Sildenafil Citrate for Erectile Dysfunction inMen Receiving Multiple Antihypertensive Agents

A Randomized Controlled Trial

Thomas G. Pickering, Alexander M.M. Shepherd, Ian Puddey,Dale B. Glasser, John Orazem, Nancy Sherman, and Giuseppe Mancia

AJH 2004; 17:1135–1142

Background: Erectile dysfunction (ED) is commonamong men taking antihypertensive drugs to control bloodpressure. We evaluated the safety and efficacy of sildenafilcitrate for treating ED in men taking multiple antihyper-tensive medications in a randomized, double-blind, place-bo-controlled trial.

Methods: A total of 568 men (�18 years) with ED andhypertension who were taking two or more antihyperten-sives were randomized to sildenafil (n � 281) or matchingplacebo (n � 287) for a 6-week double-blind trial fol-lowed by a 6-week open-label phase during which allpatients received sildenafil. Primary efficacy variableswere questions (Q) 3 and 4 (frequency of erections andpenetration) of the International Index of Erectile Function(IIEF), and secondary efficacy variables were two globalefficacy assessment (GEA) questions regarding improve-ment 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-

Milano-Bicocca (GM), Clinica Medica–Ospedale San Gerardo, Milan, Italy.

© 2004 by the American Journal of Hypertension, Ltd.Published by Elsevier Inc.

treated compared with placebo-treated patients. In regardto Q3 and Q4 there were no differences between patientstaking two and those taking three or more antihypertensiveagents. In all, 71% and 69% of sildenafil-treated patientsreported improved erections (GEA1) and intercourse(GEA2) compared with 18% and 20% of placebo-treatedpatients, respectively. By week 12, �80% of all patients(regardless of initial treatment group) had improved erec-tions and intercourse. During double-blind treatment, 40%of sildenafil-treated and 25% of placebo-treated patientsexperienced adverse events; fewer than 2% in each groupdiscontinued because of adverse events.

Conclusions: Sildenafil was an effective and well tol-erated treatment for ED in men receiving multiple antihy-pertensives. The results suggest that there were noadditional safety risks associated with the use of sildenafilin these patients. Am J Hypertens 2004;17:1135–1142© 2004 American Journal of Hypertension, Ltd.

Key Words: Impotence, hypertension, phosphodiester-

ase inhibitor, antihypertensive agents, drug safety.

H ypertension is a serious public health problem,with an overall prevalence of 26% among Amer-ican men (�18 years),1 which increases mark-

edly 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 orolder.2,3 Erectile dysfunction (ED) and hypertension arefrequently comorbid conditions.4–6 In two studies, 52%and 68% of men with hypertension also had ED.4,5 For themajority of men with ED, the etiology is organic and ismost commonly attributable to vascular disease.7,8

Although ED is clearly associated with hypertension, it is

Received April 17, 2003. First decision July 9, 2003. Accepted July 9,2004.

From the Columbia University Medical College (TGP), New York, NewYork; University of Texas Health Sciences Center (AMMS), San Antonio,Texas; University of Western Australia (IP), Perth, West Australia, Austra-lia; Pfizer Inc. (DBG, JO, NS), New York, New York; and Università di

less clear whether ED is due to the disease, treatment withantihypertensive agents, or both.9–11 Regardless, patientswith hypertension who experience “drug-induced” ED—either real or perceived—are at increased risk for nonadher-ence to antihypertensive medications. In a study of 1180 maleoutpatients,12 34% reported having ED; and 25% of thesemen attributed the problem to medications, particularly anti-hypertensive medications such as �-blockers, angiotensinconverting enzyme (ACE) inhibitors, calcium channel block-ers, and diuretics. Nonadherence to treatment was common,and the primary reason given was ED.12 In previous clinical

This study was sponsored by Pfizer Inc., New York, NY.Address correspondence and reprint requests to Dr. Thomas G.

