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161

Blackwell Science, LtdOxford, UKJSMJournal of Sexual Medicine1743-6095Journal of Sexual Medicine 2004200412161167Original Article

Update on Clinical Trials of TadalafilJackson et al.

Update on Clinical Trials of Tadalafil Demonstrates No Increased Risk of Cardiovascular Adverse Events

Graham Jackson, MD,

1

Robert A. Kloner, MD, PhD,

2

Timothy M. Costigan, PhD,

3

Margaret R. Warner, PhD, DVM,

3

and Jeffrey T. Emmick, MD, PhD

3

1

Guy’s and St. Thomas Hospital, London, UK;

2

The Heart Institute, Good Somaritan Hospital Cardiovascular Division, Keck School of Medicine, University of Southern California, Los Angeles, CA;

3

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA

Conflict of Interest. Supported by Lilly ICOS VC (Indianapolis, IN, and Bothell, WA. Bothell, Drs. Costigan, Emmick andWarner are employees of Eli Lilly and Company.

A B S T R A C T

Introduction.

Cardiovascular disease and erectile dysfunction (ED) share similar risk factors andoften occur concomitantly. Therefore, men with ED may be at increased risk for cardiovascularadverse events.

Aim.

The aim of this retrospective analysis was to evaluate the cardiovascular adverse events inclinical trials of tadalafil, an effective medication for the treatment of ED.

Methods.

An integrated analysis of cardiovascular adverse events was performed on a database from35 controlled clinical trials (placebo [N

=

2,118] and tadalafil [N

=

5,228]) and eight open-labeltrials of tadalafil (tadalafil [N

=

6,939]). Some patients in controlled trials also received tadalafil inthe open-label extension phase of four trials. Across all trials, the dose range of tadalafil was 2–25 mg, with the majority of patients receiving tadalafil 20 mg. This analysis represents an updateof previous published results.

Results.

In 35 controlled tadalafil clinical trials, the incidence of cardiovascular adverse events waslow and comparable in tadalafil- and placebo-treated patients. The rate of myocardial infarction(MI) across all controlled and open-label studies was 0.33 per 100 patient-years in tadalafil-treatedpatients (N

=

10,460, patient exposure

=

5,088 patient-years). The MI rate in tadalafil-treatedpatients was comparable to that in placebo-treated patients (0.41 per 100 patient-years; N

=

2,118;489 patient-years), and to that in an age-standardized male population (0.6 per 100 patient-years).The cardiac mortality rate in tadalafil-treated patients across all studies (N

=

10,460) was 0.12 per100 patient-years which was not increased compared with the cardiac mortality rate of 0.26 per 100patient-years reported in an age-standardized male population.

Conclusions.

In tadalafil clinical trials, the incidence of cardiovascular adverse events in patientsreceiving tadalafil was low and comparable to placebo. Tadalafil did not increase the rate of MI orcardiac mortality compared with reported rates from epidemiological studies. This favorable car-diovascular safety profile for tadalafil is important, because men with ED commonly have cardio-vascular disease and may seek medical therapy for ED.

Key Words.

Tadalafil; Erectile Dysfunction; Cardiovascular; Myocardial Infarction; Placebo; Safety

Introduction

ardiovascular and cerebrovascular diseasesaffect millions of men world-wide. Although

erectile dysfunction (ED) can be due to psy-C

chogenic or neurologic disorders, vascular diseaseis the most common etiology for ED (e.g., athero-sclerosis, endothelial dysfunction) [1]. Cardiovas-cular disease and ED share numerous risk factors,including age, smoking, hyperlipidemia, hyperten-

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sion, and diabetes mellitus [2–4]. Additionally, theseverity of coronary artery disease has been shownto correlate with the severity of ED [5].

