Sildenafil citrate for erectile dysfunction in men receiving multiple antihypertensive agents: A randomized controlled trial

Abstract

Background:

Erectile dysfunction (ED) is common among men taking antihypertensive drugs to control blood pressure. We evaluated the safety and efficacy of sildenafil citrate for treating ED in men taking multiple antihypertensive medications in a randomized, double-blind, placebo-controlled trial.

Methods:

A total of 568 men (≥18 years) with ED and hypertension who were taking two or more antihypertensives were randomized to sildenafil (n = 281) or matching placebo (n = 287) for a 6-week double-blind trial followed by a 6-week open-label phase during which all patients received sildenafil. Primary efficacy variables were questions (Q) 3 and 4 (frequency of erections and penetration) of the International Index of Erectile Function (IIEF), and secondary efficacy variables were two global efficacy assessment (GEA) questions regarding improvement in erections and intercourse.

Results:

A total of 562 men (mean age, 59 years) took ≥1 dose of study drug. At week 6, mean scores on both Q3 and Q4 improved significantly among sildenafil-treated compared with placebo-treated patients. In regard to Q3 and Q4 there were no differences between patients taking two and those taking three or more antihypertensive agents. In all, 71% and 69% of sildenafil-treated patients reported improved erections (GEA1) and intercourse (GEA2) compared with 18% and 20% of placebo-treated patients, respectively. By week 12, >80% of all patients (regardless of initial treatment group) had improved erections and intercourse. During double-blind treatment, 40% of sildenafil-treated and 25% of placebo-treated patients experienced adverse events; fewer than 2% in each group discontinued because of adverse events.

Conclusions:

Sildenafil was an effective and well tolerated treatment for ED in men receiving multiple antihypertensives. The results suggest that there were no additional safety risks associated with the use of sildenafil in these patients.

Impotence, hypertension, phosphodiesterase inhibitor, antihypertensive agents, drug safety

Hypertension is a serious public health problem, with an overall prevalence of 26% among American men (≥18 years),¹ which increases markedly with age from 12% in men age 20 to 34 years, to 51% in those 55 to 64 years, and 71% in men 75 years or older.^2,3 Erectile dysfunction (ED) and hypertension are frequently comorbid conditions.^4–6 In two studies, 52% and 68% of men with hypertension also had ED.^4,5 For the majority of men with ED, the etiology is organic and is most commonly attributable to vascular disease.^7,8

Although ED is clearly associated with hypertension, it is less clear whether ED is due to the disease, treatment with antihypertensive agents, or both.^9–11 Regardless, patients with hypertension who experience “drug-induced” ED—either real or perceived—are at increased risk for nonadherence to antihypertensive medications. In a study of 1180 male outpatients,¹² 34% reported having ED; and 25% of these men attributed the problem to medications, particularly antihypertensive medications such as -blockers, angiotensin converting enzyme (ACE) inhibitors, calcium channel blockers, and diuretics. Nonadherence to treatment was common, and the primary reason given was ED.¹² In previous clinical trials of hypertension treatment, ED was also the primary reason for study withdrawal among male patients.^13,14

Sildenafil citrate is an effective oral treatment for ED of diverse etiologies,^15–17 including ED associated with medications such as antidepressants.¹⁸ Thus, it is reasonable to hypothesize that sildenafil would be well tolerated and effective in men with ED and hypertension who are taking multiple antihypertensives. However, data from previous studies are limited because relatively few patients with this profile have been included in double-blind, placebo-controlled trials of sildenafil. When the American College of Cardiology (ACC) and the American Heart Association (AHA) published their “Expert Consensus Document on the Use of Sildenafil in Patients With Cardiovascular Disease,”¹⁹ there was concern that although sildenafil was generally safe in most patients with cardiovascular disease, it could be “potentially hazardous” in patients taking multidrug antihypertensive regimens, despite a lack of data available at that time. We conducted this study to address this concern. Our aims were: 1) to assess the efficacy and safety of sildenafil in men with ED and treated hypertension and 2) to expand our clinical experience in patients taking multiple antihypertensive medications.