Pickering, Behavioral Cardiovascular Health and Hypertension Program,Columbia Presbyterian Medical Center, PH 9-946, 622 West 168thStreet, New York, NY 10032; e-mail tp2114@columbia.edu

0895-7061/04/$30.00doi:10.1016/j.amjhyper.2004.07.004

1136 AJH–December 2004–VOL. 17, NO. 12, Part 1USE OF SILDENAFIL WITH ANTIHYPERTENSIVE AGENTS

trials of hypertension treatment, ED was also the primaryreason for study withdrawal among male patients.13,14

Sildenafil citrate is an effective oral treatment for ED ofdiverse etiologies,15–17 including ED associated with med-ications such as antidepressants.18 Thus, it is reasonable tohypothesize that sildenafil would be well tolerated andeffective in men with ED and hypertension who are takingmultiple antihypertensives. However, data from previousstudies are limited because relatively few patients with thisprofile have been included in double-blind, placebo-con-trolled trials of sildenafil. When the American College ofCardiology (ACC) and the American Heart Association(AHA) published their “Expert Consensus Document onthe Use of Sildenafil in Patients With CardiovascularDisease,”19 there was concern that although sildenafil wasgenerally safe in most patients with cardiovascular dis-ease, it could be “potentially hazardous” in patients takingmultidrug antihypertensive regimens, despite a lack ofdata available at that time. We conducted this study toaddress this concern. Our aims were: 1) to assess theefficacy and safety of sildenafil in men with ED and treatedhypertension and 2) to expand our clinical experience inpatients taking multiple antihypertensive medications.

MethodsStudy Design and Patient Population

This was a multicenter, randomized, double-blind, place-bo-controlled, flexible-dose study conducted at 58 sites inAustralia, Europe, Canada, and the United States. Totalstudy 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 ifthey were in a stable sexual relationship and had a diag-nosis of ED, defined as the inability to achieve or tomaintain an erection sufficient for satisfactory sexual per-formance.20 We documented ED based on a score of �21on the Sexual Health Inventory for Men.21 Patients wererequired to have a diagnosis of arterial hypertension thatwas being treated with two or more different classes ofantihypertensive drugs, with stable dosing for �4 weeks.Key exclusion criteria included the following: hypotension(�90/50 mm Hg) or uncontrolled hypertension (�170/110mm Hg); significant cardiovascular disease (cardiac fail-ure, myocardial infarction, unstable angina, stroke, symp-tomatic or clinically significant cardiac arrhythmias) in theprevious 6 months; and current use of nitrates in any formon a regular or intermittent basis. Men who had previouslybeen treated with sildenafil were also excluded.

At screening, patients who provided written informedconsent were evaluated for eligibility. Study investigatorsobtained a complete medical history and performed aphysical examination, including measurement of bloodpressure (BP) and standard laboratory tests. Patients wererandomized to 50 mg of oral sildenafil or matching pla-cebo, which could be adjusted to 100 mg or 25 mg (after

the first 2 weeks) based on efficacy and tolerability. Pa-

tients were instructed to record on an Event Log worksheetthe date, when study drug was taken, what sexual activitywas attempted, and the number of doses taken. Patientswho completed double-blind treatment were eligible forthe open-label phase.

Outcome Measures

Primary outcomes were Question (Q) 3 and 4 of theInternational Index of Erectile Function (IIEF; Q3: “Whenyou attempted intercourse, how often were you able topenetrate your partner?” Q4: “During sexual intercourse,how often were you able to maintain your erection afteryou had penetrated your partner?”).22 Secondary outcomesincluded the remaining IIEF questions, two global efficacyassessment (GEA) questions (GEA1, “Has treatment im-proved your erections?” GEA2, “Has treatment improvedyour ability for sexual intercourse?”), intercourse successrate, Life Satisfaction Checklist (LSC),23 and ErectileDysfunction Inventory of Treatment Satisfaction(EDITS).24 The 8-item LSC addresses satisfaction withsexual life and partner relationship, relationships withfamily and friends, life as a whole, and satisfaction withleisure, vocational, and financial situations. The 11-itemEDITS questionnaire assesses patient satisfaction withtreatment 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 atweek 6. At the end of the open-label phase (week 12),patients were asked the GEA questions. The blind was notbroken until all subjects completed open-label treatmentand the study database was locked.

