ORIGINAL
Preference for Tadalafil versus Sildenafil in Spanish patients with erectile dysfunction: results from an international, multicenter study
L. Rodríguez‑Vela*, E. Lledó‑García**,
O. Rajmil***, D. Mo****, A.
Cassinello*****, J. Casariego*****
*Hospital Miguel Servet,
Zaragoza. **Hospital Gregorio Marañón, Madrid. ***Fundación Puigvert,
Barcelona. ****Eli Lilly
& Co. Indianapolis
(Indiana). USA. *****Lilly S.A. Alcobendas
(Madrid).
Actas Urol Esp
2006; 30 (1): 67‑79
ABSTRACT
|
|
PREFERENCE
FOR TADALAFIL VERSUS SILDENAFIL IN SPANISH PATIENTS WITH ERECTILE
DYSFUNCTION: RESULTS FROM AN INTERNATIONAL, MULTICENTER STUDY |
|
Objective: To
compare patient preference for sildenafil citrate (sildenafil) versus tadalafil
and for their respective dosing instructions in a cohort of Spanish patients
with erectile dysfunction (ED). |
|
Material and
methods: Sixty‑four Spanish patients from a multicenter,
two period, cross‑over, double‑blind study (265 patients
enrolled in total) were randomized to receive on‑demand sildenafil 50 mg or tadalafil
20 mg for 12 weeks, and posteriorly were
crossed over to the alternate regimen for another 12 weeks to assess
drug preference in an extension period of the study. Similarly, to evaluate
preference for their respective dosing instructions, 30 patients were
randomized to one of the two arms treated with tadalafil:
one with sildenafil (S) dosing instructions and the
other with tadalafil (T) dosing instructions. |
|
Results:
Seventy percent of 56 patients completing the study chose to receive tadalafil treatment versus sildenafil
treatment (30%) in the extension period (p<0.01). In turn, 73% of
13 subjects evaluating each of the drug dosing instructions preferred T
dosing instructions (p>0.05). Preference did not vary with age, concomitant
diseases or previous use of sildenafil. |
|
Conclusions:
In this study, 7 out of 10 patients preferred tadalafil
and its dosing instructions to sildenafil, for the
treatment of ED. |
|
Keywords:
Erectile dysfunction. Tadalafil. Sildenafil. Phosphodiesterase
inhibitors. Preference study. Randomized clinical trial. |
Erectile dysfunction (ED) is defined
as the inability to achieve or maintain an erection sufficiently firm to allow
satisfactory sexual intercourse. The disorder affects an important proportion of
the male population and leads, among other problems, to psychological disorders
in the form of impaired self image, altered relations with the couple, and
deteriorated quality of life (QoL)1‑3. According to the world Health Organization (WHO), the prevalences of ED for the years 2004, 2005, and
2006 come close to 189, 193, and 198 million affected males worldwide4, with about two million cases in
Sildenafil citrate
(Viagra, Pfizer), marketed since 1998, is the oldest of these oral drugs, and
has demonstrated its efficacy in clinical trials of erectile dysfunction and
also in clinical practice8. It is the foremost
representative of the short‑action PDE5 inhibitors, since its
efficacy has an approximate duration of 4‑5 hours. The ingestion of
food can affect the magnitude of absorption of the drug and delay the onset of
action9. Despite important efficacy and generally
good tolerability at the usual doses, between 20‑50%
of patients who respond to sildenafil are known to
abandon treatment over the long term for different reasons10.
This observation alerts to the existence and persistence of needs that are not
covered by the treatment in patients with ED. Tadalafil
(Cialis, Lilly ICOS) is a PDE5 inhibitor that
was approved as oral treatment for ED in 200211.
In the clinical studies conducted to date it has been shown that the drug is
effective and well tolerated in application to erectile dysfunction12-14. Its unique pharmacokinetic
characteristics (with a half‑life of 17.5 hours) are clinically
expressed by a longer response time, whereby some men have experienced
satisfactory sexual intercourse as soon as 16 minutes after administration
of the drug and for up to 36 hours afterwards11-13,15-17.
