Abstract

Oral sildenafil is an effective treatment for erectile dysfunction (ED), which is a common complaint for patients with hypertension and those taking antihypertensive agents. This post hoc subanalysis assessed the efficacy and safety of sildenafil in men with ED who were receiving concomitant antihypertensive medication. Efficacy was assessed in 3414 men (1218 of whom were taking antihypertensive medication) who received sildenafil (5 to 200 mg) or placebo for 6 weeks to 6 months in 10 double-blind, placebo-controlled studies. The significant improvements in erectile function demonstrated by sildenafil-treated patients were comparable in patients taking and those not taking antihypertensive medication. Safety was assessed in 3975 men (1094 of whom were taking one or more antihypertensive agent, classified as a diuretic, β-blocker, α1-blocker, angiotensin converting enzyme inhibitor, or calcium channel blocker), who received sildenafil or placebo in 18 double-blind, placebo-controlled studies. For patients taking sildenafil and antihypertensive medication, the incidence of treatment-related adverse events (34%) was similar to that for sildenafil-treated patients not taking any antihypertensive agent (38%). The incidences of the most common adverse events and of adverse events potentially related to blood pressure decreases (eg, hypotension, dizziness, and syncope) were similar in both sildenafil groups. The number of antihypertensive medications taken from among the five classes had no effect on the adverse event profile of sildenafil. Sildenafil is an effective and well-tolerated treatment for ED in patients taking concomitant antihypertensive medication, including those on multidrug regimens. Am J Hypertens 2001;14:70–73 © 2001 American Journal of Hypertension, Ltd.

Erectile dysfunction (ED), the inability to achieve or maintain an erection sufficient for satisfactory sexual activity,1 is a common problem in patients with hypertension and in those being treated with antihypertensive agents.2,3 In the Massachusetts Male Aging Study, a random sample survey of 1290 men aged 40 to 70 years, the age-adjusted prevalence of complete ED (no erections) was 15% in those with treated hypertension and 14% in those taking antihypertensive agents compared with a prevalence of 9.6% in the entire sample.2

Sildenafil, an orally active and selective inhibitor of cGMP-specific phosphodiesterase type 5, is an effective and well-tolerated treatment for ED of various causes.4 By inhibiting the degradation of cGMP in the corpus cavernosum of the penis, sildenafil enables smooth muscle relaxation and penile erection in patients with ED. The most common adverse events associated with sildenafil treatment are headache and flushing,5 which reflect its modest vasodilating properties.6 Oral sildenafil (100 mg) produces transient decreases in systolic (8 to 10 mm Hg) and diastolic (3 to 6 mm Hg) blood pressure in healthy male volunteers.5 Peak decreases are observed 1 h after dosing and coincide with peak plasma concentrations of drug. These changes in blood pressure generally return to pretreatment values by 4 to 8 h after dosing in healthy men.6 This post hoc analysis assessed the efficacy and safety of sildenafil in men with ED who were receiving concomitant treatment with antihypertensive agents.

Patients and methods

Patient populations and design

Efficacy data were analyzed post hoc for groups of patients enrolled in 10 of 18 randomized, double-blind, placebo-controlled studies of sildenafil in the treatment of ED of various causes. In these 10 studies that assessed efficacy with the same outcome measure, a total of 3414 patients, 1218 (36%) of whom were taking concomitant antihypertensive medication, were randomized to sildenafil (5 to 200 mg) or placebo for 6 weeks to 6 months. The patients enrolled were 18 years of age or older with a clinical diagnosis of ED of at least 6 months’ duration and in a stable relationship with a female partner for at least 6 months. Patients were excluded if they had penile anatomic defects, a recent (within the previous 6 months) history of stroke, myocardial infarction, or life-threatening arrhythmia, a resting blood pressure <90/50 mm Hg or >170/110 mm Hg, a known history of retinitis pigmentosa, any significant concomitant medical condition that would impair participation in the study, or were receiving regular treatment with nitrates or anticoagulants. All patients provided written informed consent before enrollment. The patients were instructed to take study medication approximately 1 h before sexual activity but not more than one dose daily. Safety data were analyzed for 3975 patients from 18 randomized, double-blind, placebo-controlled studies lasting from 6 weeks to 6 months, which included the 10 studies analyzed for efficacy data. In the 18 studies, of the 4274 patients randomized to sildenafil (5 to 200 mg) or placebo, 2881 (n = 1837 sildenafil, n = 1044 placebo) were not taking any antihypertensive medication, 1094 (n = 704 sildenafil, n = 390 placebo) were taking concomitant antihypertensive medication classified as a diuretic, β-blocker, α1-blocker, angiotensin converting enzyme inhibitor, or calcium channel blocker, and 346 (n = 217 sildenafil, n = 129 placebo) were taking two or more of these classes of antihypertensive agent during the studies. The inclusion and exclusion criteria for the 18 studies were the same as mentioned above for the 10 studies.