Assessment of Tolerability

All treatment-emergent adverse events (AE) were re-corded regardless of treatment group or suspected causalrelationship to the study drug, although this informationwas also recorded. “Treatment emergent” was defined asany event that occurred for the first time or worsenedbetween the dates when the study drug was first dispensedand up to 7 days after the last dose. A serious adverseevent (SAE) was defined as any event that: 1) resulted indeath; 2) was life threatening; 3) resulted in hospitalizationor prolongation of existing hospitalization; or 4) resultedin a persistent or significant disability.

Statistical Analyses

Analysis of covariance (ANCOVA) was used for all out-come measures except the GEA questions and intercoursesuccess rate. We used the intent-to-treat (ITT) principle forall analyses and the last observation carried forward algo-rithm for early withdrawals. All tests were two-sided and� � 0.05. Logistic regression was used to analyze GEAquestions and intercourse success rate. The IIEF Q3 andQ4 were analyzed for two subgroups of patients based on

the number and type of prescribed antihypertensives. The

1137AJH–December 2004–VOL. 17, NO. 12, Part 1 USE OF SILDENAFIL WITH ANTIHYPERTENSIVE AGENTS

subgroups for analysis were 1) patients taking two classesof antihypertensives and 2) patients taking three or moreclasses of antihypertensives. Each antihypertensive wascategorized into one of seven classes: �-blockers, diuret-ics, �-blockers, ACE inhibitors, calcium channel blockers,angiotensin II receptor antagonists, and other antihyper-tensives.

ResultsDemographic Characteristics

Of 670 patients screened, 568 were randomized to treat-ment (Fig. 1). Of these, 279 sildenafil-treated and 283placebo-treated patients took �1 dose of study medica-tion. Patients who took �1 dose of study drug and pro-vided �1 post-treatment assessment were included in theITT efficacy analysis. A total of 29 patients prematurelyterminated treatment, leaving 261 sildenafil- and 272 pla-cebo-treated completers. A total of 531 patients weretreated during the open-label phase; of these, there were519 completers. Of the patients evaluable for efficacy, 324(58%) were taking two classes and 235 (42%) were takingthree or more classes of antihypertensives. Three patientswho were taking one class of antihypertensive medicationwere not included in the efficacy analysis of stratificationby the number of antihypertensives.

There were no differences in baseline characteristics

FIG. 1. Progress of patients through the course of the study. DB �double-blind; OL � open-label.

between sildenafil- and placebo-treated patients (Table 1).

Mean patient age was 59 years, and mean duration of EDwas 4.5 years. Mean duration of hypertension was approx-imately 12 years. Table 1 lists the patient distribution byprescribed class of antihypertensives. The majority of pa-tients (�60%) were taking one or more diuretics.

Efficacy During Double-Blind Treatment

At week 6, sildenafil-treated patients had significantlyimproved scores compared with placebo-treated patientson 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 theerectile function domain (P � .0003) (Fig. 2). Amongsildenafil-treated patients, there were no significant differ-ences in Q3 and Q4 mean responses between patientstaking two classes (3.9 � 0.16 and 3.9 � 0.15, respec-tively) and those taking three or more classes of antihy-pertensives (3.3 � 0.19 and 3.4 � 0.19, respectively). Inaddition to the improvements in erectile function, silde-nafil-treated patients had significantly higher scores on thefour other domains than placebo-treated patients (P�.0001) (Fig. 3).

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

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

Efficacy During Open-Label Treatment

After 6 weeks of open-label sildenafil, patients had com-parable response rates on the GEA questions regardless ofwhether they initially took double-blind sildenafil or pla-cebo. 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 sildenafilor placebo, respectively, reported that sildenafil had im-proved their ability to have intercourse. The intercoursesuccess rate among patients who had double-blind silde-nafil was 72%, and the rate among those who had placebowas 70%.