Unlike sildenafil, the absorption of tadalafil is not affected by the ingestion of food11.
Medicine in the XXI century
advocates active implication of the patient in the taking of clinical
decisions, in contrast to the principle of authority prevalent in traditional
medical practice. Particularly in the case of ED, there are numerous
sociological, psychological, cultural and sexual factors to be taken into
account when indicating a given type of treatment. The latter should be
adjusted as far as possible to the requirements, expectations and needs of the
patient and his couple. In other words, therapy should adapt to the preferences
of the patient. In this context, at present, and having demonstrated the
efficacy of these drugs in adequately designed studies with the use of
traditional efficacy measurement scales – the International Index of Erectile Function
(IIEF), the Sexual Encounter Profile (SEP) diary, and the Global Assessment
Questionnaire (GAQ) – great importance is being focused on evaluation of the
preferences and needs of patients to complement the information on comparative
efficacy and safety18. A number of authors have
evaluated patient preference for different ED treatment modalities18,19,
while some preference studies have compared different PDE5 inhibitors
based on a range of designs and methodologies20-24. The great majority of these studies reveal a clear
preference among patients for tadalafil, based on an
open design, i.e., without masking of the study medication, due to the
complexity of preserving double blind status in the comparison of two drugs
with different dosing instructions.
A study was designed to evaluate the
preference of patients for tadalafil or sildenafil, and their preference for the different dosing
instructions, though using a special masking method to preserve study blinding24. The present study reports the results obtained in a
cohort of Spanish patients with ED who participated in this study of
preference, conducted in the
MATERIAL AND METHODS
Methods
A total of 84 patients with
erectile dysfunction seen in different Spanish hospital centers
were offered the possibility of participating in a multicenter,
two period, cross‑over, double‑blind study comprising
265 patients of 15 centers in the
Patients
Patients eligible for inclusion were
males between 18 and 66 years of age maintaining sexual relations
with a female and suffering from ED for at least three months. ED was defined
as a sustained change in erection quality, exerting a negative effect upon
patient satisfaction with sexual intercourse. The eligible patients agreed not
to use any other form of treatment for ED during the entire study period,
including the initial assessment period, the treatment cross‑over and
extension periods, and the interval of 96 hours after conclusion of the
extension period. The inclusion of patients who had not responded to sildenafil in the past was allowed. Patients with premature
ejaculation were excluded, as were those with ED secondary to some untreated
endocrine disorder (e.g., hypopituitarism,
hypothyroidism or hypogonadism), a history of pelvic
surgery without signs of preservation of erectile function, stroke or spinal
cord injuries in the preceding 6 months, antecedents of HIV infection,
current treatment with nitrates, myocardial infarction in the previous
90 days, coronary revascularization in the previous 90 days, or a
history of unstable angina in the previous 6 months. Patients with pigmentary retinitis were also excluded, since the
packaging insert for sildenafil includes a warning
against use of the drug in such cases.
Study design
The principal objective of the study
was assessment of preference for the medication (PM). This was evaluated in a
cohort of patients with ED who were randomized to receive on‑demand sildenafil at a starting dose of 50 mg or tadalafil 20 mg for 12 weeks, and posteriorly were crossed over to the alternate regimen for
another 12 weeks to assess drug preference in an extension period of the
study, as detailed below.
Preference for the dosing
instructions (PDI) was examined in a different cohort of patients, treated with
tadalafil 20 mg, to assess their preference for
the use of tadalafil under the conditions imposed by
the dosing instructions corresponding to sildenafil
and tadalafil. In both the assessment of patient
preference for the medication and in the evaluation of preference for the
dosing instructions, all subjects following the dosing instructions for sildenafil were offered the possibility of increasing the
dose after four weeks of treatment. Based on a double blind design, all
patients requesting a dose increment received additional drug capsules. The
number of patients given additional active medication in the double blind
design was limited to 35% of the total patients treated with sildenafil in each treatment period, in each country. The rest of patients belonging to the sildenafil
group, and all those in the tadalafil group who
requested a dose increment, received placebo on a double blind basis.