Compounds that inhibit phosphodiesterase 5(PDE5) have become the first line of therapy formost men with ED [6–9]. The hemodynamiceffects of the PDE5 inhibitors have received muchattention, especially in men with ED and concom-itant cardiovascular disease [10]. In smooth musclecells, the inhibition of PDE5 increases cGMP lev-els, reduces intracellular calcium, and promotesvasodilation [1]. In healthy patients and in thosewith cardiovascular disease, PDE5 inhibitorsevoke mild decreases in systolic (

<

10 mm Hg) anddiastolic (

<

5 mm Hg) blood pressure [10–13]. Inthe penis, inhibition of PDE5 increases blood flowand promotes penile erection [1]. Sexual stimula-tion and the release of nitric oxide from nerveendings and endothelium are required for PDE5inhibitors to increase penile blood flow [1].

Tadalafil has a half-life of 17.5 hours and iseffective for treating ED for up to 36 hours afterdosing [6,9,14,15]. Additionally, tadalafil is effec-tive for the treatment of ED in a diverse popula-tion of patients, including the general populationof men with ED, men with concomitant ED andhypertension or diabetes mellitus, and in men withED occurring postprostatectomy [6,7,15–17].Because many men with cardiovascular diseasemay seek medical therapy for ED, it is importantto continually evaluate the cardiovascular safetyprofile of all PDE5 inhibitors, including tadalafil.We report the results of an integrated analysis ofthe cardiovascular adverse event data from 35 con-trolled clinical trials and 8 open-label clinical trialsof tadalafil representing over 10,000 patientsreceiving tadalafil.

Methods

Studies were approved by institutional reviewboards, and each patient gave informed consent.Studies were conducted in accordance with theDeclaration of Helsinki and guidelines for GoodClinical Practice.

Patients (

≥

18 years) were enrolled in 35 con-trolled trials and/or eight open-label trials oftadalafil (N

=

10,460 tadalafil-treated; N

=

2,118plaecebo-treated). Across all trials, doses of tadala-fil ranged from 2 mg to 25 mg given a maximumof once daily. The majority of patients wereexposed to tadalafil 20 mg [3,346 of 5,228 patients(64%) in 35 controlled trials; and 6,414 of 6,939patients (92%) in eight open-label clinical trials].

Tadalafil 20 mg is the highest recommended ther-apeutic dose [14]. Dosing regimens varied by clin-ical trial design and included daily dosing, threetimes per week dosing, and “as-needed”/“ondemand” dosing (maximum once daily).

Patients were excluded from clinical trials onlyif they had an underlying cardiovascular disorderthat was sufficiently severe or unstable to makesexual intercourse inadvisable (e.g., unstableangina, history of myocardial infarction (MI)90 days prior to study, systolic blood pressure

>

170 mm Hg or

<

90 mm Hg, diastolic bloodpressure

>

100 mm Hg or

<

50 mm Hg).

Clinical Trials of Tadalafil

Characteristics of the 35 controlled clinical trialsof tadalafil included the following: (1) 30 trialswere placebo-controlled and five were active-controlled; (2) 34 trials were randomized anddouble-blind; (3) 31 trials enrolled only men(

≥

18 years) with a history of ED of at least3 months duration; (4) two trials enrolled onlywomen who were healthy or had female sexualdysfunction (N

=

267); and (5) two trials enrolledmen with no or mild ED (N

=

421).The cardiovascular adverse event data were also

analysed from eight open-label clinical trials oftadalafil. Four of the eight open-label trials werelong-term safety studies with a treatment durationof up to 2 years and four were extension phases ofthe controlled clinical trials of tadalafil describedabove.

Data Analysis

Adverse events reported herein included all treat-ment-emergent cardiovascular adverse eventsreported in patients assigned to treatmentthroughout each clinical trial. Because of the smallnumber of cardiovascular adverse events reportedin individual trials, data were pooled and groupedinto 10 cardiovascular adverse event categories(the categories and their descriptions are listed inthe footnote of Table 1). The tadalafil dose groups(2–25 mg) were also pooled due to the low cardio-vascular adverse event rates across clinical trials.Cardiovascular adverse events were recordedusing the Medical Dictionary for RegulatoryActivities (MedDRA) preferred terms (MedDRAversion 5.0 was used for all clinical trials, exceptone (study LVDY) in which MedDRA version 6.1was used). Patients who had an adverse event inmore than one event category were included ineach of the categories.