Safety

During double-blind treatment, 40% of sildenafil-treatedand 25% of placebo-treated patients experienced AE. Fourpatients in each group discontinued treatment because ofAE. In the sildenafil group, three patients reported AE thatwere considered to be treatment related (mild headaches,

moderately blurred vision, chromatopsia). One patient ex-

rectile

1138 AJH–December 2004–VOL. 17, NO. 12, Part 1USE OF SILDENAFIL WITH ANTIHYPERTENSIVE AGENTS

perienced asthenia and hypotension; however, these eventswere not considered to be related to the study drug. In theplacebo group, two patients reported AE that were deemedto be treatment related (moderate chest pain, moderatearthralgia). One placebo-treated patient discontinued be-cause of a viral infection that was not considered to berelated to treatment. The fourth placebo-treated patientdiscontinued because of an SAE (namely, a motor vehiclecrash).

Table 1. Demographic and clinical characteristics o

Characteristic

Age, y (mean � SD)ED duration, y (mean � SD)ED etiology, n (%)

MixedOrganicPsychogenic

Hypertension duration, y (mean � SD)Concomitant antihypertensive agents, n (%)

�-BlockersDiuretics�-BlockersACE inhibitorsCalcium channel blockersAngiotensin II receptor antagonistsOther antihypertensive agents

Treatment duration, days (mean � SD)DBOL

Last DB dose, n (%)0 mg25 mg50 mg100 mg

Number of doses taken (mean � SD)DBOL

ACE � angiotensin converting enzyme; DB � double-blind; ED � e

FIG. 2. Baseline mean scores (sildenafil and placebo combined)and end-of-treatment least squares (LS; � SE) mean scores on thesix questions (Q) representing the Erectile Function domain of theInternational Index of Erectile Function for patients treated with

double-blind sildenafil (n � 263) or placebo (n � 274).*P � .0003compared with placebo.

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

udy subjects

Placebo(n � 283)

Sildenafil(n � 279)

59 � 9 59 � 84.5 � 4.6 4.6 � 4.1

117 (41.3) 111 (39.8)142 (50.2) 145 (52.0)24 (8.5) 23 (8.2)

11.4 � 9.3 12.1 � 8.9

104 (36.5) 114 (40.9)170 (60.1) 164 (58.8)47 (16.6) 52 (18.6)

133 (47.0) 123 (44.1)148 (52.3) 137 (49.1)39 (13.8) 27 (9.7)17 (6.0) 26 (9.3)

40.0 � 7.9 40.4 � 8.942.1 � 7.1 42.3 � 6.7

283 (100) 0 (0)— 6 (2.2)— 106 (38.0)— 167 (59.9)

14.9 � 9.5 16.2 � 9.220.8 � 11.3 20.0 � 10.1

dysfunction; OL � open-label.

FIG. 3. Baseline mean scores (sildenafil and placebo combined)and end-of-treatment least squares (LS; � SE) mean scores onquestions (Q) in the five functional domains of the InternationalIndex of Erectile Function (IIEF) for patients treated with double-

f st

blind sildenafil (n � 264) or placebo (n � 275). *P � .0001 com-pared with placebo.

1139AJH–December 2004–VOL. 17, NO. 12, Part 1 USE OF SILDENAFIL WITH ANTIHYPERTENSIVE AGENTS

During open-label treatment, 37% of patients experiencedAE, and 2% experienced SAE. Only four patients (3%) fromthe double-blind placebo group discontinued open-label treat-ment because of AE. No patient from the double-blind sil-denafil group discontinued open-label treatment because ofAE. Again, there were no differences in the incidence of AEbetween patients taking two classes and three or more classesof antihypertensives. The most frequently reported AE duringopen-label treatment were comparable with those reportedduring double-blind treatment. The incidence of treatment-related AE among double-blind placebo patients was com-parable to that among sildenafil-treated patients during

FIG. 4. End-of-treatment least squares (LS; � SE) mean scores ofquestions (Q) on the Erectile Dysfunction Inventory of TreatmentSatisfaction (EDITS) questionnaire for patients treated with double-blind sildenafil (n � 261) or placebo (n � 268). *P � .001 comparedwith placebo.