The limit in the number of patients treated with sildenafil
who could increase the dose was established to simulate the observed pattern of
use in clinical practice (i.e., an estimation based on the existing data on the
proportion of patients using sildenafil who actually
increase their dosage)25-27.
At the end of the 12‑week
cross‑over treatment period, the patients were questioned about which of
the two treatments they would prefer to receive during an optional extension
period of another 12 weeks, preserving double blinding, and with no cost
to the participating subjects – with the purpose of eliminating purchasing cost
as a variable potentially influencing preference. The extension period was
preceded by a 96‑hour pharmacological washout interval.
During both the cross‑over
treatment period and the extension period (Fig. 1), the patients recorded the
date and time of administration of the study drug by means of a drug diary,
along with the date and time of attempted sexual intercourse in a sexual
intercourse diary.
FIGURE 1. Design of the multicenter study.
IT: Dosing instructions for tadalafil. IS: Dosing instructions for sildenafil.
Treatment arms and blinding
The protocol delivered to the
investigators specified that following an initial evaluation period of
approximately one week without treatment, the patients were to be randomized to
the groups of treatment with tadalafil 20 mg
(using the dosing instructions for sildenafil or tadalafil), sildenafil 50 mg
(with the dosing instructions for sildenafil only) or
placebo (with the dosing instructions for sildenafil
or tadalafil). The protocol also specified that the
patients were to receive active treatment in at least one of the phases of the
cross‑over treatment period. In fact, none of the patients received
placebo. The subjects were randomly assigned to the different treatment arms
for the evaluation of preference for the medication or evaluation of preference
for the dosing instructions for treatment with tadalafil.
The information relating to the actual treatment arm was exclusively supplied
to each of the ethics committees as a supplement to the protocol.
Simulated placebo arms constitute a
special method for masking treatment assignation when using two different
dosing instructions for two drugs with different pharmacokinetic profiles. The
patients treated with sildenafil only received the
dosing instructions corresponding to this drug, since administering the
medication with the instructions corresponding to tadalafil
would probably exert a negative influence upon the perception of efficacy if
the patient participated in sexual activities after more than four hours or
ingested food. In contrast, the patients treated with tadalafil
received the dosing instructions for sildenafil or tadalafil, since the clinical profile of tadalafil is compatible with both. It is clear that without
the simulated placebo arms, delivery of the dosing
instructions for tadalafil would have eliminated
double blinding with respect to the patients and their physicians, since it
would imply that the patient was inevitably taking tadalafil.
Moreover, sildenafil and tadalafil
was administered in identical capsules to ensure blinding. Encapsulation did
not significantly influence the dissolution characteristics of both drugs.
Dosing instructions
The dosing instructions for sildenafil were based on the instructions supplied by the
manufacturer9, and were provided to maximize the
efficacy of sildenafil. The dosing instructions for tadalafil were based on the instructions used in previous
clinical trials with this drug, and on the language characteristics of the
patients24. The packaging insert or leaflet for sildenafil advises the patient to take the medication one
hour before sexual activity, but specifies that the medication is effective
between 30 minutes and 4 hours after administration. In contrast, the
longer duration of the effect of tadalafil was
included in the dosing instructions employed in this study (see below).
Study variables
The principal study variable was
patient preference regarding the treatment of ED, i.e., tadalafil
or sildenafil, assessed on the basis of patient
choice with a double blind design, used with the respective dosing
instructions, for the medication corresponding to the extension period. The
secondary variables were patient preference regarding the dosing instructions
for tadalafil or sildenafil
during treatment with tadalafil, and the time elapsed
between drug administration and attempted sexual intercourse. The evaluations
of treatment safety included a complete anamnesis, physical examination, 12‑lead
electrocardiogram and standard hematological and
serum biochemistry tests on occasion of the initial selection visit. Arterial
pressure, pulse and the incidence of adverse events at each outpatient visit
were recorded. The adverse events were summarized according to the Medical
Dictionary for Regulatory Activities (MedDRA version
4.0) for event intensity and relation to the study drug.