Update on Clinical Trials of Tadalafil

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The myocardial infarction (MI) rate and cardiacmortality rate were assessed across the 35 con-trolled and eight open-label clinical trials of tad-alafil. Myocardial infarction and cardiac mortalityrates are presented as absolute number of eventsand as rate per 100 patient-years (the rates per 100patient-years were calculated by dividing the abso-lute number of events by the patient-year exposureand multiplying by 100). All reported deaths wereclassified as having been due to either cardiovas-cular or non-cardiovascular causes.

Results

Demographics and Cardiovascular Risk Factors at Baseline in Patients Enrolled in 35 Controlled Tadalafil Clinical Trials

The mean age of patients receiving placebo ortadalafil was 55 years (Table 2). As shown inTable 2, the ethnicity was also comparablebetween placebo- and tadalafil-treated patients.

Table 3 shows the frequency (at baseline) ofthree common risk factors for cardiovascular dis-ease in patients enrolled in the 35 controlled tad-alafil clinical trials. Over 43% of placebo-treatedand over 44% of tadalafil-treated patients had dia-betes mellitus, hyperlipidemia, and/or hyperten-sion at baseline.

Cardiovascular Adverse Events in 35 Controlled Tadalafil Clinical Trials

In 35 controlled trials of tadalafil, the total patient-year exposure was 489 years for placebo-treatedpatients (N

=

2,118), and 1,152 patient-years fortadalafil-treated patients (N

=

5,228). Table 1

summarizes the treatment-emergent cardiovascu-lar adverse event data from these groups ofpatients. For each category (Table 1), the inci-dence of cardiovascular adverse events was low andcomparable between tadalafil- and placebo-treatedpatients.

Myocardial Infarction Rates Across 35 Controlled and Eight Open-Label Tadalafil Clinical Trials

In controlled clinical trials the rate of MI was 0.26per 100 patient-years in tadalafil-treated patients(N

=

5,228), and 0.41 per 100 patient-years in pla-cebo-treated patients (N

=

2,118) (Table 4). Inopen-label studies of tadalafil, the MI rate was 0.36per 100 patient-years, and in the controlled andopen-label studies combined, the rate of MI was0.33 per 100 patient-years (the combined studiesinclude 10,460 tadalafil-treated patients with apatient exposure of 5,088 patient-years). The MI

Table 1

Treatment-emergent cardiovascular adverse events across 35 controlled clinical trials of tadalafil

Adverse event categoryPlacebo (N

=

2,118)

†

% (N)Tadalafil* (N

=

5,228)

†

% (N)

MI/ischemia/possible ischemic symptoms/CAD

‡

0.80 (17) 0.82 (43)Congestive heart failure 0.05 (1) 0.02 (1)Ventricular arrhythmia 0.05 (1) 0.02 (1)Cerebrovascular events 0 (0) 0.08 (4)Syncope/hypotension/possible hypotensive symptoms 0.28 (6) 0.23 (12)Supraventricular arrhythmias 0.05 (1) 0.02 (1)Other arrhythmias 0 (0) 0.02 (1)Other cardiovascular events

§

0.05 (1) 0 (0)Conduction defects 0.05 (1) 0.06 (3)Subjective rhythm/rate

¶

0.33 (7) 0.73 (38)

* Doses of tadalafil ranged from 2 to 25 mg.

†

Patient-year exposure for placebo-treated patients

=

489 patient-years, and for tadalafil-treated patients

=

1,152 patient-years.

‡

Category includes angina pectoris, chest pain, chest tightness, chest pressure sensation, unstable angina, acute MI, chest discomfort, MI, myocardial ischemia,coronary artery atherosclerosis, CAD (not otherwise specified), coronary artery insufficiency, coronary artery occlusion, and/or coronary artery stenosis.

§

Category includes cardiovascular disorders (not otherwise specified), pulmonary embolism, and/or pulmonary hypertension (not otherwise specified).

¶

Category includes palpitations, heart rate irregular, heart rate increased, and tachycardia (not otherwise specified).MI, myocardial infarction; CAD, coronary artery disease.Values represent percent of patients with an event, with the absolute number of events in parentheses [% (N)].