Table 2. Baseline and end-of-treatment scores on

ItemBaseline

Mean*

Whole life 4.73Sexual life 2.48Partner relationship 4.79Family life 5.06Friends, acquaintances 5.00Leisure situation 4.70Vocational situation 4.64Financial situation 4.47

EOT � end of treatment; LS � least squares.* Placebo group (n � 275) and sildenafil group (n � 263) scores comb

double-blind treatment. This was expected, as double-blindplacebo-treated patients were exposed to sildenafil for thefirst time when they entered the open-label phase. Overall,AE reported during double-blind and open-label treatmentperiods were transient and mild to moderate in severity.

DiscussionThis is the first large prospective study to evaluate the effi-cacy and tolerability of sildenafil in men with ED and hy-pertension who were taking multiple classes ofantihypertensives. The study was important because: 1) itdirectly assessed the effectiveness of sildenafil in a largerepresentative population of men with hypertension; and 2) itdirectly addressed the concerns raised by the American Col-lege of Cardiology and American Heart Association regard-ing the cardiovascular safety of sildenafil among men takingmultiple antihypertensives. Our results showed that sildenafilwas both effective and well tolerated in men with ED andhypertension who were taking two or more antihyperten-sives.

Sildenafil-treated patients had significantly higher meanscores on all measures of erectile function than placebo-treated patients after 6 weeks of double-blind treatment. Dur-ing open-label treatment, patients who previously tookdouble-blind placebo experienced a level of improvement inerectile function and reported an intercourse success ratecomparable to those attained by patients who took double-blind sildenafil. Sildenafil-treated patients were highly satis-fied with treatment and showed significantly greaterimprovements in satisfaction with sexual life, family life, andpartner relationships than placebo-treated patients.

Kloner et al demonstrated similar results for patients withED who were or were not taking antihypertensives in aretrospective analysis of data from 10 randomized controlledtrials (RCT; N � 3414).25 After double-blind treatment,sildenafil-treated patients had significantly higher meanscores on Q3 and Q4 than placebo-treated patients, regardlessof whether concomitant antihypertensives were taken. At theend of treatment, 70% of sildenafil-treated patients takingantihypertensives and 72% of those not taking antihyperten-

Life Satisfaction Checklist, by treatment group

EOTcebo, LSan (SE)

EOTSildenafil LSMean (SE)

PValue

8 (0.06) 4.78 (0.07) .10923 (0.10) 3.90 (0.11) �.00014 (0.07) 4.90 (0.08) .03259 (0.06) 5.14 (0.06) .01281 (0.06) 4.97 (0.06) .28977 (0.07) 4.62 (0.07) .48182 (0.07) 4.58 (0.08) .58099 (0.06) 4.46 (0.06) .6458

the

PlaMe

4.62.84.74.94.94.54.64.4

ined.

nsive

1140 AJH–December 2004–VOL. 17, NO. 12, Part 1USE OF SILDENAFIL WITH ANTIHYPERTENSIVE AGENTS

sives reported improved erections. The corresponding per-centages 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, mostAE were transient and mild or moderate in severity, and onlythree patients discontinued because of treatment-related AE.The observation that a larger percentage of patients who tooksildenafil experienced AE can be attributed to the drug’smodest vasodilatory properties. The occurrence of AE poten-tially related to hypotensive effects (dizziness, hypotension,labile BP, vertigo) was low (�4%). Importantly, there wereno differences in the incidence of AE between patients takingtwo classes (41%) and three or more classes of antihyperten-

Table 3. Occurrence of adverse events during doupertensive agents and treatment group

Patients Evaluable forAE

2 AntihypertensiveAgents

Placebo(n � 162)

Sildenafi(n � 162)

Patients with AE 40 (24.7) 66 (40.7)Discontinuations from AE 2 (1.2) 3 (1.9)Temporary discontinuation

or dose reduction due toAE

1 (0.6) 3 (1.9)

SAE 0 (0.0) 1 (0.6)

AE � adverse events; SAE � serious adverse events.Data are n (%).* Numbers do not add from double-blind treatment groups be

included in all analyses where the number of classes of antihyperte

Table 4. Most commonly reported adverse eventscomitant antihypertensive agents, treatment group,

2 AntihypertensiveAgents

Placebo(n � 162)

Sildenafil(n � 162)

