0.1972, SEP2: P = 0.0607, SEP3: P = 0.0986 for comparison of all antidiabetic medications). Placebo-treated patients showed increases from baseline of 12.1 to 14.0 in LS mean IIEF-EF scores; 42.9% to 45.9% in LS mean SEP2 success rates; and 14.7% to 27.5% in LS mean SEP3 success rates (Figures 1 and 2; SEP2 data not shown). In men with ED and hypertension taking vardenafil, compared with those taking placebo, a similar significant improvement from baseline was observed in LS mean IIEF-EF scores, and SEP2 and SEP3 success rates at week 12, irrespective of the use of concomitant antihypertensive medications (IIEF-EF: P = 0.1651, SEP2: P = 0.8572, SEP3: P = 0.7957 for comparison of all antihypertensive medications) (Figures 3 and 4; SEP2 data not shown). After 12 weeks of vardenafil treatJ Sex Med 2010;7:244–255
ment, LS mean IIEF-EF scores were 22.2 (12.6 at baseline); LS mean SEP2 success rates were 77.0% (44.1% at baseline); and LS mean SEP3 success rates were 63.6% (14.5% at baseline) (all P < 0.0001). Corresponding increases in placebotreated patients were: LS mean IIEF-EF scores, 14.3 from 13.0 at baseline; LS mean SEP2 success rates, 49.0% from 47.2% at baseline; LS mean SEP3 success rates, 30.8% from 16.3% at baseline. In men with ED and dyslipidemia, vardenafil use was associated with a significant improvement from baseline in LS mean IIEF-EF scores, and SEP2 and SEP3 success rates at week 12, compared with placebo; LS mean IIEF-EF scores increased from 12.2 at baseline to 21.2, LS mean SEP2 success rates increased from 44.3% to 73.8%, and LS mean SEP3 success rates increased from 14.6% to 58.1% (all P < 0.0001). This improvement with vardenafil was achieved regardless of patients’ concomitant use of lipid-lowering drugs (IIEF-EF: P = 0.9169, SEP2: P = 0.9343, SEP3: P = 0.3536 for comparison of all lipidlowering medications). In patients taking placebo, LS mean IIEF-EF scores increased from 12.8 to 13.7; LS mean SEP2 success rates decreased from 46.7% to 45.6%; and LS mean SEP3 success rates
249
Vardenafil in Men with Underlying Conditions Placebo
Vardenafil
Baseline
n= Men with ED and diabetes
453 486
Good (HbA1c <7%)
121 147
Moderate (HbA1c >7 to <8%)
114 121
Poor (HbA1c >8 to <10%)
96 91
Very poor (HbA1c >10%)
24 21
No drugs used
28 39
Insulin and analogs + other drugs
198 202
Oral blood glucose-lowering drugs + other drugs
182 202
26.8
Both + other drugs
41 42
26.2
Level of glycemic control
27.5 52.3* 23.5 52.8* 26.1 48.4* ** 24.5 45.3* 32.4 48.9* 18.4 59.5* 25.0 48.7*
51.9*
40.4*
0
10
20
30
40
50
60
LS mean SEP3 success rate at week 12 LOCF (%)
Figure 2 LS mean SEP3 success rates in patients with ED and diabetes, stratified by level of glycemic control and type of antidiabetic medication, at baseline and following 12 weeks of treatment with vardenafil or placebo. *P < 0.0001 for vardenafil vs. placebo, **P = 0.4121 for comparison of glycemic control subgroups, 䉫P = 0.0986 for comparison of antidiabetic medication subgroups. ED = erectile dysfunction; HbA1c = glycosylated hemoglobin; LOCF = last observation carried forward; LS = least squares; SEP = Sexual Encounter Profile question.
increased from 15.7% to 26.9% (Figures 5 and 6; SEP2 data not shown). Vardenafil therapy was also associated with a significant improvement from baseline in LS mean IIEF-EF scores, and SEP2 and SEP3 success rates at week 12 in patients with ED and metabolic syndrome (defined according to IDF criteria), compared with placebo therapy. After 12 weeks of vardenafil treatment, LS mean IIEF-EF scores increased to 21.4 (from 10.6 at baseline); LS mean SEP2 success rates increased to 70.7% (from 42.1% at baseline); and LS mean SEP3 success rates increased to 54.1% (from 16.5% at baseline) (all P < 0.0001). Patients taking placebo showed corresponding increases in LS mean IIEF-EF scores from 11.6 to 13.9; LS mean SEP2 success rates from 39.7% to 47.8%; and LS mean SEP3 success rates from 14.8% to 28.9%.
Safety In general, vardenafil was well tolerated in men with coexisting diabetes, hypertension, dyslipidemia or metabolic syndrome, with 61.4% of men reporting no adverse events. The most common treatment-related adverse events were headache (11.0%), flushing (6.7%), and nasal congestion (3.0%); these were mild to moderate across all
studies and consistent with the pharmacology of PDE-5 inhibition. For the overall safety population, the incidence of treatment-emergent adverse events (38.6%) was comparable with other studies of vardenafil therapy in men with ED [21–23,29]. The incidence of treatment-emergent adverse events across all concomitant medication subgroups ranged from 22.0% to 41.7%, which was comparable with that seen in the overall safety population (Table 2). Discussion
This pooled retrospective analysis demonstrated the favorable safety and efficacy of vardenafil in men with ED and underlying conditions such as diabetes, hypertension, dyslipidemia, and metabolic syndrome. Vardenafil promoted significant improvements in erectile function and rates of penetration and successful intercourse, confirming the findings of previous studies of this PDE-5 inhibitor in men with ED and associated underlying conditions [25,36,37]. Men with ED and diabetes are a notoriously difficult-to-treat population. Studies have shown that ED is more severe and resistant to therapy in men with diabetes, than in men without this conJ Sex Med 2010;7:244–255
250
Eardley et al. Placebo
Baseline
Vardenafil
n= 14.3
Men with ED and hypertension
1537 1887
No drugs used
756 941
14.0
ACE inhibitors only
177 164
14.1
B only
75 92
13.7
ARB only
55 103
15.3
C monotherapy or + other drugs
95 145
ACE inhibitors + B + other drugs
95 110
14.0
ACE inhibitors + D
81 93
14.0
ARB + B
48 54
13.9
ARB + D + other drugs
51 67
Other drugs
104 118
22.2*
22.6*
21.8*
22.8*
24.1* 14.4 20.7* ** 20.2*
21.3*
21.0* 15.2 21.5* 14.2 21.9*
0
5
10
15
20
25
LS mean IIEF-EF score at week 12 LOCF
Figure 3 LS mean IIEF-EF scores in patients with ED and hypertension, stratified by type of antihypertensive medication, at baseline and following 12 weeks of treatment with vardenafil or placebo. *P < 0.0001 for vardenafil vs. placebo, **P = 0.1651 for comparison of antihypertensive medication subgroups. ACE = angiotensin-converting enzyme; ARB = angiotensin II receptor antagonists; B = beta blockers; C = calcium channel antagonists; D = thiazide or thiazide-like diuretics; ED = erectile dysfunction; IIEF-EF = erectile function domain of the International Index of Erectile Function; LOCF = last observation carried forward; LS = least squares.
dition [13,14]. Biochemical changes, neuropathy, angiopathy, and other vascular complications that are a consequence of poorly controlled hyperglycemia can all contribute to the neurogenic impairment and endothelial dysfunction that leads to ED [38,39]. Despite this poor prognosis, the current analysis showed that vardenafil was efficacious for the treatment of ED in men with diabetes, regardless of their level of glycemic control or use of concomitant antidiabetic medication. These findings are consistent with clinical studies of vardenafil and other PDE-5 inhibitors in this population [37,40–42], and a recent meta-analysis of PDE-5 inhibitor use in men with diabetes [43]. It has previously been shown that vardenafil is effective in men with ED and hypertension who may be taking multiple antihypertensive drugs [36], and the current study confirms those findings. Because of their pharmacology, certain antihypertensive medications, chiefly nonselective beta blockers and thiazide diuretics, can cause and/or J Sex Med 2010;7:244–255
exacerbate ED [44]. However, no significant decrease in the efficacy of vardenafil was seen in the subgroups of men taking these particular antihypertensive medications in the present analysis. There was no significant change in the efficacy of vardenafil in the presence of concomitant medications for the treatment of dyslipidemia (statins monotherapy, combination therapy with statins or any other lipid-lowering medication). As well as inhibiting cholesterol biosynthesis, statins can activate several other signal transduction pathways to ultimately improve endothelial function [45], and thus may show synergistic effects when used with PDE-5 inhibitors. However, in our present study, no significant difference in IIEF-EF scores, or SEP2 and SEP3 success rates, was observed between lipid-lowering medication subgroups. Vardenafil, in common with all PDE-5 inhibitors, is contraindicated in patients taking nitrates, and is also not recommended in patients taking class Ia or III antiarrhythmic agents. Caution is
251
Vardenafil in Men with Underlying Conditions Placebo
Vardenafil
Baseline
n= 30.8
Men with ED and hypertension
1424 1525
No drugs used
686 717
ACE inhibitors only
171 144
31.4
B only
72 81
30.9
ARB only
55 94
C monotherapy or + other drugs
83 105
25.8
ACE inhibitors + B + other drugs
95 97
25.6
ACE inhibitors + D
77 74
ARB + B
44 51
ARB + D + other drugs
48 60
Other drugs
93 102
63.6* 29.3 64.4*
60.6*
69.3* 36.8 67.1*
57.8* ** 55.0* 26.6 57.8* 20.0 57.7* 28.0 58.4* 29.0 60.3*
0
10
20
30
40
50
60
70
LS mean SEP3 success rate at week 12 LOCF (%)
Figure 4 LS mean SEP3 success rates in patients with ED and hypertension, stratified by type of antihypertensive medication, at baseline and following 12 weeks of treatment with vardenafil or placebo. *P < 0.0001 for vardenafil vs. placebo, **P = 0.7957 for comparison of antihypertensive medication subgroups. ACE = angiotensin-converting enzyme; ARB = angiotensin II receptor antagonists; B = beta blockers; C = calcium channel antagonists; D = thiazide or thiazide-like diuretics; ED = erectile dysfunction; LOCF = last observation carried forward; LS = least squares; SEP = Sexual Encounter Profile question.
also advised in the presence of alpha blockers; potent cytochrome P450, family 3, subfamily A (CYP3A) inhibitors, such as azole antifungal medication; antiretroviral protease inhibitors; or macrolide antibiotics [45].