Statistical analysis
The present study only analyzes the
data corresponding to the Spanish patients that participated in the trial. The
analysis of preference for medication includes those patients who decided to
continue receiving treatment for their ED in the extension period. A bilateral
z‑test was used to test the null hypothesis that the proportion of
patients choosing tadalafil or sildenafil
at the start of the extension period was equal, with a level of statistical
significance of 0.05.
Calculation of the sample size
estimated that 56 patients answering the question relating to preference
would afford a statistical power of 87% for rejecting the null hypothesis,
considering that close to 70% of the patients would choose tadalafil.
A sample of 64 randomized patients, with a study completion rate of 88%
was considered sufficient for the evaluation of medication preference. A chi‑square
test was used to evaluate the distribution of preference among Spanish and non‑Spanish
patients. A descriptive analysis was made in relation to the time distribution
of attempted intercourse. The total number of intercourse attempts, and the
percentage intercourse attempts over time (in hours) after administration of
the medication, were recorded according to the drug administered.
The analysis of safety includes a
summary of the adverse events by treatment modality, for all randomized
patients.
RESULTS
ERECTILE DYSFUNCTION CHARACTERISTICS OF THE PATIENTS
Of the 84 Spanish patients
included, 77 were randomized; accordingly, 64 subjects were
randomized to the two arms of evaluation of patient preference for treatment
(PT), and 13 patients were distributed between the two arms of evaluation
of preference for the dosing instructions (PDI) (Fig. 2). The cross‑over
period was completed by 56 of the 64 patients of treatment arms
1 and 2 (87.5%), and by 11 of the 13 (84.6%) corresponding
to arms 3 and 4, that decided to continue the extension phase with the
treatment received in the double blind phase. The reasons why 10 of the
77 eligible patients abandoned the study were: loss to follow‑up
(n=6), adverse events (n=3) and physician decision in the remaining case (Fig.
2). No patient abandoned the study due to a lack of efficacy.
FIGURE 2. Patient distribution.
IT: Dosing instructions for tadalafil. IS: Dosing instructions for sildenafil.
The mean age of the participating
patients was 52 years (range 24‑65 years). The majority (91%)
had a history of erectile dysfunction for more than one year, fundamentally of
organic or mixed etiology. Over half of the patients
had used sildenafil in the past (53%). Cardiovascular
risk factors commonly associated to ED were identified, such as smoking
(51.9%), diabetes mellitus (22.1%) or arterial hypertension (22.1%). All
patient characteristics are reported in Table 1.
Table 1
Demographic characteristics and
baseline clinical history of the patients and causes of erectile dysfunction
(ED)
|
|
T.+IT/ S.+IS |
S.+IS/ T.+IT |
T+IT/T+IS |
T+IT/T+IS |
Total |
|
|
(n=29) |
(n=35) |
(n=7) |
(n=6) |
(n=77) |
|
Mean age, years |
|
|
|
|
|
|
(max-min)
|
50,9 |
52,7 |
54,4 |
50,9 |
52,0 |
|
|
(25,7–64,2) |
(24,7–65,9) |
(42,9–64,6) |
(31,0-61,9) |
(24,7-65,9) |
|
Smokers |
|
|
|
|
|
|
No |
13
(45%) |
15
(43%) |
4
(57%) |
4
(67%) |
36
(47%) |
|
Yes Not known |
16
(55%) 0
(0%) |
19
(54%) 1
(3%) |
3
(43%) 0
(0%) |
2
(33%) 0
(0%) |
40
(52%) 1
(1%) |
|
Etiology ED, n (%) |
|
|
|
|
|
|
Psychogenic |
1
(3%) |
1
(3%) |
1
(14%) |
1
(17%) |
4
(5%) |
|
Organic |
20
(69%) |
17
(49%) |
3
(43%) |
3
(50%) |
43
(56%) |
|
Mixed |
8
(28%) |
17
(49%) |
3
(43%) |
2
(33%) |
30
(39%) |
|
Severity ED, n (%) |
|
|
|
|
|
|
Mild |
5
(17%) |
3
(9%) |