All causalityHeadache 5 (3.1) 17 (10.5)Flushing 1 (0.6) 11 (6.8)Dyspepsia 2 (1.2) 11 (6.8)Dizziness 0 (0.0) 7 (4.3)Nasal congestion 1 (0.6) 5 (3.1)Abnormal vision 0 (0.0) 1 (0.6)

Treatment-related n (%) n (%)Headache 0 (0.0) 15 (9.3)Flushing 1 (0.6) 11 (6.8)Dyspepsia 1 (0.6) 6 (3.7)Dizziness 0 (0.0) 6 (3.7)Nasal congestion 0 (0.0) 1 (0.6)Abnormal vision 0 (0.0) 1 (0.6)

*Numbers do not add from double-blind treatment groups because threein all analyses where the number of classes of antihypertensive agents w

sives (39%). Four patients (�1%; two from each treatmentgroup) experienced SAE, but none was considered by theinvestigators to be related to treatment.

Kloner et al reported similar AE rates.25 Among pa-tients taking two antihypertensives, the incidence of all-cause AE was 31%, and in patients taking three or moreagents the incidence was 41%. The incidence of AEamong patients not taking antihypertensives was 38%.Discontinuation rates due to all-cause AE were also sim-ilar to our results: 2.4% of patients whether taking or nottaking antihypertensives discontinued prematurely. Over-all, these results suggest that sildenafil was well toleratedand that there were no additional safety risks associatedwith the use of sildenafil among men with ED and hyper-tension who were taking multiple antihypertensives.

blind treatment by number of concomitant antihy-

3 AntihypertensiveAgents All Patients

Placebon � 119)

Sildenafil(n � 116)

Placebo(n � 283)*

Sildenafil(n � 279)*

3 (27.7) 45 (38.8) 73 (26.0) 111 (39.9)2 (1.7) 1 (0.9) 4 (1.4) 4 (1.4)0 (0.0) 2 (1.7) 1 (0.4) 5 (1.8)

2 (1.7) 1 (0.9) 2 (0.7) 2 (0.7)

data from three patients were taking one antihypertensive ands were collapsed.

) during double-blind treatment by number of con-causality

AntihypertensiveAgents All Patients

cebo119)

Sildenafil(n � 116)

Placebo(n � 283)

Sildenafil(n � 279)

(4.2) 11 (9.5) 10 (3.6) 28 (10.1)(0.0) 6 (5.2) 1 (0.4) 17 (6.1)(0.8) 4 (3.4) 3 (1.1) 15 (5.4)(0.8) 4 (3.4) 1 (0.4) 11 (4.0)(0.0) 2 (1.7) 1 (0.4) 7 (2.5)(0.0) 6 (5.2) 0 (0.0) 7 (2.5)(%) n (%) n (%) n (%)(1.7) 7 (6.0) 2 (0.7) 22 (7.9)(0.0) 6 (5.2) 1 (0.4) 17 (6.1)(0.0) 2 (1.7) 1 (0.4) 8 (2.9)(0.8) 2 (1.7) 1 (0.4) 8 (2.9)(0.0) 1 (0.9) 0 (0.0) 2 (0.7)(0.0) 4 (3.4) 0 (0.0) 5 (1.8)

ble-

>

l(

3

cause

(AEand

>3

Pla(n �

501100n200100

patients were taking one antihypertensive agent and were includedere collapsed.

1141AJH–December 2004–VOL. 17, NO. 12, Part 1 USE OF SILDENAFIL WITH ANTIHYPERTENSIVE AGENTS

Our results can be generalized to the general populationof men with ED and treated hypertension. Patients rangedin age from 29 to 86 years, which is representative of thegeneral population of men with hypertension.1 With theexception of patients who had a recent history of signifi-cant cardiovascular disease, patients with common comor-bid conditions and other vascular risk factors were eligibleto participate. Given that hypertension treatment typicallyconsists of a combination of antihypertensives, we evalu-ated the five major classes of antihypertensive agentsamong patients who were taking at least two from theseclasses. These classes and combinations also have beenevaluated in two large-scale RCT on the effects of antihy-pertensives on sexual function.26,27 Finally, the dosingregimen for sildenafil was in the recommended range (25to 100 mg) used in clinical practice.