Vardenafil has shown an excellent tolerability profile in numerous clinical trials [21–23]. In the present analysis of men with ED and underlying conditions, the incidence and type of treatmentrelated adverse events associated with vardenafil Placebo
Vardenafil
Baseline
n= Men with ED and dyslipidemia
484 559
Statins monotherapy
358 427
Statins + other drugs
64 71
Other drugs
57 56
13.7 21.2* 13.8 21.6* 13.5
**
20.7* 12.2 19.7*
0
5
10
15
20
25
LS mean IIEF-EF score at week 12 LOCF
Figure 5 LS mean IIEF-EF scores in patients with ED and dyslipidemia, stratified by type of lipid-lowering medication, at baseline and following 12 weeks of treatment with vardenafil or placebo. *P < 0.0001 for vardenafil vs. placebo, **P = 0.9169 for comparison of lipid-lowering medication subgroups. ED = erectile dysfunction; IIEF-EF = erectile function domain of the International Index of Erectile Function; LOCF = last observation carried forward; LS = least squares.
J Sex Med 2010;7:244–255
252
Eardley et al. Placebo
Vardenafil
Baseline
n= Men with ED and dyslipidemia
455 474
Statins monotherapy
334 352
28.6
Statins + other drugs
64 68
29.3
Other drugs
52 50
26.9 58.1*
61.4*
**
55.3* 22.4 47.7*
0
10
20
30
40
50
60
70
LS mean SEP3 success rate at week 12 LOCF (%)
Figure 6 LS mean SEP3 success rates in patients with ED and dyslipidemia, stratified by type of lipid-lowering medication, at baseline and following 12 weeks of treatment with vardenafil or placebo. *P < 0.0001 for vardenafil vs. placebo, **P = 0.3536 for comparison of lipid-lowering medication subgroups. ED = erectile dysfunction; LOCF = last observation carried forward; LS = least squares; SEP = Sexual Encounter Profile question.
therapy were comparable with findings from previous studies in the general population of men with ED. Given the close association between ED, underlying conditions and increasing age, the safety and tolerability of vardenafil is of particular importance to older patients who are likely to be taking multiple medications. A study of 243 men aged 65 years or older showed that 71% took at least one prescription medication per week, and 19% took at least five [46]. Crucially, the current study found that the safety profile of vardenafil in men taking concomitant medications was comTable 2
parable with that seen in men not taking medication. This provides further reassurance that vardenafil can be used in the presence of a range of medications for the treatment of underlying conditions, without the risk of adverse drug interactions. There are some potential limitations to this study. As patient subgroups were identified post hoc, there is the possibility of mislabeling and subsequent assignment of patients to an incorrect subgroup. For example, inclusion of a patient in the hypertension subgroup could have been based on
Incidence of treatment-emergent adverse events associated with each concomitant medication subgroup Placebo
Overall safety population Diabetes mellitus population No drugs used Insulin and analogs + other drugs Oral blood glucose-lowering drugs + other drugs Both + other drugs Arterial hypertension population No drugs used ACE inhibitors (monotherapy) Beta blockers (monotherapy) ARB (monotherapy) Calcium channel antagonists (monotherapy + other drugs) ACE inhibitors + beta blockers + other drugs ACE inhibitors + thiazide or thiazide-like diuretics + other drugs ARB + beta blockers + other drugs ARB + thiazide or thiazide-like diuretics + other drugs Other drugs Dyslipidemia population Statins (monotherapy) Statins + other drugs Other drugs Missing data not shown. ACE = angiotensin-converting enzyme; ARB = angiotensin II receptor antagonists.
J Sex Med 2010;7:244–255
Vardenafil
n/N
(%)
n/N
(%)
453/1,919 115/486 8/30 50/211 44/195 12/46 386/1,627 197/795 38/196 17/82 10/56 22/102 26/99 24/84 12/49 8/55 32/109 131/496 96/367 18/65 15/59
(23.6) (23.7) (26.7) (23.7) (22.6) (26.1) (23.7) (24.8) (19.4) (20.7) (17.9) (21.6) (26.3) (28.6) (24.5) (14.5) (29.4) (26.4) (26.2) (27.7) (25.4)
905/2,347 185/553 12/45 73/228 89/229 11/50 737/1,964 405/968 55/177 24/93 33/108 59/153 45/116 32/97 17/57 27/73 40/122 223/579 175/444 30/72 14/58
(38.6) (33.5) (26.7) (32.0) (38.9) (22.0) (37.5) (41.8) (31.1) (25.8) (30.6) (38.6) (38.8) (33.0) (29.8) (37.0) (32.8) (38.5) (39.4) (41.7) (24.1)
253
Vardenafil in Men with Underlying Conditions an isolated elevated blood pressure measurement, with the patient not necessarily meeting any other diagnostic criteria for hypertension. ACE inhibitors were the single most commonly prescribed concomitant medication used by men with ED and hypertension in this study, but they are also routinely used to treat congestive heart failure and diabetic nephropathy [47]. Therefore, a small number of patients may have been assigned to the hypertension subgroup, based solely on the use of these drugs, when inclusion in the diabetic subgroup alone may have been more appropriate. It would have been desirable to correlate efficacy data with a validated comorbidity index, to assess any potential effects because of number and/or severity of underlying conditions. However, this was not possible, as a comprehensive retrospective medical history could not be retrieved for all subjects.
Statement of Authorship
Conclusions
Category 3
Vardenafil treatment significantly improved erectile function and rates of penetration and successful intercourse in this large pool of men with ED and associated diabetes, hypertension, dyslipidemia, and/or metabolic syndrome. Importantly, the concomitant use of medications for these underlying conditions was not associated with any noteworthy changes in the efficacy or safety of vardenafil. This analysis adds to the considerable body of evidence showing the favorable efficacy and tolerability profile of vardenafil in men with ED and underlying conditions, providing clinicians with the confidence to prescribe vardenafil as a first-line treatment for ED in this patient group. Corresponding Author: Ian Eardley, MA, MChir, FRCS (Urol), FEBU, Pyrah Department of Urology, St. James’s University Hospital, Beckett Street, Leeds, LS9 7TF, UK. Tel: 44 113 2066994; Fax: 44 113 2064920; E-mail: [email protected] Conflict of Interest: Ian Eardley has acted as a paid consultant, investigator, and speaker for Bayer Schering, Boehringer Ingelheim, Lilly and Pfizer; Jay C. Lee has acted as a paid consultant, clinical trial investigator, and speaker for Bayer Schering; Ridwan Shabsigh and Mario Maggi have acted as speakers for Bayer Schering; John Dean has acted as a paid consultant or clinical trial investigator for, or has received hospitality from, Auxilium, Bayer Schering, Boehringer Ingelheim, Ipsen, Johnson & Johnson, Lilly, Pfizer, Plethora and ProStrakan; and Dieter Neuser and Christiane Norenberg are both employees of Bayer Schering.