Table 2

Patient demographics across 35 controlled clinical trials of tadalafil*

Placebo(N

=

2,118)Tadalafil(N

=

5,228)

Mean age (range), years 55 (20–86) 55 (20–88)Ethnicity, N (%)

White 1,554 (73%) 3,946 (75%)Black 78 (4%) 221 (4%)Hispanic 80 (4%) 218 (4%)East and South-east Asian 330 (16%) 638 (12%)West Asian 48 (2%) 110 (2%)Other 28 (1%) 95 (2%)

* The 35 controlled trials were: LVAC, LVBJ, LVBK, LVBN, LVBO, LVBQ, LVBR,LVCD, LVCE, LVCF, LVCG (pre-extension), LVCI, LVCK, LVCO, LVCQ (final),LVCR, LVCU, LVCV (pre-extension), LVCY, LVCZ, LVDG, LVDJ, LVDU, LVDW,LVDX, LVDY, LVDZ, LVEB (pre-extension), LVEF, LVEG, LVEH, LVEI, LVEK,LVEL, LVFD (pre-extension).

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rates for tadalafil-treated patients were compara-ble to the MI rate for placebo-treated patients, andno higher than the MI rate of 0.6 per 100 patient-years reported for an age-standardized population(men under 75 years of age) (Table 4).

Cardiac Mortality Rates Across 35 Controlled and Eight Open-Label Tadalafil Clinical Trials

Across the 35 controlled and eight open-label tad-alafil clinical trials, cardiac-related deaths werereported in six of 10,460 tadalafil-treated patients.Based on the total patient-year exposure(5,088 years) and number of cardiac-relateddeaths, the cardiac mortality rate was 0.12 per 100patient-years. There were no cardiac-relateddeaths reported in patients receiving placebo;however, for placebo-treated patients (N

=

2,118)the patient-year exposure was 489 patient-yearscompared with 5,088 patient-years for tadalafil-treated patients. Thus, based on the cardiac mor-tality rate for tadalafil-treated patients of 0.12 per100 patient-years, there would have only been 0.6deaths expected in placebo-treated patients (basedon a total patient exposure of 489 years). The largepatient-year exposure for tadalafil- vs. placebo-

treated patients is due, in part, to the results fromthe long-term, open-label studies (i.e., the open-label studies lack a placebo treatment arm). Thecardiac mortality rate for an age-standardizedpopulation (men under 75 years of age) was 0.26per 100 patient-years [18–20].

Discussion

This comprehensive retrospective analysis of datafrom clinical trials of tadalafil demonstrates thatthe incidence of cardiovascular adverse events waslow in tadalafil-treated patients and comparable toplacebo-treated patients. The data also show thattadalafil did not increase the rate of MI comparedwith placebo, and the rates of MI and cardiac mor-tality were not increased compared with rates inage-standardized male populations. Our demo-graphic data show that the study population wasolder, ethnically diverse, and over 43% of patientsenrolled in controlled trials had diabetes mellitus,hyperlipidemia, and/or hypertension. The resultsof this update on the clinical trials of tadalafil pro-vide further support for a favorable cardiovascularsafety profile for tadalafil and are consistent withthose from earlier analyses of cardiovascularadverse event data from tadalafil clinical trials[11,12].

The majority of patients enrolled in tadalafilclinical trials were older men with ED, and a sub-stantial proportion had at least one underlying riskfactor for cardiovascular disease. Thus, this clini-cal trial population included patients with coro-nary artery disease, peripheral vascular disease,and cerebrovascular disease. It is now well estab-lished that many men diagnosed with ED havesome degree of concomitant cardiovascular dis-ease [2–4], whereas many men diagnosed with

Table 3

Frequency of underlying conditions that constitute coronary risk factors in patients enrolled in 35 controlled clinical trials of tadalafil

Placebo(N

=

2,118)Tadalafil(N

=

5,228)

N % N %

Patients with

≥

1 Risk Factor 912 43.1% 2,336 44.7%Diabetes Mellitus 419 19.8% 1,027 19.6%Hyperlipidemia 331 15.6% 781 14.9%Hypertension 549 25.9% 1,426 27.3%