Endothelial function, and specifically the nitric oxide(NO)–cyclic guanosine monophosphate (cGMP)–medi-ated pathway of vasodilation can be impaired in both ED28

and hypertension.29,30 Thus, it was important to determinewhether treatment with sildenafil might potentiate the de-creases in BP achieved with different classes of antihyper-tensive agents. A few studies have demonstrated thatsildenafil caused decreases in BP among patients withtreated hypertension.31–33 Vardi et al used ambulatory BPmonitoring and found that the decreases in BP were sim-ilar between hypertensive and normotensive men33 andthat there were no significant differences between hyper-tensive men taking one antihypertensive agent comparedwith those taking two or more of these agents. In aretrospective analysis of data from five RCT in whichpatients took their dose of study medication on the morn-ing of their clinic visit, Zusman et al showed no significanteffects on BP within a few hours of dosing. In addition, theincidence of all-causality AE was comparable in patientstaking and not taking antihypertensives. The incidence ofAE related to BP changes was low and comparable be-tween patients taking and not taking antihypertensives.34

Together, these findings suggest that the small transienteffects on BP are not likely to be clinically significant,even among patients taking multiple antihypertensives.34

The health risks associated with uncontrolled hyperten-sion can be serious, and priority should be given to achiev-ing adequate BP control. One approach to the managementof a patient with hypertension and ED is to prescribeantihypertensives that have the lowest potential for caus-ing sexual side effects. The risk of ED is greater with someclasses of antihypertensive agents (�-blockers) than withothers (ACE inhibitors, �-blockers).10,26,27 However, ifED is a comorbid condition in men with hypertension or ifit occurs after use of antihypertensives has begun, adjunc-tive treatment with sildenafil can be a safe and effectiveoption, as demonstrated in this study. Furthermore, be-cause the sexual side effects associated with some antihy-pertensives frequently lead to nonadherence, effectivetreatment of ED associated with antihypertensive medica-

tion may improve adherence, which is important for the

consistent control of hypertension. Because simultaneousadministration of sildenafil and �-blockers may lead tosymptomatic hypotension in some patients, sildenafildoses �25 mg should not be taken within 4 hours oftaking an �-blocker.36 Also, because sildenafil potentiatesthe hypotensive effects of nitrates and nitric oxide donors,use of these drugs on a regular or intermittent basis is theonly absolute contraindication.

In conclusion, ED may be an early symptom related tohypertension and should be the subject of inquiry in everypatient newly diagnosed with hypertension, both beforeand after initiation of pharmacologic therapy. If ED stemsfrom the pharmacologic management of hypertension,physicians can modify treatment or add adjunctive therapysuch as sildenafil to ensure adherence. This study showedthat sildenafil is an effective and well tolerated treatmentfor ED among patients with hypertension who are takingmultiple classes of antihypertensive agents. Sildenafiltreatment was not associated with additional safety risks inthis patient population.

References

1. Burt VL, Whelton P, Roccella EJ, Brown C, Cutler JA, Higgins M,Horan MJ, Labarthe D: Prevalence of hypertension in the US adultpopulation. Results from the Third National Health and NutritionExamination Survey, 1988–1991. Hypertension 1995;25:305–313.

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AppendixList of Multicenter Principal Investigatorsby CountryAustralia: Robert McLachlan, MD, Clayton, VIC; CarolPollock, 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 Cha-loupka, MD, Brno-Bohunice; Michal Padour, MD, Pra-gue; Jan Pavlas, MD, Ostrava-Kuncice; MiroslavSoucek, 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: MirosawDluzniewski, 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. Swe-den: 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, New-port Beach, CA; David Calhoun, MD, Birmingham, AL;William Cleveland, MD, Atlanta, GA; Louis K. Essan-doh, MD, Annapolis, MD; Harry Geisberg, MD, Ander-son, SC; Jeffrey Geohas, MD, Chicago, IL; PatriciaGilhooly, 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 Mohiud-din, 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.