1
(14%) |
1
(17%) |
10
(13%) |
|
Moderate |
19
(66%) |
21
(60%) |
4
(57%) |
3
(50%) |
47
(61%) |
|
Severe |
5
(17%) |
11
(31%) |
2
(29%) |
2
(33%) |
20
(26%) |
|
Duration ED, n (%) |
|
|
|
|
|
|
≥
12 months |
24
(83%) |
33
(94%) |
7
(100%) |
6
(100%) |
70
(91%) |
|
Previous sildenafil use, n (%) |
12
(41%) |
23
(65%) |
3
(43%) |
3
(50%) |
41
(53%) |
|
Medical history, n (%) |
|
|
|
|
|
|
Coronary
disease |
1
(3%) |
2
(6%) |
0
( 0%) |
0
(0%) |
3
(4%) |
|
Depression |
1
(3%) |
2
(6%) |
0
( 0%) |
1
(17%) |
4
(5%) |
|
Diabetes
mellitus |
4
(14%) |
9
(26%) |
2
(29%) |
2
(33%) |
17
(22%) |
|
Hypertension |
5
(17%) |
8
(23%) |
2
(29%) |
2
(33%) |
17
(22%) |
T: Tadalafil; S: Sildenafil;
IT: Instructions tadalafil; IS: Instructions sildenafil
Twenty‑seven (45.8%) and
7 (58.3%) patients of the PT and PDI evaluation arms, respectively,
requested dose adjustments of among those patients presenting to the dose
titration visits (59 in the PT group and 12 in the PDI group). Dose
adjustment was granted in 81.5% of the 27 patients who requested it in the
PT evaluation group, following the indications of a maximum of 35% according to
protocol specification. As a result, finally, of the 64 patients
randomized to PT evaluation group, 61 (95.3%) received sildenafil
50 mg and 22 (34.4%) received sildenafil
100 mg.
PREFERENCE
Principal variable
Patient preference for the
medication
At the end of the treatment phase, a
total of 56 of the 64 patients answered the question: ”What treatment
regimen do you prefer for the extension phase? (That received in period
1 / period 2)”. Based on the percentage responses, a significantly
greater number of patients preferred to receive tadalafil
(69.6% vs. 30.4% (p<0.01) in the
extension phase of the study (Fig. 3).
FIGURE 3. Patient preference for treatment with tadalafil
+ its instructions versus treatment with sildenafil +
its instructions.
This predominant preference for tadalafil was similar in all the study groups,
independently of the presence of baseline concomitant co‑morbidity
(arterial hypertension, diabetes or cardiovascular disease), the patient age
range or the etiology or severity of ED at the start
of the study (Fig.s 4A‑4C). Nevertheless, as
can be seen in Fig. 4A, the preference for tadalafil
was significantly greater among the patients aged < 50 years (80.9%),
and in those with moderate ED (79.4%) and of mixed origin (75.0%). Likewise, no
significant influence upon the choice of preferred regimen was exerted by the
prior use or not of sildenafil (66.7% and 73.1%
patients preferred tadalafil, respectively), or by
the treatment sequence to which the patients were randomized (Figs. 4D and 4E).
Lastly, the requirement or not of sildenafil
dose adjustment (titration), and the fact of whether such adjustment was
granted or not, exerted no influence upon the global preference result.
Thus, an approximate proportion of 3 of every 4 patients preferred tadalafil, versus 1 of every 4 who preferred sildenafil. However, 3 patients (60.0%) in whom dose
escalation was denied preferred sildenafil, versus
2 (40.0%) that preferred tadalafil.
FIGURE 4A. Patient preference for treatment with tadalafil
or sildenafil, analyzed by age subgroup.
FIGURE 4B. Patient preference for treatment with tadalafil
or sildenafil, analyzed by concomitant disease
subgroup.
FIGURE 4C. Patient preference for
treatment with tadalafil or sildenafil,
analyzed according to the degree of ED.
FIGURE 4D. Patient preference for
treatment with tadalafil or sildenafil,
analyzed according to prior sildenafil use.
FIGURE 4E. Patient
preference for treatment with tadalafil or sildenafil, analyzed according to the sequence of treatment
received.