Category 1 (a) Conception and Design Ian Eardley; Dieter Neuser; Christiane Norenberg (b) Acquisition of Data Dieter Neuser; Christiane Norenberg (c) Analysis and Interpretation of Data Ian Eardley; Jay C. Lee; Ridwan Shabsigh; John Dean; Mario Maggi; Dieter Neuser; Christiane Norenberg
Category 2 (a) Drafting the Article Ian Eardley; Jay C. Lee; Ridwan Shabsigh; John Dean; Mario Maggi; Dieter Neuser; Christiane Norenberg (b) Revising It for Intellectual Content Ian Eardley; Jay C. Lee; Ridwan Shabsigh; John Dean; Mario Maggi; Dieter Neuser; Christiane Norenberg
(a) Final Approval of the Completed Article Ian Eardley; Jay C. Lee; Ridwan Shabsigh; John Dean; Mario Maggi; Dieter Neuser; Christiane Norenberg References
1 NIH Consensus Conference. Impotence. NIH consensus development panel on impotence. JAMA 1993;270:83–90. 2 Kubin M, Wagner G, Fugl-Meyer AR. Epidemiology of erectile dysfunction. Int J Impot Res 2003; 15:63–71. 3 Parazzini F, Menchini Fabris F, Bortolotti A, Calabro A, Chatenoud L, Colli E, Landoni M, Lavezzari M, Turchi P, Sessa A, Mirone V. Frequency and determinants of erectile dysfunction in Italy. Eur Urol 2000;37:43–9. 4 Corona G, Mannucci E, Forti G, Maggi M. Hypogonadism, ED, metabolic syndrome and obesity: A pathological link supporting cardiovascular diseases. Int J Androl 2009 Feb 10 [Epub ahead of print] doi: 10.1111/j.1365-2605.2008.00951.x. 5 Gaskell P. The importance of penile blood pressure in cases of impotence. Can Med Assoc J 1971; 105:1047–51. 6 Inman BA, Sauver JL, Jacobson DJ, McGree ME, Nehra A, Lieber MM, Roger VL, Jacobsen SJ. A population-based, longitudinal study of erectile dysfunction and future coronary artery disease. Mayo Clin Proc 2009;84:108–13. 7 Jackson G, Rosen RC, Kloner RA, Kostis JB. The second Princeton consensus on sexual dysfunction and cardiac risk: New guidelines for sexual medicine. J Sex Med 2006;3:28–36. discussion 36. J Sex Med 2010;7:244–255
254 8 Eardley I, Fisher W, Rosen RC, Niederberger C, Nadel A, Sand M. The multinational Men’s Attitudes to Life Events and Sexuality Study: The influence of diabetes on self-reported erectile function, attitudes and treatment-seeking patterns in men with erectile dysfunction. Int J Clin Pract 2007; 61:1446–53. 9 Rosen RC, Fisher WA, Eardley I, Niederberger C, Nadel A, Sand M. The multinational Men’s Attitudes to Life Events and Sexuality (MALES) study: I. Prevalence of erectile dysfunction and related health concerns in the general population. Curr Med Res Opin 2004;20:607–17. 10 De Berardis G, Franciosi M, Belfiglio M, Di Nardo B, Greenfield S, Kaplan SH, Pellegrini F, Sacco M, Tognoni G, Valentini M, Nicolucci A. Erectile dysfunction and quality of life in type 2 diabetic patients: A serious problem too often overlooked. Diabetes Care 2002;25:284–91. 11 Sasaki H, Yamasaki H, Ogawa K, Nanjo K, Kawamori R, Iwamoto Y, Katayama S, Shirai M. Prevalence and risk factors for erectile dysfunction in Japanese diabetics. Diabetes Res Clin Pract 2005;70:81–9. 12 Burchardt M, Burchardt T, Baer L, Kiss AJ, Pawar RV, Shabsigh A, de la Taille A, Hayek OR, Shabsigh R. Hypertension is associated with severe erectile dysfunction. J Urol 2000;164:1188–91. 13 Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. Impotence and its medical and psychosocial correlates: Results of the Massachusetts Male Aging Study. J Urol 1994;151:54–61. 14 Penson DF, Latini DM, Lubeck DP, Wallace KL, Henning JM, Lue TF. Do impotent men with diabetes have more severe erectile dysfunction and worse quality of life than the general population of impotent patients? Results from the Exploratory Comprehensive Evaluation of Erectile Dysfunction (ExCEED) database. Diabetes Care 2003;26: 1093–9. 15 Walczak MK, Lokhandwala N, Hodge MB, Guay AT. Prevalence of cardiovascular risk factors in erectile dysfunction. J Gend Specif Med 2002;5:19–24. 16 Nikoobakht M, Nasseh H, Pourkasmaee M. The relationship between lipid profile and erectile dysfunction. Int J Impot Res 2005;17:523–6. 17 Ponholzer A, Temml C, Rauchenwald M, Madersbacher S. Vascular risk factors and erectile dysfunction in a cohort of healthy men. Int J Impot Res 2006;18:489–93. 18 Montague DK, Jarow JP, Broderick GA, Dmochowski RR, Heaton JP, Lue TF, Milbank AJ, Nehra A, Sharlip ID. Chapter 1: The management of erectile dysfunction: An AUA update. J Urol 2005;174:230–9. 19 Wespes E, Amar E, Hatzichristou D, Hatzimouratidis K, Montorsi F, Pryor J, Vardi Y. EAU guidelines on erectile dysfunction: An update. Eur Urol 2006;49:806–15. J Sex Med 2010;7:244–255
Eardley et al. 20 Sadovsky R, Brock GB, Gutkin SW, Sorsaburu S. Toward a new “EPOCH”: Optimising treatment outcomes with phosphodiesterase type 5 inhibitors for erectile dysfunction. Int J Clin Pract 2009;63: 1214–30. 21 Hatzichristou D, Montorsi F, Buvat J, Laferriere N, Bandel TJ, Porst H. The efficacy and safety of flexible-dose vardenafil (Levitra®) in a broad population of European men. Eur Urol 2004;45:634–41. discussion 641. 22 Hellstrom WJ, Gittelman M, Karlin G, Segerson T, Thibonnier M, Taylor T, Padma-Nathan H. Vardenafil for treatment of men with erectile dysfunction: Efficacy and safety in a randomized, double-blind, placebo-controlled trial. J Androl 2002;23:763–71. 23 Stief C, Porst H, Saenz De Tejada I, Ulbrich E, Beneke M. Sustained efficacy and tolerability with vardenafil over 2 years of treatment in men with erectile dysfunction. Int J Clin Pract 2004;58:230–9. 24 Jannini EA, Isidori AM, Gravina GL, Aversa A, Balercia G, Bocchio M, Boscaro M, Carani C, Corona G, Fabbri A, Foresta C, Forti G, Francavilla S, Granata AR, Maggi M, Mansani R, Palego P, Spera G, Vetri M, Lenzi A. The ENDOTRIAL study: A spontaneous, open-label, randomized, multicenter, crossover study on the efficacy of sildenafil, tadalafil, and vardenafil in the treatment of erectile dysfunction. J Sex Med 2009;6:2547–60. 25 Miner M, Gilderman L, Bailen J, Cook D, Dawson K, Stanislaus M, Beresford E, Barnes A. Vardenafil in men with stable statin therapy and dyslipidemia. J Sex Med 2008;5:1455–67. 26 Welcome to MedDRA and the MSSO. March 1, 2009. Available at: http://www.meddramsso.com/ MSSOWeb/index.htm (accessed April 22, 2009). 27 Complete ATC/DDD Index 2009. April 15, 2009. Available at: http://www.whocc.no/atcddd/ (accessed April 22, 2009). 28 IDF Writing Group. The IDF consensus worldwide definition of the metabolic syndrome. Brussels: IDF Communications; 2006:24. 29 Giuliano F, Rubio-Aurioles E, Kennelly M, Montorsi F, Kim ED, Finkbeiner AE, Pommerville PJ, Colopy MW, Wilkins HJ, Wachs BH. Efficacy and safety of vardenafil in men with erectile dysfunction caused by spinal cord injury. Neurology 2006;66: 210–6. 30 Rosen R, Shabsigh R, Berber M, Assalian P, Menza M, Rodriguez-Vela L, Porto R, Bangerter K, Seger M, Montorsi F. Efficacy and tolerability of vardenafil in men with mild depression and erectile dysfunction: The depression-related improvement with vardenafil for erectile response study. Am J Psychiatry 2006;163:79–87. 31 Carson CC, Hatzichristou DG, Carrier S, Lording D, Lyngdorf P, Aliotta P, Auerbach S, Murdock M, Wilkins HJ, McBride TA, Colopy MW. Erectile response with vardenafil in sildenafil nonresponders:
Vardenafil in Men with Underlying Conditions
32
33
34
35
36
37
A multicentre, double-blind, 12-week, flexible-dose, placebo-controlled erectile dysfunction clinical trial. BJU Int 2004;94:1301–9. Ralph D, Eardley I, Kell P, Dean J, Hackett G, Collins O, Edwards D. Improvement in erectile function on vardenafil treatment correlates with treatment satisfaction in both patients and their partners. BJU Int 2007;100:130–6. Martin-Morales A, Meijide F, Garcia N, Artes M, Munoz A. Efficacy of vardenafil and influence on self-esteem and self-confidence in patients with severe erectile dysfunction. J Sex Med 2007;4:440–7. Edwards D, Hackett G, Collins O, Curram J. Vardenafil improves sexual function and treatment satisfaction in couples affected by erectile dysfunction (ED): A randomized, double-blind, placebocontrolled trial in PDE5 inhibitor-naive men with ED and their partners. J Sex Med 2006;3:1028–36. Fisher WA, Rosen RC, Mollen M, Brock G, Karlin G, Pommerville P, Goldstein I, Bangerter K, Bandel TJ, Derogatis LR, Sand M. Improving the sexual quality of life of couples affected by erectile dysfunction: A double-blind, randomized, placebocontrolled trial of vardenafil. J Sex Med 2005;2: 699–708. van Ahlen H, Wahle K, Kupper W, Yassin A, Reblin T, Neureither M. Safety and efficacy of vardenafil, a selective phosphodiesterase 5 inhibitor, in patients with erectile dysfunction and arterial hypertension treated with multiple antihypertensives. J Sex Med 2005;2:856–64. Goldstein I, Young JM, Fischer J, Bangerter K, Segerson T, Taylor T. Vardenafil, a new phosphodiesterase type 5 inhibitor, in the treatment of erectile dysfunction in men with diabetes: A multicenter double-blind placebo-controlled fixed-dose study. Diabetes Care 2003;26:777–83.
255 38 Malavige LS, Levy JC. Erectile dysfunction in diabetes mellitus. J Sex Med 2009;6:1232–47. 39 Saenz de Tejada I, Goldstein I, Azadzoi K, Krane RJ, Cohen RA. Impaired neurogenic and endotheliummediated relaxation of penile smooth muscle from diabetic men with impotence. N Engl J Med 1989; 320:1025–30. 40 Fonseca V, Seftel A, Denne J, Fredlund P. Impact of diabetes mellitus on the severity of erectile dysfunction and response to treatment: Analysis of data from tadalafil clinical trials. Diabetologia 2004;47: 1914–23. 41 Rendell MS, Rajfer J, Wicker PA, Smith MD. Sildenafil for treatment of erectile dysfunction in men with diabetes: A randomized controlled trial. Sildenafil Diabetes Study Group. JAMA 1999;281: 421–6. 42 Ziegler D, Merfort F, van Ahlen H, Yassin A, Reblin T, Neureither M. Efficacy and safety of flexibledose vardenafil in men with type 1 diabetes and erectile dysfunction. J Sex Med 2006;3:883–91. 43 Vardi M, Nini A. Phosphodiesterase inhibitors for erectile dysfunction in patients with diabetes mellitus. Cochrane Database Syst Rev 2007:CD002187. 44 Weiss RJ. Effects of antihypertensive agents on sexual function. Am Fam Physician 1991;44:2075– 82. 45 Corona G, Razzoli E, Forti G, Maggi M. The use of phosphodiesterase 5 inhibitors with concomitant medications. J Endocrinol Invest 2008;31:799–808. 46 Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA. Recent patterns of medication use in the ambulatory adult population of the United States: The Slone survey. JAMA 2002;287:337–44. 47 Wong J, Patel RA, Kowey PR. The clinical use of angiotensin-converting enzyme inhibitors. Prog Cardiovasc Dis 2004;47:116–30.