Methods

Study design and patient population

This was a multicenter, randomized, double-blind, placebo-controlled, flexible-dose study conducted at 58 sites in Australia, Europe, Canada, and the United States. Total study duration was 14 weeks: a 2-week screening period, 6 weeks of double-blind treatment, and 6 weeks of open-label sildenafil. Male patients (≥18 years) were eligible if they were in a stable sexual relationship and had a diagnosis of ED, defined as the inability to achieve or to maintain an erection sufficient for satisfactory sexual performance.²⁰ We documented ED based on a score of ≤21 on the Sexual Health Inventory for Men.²¹ Patients were required to have a diagnosis of arterial hypertension that was being treated with two or more different classes of antihypertensive drugs, with stable dosing for ≥4 weeks. Key exclusion criteria included the following: hypotension (<90/50 mm Hg) or uncontrolled hypertension (>170/110 mm Hg); significant cardiovascular disease (cardiac failure, myocardial infarction, unstable angina, stroke, symptomatic or clinically significant cardiac arrhythmias) in the previous 6 months; and current use of nitrates in any form on a regular or intermittent basis. Men who had previously been treated with sildenafil were also excluded.

At screening, patients who provided written informed consent were evaluated for eligibility. Study investigators obtained a complete medical history and performed a physical examination, including measurement of blood pressure (BP) and standard laboratory tests. Patients were randomized to 50 mg of oral sildenafil or matching placebo, which could be adjusted to 100 mg or 25 mg (after the first 2 weeks) based on efficacy and tolerability. Patients were instructed to record on an Event Log worksheet the date, when study drug was taken, what sexual activity was attempted, and the number of doses taken. Patients who completed double-blind treatment were eligible for the open-label phase.

Outcome measures

Primary outcomes were Question (Q) 3 and 4 of the International Index of Erectile Function (IIEF; Q3: “When you attempted intercourse, how often were you able to penetrate your partner?” Q4: “During sexual intercourse, how often were you able to maintain your erection after you had penetrated your partner?”).²² Secondary outcomes included the remaining IIEF questions, two global efficacy assessment (GEA) questions (GEA1, “Has treatment improved your erections?” GEA2, “Has treatment improved your ability for sexual intercourse?”), intercourse success rate, Life Satisfaction Checklist (LSC),²³ and Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS).²⁴ The 8-item LSC addresses satisfaction with sexual life and partner relationship, relationships with family and friends, life as a whole, and satisfaction with leisure, vocational, and financial situations. The 11-item EDITS questionnaire assesses patient satisfaction with treatment for ED.

Patients completed the IIEF and LSC at baseline (week 0) and at the end of double-blind treatment (week 6), and they completed the GEA and EDITS at week 6. At the end of the open-label phase (week 12), patients were asked the GEA questions. The blind was not broken until all subjects completed open-label treatment and the study database was locked.

Assessment of tolerability

All treatment-emergent adverse events (AE) were recorded regardless of treatment group or suspected causal relationship to the study drug, although this information was also recorded. “Treatment emergent” was defined as any event that occurred for the first time or worsened between the dates when the study drug was first dispensed and up to 7 days after the last dose. A serious adverse event (SAE) was defined as any event that: 1) resulted in death; 2) was life threatening; 3) resulted in hospitalization or prolongation of existing hospitalization; or 4) resulted in a persistent or significant disability.

Statistical analyses

Analysis of covariance (ANCOVA) was used for all outcome measures except the GEA questions and intercourse success rate. We used the intent-to-treat (ITT) principle for all analyses and the last observation carried forward algorithm for early withdrawals. All tests were two-sided and = 0.05. Logistic regression was used to analyze GEA questions and intercourse success rate. The IIEF Q3 and Q4 were analyzed for two subgroups of patients based on the number and type of prescribed antihypertensives. The subgroups for analysis were 1) patients taking two classes of antihypertensives and 2) patients taking three or more classes of antihypertensives. Each antihypertensive was categorized into one of seven classes: -blockers, diuretics, -blockers, ACE inhibitors, calcium channel blockers, angiotensin II receptor antagonists, and other antihypertensives.