Table 4

Incidence of myocardial infarction (MI) across tadalafil clinical trials

Referencepopulation*

Tadalafil clinical trials

Placebo

Tadalafil-treatedpatients in controlledtrials

‡

Tadalafil-treatedpatients in open-labeltrials

§

Tadalafil-treatedpatients in all trials

¶

Patients (N) — 2,118 5,228 6,939 10,460Total patient exposure (patient-years) — 489 1,152 3,936 5,088Number of MI — 2 3 14 17Rate of MI per 100 patient-years

†

0.6 0.41 0.26 0.36 0.33

* Age-standardized population: men under 75 years of age [18–20].

†

One patient reported to have had an MI had been randomized to tadalafil, but had not taken any study drug. This patient was excluded from the MI incidencerate analyses.

‡

The 35 controlled trials are listed in the footnote of Table 2.

§

Open-label trials were: LVBD, LVBL, LVDR, LVEM, LVCG (extension), LVCV (extension), LVEB (extension), LVFD (extension).

¶

The 35 controlled trials plus 8 open-label trials: Sample sizes do not add because some patients who received tadalafil in controlled trials also received tadalafilin open-label trials.

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cardiovascular disease have some degree of ED[21,22]. The results of this integrated analysis(which included patients with hypertension,hyperlipidemia, and/or diabetes mellitus) showthat there was no increased risk of cardiovascularadverse events in tadalafil-treated patients com-pared with placebo-treated patients.

Based on the age and comorbid conditions ofpatients in tadalafil clinical trials, some cases of MIwould be expected in a population of over 10,000patients. The rate of MI in patients receivingtadalafil was 0.33 per 100 patient-years, and inpatients receiving placebo was 0.41 per 100patient-years. For comparison, the reported ratesof MI based on 36-year follow-up data from theFramingham study [23] ranged from 0.61 per 100patient-years in men aged 45–54 years to 2.25 per100 patient-years in men aged 75–84 years [23].The MI rates derived from the Framingham Studydata [23] are comparable to those reported in menunder 75 years of age in England (MI rate of 0.6per 100 patient-years) [18–20]. The MI ratesreported from these epidemiological studies wereobtained from men in the “general” populationand may therefore underestimate the rate of MIfor men with ED who have a higher incidence ofcomorbid cardiovascular disease than men in the“general” population [2–4].

The MI rates reported herein from tadalafilclinical trials are similar to those reported fromclinical trials of the PDE5 inhibitor, sildenafil [24].Analysis of cardiovascular adverse events fromdouble-blind clinical trials of sildenafil [24],showed that the rate of MI was 0.80 per 100patient-years for sildenafil-treated patients(N

=

7,462; 1,758 patient-year exposure) com-pared with 0.84 per 100 patient-years for placebo-treated patients (N

=

5,753; 1,066 patient-yearexposure). For open-label studies the rate of MIin sildenafil-treated patients was 0.53 per 100patient-years (11,540 patient-year exposure) [24].The MI rates from our integrated tadalafil clinicaltrial data (e.g., 0.33 per 100 patient-years acrossall tadalafil-treated patients; N

=

10,460 with5,088 patient-year exposure) are comparable tothe MI rates reported from sildenafil clinical trials,as well as to the MI rates reported in various epi-demiological studies in similarly aged male popu-lations [13,18–20,23].

Similar to the low incidence rate of myocardialinfarction in tadalafil clinical trials, the incidenceof all cardiovascular adverse events was low inpatients treated with either placebo or tadalafil(Table 1). In addition, for some cardiovascular

adverse event categories there were no adverseevents reported (i.e., category of “other cardiovas-cular events” for tadalafil-treated patients, and cat-egories of “cerebrovascular events” and “otherarrhythmias” for placebo-treated patients). Thecerebrovascular event category included theevents of cerebral infarction, cerebral ischemia,cerebrovascular accident, transient ischemicattack, thrombotic stroke, ischemic stroke (nototherwise specified), hemiparesis, and/or hemian-opia (not otherwise specified). In controlled trials,cerebrovascular adverse events were reported infour of 5,228 tadalafil-treated patients (incidenceof 0.08%), which corresponds to a cerebrovascularadverse event rate of 0.35 per 100 patient-years(1,152 patient-year exposure). Based on this cere-brovascular adverse event rate for tadalafil-treatedpatients, it might be expected that 1.7 placebo-treated patients would have reported a cere-brovascular adverse event in controlled trials(placebo-treated patients N