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Vardenafil Improves Erectile Function in Men with Erectile Dysfunction and Associated Underlying Conditions, Irrespective of the Use of Concomitant Medications jsm_1547
244..255
Ian Eardley, MA, MChir, FRCS (Urol), FEBU,* Jay C. Lee, MD, FRCSC,† Ridwan Shabsigh, MD,‡ John Dean, MBBS, FRCGP,§ Mario Maggi, MD,¶ Dieter Neuser, MD, PhD,** and Christiane Norenberg, Dipl. Stat** *Pyrah Department of Urology, St. James’s University Hospital, Leeds, UK; †Division of Urology, University of Calgary, Calgary, Alberta, Canada; ‡Division of Urology, Maimonides Medical Center, Columbia University, Brooklyn, NY, USA; § St. Peter’s Andrology Centre, London, UK; ¶Andrology Unit, Department of Clinical Pathophysiology, University of Florence, Florence, Italy; **Bayer Healthcare AG, Wuppertal, Germany DOI: 10.1111/j.1743-6109.2009.01547.x
ABSTRACT
Introduction. Men with erectile dysfunction (ED) are also likely to have associated underlying conditions. Aim. This retrospective analysis evaluated the efficacy and safety of vardenafil in men with ED and underlying conditions, including those taking concomitant medications. Methods. A total of 13 randomized, double-blind, placebo-controlled clinical studies were included. Vardenafil was administered at a starting dose of 10 mg, adjustable to 5 or 20 mg after 4 weeks. Efficacy analyses were performed on the intent-to-treat (ITT) population, using a last observation carried forward approach. Efficacy was assessed for subgroups of patients with diabetes, hypertension, dyslipidemia, or metabolic syndrome (as defined by International Diabetes Federation criteria). Incidence rates of treatment-emergent adverse events were analyzed overall and by subgroup for patients in the safety population. Main Outcome Measures. Primary efficacy measures were the erectile function domain of the International Index of Erectile Function (IIEF-EF), and Sexual Encounter Profile questions 2 and 3 (SEP2, SEP3). Results. In total, 4,326 patients were randomized to treatment; the ITT population included 4,143 patients, with 4,266 patients valid for safety. At 12 weeks, vardenafil therapy was associated with statistically significant improvements from baseline in IIEF-EF scores, and SEP2 and SEP3 success rates, including patients with ED and diabetes, hypertension, dyslipidemia, or metabolic syndrome. These improvements were irrespective of level of glycemic control, or use of concomitant medications for the treatment of diabetes, hypertension, or dyslipidemia. Across all subgroups, the number and type of treatment-emergent adverse events were consistent with results from previous studies of phosphodiesterase type 5 inhibitors in men with ED and underlying conditions. Conclusions. Vardenafil demonstrated favorable efficacy and tolerability in this large pool of patients with ED and underlying conditions. Importantly, the use of concomitant medications was not associated with any noteworthy changes in the efficacy or safety profile of vardenafil. Eardley I, Lee JC, Shabsigh R, Dean J, Maggi M, Neuser D, and Norenberg C. Vardenafil improves erectile function in men with erectile dysfunction and associated underlying conditions, irrespective of the use of concomitant medications. J Sex Med 2010;7:244–255. Key Words. Vardenafil; Erectile Dysfunction; Phosphodiesterase Type 5 Inhibitor; Underlying Conditions; Concomitant Medications; Retrospective Analysis
Introduction
E
rectile dysfunction (ED), the “persistent inability to achieve and/or maintain a penile erection sufficient for satisfactory sexual perfor-
J Sex Med 2010;7:244–255
mance” [1], is a common condition that increases in prevalence with age [2,3]. Organic ED shares many of the same risk factors as cardiovascular disease, including conditions such as diabetes mellitus, arterial hypertension, dyslipidemia, and the © 2009 International Society for Sexual Medicine
Vardenafil in Men with Underlying Conditions cluster of cardiovascular and metabolic factors that comprise the metabolic syndrome [4]. The link between ED, cardiovascular risk factors, and cardiovascular disease has been known since the early 1970s [5], and ED is now commonly considered a predictor of future cardiovascular disease [6,7]. ED prevalence is greater in patients with diabetes or other cardiovascular risk factors, compared with men without these risk factors [8,9]. Conversely, men with ED are also more likely to have cardiovascular risk factors [9]. In men with diabetes, ED prevalence varies from 34% to 90% [10,11], while ED prevalence in men with hypertension ranges from 26% to 68% [9,12]. Moreover, ED tends to be more severe in men with diabetes or hypertension than in men with ED without these underlying conditions [13,14]. Concurrent dyslipidemia is often seen in men with ED, and elevated levels of total and low-density lipoprotein cholesterol have been correlated with decreases in erectile function [15–17]. The use of oral phosphodiesterase type 5 (PDE-5) inhibitors, such as vardenafil, is currently recommended as first-line therapy for ED [18–20]. The efficacy and safety of vardenafil for the treatment of ED in the general population has previously been demonstrated [21–24]. Many men with ED will also be taking medications that are essential to control the short- and long-term complications of diabetes, hypertension, dyslipidemia, or any combination of the three [25]. Therefore, the current retrospective analysis sought to evaluate the efficacy and safety of vardenafil in men with ED and these associated underlying conditions, who may also be taking concomitant medications.
Methods
Study Design and Inclusion Criteria A retrospective analysis of randomized, doubleblind, placebo-controlled, flexible-dose clinical trials of vardenafil of at least 12 weeks’ duration was performed. Study participants were men aged ⱖ18 years in a stable heterosexual relationship, with ED as defined by the National Institutes of Health Consensus Statement [1] for at least 6 months. For all trials, patients started on vardenafil 10 mg with the option to titrate to 20 mg or 5 mg at week 4 of the study. In total, 15 published and unpublished flexible-dose trials of vardenafil were identified and screened for inclusion.
245
Main Outcome Measures The primary measures of efficacy were the erectile function domain of the International Index of Erectile Function (IIEF-EF) questionnaire and Sexual Encounter Profile questions 2 (SEP2: “Were you able to insert your penis into your partner’s vagina?”) and 3 (SEP3: “Did your erection last long enough for you to have successful intercourse?”), reported at baseline and at least once prior to, or at, week 12 of the study. Safety The safety population included all subjects taking at least one dose of vardenafil or placebo and having at least one postbaseline measurement reported. The incidence rates of treatmentemergent adverse events were analyzed overall and by subgroup. Statistical Analysis The intent-to-treat population (ITT) was defined as subjects who took at least one dose of vardenafil or placebo and who had baseline and any postbaseline efficacy data. The primary efficacy variables were evaluated at baseline and week 12. Comparisons of treatment effect were conducted with analysis of covariance, using the last observation carried forward approach to account for missing values. A common algorithm was applied to identify patients with associated underlying conditions and to allow for valid subgroup comparisons across studies. For diabetes, the definition was based on a medical history of diabetes {all Medical Dictionary for Regulatory Activities [MedDRA] [26] Preferred Terms [PT] covered by the MedDRA HighLevel Terms: “diabetes mellitus (including subtypes)” or treatment with antidiabetic medication at baseline [Anatomical Therapeutic Chemical (ATC)] [27] code A10}. Hypertension was defined by a medical history of hypertension (all MedDRA PT covered by the MedDRA Medical Entity: “hypertension”), blood pressure measurements (systolic blood pressure [SBP] ⱖ130 mm Hg or diastolic blood pressure [DBP] ⱖ85 mm Hg at baseline) or treatment with antihypertensive drugs at baseline (ATC codes C02, C03, C07, C08, and C09). Dyslipidemia was based on treatment with lipid-lowering medication at baseline (ATC code C10). Metabolic syndrome was defined using International Diabetes Federation (IDF) criteria [28] as central obesity (body mass index [BMI] >30 kg/m2 used as a J Sex Med 2010;7:244–255
246 surrogate for central obesity) and at least two of the following four conditions: history of hyperlipidemia based upon triglyceride levels ⱖ150 mg/dL (1.7 mmol/L) at baseline or treatment with lipidlowering drugs at baseline (ATC code C10); history of high-density lipoprotein cholesterol <40 mg/dL (1.03 mmol/L) at baseline; history of hypertension (SBP ⱖ 130 mm Hg or DBP ⱖ 85 mm Hg) at baseline, treatment with antihypertensive drugs at baseline or medical history of hypertension, as above; and fasting plasma glucose levels ⱖ100 mg/dL (5.6 mmol/L) and <125 mg/dL (6.9 mmol/L) at baseline or history of diabetes, as above. Patients were excluded from the metabolic syndrome subgroup if BMI data were missing. Retrospective analyses were performed to evaluate efficacy in different patient subgroups. The following subgroups were analyzed: men with diabetes and good, moderate, poor, or very poor glycemic control (glycosylated hemoglobin [HbA1c] levels ⱕ7%, >7–ⱕ8%, >8–ⱕ10%, >10%); men with diabetes treated with insulin, oral blood glucose-lowering drugs, both types of drug, or no antidiabetic drugs at all; men with hypertension treated with angiotensin-converting enzyme (ACE) inhibitors (monotherapy), beta blockers (monotherapy), angiotensin II receptor antagonists (ARB) (monotherapy), ACE inhibitors and beta blockers (combination therapy), ACE inhibitors and thiazide or thiazide-like diuretics (combination therapy), ARB and beta blockers (combination therapy), ARB and diuretics (combination therapy), calcium channel blockers (both mono- and combination therapy), other antihypertensive drugs or no antihypertensive drugs at all; men with dyslipidemia treated with statins (monotherapy), statins plus other lipid-lowering drugs (combination therapy), other lipid-lowering drugs (not including statins), or no lipid-lowering drugs at all; and men with metabolic syndrome. Results
Clinical Trials Of the 15 randomized, double-blind, placebocontrolled, flexible dose clinical trials of vardenafil for the treatment of ED in men with underlying conditions, 13 satisfied the inclusion criteria: study numbers 10473 [29], 10621 [30], 10769 [21], 10898 [31], 10940 [32], 11139 [33], 11334 [34], 11382, 12146, 12165 [25], 100519 [35], 100539 [36], and 100540 [37]. Patients with hypertension, dyslipidemia, and metabolic syndrome were found J Sex Med 2010;7:244–255
Eardley et al. in all trials. Patients with diabetes were present in all trials except 10473 and 100539, and glycemic control data were based on eight trials (10621, 10769, 10898, 10940, 11139, 12165, 100519, and 100540). The selected trials were conducted in Europe, United States, Latin America and AsiaPacific, and most were individually published between 2004 and 2008 (Table 1).