Results

Demographic characteristics

Of 670 patients screened, 568 were randomized to treatment (Fig. 1). Of these, 279 sildenafil-treated and 283 placebo-treated patients took ≥1 dose of study medication. Patients who took ≥1 dose of study drug and provided ≥1 post-treatment assessment were included in the ITT efficacy analysis. A total of 29 patients prematurely terminated treatment, leaving 261 sildenafil- and 272 placebo-treated completers. A total of 531 patients were treated during the open-label phase; of these, there were 519 completers. Of the patients evaluable for efficacy, 324 (58%) were taking two classes and 235 (42%) were taking three or more classes of antihypertensives. Three patients who were taking one class of antihypertensive medication were not included in the efficacy analysis of stratification by the number of antihypertensives.

Progress of patients through the course of the study. DB = double-blind; OL = open-label.

Figure 1.

There were no differences in baseline characteristics between sildenafil- and placebo-treated patients (Table 1). Mean patient age was 59 years, and mean duration of ED was 4.5 years. Mean duration of hypertension was approximately 12 years. Table 1 lists the patient distribution by prescribed class of antihypertensives. The majority of patients (∼60%) were taking one or more diuretics.

Table 1

Demographic and clinical characteristics of study subjects

Characteristic	Placebo (n = 283)	Sildenafil (n = 279)
Age, y (mean ± SD)	59 ± 9	59 ± 8
ED duration, y (mean ± SD)	4.5 ± 4.6	4.6 ± 4.1
ED etiology, n (%)
Mixed	117 (41.3)	111 (39.8)
Organic	142 (50.2)	145 (52.0)
Psychogenic	24 (8.5)	23 (8.2)
Hypertension duration, y (mean ± SD)	11.4 ± 9.3	12.1 ± 8.9
Concomitant antihypertensive agents, n (%)
-Blockers	104 (36.5)	114 (40.9)
Diuretics	170 (60.1)	164 (58.8)
-Blockers	47 (16.6)	52 (18.6)
ACE inhibitors	133 (47.0)	123 (44.1)
Calcium channel blockers	148 (52.3)	137 (49.1)
Angiotensin II receptor antagonists	39 (13.8)	27 (9.7)
Other antihypertensive agents	17 (6.0)	26 (9.3)
Treatment duration, days (mean ± SD)
DB	40.0 ± 7.9	40.4 ± 8.9
OL	42.1 ± 7.1	42.3 ± 6.7
Last DB dose, n (%)
0 mg	283 (100)	0 (0)
25 mg	—	6 (2.2)
50 mg	—	106 (38.0)
100 mg	—	167 (59.9)
Number of doses taken (mean ± SD)
DB	14.9 ± 9.5	16.2 ± 9.2
OL	20.8 ± 11.3	20.0 ± 10.1

ACE = angiotensin converting enzyme; DB = double-blind; ED = erectile dysfunction; OL = open-label.

Efficacy during double-blind treatment

At week 6, sildenafil-treated patients had significantly improved scores compared with placebo-treated patients on Q3 (3.6 ± 0.1 v 2.7 ± 0.1) and Q4 (3.6 ± 0.1 v 2.5 ± 0.1), and on the other IIEF questions that comprise the erectile function domain (P < .0003) (Fig. 2). Among sildenafil-treated patients, there were no significant differences in Q3 and Q4 mean responses between patients taking two classes (3.9 ± 0.16 and 3.9 ± 0.15, respectively) and those taking three or more classes of antihypertensives (3.3 ± 0.19 and 3.4 ± 0.19, respectively). In addition to the improvements in erectile function, sildenafil-treated patients had significantly higher scores on the four other domains than placebo-treated patients (P< .0001) (Fig. 3).

Baseline mean scores (sildenafil and placebo combined) and end-of-treatment least squares (LS; ± SE) mean scores on the six questions (Q) representing the Erectile Function domain of the International Index of Erectile Function for patients treated with double-blind sildenafil (n = 263) or placebo (n = 274).*P < .0003 compared with placebo.

Figure 2.

Baseline mean scores (sildenafil and placebo combined) and end-of-treatment least squares (LS; ± SE) mean scores on questions (Q) in the five functional domains of the International Index of Erectile Function (IIEF) for patients treated with double-blind sildenafil (n = 264) or placebo (n = 275). *P < .0001 compared with placebo.

Figure 3.