Outcome measures

Efficacy was assessed for patients in the sildenafil and placebo groups who were taking antihypertensive medication or who were not taking any antihypertensive agent using end-of-treatment responses to question 3 (ability to achieve an erection) and question 4 (ability to maintain an erection) of the International Index of Erectile Function (IIEF)7 and responses to a global efficacy question (“Did the treatment improve your erections?”). The responses to the two IIEF questions were graded on a scale of 1 (almost never or never) to 5 (almost always or always), with a score of 0 indicating no attempt at sexual intercourse. Physical examinations and standard laboratory tests were performed throughout the studies. In all studies, investigators recorded all observed and patient-reported adverse events and classified the relationship of the adverse event to the study medication as definitely related, uncertain, or not related. A treatment-related adverse event was defined as any event classified as definitely related, of uncertain relation, or of unspecified relation to the study medication. Adverse events were analyzed for the 2881 patients not taking any antihypertensive medication and for the 1094 patients taking one or more of the following classes of antihypertensive agent: diuretic, β-blocker, α1-blocker, angiotensin converting enzyme inhibitor, or calcium channel blocker.

Statistical analysis

The mean responses to the two questions of the IIEF for each of the treatment groups were calculated and the treatment effect was analyzed using an analysis of covariance model, as described previously.4 Comparisons between mean responses for patients taking versus not taking antihypertensive agents were analyzed using an analysis of covariance model that accounted for the treatment effect. The responses to the global efficacy question were analyzed using a logistic regression model.4 Intention to treat analyses were performed on all variables, and all statistical tests were two-sided and evaluated at the 5% significance level.

Results

In the 10 double-blind, placebo-controlled studies in which efficacy was assessed, the mean age of the patients was 58 years for those taking antihypertensive medication and 55 years for those not taking any antihypertensive agent. The mean duration of ED in the two groups was 4.7 years and 5.2 years, respectively. The etiology of ED was 67% organic, 11% psychogenic, and 22% mixed for the patients taking concomitant antihypertensive medication compared with 56% organic, 17% psychogenic, and 27% mixed for those not taking an antihypertensive agent. The characteristics of the patients randomized to treatment in the 18 double-blind, placebo-controlled studies from which safety data were collected were similar to those described above.

The mean end of treatment scores for question 3 (achieving an erection) and question 4 (maintaining an erection) of the IIEF were significantly higher for the sildenafil group than for the placebo group for both patients taking and those not taking antihypertensive agents (P values <.0001). The mean score for question 3 for patients in the sildenafil group was 3.4 regardless of whether concomitant antihypertensive medication was taken, as compared with mean scores of 2.1 and 2.0 for patients on placebo who were taking and not taking antihypertensive medication, respectively. The mean scores for question 4 were 3.3 and 3.4 for patients receiving sildenafil among those taking and those not taking antihypertensive agents, respectively. The corresponding mean scores for question 4 for patients receiving placebo were 1.9 and 1.8. There were no statistical differences between the mean scores for the sildenafil groups taking and not taking antihypertensive agents for either IIEF question (question 3, P = .69; question 4, P = .93). At the end of treatment, improved erections were reported by 70% of patients receiving sildenafil and taking concomitant antihypertensive medication and by 72% of patients in the sildenafil group who were not taking any antihypertensive agent (P = .97). The values for the placebo groups were 21% and 27%, respectively, and were significantly different from the values for the corresponding sildenafil groups (P < .0001).

In the 18 double-blind, placebo-controlled studies, the overall incidence of treatment-related adverse events and the incidences of treatment-related adverse events potentially related to blood pressure decreases, such as hypotension, dizziness, and syncope, were comparable in patients receiving sildenafil who were taking each of the five classes of antihypertensive agents and in those not taking any antihypertensive agent (Table 1). Furthermore, the incidences of the most common adverse events (eg, headache, flushing, and dyspepsia) also were not affected by whether the patients receiving sildenafil were taking antihypertensive medication.