Study Population In total, 4,266 patients were valid for safety (vardenafil, N = 2,347; placebo, N = 1,919), and the ITT population comprised 4,143 men (vardenafil, N = 2,289; placebo, N = 1,854). The baseline characteristics of each individual trial are presented in Table 1. For the ITT population, least squares (LS) mean baseline IIEF-EF scores were 12.7 and 13.0 for men taking vardenafil or placebo, respectively, indicating moderate-to-severe ED; SEP2 scores were 45.0% (vardenafil) and 48.0% (placebo); and SEP3 scores were 15.0% (vardenafil) and 16.4% (placebo). A total of 1,011 patients had diabetes (vardenafil, N = 537; placebo, N = 474), 3,481 patients had hypertension (vardenafil, N = 1910; placebo, N = 1571), 1,055 patients had dyslipidemia (vardenafil, N = 567; placebo, N = 488), and 495 patients had metabolic syndrome (vardenafil, N = 283; placebo, N = 212). Treatment groups were well matched in terms of age, race, BMI, and prior use of PDE-5 inhibitors. Efficacy For the overall ITT population, vardenafil treatment resulted in statistically significant improvements from baseline in erectile function (IIEF-EF), rates of successful penetration (SEP2), and rates of successful intercourse (SEP3), when compared with placebo. After 12 weeks of vardenafil treatment, LS mean IIEF-EF scores increased from 12.7 at baseline to 22.4; LS mean SEP2 success rates increased from 45.0% to 78.5%; and LS mean SEP3 success rates increased from 15.0% to 64.8% (all P < 0.0001). In placebo-treated patients, corresponding LS mean IIEF-EF scores increased from 13.0 to 14.5; LS mean SEP2 success rates increased from 48.0% to 49.5%; and LS mean SEP3 success rates increased from 16.4% to 30.8%. In men with ED and diabetes, a significant improvement from baseline was observed in LS mean IIEF-EF scores, and SEP2 and SEP3 success rates at week 12 following treatment with vardenafil compared with placebo treatment. After 12 weeks of vardenafil treatment, LS mean IIEF-EF scores increased from 11.3 at baseline to 19.8; LS
588
121
254
151
343
385
225
10940 [32]
11139 [33]
11334 [34]
11382
12146
12165 [25]
100519 [35]
Canada, United States
Germany
Canada, United States
Belgium, France, Germany, Italy, Netherlands, South Africa, Spain United States
Turkey
Belgium, Denmark, Finland, France, Germany, UK
Spain
UK
Australia, Canada, France, Hong Kong, Italy, Mexico, Portugal, Spain, United States Canada, France, Italy, Spain, United States Austria, Germany, UK, Greece, France, Italy, Netherlands, Spain, Switzerland United States
Trial location
Men with ED and hypertension taking at least one antihypertensive medication Men with ED and diabetes
Men with ED and dyslipidemia on stable statin therapy Men with ED
Men with ED
Men with ED previously untreated with PDE-5 inhibitors Men with ED
Men with ED
Men with ED previously unresponsive to sildenafil therapy Men with ED
Men with ED and depression Men with ED
Men with ED as a result of traumatic spinal cord injury
Patient population
65
71
55
89
81
68
75
79
60
59
67
67
29
Aged 45–64 years, %
NI
NI
50.2
20.3
53.4
53.0
55.5
48.8
55.7
33.0
39.5
54.2
0
Mixed
NI
NI
44*
75.3
28.6
19.9
27.6
28.9
30.1
60.8
39.1
15.4
100.0
Organic
NI
NI
5.3
4.2
18.1
27.2
16.9
22.3
14.1
6.2
21.4
30.4
0
Psychogenic
0
0
78
69
63
60
45
41
67
77
60
65
79
Time since onset of ED ⱖ3 years, %
Vn Pl Vn Pl
Vn Pl Vn Pl
Vn Pl Vn Pl
12.6 Vn 13.5 Pl
13.2 13.5 13.9 14.5
12.0 Vn 12.4 Pl
15.0 15.4 13.3 13.3
9.5 Vn 9.5 Pl 15.3 Vn 15.6 Pl 13.6 Vn 13.3 Pl
9.6 Vn 10.0 Pl
12.7 13.1 12.6 13.1
11.6 Vn 12.1 Pl
Mean IIEF-EF score
Baseline
Vn Pl Vn Pl
Vn Pl Vn Pl
Vn Pl Vn Pl
Vn Pl Vn Pl
41.1 Vn 48.0 Pl
45.3 50.1 50.6 49.1
46.1 Vn 47.2 Pl
54.1 63.8 45.2 45.0
63.4 66.2 46.6 45.9
NI
30.3 Vn 33.9 Pl
40.7 42.5 38.7 43.5
35.6 Vn 41.0 Pl
Mean SEP2 success rate (%)
Vn Pl Vn Pl
Vn Pl Vn Pl
Vn Pl Vn Pl
14.1 Vn 20.1 Pl
17.8 19.6 18.5 18.2
17.4 Vn 16.0 Pl
11.0 Vn 8.8 Pl 9.5 Vn 12.4 Pl
22.5 25.1 18.9 20.9
NI
10.5 Vn 12.4 Pl
16.4 15.0 14.5 18.1
9.6 Vn 9.8 Pl
Mean SEP3 success rate (%)
*Total percentage does not equal 100% because of “no information” indicated for one patient. Missing data not shown. ED = erectile dysfunction; IIEF-EF = erectile function domain of the International Index of Erectile Function; ITT = intent-to-treat; NI = no information; PDE-5 = phosphodiesterase type 5; Pl = placebo group; SEP = Sexual Encounter Profile question; Vn = vardenafil group.
303
454
10898 [31]
100540 [37]
309
10769 [21]
354
260
10621 [30]
100539 [36]
396
ITT population (N)
ED etiology, %
Double-blind, placebo-controlled trials of flexible-dose vardenafil selected for analysis
10473 [29]
Study
Table 1
Vardenafil in Men with Underlying Conditions 247
J Sex Med 2010;7:244–255
248
Eardley et al. Placebo
Vardenafil
Baseline
n= Men with ED and diabetes
460 524
Good (HbA1c <7%)
127 160
Moderate (HbA1c >7 to <8%)
119 134
Poor (HbA1c >8 to <10%)
95 101
Very poor (HbA1c >10%)
24 24
No drugs used
28 41
Insulin and analogs + other drugs
198 214
Oral blood glucose-lowering drugs + other drugs
188 223
13.4
Both + other drugs
42 45
13.5
Level of glycemic control
14.0 19.8* 12.7 19.9* 13.8 19.7* ** 13.4 17.8* 14.5 20.8* 11.8 21.1* 14.2 19.6*
19.6*
18.6*
0
5
10
15
20
25
LS mean IIEF-EF score at week 12 LOCF
Figure 1 LS mean IIEF-EF scores in patients with ED and diabetes, stratified by level of glycemic control and type of antidiabetic medication, at baseline and following 12 weeks of treatment with vardenafil or placebo. *P < 0.0001 for vardenafil vs. placebo, **P = 0.2421 for comparison of glycemic control subgroups, 䉫P = 0.1972 for comparison of antidiabetic medication subgroups. ED = erectile dysfunction; HbA1c = glycosylated hemoglobin; IIEF-EF = erectile function domain of the International Index of Erectile Function; LOCF = last observation carried forward; LS = least squares.