Significantly larger percentages of patients who took sildenafil reported that treatment had improved their erections (71%) and their ability to have intercourse (69%) than those who took placebo (18% and 20%, respectively; P < .0001). Similarly, the intercourse success rate was significantly higher among sildenafil-treated (62%) than placebo-treated patients (26%; P< .0001).

Patients who took sildenafil had significantly higher mean scores on 10 EDITS items than did those who took placebo (P < .001) (Fig. 4). Similarly, sildenafil-treated patients had significantly higher mean scores on the LSC than placebo-treated patients with respect to three items: sexual life, partner relationship, and family life (P < .05) (Table 2).

End-of-treatment least squares (LS; ± SE) mean scores of questions (Q) on the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) questionnaire for patients treated with double-blind sildenafil (n = 261) or placebo (n = 268). *P < .001 compared with placebo.

Figure 4.

Table 2

Baseline and end-of-treatment scores on the Life Satisfaction Checklist, by treatment group

Item	Baseline Mean*	EOT Placebo, LS Mean (SE)	EOT Sildenafil LS Mean (SE)	P Value
Whole life	4.73	4.68 (0.06)	4.78 (0.07)	.1092
Sexual life	2.48	2.83 (0.10)	3.90 (0.11)	<.0001
Partner relationship	4.79	4.74 (0.07)	4.90 (0.08)	.0325
Family life	5.06	4.99 (0.06)	5.14 (0.06)	.0128
Friends, acquaintances	5.00	4.91 (0.06)	4.97 (0.06)	.2897
Leisure situation	4.70	4.57 (0.07)	4.62 (0.07)	.4818
Vocational situation	4.64	4.62 (0.07)	4.58 (0.08)	.5809
Financial situation	4.47	4.49 (0.06)	4.46 (0.06)	.6458

EOT = end of treatment; LS = least squares.

*

Placebo group (n = 275) and sildenafil group (n = 263) scores combined.

Efficacy during open-label treatment

After 6 weeks of open-label sildenafil, patients had comparable response rates on the GEA questions regardless of whether they initially took double-blind sildenafil or placebo. Of the patients in each double-blind treatment group, 84% reported that sildenafil had improved their erections; 83% and 81% of patients who took double-blind sildenafil or placebo, respectively, reported that sildenafil had improved their ability to have intercourse. The intercourse success rate among patients who had double-blind sildenafil was 72%, and the rate among those who had placebo was 70%.

Safety

During double-blind treatment, 40% of sildenafil-treated and 25% of placebo-treated patients experienced AE. Four patients in each group discontinued treatment because of AE. In the sildenafil group, three patients reported AE that were considered to be treatment related (mild headaches, moderately blurred vision, chromatopsia). One patient experienced asthenia and hypotension; however, these events were not considered to be related to the study drug. In the placebo group, two patients reported AE that were deemed to be treatment related (moderate chest pain, moderate arthralgia). One placebo-treated patient discontinued because of a viral infection that was not considered to be related to treatment. The fourth placebo-treated patient discontinued because of an SAE (namely, a motor vehicle crash).

The most commonly reported AE among sildenafil- and placebo-treated patients are listed in Table 3. Compared with placebo, sildenafil resulted in a higher frequency of reports of headache and facial flushing. There were no differences in the frequency or type of AE reported by patients taking two classes and three or more classes of antihypertensives. Fewer than 1% of the patients (two patients per treatment group) experienced SAE; none of these SAE were considered to be treatment related (Table 4).

Table 4

Most commonly reported adverse events (AE) during double-blind treatment by number of concomitant antihypertensive agents, treatment group, and causality