=

2,118; 489 patient-year exposure). Although no cerebrovascularevents were reported in placebo-treated patients,during the treatment-free run in period there werethree cerebrovascular adverse events reported inpatients enrolled in tadalafil clinical trials (inci-dence rate

=

0.3 per 100 patient-years, 1,006patient-year exposure, N

=

12,479). In addition,after 36 years of follow-up in the FraminghamStudy [23], the incidence rate for all types of strokecombined was 0.46 per 100 patient-years for menaged 55–64 years, and 0.54 per 100 patient-yearsfor men aged 35–94 years. Additionally, in double-blind, placebo-controlled, sildenafil clinical trials[13], the incidence rate for stroke was 0.4 per 100patient-years in sildenafil-treated patients (693patient-year exposure), and 0.9 per 100 patient-years in placebo-treated patients (349 patient-yearexposure). Comparable rates were also reported insildenafil open-label clinical trials (0.3 per 100patient-years, 4,220 patient-year exposure) [13].Thus, the cerebrovascular adverse event rate fortadalafil-treated patients was not increased com-pared with the stroke rate derived from men in theFramingham Study and was comparable to ratesreported from controlled and open-label clinicaltrials of sildenafil [13,23].

The cardiac mortality rates determined fromintegrated tadalafil clinical trial data are also sim-ilar to the cardiac mortality rates reported fromsildenafil clinical trials [24]. In placebo-controlledclinical trials of sildenafil [24] the cardiac mortalityrate was 0.23 per 100 patient-years for sildenafil-treated patients (1,758 patient-year exposure)

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compared with 0.19 per 100 patient-years forplacebo-treated patients (1,066 patient-year expo-sure). For sildenafil open-label trials, the cardiacmortality rate was 0.16 per 100 patient-years(11,540 patient-year exposure) [24]. The cardiacmortality rate across tadalafil clinical trials was0.12 per 100 patient-years for tadalafil-treatedpatients (5,088 patient-year exposure). Thepatient populations were comparable in the tad-alafil and sildenafil clinical trials (i.e., the majoritywere men with ED with a substantial proportionhaving comorbid hypertension, hyperlipidemia,and/or diabetes mellitus) [24]. Thus, the cardiacmortality rate for tadalafil-treated patients wascomparable to that reported for sildenafil-treatedpatients, and was not increased compared tocardiac mortality rates reported in an age-standardized general population (0.26 per 100patient-years; men under 75 years) [18–20]. Aswith the MI rates discussed above, the cardiacmortality rate for men with ED would likely behigher than that reported for men in the “general”population, due to the increased incidence ofcomorbid cardiovascular disease in men with EDcompared to men without ED [2–4].

Conclusions

The results of this comprehensive, retrospectiveanalysis across 35 controlled and eight open-labeltadalafil clinical trials show that the incidence ofcardiovascular adverse events was low in tadalafil-treated patients and comparable to placebo. Myo-cardial infarction rates in tadalafil-treated patientswere not increased compared with placebo-treatedpatients or compared with MI rates determined inepidemiological studies of the general population.Furthermore, the incidence rate of cardiac mortal-ity in tadalafil-treated patients is consistent withthe expected rate in the general population, indi-cating no causal relationship with tadalafil ad-ministration. These results extend and supportprevious analyses of the cardiovascular safety oftadalafil, an effective medication for the treatmentof erectile dysfunction.

Acknowledgments

The authors acknowledge Hui Liu and LinglingXie for their assistance with statistical analyses.

Corresponding Author:

Dr. Graham Jackson, Guys’and St. Thomas Hospital, St. Thomas St., London, UK.Tel: (+44) 207-403-4884; Fax: (+44) 207-357-7408;E-mail:

gjcardiol@talk21.com

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