mean SEP2 success rates increased from 35.2% to 67.7%; and LS mean SEP3 success rates increased from 10.8% to 52.3% (all P < 0.0001). This improvement with vardenafil was irrespective of the level of glycemic control (IIEF-EF: P = 0.2421, SEP2: P = 0.6952, SEP3: P = 0.4121 for between-group comparison of glycemic control subgroups), or use of concomitant antidiabetic medications (IIEF-EF: P = 0.1972, SEP2: P = 0.0607, SEP3: P = 0.0986 for comparison of all antidiabetic medications). Placebo-treated patients showed increases from baseline of 12.1 to 14.0 in LS mean IIEF-EF scores; 42.9% to 45.9% in LS mean SEP2 success rates; and 14.7% to 27.5% in LS mean SEP3 success rates (Figures 1 and 2; SEP2 data not shown). In men with ED and hypertension taking vardenafil, compared with those taking placebo, a similar significant improvement from baseline was observed in LS mean IIEF-EF scores, and SEP2 and SEP3 success rates at week 12, irrespective of the use of concomitant antihypertensive medications (IIEF-EF: P = 0.1651, SEP2: P = 0.8572, SEP3: P = 0.7957 for comparison of all antihypertensive medications) (Figures 3 and 4; SEP2 data not shown). After 12 weeks of vardenafil treatJ Sex Med 2010;7:244–255
ment, LS mean IIEF-EF scores were 22.2 (12.6 at baseline); LS mean SEP2 success rates were 77.0% (44.1% at baseline); and LS mean SEP3 success rates were 63.6% (14.5% at baseline) (all P < 0.0001). Corresponding increases in placebotreated patients were: LS mean IIEF-EF scores, 14.3 from 13.0 at baseline; LS mean SEP2 success rates, 49.0% from 47.2% at baseline; LS mean SEP3 success rates, 30.8% from 16.3% at baseline. In men with ED and dyslipidemia, vardenafil use was associated with a significant improvement from baseline in LS mean IIEF-EF scores, and SEP2 and SEP3 success rates at week 12, compared with placebo; LS mean IIEF-EF scores increased from 12.2 at baseline to 21.2, LS mean SEP2 success rates increased from 44.3% to 73.8%, and LS mean SEP3 success rates increased from 14.6% to 58.1% (all P < 0.0001). This improvement with vardenafil was achieved regardless of patients’ concomitant use of lipid-lowering drugs (IIEF-EF: P = 0.9169, SEP2: P = 0.9343, SEP3: P = 0.3536 for comparison of all lipidlowering medications). In patients taking placebo, LS mean IIEF-EF scores increased from 12.8 to 13.7; LS mean SEP2 success rates decreased from 46.7% to 45.6%; and LS mean SEP3 success rates
249
Vardenafil in Men with Underlying Conditions Placebo
Vardenafil
Baseline
n= Men with ED and diabetes
453 486
Good (HbA1c <7%)
121 147
Moderate (HbA1c >7 to <8%)
114 121
Poor (HbA1c >8 to <10%)
96 91
Very poor (HbA1c >10%)
24 21
No drugs used
28 39
Insulin and analogs + other drugs
198 202
Oral blood glucose-lowering drugs + other drugs
182 202
26.8
Both + other drugs
41 42
26.2
Level of glycemic control
27.5 52.3* 23.5 52.8* 26.1 48.4* ** 24.5 45.3* 32.4 48.9* 18.4 59.5* 25.0 48.7*
51.9*
40.4*
0
10
20
30
40
50
60
LS mean SEP3 success rate at week 12 LOCF (%)
Figure 2 LS mean SEP3 success rates in patients with ED and diabetes, stratified by level of glycemic control and type of antidiabetic medication, at baseline and following 12 weeks of treatment with vardenafil or placebo. *P < 0.0001 for vardenafil vs. placebo, **P = 0.4121 for comparison of glycemic control subgroups, 䉫P = 0.0986 for comparison of antidiabetic medication subgroups. ED = erectile dysfunction; HbA1c = glycosylated hemoglobin; LOCF = last observation carried forward; LS = least squares; SEP = Sexual Encounter Profile question.
increased from 15.7% to 26.9% (Figures 5 and 6; SEP2 data not shown). Vardenafil therapy was also associated with a significant improvement from baseline in LS mean IIEF-EF scores, and SEP2 and SEP3 success rates at week 12 in patients with ED and metabolic syndrome (defined according to IDF criteria), compared with placebo therapy. After 12 weeks of vardenafil treatment, LS mean IIEF-EF scores increased to 21.4 (from 10.6 at baseline); LS mean SEP2 success rates increased to 70.7% (from 42.1% at baseline); and LS mean SEP3 success rates increased to 54.1% (from 16.5% at baseline) (all P < 0.0001). Patients taking placebo showed corresponding increases in LS mean IIEF-EF scores from 11.6 to 13.9; LS mean SEP2 success rates from 39.7% to 47.8%; and LS mean SEP3 success rates from 14.8% to 28.9%.
Safety In general, vardenafil was well tolerated in men with coexisting diabetes, hypertension, dyslipidemia or metabolic syndrome, with 61.4% of men reporting no adverse events. The most common treatment-related adverse events were headache (11.0%), flushing (6.7%), and nasal congestion (3.0%); these were mild to moderate across all
studies and consistent with the pharmacology of PDE-5 inhibition. For the overall safety population, the incidence of treatment-emergent adverse events (38.6%) was comparable with other studies of vardenafil therapy in men with ED [21–23,29]. The incidence of treatment-emergent adverse events across all concomitant medication subgroups ranged from 22.0% to 41.7%, which was comparable with that seen in the overall safety population (Table 2). Discussion
This pooled retrospective analysis demonstrated the favorable safety and efficacy of vardenafil in men with ED and underlying conditions such as diabetes, hypertension, dyslipidemia, and metabolic syndrome. Vardenafil promoted significant improvements in erectile function and rates of penetration and successful intercourse, confirming the findings of previous studies of this PDE-5 inhibitor in men with ED and associated underlying conditions [25,36,37]. Men with ED and diabetes are a notoriously difficult-to-treat population. Studies have shown that ED is more severe and resistant to therapy in men with diabetes, than in men without this conJ Sex Med 2010;7:244–255
250
Eardley et al. Placebo
Baseline
Vardenafil
n= 14.3
Men with ED and hypertension
1537 1887
No drugs used
756 941
14.0
ACE inhibitors only
177 164
14.1
B only
75 92
13.7
ARB only
55 103
15.3
C monotherapy or + other drugs
95 145
ACE inhibitors + B + other drugs
95 110
14.0
ACE inhibitors + D
81 93
14.0
ARB + B
48 54
13.9
ARB + D + other drugs
51 67
Other drugs
104 118
22.2*
22.6*
21.8*
22.8*
24.1* 14.4 20.7* ** 20.2*
21.3*
21.0* 15.2 21.5* 14.2 21.9*
0
5
10
15
20
25
LS mean IIEF-EF score at week 12 LOCF
Figure 3 LS mean IIEF-EF scores in patients with ED and hypertension, stratified by type of antihypertensive medication, at baseline and following 12 weeks of treatment with vardenafil or placebo. *P < 0.0001 for vardenafil vs. placebo, **P = 0.1651 for comparison of antihypertensive medication subgroups. ACE = angiotensin-converting enzyme; ARB = angiotensin II receptor antagonists; B = beta blockers; C = calcium channel antagonists; D = thiazide or thiazide-like diuretics; ED = erectile dysfunction; IIEF-EF = erectile function domain of the International Index of Erectile Function; LOCF = last observation carried forward; LS = least squares.
dition [13,14]. Biochemical changes, neuropathy, angiopathy, and other vascular complications that are a consequence of poorly controlled hyperglycemia can all contribute to the neurogenic impairment and endothelial dysfunction that leads to ED [38,39]. Despite this poor prognosis, the current analysis showed that vardenafil was efficacious for the treatment of ED in men with diabetes, regardless of their level of glycemic control or use of concomitant antidiabetic medication. These findings are consistent with clinical studies of vardenafil and other PDE-5 inhibitors in this population [37,40–42], and a recent meta-analysis of PDE-5 inhibitor use in men with diabetes [43]. It has previously been shown that vardenafil is effective in men with ED and hypertension who may be taking multiple antihypertensive drugs [36], and the current study confirms those findings. Because of their pharmacology, certain antihypertensive medications, chiefly nonselective beta blockers and thiazide diuretics, can cause and/or J Sex Med 2010;7:244–255
exacerbate ED [44]. However, no significant decrease in the efficacy of vardenafil was seen in the subgroups of men taking these particular antihypertensive medications in the present analysis. There was no significant change in the efficacy of vardenafil in the presence of concomitant medications for the treatment of dyslipidemia (statins monotherapy, combination therapy with statins or any other lipid-lowering medication). As well as inhibiting cholesterol biosynthesis, statins can activate several other signal transduction pathways to ultimately improve endothelial function [45], and thus may show synergistic effects when used with PDE-5 inhibitors. However, in our present study, no significant difference in IIEF-EF scores, or SEP2 and SEP3 success rates, was observed between lipid-lowering medication subgroups. Vardenafil, in common with all PDE-5 inhibitors, is contraindicated in patients taking nitrates, and is also not recommended in patients taking class Ia or III antiarrhythmic agents. Caution is
251
Vardenafil in Men with Underlying Conditions Placebo
Vardenafil
Baseline
n= 30.8
Men with ED and hypertension
1424 1525
No drugs used
686 717
ACE inhibitors only
171 144
31.4
B only
72 81
30.9
ARB only
55 94
C monotherapy or + other drugs
83 105
25.8
ACE inhibitors + B + other drugs
95 97
25.6
ACE inhibitors + D
77 74
ARB + B
44 51
ARB + D + other drugs
48 60
Other drugs
93 102
63.6* 29.3 64.4*
60.6*
69.3* 36.8 67.1*
57.8* ** 55.0* 26.6 57.8* 20.0 57.7* 28.0 58.4* 29.0 60.3*
0
10
20
30
40
50
60
70
LS mean SEP3 success rate at week 12 LOCF (%)
Figure 4 LS mean SEP3 success rates in patients with ED and hypertension, stratified by type of antihypertensive medication, at baseline and following 12 weeks of treatment with vardenafil or placebo. *P < 0.0001 for vardenafil vs. placebo, **P = 0.7957 for comparison of antihypertensive medication subgroups. ACE = angiotensin-converting enzyme; ARB = angiotensin II receptor antagonists; B = beta blockers; C = calcium channel antagonists; D = thiazide or thiazide-like diuretics; ED = erectile dysfunction; LOCF = last observation carried forward; LS = least squares; SEP = Sexual Encounter Profile question.
also advised in the presence of alpha blockers; potent cytochrome P450, family 3, subfamily A (CYP3A) inhibitors, such as azole antifungal medication; antiretroviral protease inhibitors; or macrolide antibiotics [45].