	2 Antihypertensive Agents		≥3 Antihypertensive Agents		All Patients
	Placebo (n = 162)	Sildenafil (n = 162)	Placebo (n = 119)	Sildenafil (n = 116)	Placebo (n = 283)	Sildenafil (n = 279)
All causality
Headache	5 (3.1)	17 (10.5)	5 (4.2)	11 (9.5)	10 (3.6)	28 (10.1)
Flushing	1 (0.6)	11 (6.8)	0 (0.0)	6 (5.2)	1 (0.4)	17 (6.1)
Dyspepsia	2 (1.2)	11 (6.8)	1 (0.8)	4 (3.4)	3 (1.1)	15 (5.4)
Dizziness	0 (0.0)	7 (4.3)	1 (0.8)	4 (3.4)	1 (0.4)	11 (4.0)
Nasal congestion	1 (0.6)	5 (3.1)	0 (0.0)	2 (1.7)	1 (0.4)	7 (2.5)
Abnormal vision	0 (0.0)	1 (0.6)	0 (0.0)	6 (5.2)	0 (0.0)	7 (2.5)
Treatment-related	n (%)	n (%)	n (%)	n (%)	n (%)	n (%)
Headache	0 (0.0)	15 (9.3)	2 (1.7)	7 (6.0)	2 (0.7)	22 (7.9)
Flushing	1 (0.6)	11 (6.8)	0 (0.0)	6 (5.2)	1 (0.4)	17 (6.1)
Dyspepsia	1 (0.6)	6 (3.7)	0 (0.0)	2 (1.7)	1 (0.4)	8 (2.9)
Dizziness	0 (0.0)	6 (3.7)	1 (0.8)	2 (1.7)	1 (0.4)	8 (2.9)
Nasal congestion	0 (0.0)	1 (0.6)	0 (0.0)	1 (0.9)	0 (0.0)	2 (0.7)
Abnormal vision	0 (0.0)	1 (0.6)	0 (0.0)	4 (3.4)	0 (0.0)	5 (1.8)

*Numbers do not add from double-blind treatment groups because three patients were taking one antihypertensive agent and were included in all analyses where the number of classes of antihypertensive agents were collapsed.

Table 3

Occurrence of adverse events during double-blind treatment by number of concomitant antihypertensive agents and treatment group

	2 Antihypertensive Agents		≥3 Antihypertensive Agents		All Patients
Patients Evaluable for AE	Placebo (n = 162)	Sildenafil (n = 162)	Placebo (n = 119)	Sildenafil (n = 116)	Placebo (n = 283)*	Sildenafil (n = 279)*
Patients with AE	40 (24.7)	66 (40.7)	33 (27.7)	45 (38.8)	73 (26.0)	111 (39.9)
Discontinuations from AE	2 (1.2)	3 (1.9)	2 (1.7)	1 (0.9)	4 (1.4)	4 (1.4)
Temporary discontinuation or dose reduction due to AE	1 (0.6)	3 (1.9)	0 (0.0)	2 (1.7)	1 (0.4)	5 (1.8)
SAE	0 (0.0)	1 (0.6)	2 (1.7)	1 (0.9)	2 (0.7)	2 (0.7)

AE = adverse events; SAE = serious adverse events.

Data are n (%).

*

Numbers do not add from double-blind treatment groups because data from three patients were taking one antihypertensive and included in all analyses where the number of classes of antihypertensives were collapsed.

During open-label treatment, 37% of patients experienced AE, and 2% experienced SAE. Only four patients (3%) from the double-blind placebo group discontinued open-label treatment because of AE. No patient from the double-blind sildenafil group discontinued open-label treatment because of AE. Again, there were no differences in the incidence of AE between patients taking two classes and three or more classes of antihypertensives. The most frequently reported AE during open-label treatment were comparable with those reported during double-blind treatment. The incidence of treatment-related AE among double-blind placebo patients was comparable to that among sildenafil-treated patients during double-blind treatment. This was expected, as double-blind placebo-treated patients were exposed to sildenafil for the first time when they entered the open-label phase. Overall, AE reported during double-blind and open-label treatment periods were transient and mild to moderate in severity.

Discussion

This is the first large prospective study to evaluate the efficacy and tolerability of sildenafil in men with ED and hypertension who were taking multiple classes of antihypertensives. The study was important because: 1) it directly assessed the effectiveness of sildenafil in a large representative population of men with hypertension; and 2) it directly addressed the concerns raised by the American College of Cardiology and American Heart Association regarding the cardiovascular safety of sildenafil among men taking multiple antihypertensives. Our results showed that sildenafil was both effective and well tolerated in men with ED and hypertension who were taking two or more antihypertensives.

Sildenafil-treated patients had significantly higher mean scores on all measures of erectile function than placebo-treated patients after 6 weeks of double-blind treatment. During open-label treatment, patients who previously took double-blind placebo experienced a level of improvement in erectile function and reported an intercourse success rate comparable to those attained by patients who took double-blind sildenafil. Sildenafil-treated patients were highly satisfied with treatment and showed significantly greater improvements in satisfaction with sexual life, family life, and partner relationships than placebo-treated patients.