Table 1

Combined incidence (%) of treatment-related adverse events reported in 18 double-blind placebo-controlled studies of patients with ed receiving sildenafil (Sild) or placebo (Pbo) who were taking or not taking different classes of antihypertensive medication*

 Diuretic β-Blocker α1-Blocker ACE Inhibitor Calcium Channel Blocker None 
Adverse Event (AE) Pbo (n = 83) Sild (n = 123) Pbo (n = 72) Sild (n = 13) Pbo (n = 79) Sild (n = 124) Pbo (n = 161) Sild (n = 303) Pbo (n = 150) Sild (n = 278) Pbo (n = 1044) Sild (n = 1837) 
% with any AE 35 11 34 10 31 36 33 11 38 
Headache 13 15 11 15 13 16 
Flushing 11 11 11 16 10 14 
Dyspepsia 
Abnormal vision <1 
Hypotension <1 <1 <1 <1 
Dizziness <1 <1 
Syncope 
 Diuretic β-Blocker α1-Blocker ACE Inhibitor Calcium Channel Blocker None 
Adverse Event (AE) Pbo (n = 83) Sild (n = 123) Pbo (n = 72) Sild (n = 13) Pbo (n = 79) Sild (n = 124) Pbo (n = 161) Sild (n = 303) Pbo (n = 150) Sild (n = 278) Pbo (n = 1044) Sild (n = 1837) 
% with any AE 35 11 34 10 31 36 33 11 38 
Headache 13 15 11 15 13 16 
Flushing 11 11 11 16 10 14 
Dyspepsia 
Abnormal vision <1 
Hypotension <1 <1 <1 <1 
Dizziness <1 <1 
Syncope 
*

Percentage of patients given.

Of the 704 patients in the sildenafil treatment group who were taking concomitant antihypertensive medication classified as a diuretic, β-blocker, α1-blocker, angiotensin converting enzyme inhibitor, or calcium channel blocker, the incidence rates of treatment-related adverse events were 35% (168 of 487) in those taking one agent, 31% (55 of 178) in those taking two agents, and 41% (16 of 39) in those taking three or more agents compared with 38% (692 of 1837) in those who were not taking any antihypertensive agent. The incidences of treatment-related flushing (12%), adverse events potentially related to changes in blood pressure (eg, dizziness, 2%; hypotension, <1%; syncope, 0%; hypertension, 0%), and cardiovascular adverse events (eg, angina, 0%; myocardial infarction, 0%; coronary artery disorder, 0%) were low in patients taking multiple antihypertensive agents and were similar to those observed in patients not taking any antihypertensive medication. The overall rates of discontinuation of treatment due to adverse events of all causes were comparable for sildenafil-treated patients taking antihypertensive medication from among the five classes of agents (17 of 704, 2.4%) and those not taking any antihypertensive medication (45 of 1837, 2.4%).

Discussion

A substantial number of men with hypertension and those taking antihypertensive agents have ED.3 Treatment with oral sildenafil can provide these patients with a therapy that is effective, well tolerated, and simple to use. Because sildenafil is a mixed arterial venous dilator6 and many antihypertensive agents exhibit direct or indirect vasodilating properties, it was important to determine whether treatment with sildenafil might potentiate the decreases in blood pressure achieved with different classes of antihypertensive agents. Although large-scale drug–drug interaction studies have not been conducted with sildenafil and all classes of antihypertensive agents, no synergistic interaction was observed in a double-blind, placebo-controlled, crossover study in which sildenafil (100 mg) was coadministered with the calcium channel blocker amlodipine to 16 men with essential hypertension.8

The present post hoc subanalysis assessed the efficacy and adverse event profile of patients with ED who were treated with sildenafil either with or without concomitant antihypertension medication. The therapeutic response to sildenafil in these patients with ED was not affected by whether they were taking concomitant antihypertensive medication. The overall incidence of adverse events and the incidence of adverse events potentially related to blood pressure changes were similar in sildenafil-treated patients taking one or more agent from five different classes of antihypertensive medication and those not taking any antihypertensive medication. Importantly, the number of concomitant antihypertensive agents being taken by patients had no affect on the adverse event profile of sildenafil. These results reflect the different mechanisms of action of sildenafil and the various antihypertensive agents. Sildenafil causes levels of cGMP to increase in vascular smooth muscle, thereby resulting in vasodilation,6,9 whereas antihypertensive agents exert their therapeutic effects by mechanisms other than the NO–cGMP pathway.

In conclusion, the results of this post hoc subanalysis suggest that sildenafil is an effective and well-tolerated treatment for ED in patients taking concomitant antihypertensive medication, including those on multidrug antihypertensive regimens.

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