Vardenafil has shown an excellent tolerability profile in numerous clinical trials [21–23]. In the present analysis of men with ED and underlying conditions, the incidence and type of treatmentrelated adverse events associated with vardenafil Placebo
Vardenafil
Baseline
n= Men with ED and dyslipidemia
484 559
Statins monotherapy
358 427
Statins + other drugs
64 71
Other drugs
57 56
13.7 21.2* 13.8 21.6* 13.5
**
20.7* 12.2 19.7*
0
5
10
15
20
25
LS mean IIEF-EF score at week 12 LOCF
Figure 5 LS mean IIEF-EF scores in patients with ED and dyslipidemia, stratified by type of lipid-lowering medication, at baseline and following 12 weeks of treatment with vardenafil or placebo. *P < 0.0001 for vardenafil vs. placebo, **P = 0.9169 for comparison of lipid-lowering medication subgroups. ED = erectile dysfunction; IIEF-EF = erectile function domain of the International Index of Erectile Function; LOCF = last observation carried forward; LS = least squares.
J Sex Med 2010;7:244–255
252
Eardley et al. Placebo
Vardenafil
Baseline
n= Men with ED and dyslipidemia
455 474
Statins monotherapy
334 352
28.6
Statins + other drugs
64 68
29.3
Other drugs
52 50
26.9 58.1*
61.4*
**
55.3* 22.4 47.7*
0
10
20
30
40
50
60
70
LS mean SEP3 success rate at week 12 LOCF (%)
Figure 6 LS mean SEP3 success rates in patients with ED and dyslipidemia, stratified by type of lipid-lowering medication, at baseline and following 12 weeks of treatment with vardenafil or placebo. *P < 0.0001 for vardenafil vs. placebo, **P = 0.3536 for comparison of lipid-lowering medication subgroups. ED = erectile dysfunction; LOCF = last observation carried forward; LS = least squares; SEP = Sexual Encounter Profile question.
therapy were comparable with findings from previous studies in the general population of men with ED. Given the close association between ED, underlying conditions and increasing age, the safety and tolerability of vardenafil is of particular importance to older patients who are likely to be taking multiple medications. A study of 243 men aged 65 years or older showed that 71% took at least one prescription medication per week, and 19% took at least five [46]. Crucially, the current study found that the safety profile of vardenafil in men taking concomitant medications was comTable 2
parable with that seen in men not taking medication. This provides further reassurance that vardenafil can be used in the presence of a range of medications for the treatment of underlying conditions, without the risk of adverse drug interactions. There are some potential limitations to this study. As patient subgroups were identified post hoc, there is the possibility of mislabeling and subsequent assignment of patients to an incorrect subgroup. For example, inclusion of a patient in the hypertension subgroup could have been based on
Incidence of treatment-emergent adverse events associated with each concomitant medication subgroup Placebo
Overall safety population Diabetes mellitus population No drugs used Insulin and analogs + other drugs Oral blood glucose-lowering drugs + other drugs Both + other drugs Arterial hypertension population No drugs used ACE inhibitors (monotherapy) Beta blockers (monotherapy) ARB (monotherapy) Calcium channel antagonists (monotherapy + other drugs) ACE inhibitors + beta blockers + other drugs ACE inhibitors + thiazide or thiazide-like diuretics + other drugs ARB + beta blockers + other drugs ARB + thiazide or thiazide-like diuretics + other drugs Other drugs Dyslipidemia population Statins (monotherapy) Statins + other drugs Other drugs Missing data not shown. ACE = angiotensin-converting enzyme; ARB = angiotensin II receptor antagonists.
J Sex Med 2010;7:244–255
Vardenafil
n/N
(%)
n/N
(%)
453/1,919 115/486 8/30 50/211 44/195 12/46 386/1,627 197/795 38/196 17/82 10/56 22/102 26/99 24/84 12/49 8/55 32/109 131/496 96/367 18/65 15/59
(23.6) (23.7) (26.7) (23.7) (22.6) (26.1) (23.7) (24.8) (19.4) (20.7) (17.9) (21.6) (26.3) (28.6) (24.5) (14.5) (29.4) (26.4) (26.2) (27.7) (25.4)
905/2,347 185/553 12/45 73/228 89/229 11/50 737/1,964 405/968 55/177 24/93 33/108 59/153 45/116 32/97 17/57 27/73 40/122 223/579 175/444 30/72 14/58
(38.6) (33.5) (26.7) (32.0) (38.9) (22.0) (37.5) (41.8) (31.1) (25.8) (30.6) (38.6) (38.8) (33.0) (29.8) (37.0) (32.8) (38.5) (39.4) (41.7) (24.1)
253
Vardenafil in Men with Underlying Conditions an isolated elevated blood pressure measurement, with the patient not necessarily meeting any other diagnostic criteria for hypertension. ACE inhibitors were the single most commonly prescribed concomitant medication used by men with ED and hypertension in this study, but they are also routinely used to treat congestive heart failure and diabetic nephropathy [47]. Therefore, a small number of patients may have been assigned to the hypertension subgroup, based solely on the use of these drugs, when inclusion in the diabetic subgroup alone may have been more appropriate. It would have been desirable to correlate efficacy data with a validated comorbidity index, to assess any potential effects because of number and/or severity of underlying conditions. However, this was not possible, as a comprehensive retrospective medical history could not be retrieved for all subjects.
Statement of Authorship
Conclusions
Category 3
Vardenafil treatment significantly improved erectile function and rates of penetration and successful intercourse in this large pool of men with ED and associated diabetes, hypertension, dyslipidemia, and/or metabolic syndrome. Importantly, the concomitant use of medications for these underlying conditions was not associated with any noteworthy changes in the efficacy or safety of vardenafil. This analysis adds to the considerable body of evidence showing the favorable efficacy and tolerability profile of vardenafil in men with ED and underlying conditions, providing clinicians with the confidence to prescribe vardenafil as a first-line treatment for ED in this patient group. Corresponding Author: Ian Eardley, MA, MChir, FRCS (Urol), FEBU, Pyrah Department of Urology, St. James’s University Hospital, Beckett Street, Leeds, LS9 7TF, UK. Tel: 44 113 2066994; Fax: 44 113 2064920; E-mail: [email protected] Conflict of Interest: Ian Eardley has acted as a paid consultant, investigator, and speaker for Bayer Schering, Boehringer Ingelheim, Lilly and Pfizer; Jay C. Lee has acted as a paid consultant, clinical trial investigator, and speaker for Bayer Schering; Ridwan Shabsigh and Mario Maggi have acted as speakers for Bayer Schering; John Dean has acted as a paid consultant or clinical trial investigator for, or has received hospitality from, Auxilium, Bayer Schering, Boehringer Ingelheim, Ipsen, Johnson & Johnson, Lilly, Pfizer, Plethora and ProStrakan; and Dieter Neuser and Christiane Norenberg are both employees of Bayer Schering.