Kloner et al demonstrated similar results for patients with ED who were or were not taking antihypertensives in a retrospective analysis of data from 10 randomized controlled trials (RCT; N = 3414).²⁵ After double-blind treatment, sildenafil-treated patients had significantly higher mean scores on Q3 and Q4 than placebo-treated patients, regardless of whether concomitant antihypertensives were taken. At the end of treatment, 70% of sildenafil-treated patients taking antihypertensives and 72% of those not taking antihypertensives reported improved erections. The corresponding percentages for the placebo groups were 21% and 27%.

Safety of sildenafil

The overall incidence of AE was higher among sildenafil-treated patients than placebo-treated patients. However, most AE were transient and mild or moderate in severity, and only three patients discontinued because of treatment-related AE. The observation that a larger percentage of patients who took sildenafil experienced AE can be attributed to the drug’s modest vasodilatory properties. The occurrence of AE potentially related to hypotensive effects (dizziness, hypotension, labile BP, vertigo) was low (<4%). Importantly, there were no differences in the incidence of AE between patients taking two classes (41%) and three or more classes of antihypertensives (39%). Four patients (<1%; two from each treatment group) experienced SAE, but none was considered by the investigators to be related to treatment.

Kloner et al reported similar AE rates.²⁵ Among patients taking two antihypertensives, the incidence of all-cause AE was 31%, and in patients taking three or more agents the incidence was 41%. The incidence of AE among patients not taking antihypertensives was 38%. Discontinuation rates due to all-cause AE were also similar to our results: 2.4% of patients whether taking or not taking antihypertensives discontinued prematurely. Overall, these results suggest that sildenafil was well tolerated and that there were no additional safety risks associated with the use of sildenafil among men with ED and hypertension who were taking multiple antihypertensives.

Our results can be generalized to the general population of men with ED and treated hypertension. Patients ranged in age from 29 to 86 years, which is representative of the general population of men with hypertension.¹ With the exception of patients who had a recent history of significant cardiovascular disease, patients with common comorbid conditions and other vascular risk factors were eligible to participate. Given that hypertension treatment typically consists of a combination of antihypertensives, we evaluated the five major classes of antihypertensive agents among patients who were taking at least two from these classes. These classes and combinations also have been evaluated in two large-scale RCT on the effects of antihypertensives on sexual function.^26,27 Finally, the dosing regimen for sildenafil was in the recommended range (25 to 100 mg) used in clinical practice.

Endothelial function, and specifically the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP)-mediated pathway of vasodilation can be impaired in both ED²⁸ and hypertension.^29,30 Thus, it was important to determine whether treatment with sildenafil might potentiate the decreases in BP achieved with different classes of antihypertensive agents. A few studies have demonstrated that sildenafil caused decreases in BP among patients with treated hypertension.^31–33 Vardi et al used ambulatory BP monitoring and found that the decreases in BP were similar between hypertensive and normotensive men³³ and that there were no significant differences between hypertensive men taking one antihypertensive agent compared with those taking two or more of these agents. In a retrospective analysis of data from five RCT in which patients took their dose of study medication on the morning of their clinic visit, Zusman et al showed no significant effects on BP within a few hours of dosing. In addition, the incidence of all-causality AE was comparable in patients taking and not taking antihypertensives. The incidence of AE related to BP changes was low and comparable between patients taking and not taking antihypertensives.³⁴ Together, these findings suggest that the small transient effects on BP are not likely to be clinically significant, even among patients taking multiple antihypertensives.³⁴

The health risks associated with uncontrolled hypertension can be serious, and priority should be given to achieving adequate BP control. One approach to the management of a patient with hypertension and ED is to prescribe antihypertensives that have the lowest potential for causing sexual side effects. The risk of ED is greater with some classes of antihypertensive agents (-blockers) than with others (ACE inhibitors, -blockers).^10,26,27 However, if ED is a comorbid condition in men with hypertension or if it occurs after use of antihypertensives has begun, adjunctive treatment with sildenafil can be a safe and effective option, as demonstrated in this study. Furthermore, because the sexual side effects associated with some antihypertensives frequently lead to nonadherence, effective treatment of ED associated with antihypertensive medication may improve adherence, which is important for the consistent control of hypertension. Because simultaneous administration of sildenafil and -blockers may lead to symptomatic hypotension in some patients, sildenafil doses >25 mg should not be taken within 4 hours of taking an -blocker.³⁶ Also, because sildenafil potentiates the hypotensive effects of nitrates and nitric oxide donors, use of these drugs on a regular or intermittent basis is the only absolute contraindication.