Category 1 (a) Conception and Design Ian Eardley; Dieter Neuser; Christiane Norenberg (b) Acquisition of Data Dieter Neuser; Christiane Norenberg (c) Analysis and Interpretation of Data Ian Eardley; Jay C. Lee; Ridwan Shabsigh; John Dean; Mario Maggi; Dieter Neuser; Christiane Norenberg
Category 2 (a) Drafting the Article Ian Eardley; Jay C. Lee; Ridwan Shabsigh; John Dean; Mario Maggi; Dieter Neuser; Christiane Norenberg (b) Revising It for Intellectual Content Ian Eardley; Jay C. Lee; Ridwan Shabsigh; John Dean; Mario Maggi; Dieter Neuser; Christiane Norenberg
(a) Final Approval of the Completed Article Ian Eardley; Jay C. Lee; Ridwan Shabsigh; John Dean; Mario Maggi; Dieter Neuser; Christiane Norenberg References
1 NIH Consensus Conference. Impotence. NIH consensus development panel on impotence. JAMA 1993;270:83–90. 2 Kubin M, Wagner G, Fugl-Meyer AR. Epidemiology of erectile dysfunction. Int J Impot Res 2003; 15:63–71. 3 Parazzini F, Menchini Fabris F, Bortolotti A, Calabro A, Chatenoud L, Colli E, Landoni M, Lavezzari M, Turchi P, Sessa A, Mirone V. Frequency and determinants of erectile dysfunction in Italy. Eur Urol 2000;37:43–9. 4 Corona G, Mannucci E, Forti G, Maggi M. Hypogonadism, ED, metabolic syndrome and obesity: A pathological link supporting cardiovascular diseases. Int J Androl 2009 Feb 10 [Epub ahead of print] doi: 10.1111/j.1365-2605.2008.00951.x. 5 Gaskell P. The importance of penile blood pressure in cases of impotence. Can Med Assoc J 1971; 105:1047–51. 6 Inman BA, Sauver JL, Jacobson DJ, McGree ME, Nehra A, Lieber MM, Roger VL, Jacobsen SJ. A population-based, longitudinal study of erectile dysfunction and future coronary artery disease. Mayo Clin Proc 2009;84:108–13. 7 Jackson G, Rosen RC, Kloner RA, Kostis JB. The second Princeton consensus on sexual dysfunction and cardiac risk: New guidelines for sexual medicine. J Sex Med 2006;3:28–36. discussion 36. J Sex Med 2010;7:244–255
254 8 Eardley I, Fisher W, Rosen RC, Niederberger C, Nadel A, Sand M. The multinational Men’s Attitudes to Life Events and Sexuality Study: The influence of diabetes on self-reported erectile function, attitudes and treatment-seeking patterns in men with erectile dysfunction. Int J Clin Pract 2007; 61:1446–53. 9 Rosen RC, Fisher WA, Eardley I, Niederberger C, Nadel A, Sand M. The multinational Men’s Attitudes to Life Events and Sexuality (MALES) study: I. Prevalence of erectile dysfunction and related health concerns in the general population. Curr Med Res Opin 2004;20:607–17. 10 De Berardis G, Franciosi M, Belfiglio M, Di Nardo B, Greenfield S, Kaplan SH, Pellegrini F, Sacco M, Tognoni G, Valentini M, Nicolucci A. Erectile dysfunction and quality of life in type 2 diabetic patients: A serious problem too often overlooked. Diabetes Care 2002;25:284–91. 11 Sasaki H, Yamasaki H, Ogawa K, Nanjo K, Kawamori R, Iwamoto Y, Katayama S, Shirai M. Prevalence and risk factors for erectile dysfunction in Japanese diabetics. Diabetes Res Clin Pract 2005;70:81–9. 12 Burchardt M, Burchardt T, Baer L, Kiss AJ, Pawar RV, Shabsigh A, de la Taille A, Hayek OR, Shabsigh R. Hypertension is associated with severe erectile dysfunction. J Urol 2000;164:1188–91. 13 Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. Impotence and its medical and psychosocial correlates: Results of the Massachusetts Male Aging Study. J Urol 1994;151:54–61. 14 Penson DF, Latini DM, Lubeck DP, Wallace KL, Henning JM, Lue TF. Do impotent men with diabetes have more severe erectile dysfunction and worse quality of life than the general population of impotent patients? Results from the Exploratory Comprehensive Evaluation of Erectile Dysfunction (ExCEED) database. Diabetes Care 2003;26: 1093–9. 15 Walczak MK, Lokhandwala N, Hodge MB, Guay AT. Prevalence of cardiovascular risk factors in erectile dysfunction. J Gend Specif Med 2002;5:19–24. 16 Nikoobakht M, Nasseh H, Pourkasmaee M. The relationship between lipid profile and erectile dysfunction. Int J Impot Res 2005;17:523–6. 17 Ponholzer A, Temml C, Rauchenwald M, Madersbacher S. Vascular risk factors and erectile dysfunction in a cohort of healthy men. Int J Impot Res 2006;18:489–93. 18 Montague DK, Jarow JP, Broderick GA, Dmochowski RR, Heaton JP, Lue TF, Milbank AJ, Nehra A, Sharlip ID. Chapter 1: The management of erectile dysfunction: An AUA update. J Urol 2005;174:230–9. 19 Wespes E, Amar E, Hatzichristou D, Hatzimouratidis K, Montorsi F, Pryor J, Vardi Y. EAU guidelines on erectile dysfunction: An update. Eur Urol 2006;49:806–15. J Sex Med 2010;7:244–255
Eardley et al. 20 Sadovsky R, Brock GB, Gutkin SW, Sorsaburu S. Toward a new “EPOCH”: Optimising treatment outcomes with phosphodiesterase type 5 inhibitors for erectile dysfunction. Int J Clin Pract 2009;63: 1214–30. 21 Hatzichristou D, Montorsi F, Buvat J, Laferriere N, Bandel TJ, Porst H. The efficacy and safety of flexible-dose vardenafil (Levitra®) in a broad population of European men. Eur Urol 2004;45:634–41. discussion 641. 22 Hellstrom WJ, Gittelman M, Karlin G, Segerson T, Thibonnier M, Taylor T, Padma-Nathan H. Vardenafil for treatment of men with erectile dysfunction: Efficacy and safety in a randomized, double-blind, placebo-controlled trial. J Androl 2002;23:763–71. 23 Stief C, Porst H, Saenz De Tejada I, Ulbrich E, Beneke M. Sustained efficacy and tolerability with vardenafil over 2 years of treatment in men with erectile dysfunction. Int J Clin Pract 2004;58:230–9. 24 Jannini EA, Isidori AM, Gravina GL, Aversa A, Balercia G, Bocchio M, Boscaro M, Carani C, Corona G, Fabbri A, Foresta C, Forti G, Francavilla S, Granata AR, Maggi M, Mansani R, Palego P, Spera G, Vetri M, Lenzi A. The ENDOTRIAL study: A spontaneous, open-label, randomized, multicenter, crossover study on the efficacy of sildenafil, tadalafil, and vardenafil in the treatment of erectile dysfunction. J Sex Med 2009;6:2547–60. 25 Miner M, Gilderman L, Bailen J, Cook D, Dawson K, Stanislaus M, Beresford E, Barnes A. Vardenafil in men with stable statin therapy and dyslipidemia. J Sex Med 2008;5:1455–67. 26 Welcome to MedDRA and the MSSO. March 1, 2009. Available at: http://www.meddramsso.com/ MSSOWeb/index.htm (accessed April 22, 2009). 27 Complete ATC/DDD Index 2009. April 15, 2009. Available at: http://www.whocc.no/atcddd/ (accessed April 22, 2009). 28 IDF Writing Group. The IDF consensus worldwide definition of the metabolic syndrome. Brussels: IDF Communications; 2006:24. 29 Giuliano F, Rubio-Aurioles E, Kennelly M, Montorsi F, Kim ED, Finkbeiner AE, Pommerville PJ, Colopy MW, Wilkins HJ, Wachs BH. Efficacy and safety of vardenafil in men with erectile dysfunction caused by spinal cord injury. Neurology 2006;66: 210–6. 30 Rosen R, Shabsigh R, Berber M, Assalian P, Menza M, Rodriguez-Vela L, Porto R, Bangerter K, Seger M, Montorsi F. Efficacy and tolerability of vardenafil in men with mild depression and erectile dysfunction: The depression-related improvement with vardenafil for erectile response study. Am J Psychiatry 2006;163:79–87. 31 Carson CC, Hatzichristou DG, Carrier S, Lording D, Lyngdorf P, Aliotta P, Auerbach S, Murdock M, Wilkins HJ, McBride TA, Colopy MW. Erectile response with vardenafil in sildenafil nonresponders:
Vardenafil in Men with Underlying Conditions
32
33
34
35
36
37
A multicentre, double-blind, 12-week, flexible-dose, placebo-controlled erectile dysfunction clinical trial. BJU Int 2004;94:1301–9. Ralph D, Eardley I, Kell P, Dean J, Hackett G, Collins O, Edwards D. Improvement in erectile function on vardenafil treatment correlates with treatment satisfaction in both patients and their partners. BJU Int 2007;100:130–6. Martin-Morales A, Meijide F, Garcia N, Artes M, Munoz A. Efficacy of vardenafil and influence on self-esteem and self-confidence in patients with severe erectile dysfunction. J Sex Med 2007;4:440–7. Edwards D, Hackett G, Collins O, Curram J. Vardenafil improves sexual function and treatment satisfaction in couples affected by erectile dysfunction (ED): A randomized, double-blind, placebocontrolled trial in PDE5 inhibitor-naive men with ED and their partners. J Sex Med 2006;3:1028–36. Fisher WA, Rosen RC, Mollen M, Brock G, Karlin G, Pommerville P, Goldstein I, Bangerter K, Bandel TJ, Derogatis LR, Sand M. Improving the sexual quality of life of couples affected by erectile dysfunction: A double-blind, randomized, placebocontrolled trial of vardenafil. J Sex Med 2005;2: 699–708. van Ahlen H, Wahle K, Kupper W, Yassin A, Reblin T, Neureither M. Safety and efficacy of vardenafil, a selective phosphodiesterase 5 inhibitor, in patients with erectile dysfunction and arterial hypertension treated with multiple antihypertensives. J Sex Med 2005;2:856–64. Goldstein I, Young JM, Fischer J, Bangerter K, Segerson T, Taylor T. Vardenafil, a new phosphodiesterase type 5 inhibitor, in the treatment of erectile dysfunction in men with diabetes: A multicenter double-blind placebo-controlled fixed-dose study. Diabetes Care 2003;26:777–83.
255 38 Malavige LS, Levy JC. Erectile dysfunction in diabetes mellitus. J Sex Med 2009;6:1232–47. 39 Saenz de Tejada I, Goldstein I, Azadzoi K, Krane RJ, Cohen RA. Impaired neurogenic and endotheliummediated relaxation of penile smooth muscle from diabetic men with impotence. N Engl J Med 1989; 320:1025–30. 40 Fonseca V, Seftel A, Denne J, Fredlund P. Impact of diabetes mellitus on the severity of erectile dysfunction and response to treatment: Analysis of data from tadalafil clinical trials. Diabetologia 2004;47: 1914–23. 41 Rendell MS, Rajfer J, Wicker PA, Smith MD. Sildenafil for treatment of erectile dysfunction in men with diabetes: A randomized controlled trial. Sildenafil Diabetes Study Group. JAMA 1999;281: 421–6. 42 Ziegler D, Merfort F, van Ahlen H, Yassin A, Reblin T, Neureither M. Efficacy and safety of flexibledose vardenafil in men with type 1 diabetes and erectile dysfunction. J Sex Med 2006;3:883–91. 43 Vardi M, Nini A. Phosphodiesterase inhibitors for erectile dysfunction in patients with diabetes mellitus. Cochrane Database Syst Rev 2007:CD002187. 44 Weiss RJ. Effects of antihypertensive agents on sexual function. Am Fam Physician 1991;44:2075– 82. 45 Corona G, Razzoli E, Forti G, Maggi M. The use of phosphodiesterase 5 inhibitors with concomitant medications. J Endocrinol Invest 2008;31:799–808. 46 Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA. Recent patterns of medication use in the ambulatory adult population of the United States: The Slone survey. JAMA 2002;287:337–44. 47 Wong J, Patel RA, Kowey PR. The clinical use of angiotensin-converting enzyme inhibitors. Prog Cardiovasc Dis 2004;47:116–30.
J Sex Med 2010;7:244–255