In conclusion, ED may be an early symptom related to hypertension and should be the subject of inquiry in every patient newly diagnosed with hypertension, both before and after initiation of pharmacologic therapy. If ED stems from the pharmacologic management of hypertension, physicians can modify treatment or add adjunctive therapy such as sildenafil to ensure adherence. This study showed that sildenafil is an effective and well tolerated treatment for ED among patients with hypertension who are taking multiple classes of antihypertensive agents. Sildenafil treatment was not associated with additional safety risks in this patient population.³⁵

Appendix

List of multicenter principal investigators by country

Australia: Robert McLachlan, MD, Clayton, VIC; Carol Pollock, MD, St. Leonards, NSW; Ian Puddey, MD, Perth, WA; Michael Stowasser, MD, Woolloongabba, QLD; Peter Sutherland, MD, Adelaide, SA. Canada: Norman R. Campbell, MD, Calgary, Alberta; Paul V. Nguyen, MD, Montreal, Quebec; Ernesto Schiffrin, MD, Montreal, Quebec. Czech Republic: Vaclav Chaloupka, MD, Brno-Bohunice; Michal Padour, MD, Prague; Jan Pavlas, MD, Ostrava-Kuncice; Miroslav Soucek, MD, Brno. Germany: Hans-Lewis Brill, MD, Luenen; Herbert Mauersberger, MD, Schwenningen; Verena Stangl, MD, Berlin. Italy: Roberto Fogari, MD, Pavia; Bruno Trimarco, MD, Napoli. Poland: Mirosaw Dluzniewski, MD, Warszawa; Janusz Dubejko, MD, Lublin; Joanna Niegowska, MD, Warszawa-Anin. Spain: Pedro Aranda, MD, Malaga; Carlos Calvo, MD, Santiago de Compostela;; Manuel Luque-Otero, MD, Madrid; Francisco Fernandez Vega, MD, Oviedo. Sweden: Björn Dahlöf, MD, Gothenburg; Anders Dahlqvist, MD, Gävle; Ronnie Willenheimer, MD, PhD, Malmö. Turkey: Nergiz Domanic, MD, Istanbul; Ali Oto, MD, Ankara. United Kingdom: John Hole, MD, Trowbridge, Wiltshire; James Rudge, MD, Stratford-upon-Avon; Andrew Smithers, MD, Coventry; Susan Taylor, MD, Chorley. United States: Stephen Auerbach, MD, Newport Beach, CA; David Calhoun, MD, Birmingham, AL; William Cleveland, MD, Atlanta, GA; Louis K. Essandoh, MD, Annapolis, MD; Harry Geisberg, MD, Anderson, SC; Jeffrey Geohas, MD, Chicago, IL; Patricia Gilhooly, MD, East Orange, NJ; Emilio Gomez, MD, Miami, FL; Richard Grimm, Jr, MD, Minneapolis, MN; Terrence C. Hack, MD, Ayer, MA; Robert Kaufmann, MD, Atlanta, GA; Thomas Marbury, MD, Orlando, FL; Franz Messerli, MD, New Orleans, LA; Syed Mohiuddin, MD, Omaha, NE; Joel Neutel, MD, Orange, CA; Frank Pettyjohn, MD, Mobile, AL; Robert Philips, MD, New York, NY; Leopoldo Raij, MD, Minneapolis, MN; Promad Raval, MD, Oak Park, MI; Ridwan Shabsigh, MD, New York, NY; Alexander Shepherd, MD, PhD, San Antonio, TX; William Smith, MD, New Orleans, LA; Barton Wachs, MD, Long Beach, CA; Jay M. Young, MD, Laguna Hills, CA.