Secondary variables
Preference for the dosing
instructions
Eleven of the 13 patients of
the PDI evaluation group answered the question concerning the option chosen for
the extension phase. Of these patients, a larger proportion (72.7%; n=8)
preferred the option corresponding to the instructions for tadalafil
(Instructions T) versus those for sildenafil (27.3%,
n=3; Instructions S)(p>0.05). The order in which
the treatment sequences were received (instructions T / instructions S or
instructions S / instructions T) did not influence the results regarding
preference for the instructions (p>0.05) (Fig. 5).
FIGURE 5. Patient preference for instructions for sildenafil
or tadalafil at the end of the study and according to
the treatment sequence.
Number of attempted intercourses and
relation to medication
In the patients where PT was
evaluated, the total number of attempted intercourses was slightly higher while
receiving tadalafil (1531 attempts) than when
receiving sildenafil (1369 attempts). In the
evaluation of preference for medication, 51.6% (n=33) of the patients who
received tadalafil attempted sexual intercourse at
least once 12 or more hours after taking tadalafil,
compared with 23.4% (n=15) of the patients administered sildenafil.
Considering all attempts of intercourse with tadalafil,
58.3% of them took place in the four hours after drug dosing, 28% after between
4‑12 hours, and 13.7% more than 12 hours after administration.
When the patients received sildenafil, 85.1% of all
attempts occurred within four hours, 9.5% between 4‑12 hours after
dosing, and 5.4% more than 12 hours after medication. On the other hand,
in the dosing instructions evaluation group, an increased number of attempted
intercourses was likewise recorded with the instructions for tadalafil (n=341) versus sildenafil
(n=256), and the proportion of patients who attempted sexual intercourse
12 hours or more after dosing was likewise greater (46.2% with T (n=6) vs 30.8% with S (n=4).
SAFETY
Both tadalafil
and sildenafil were well tolerated. In the evaluation
of preference for the medication, three patients (4.7%) discontinued treatment
because of adverse events. Two of these (moderate heart failure and moderate
headache) were reported while receiving treatment with tadalafil.
The third patient abandoned treatment due to acute myocardial infarction while
taking sildenafil. Of the aforementioned events, only
headache was considered to be related to the study treatment. In the evaluation
of preference for the instructions, no withdrawals due to adverse events were
recorded.
In the evaluation of preference for
treatment, the most frequent adverse events were dyspepsia, headache, flu
symptoms and back pain. Table 2 reports those events with an incidence
≥2% observed during treatment with tadalafil
and sildenafil.
Table 2
List of
reported adverse events related with the treatment, and presenting an incidence
of >2%.
|
T |
S |
|||
|
|
N |
(%) |
n |
(%) |
|
Dyspepsia |
10 |
13,0 |
9 |
14,1 |
|
Headache |
9 |
11,7 |
3 |
4,7 |
|
Flu symptoms |
5 |
6,5 |
6 |
9,4 |
|
Back pain |
4 |
5,2 |
1 |
1,6 |
|
Muscle pain |
3 |
3,9 |
|
|
|
Upper
abdominal pain |
3 |
3,9 |
|
|
|
Diarrhea |
|
|
2 |
3,1 |
|
Nausea |
2 |
2,6 |
|
|
|
Rhinitis |
1 |
1,3 |
1 |
1,6 |
|
Stomach
discomfort |
1 |
1,3 |
|
|
T:
tadalafil* (including the 13 PDI patients); S: sildenafil
In the evaluation of preference for
the dosing instructions (PDI), the most frequent adverse events were flu
syndrome (15%), dyspepsia (7.7%) and headache (7.7%), though in view of the
small sample size involved (n=13), the representativeness
of these data is questionable.
In general, the tolerability of both
drugs was good and similar to that observed in the global study population (
DISCUSSION
This study documents the results
obtained in a cohort of 77 patients recruited in
In relation to the principal study
variable, i.e., preference for the medication, 69.6% of the patients preferred tadalafil versus 30.4% who preferred sildenafil
in the extension phase (p<0.01). These percentages are similar to those
observed in the global study population (73% and 27%, respectively, for tadalafil and sildenafil;
p<0.01). The chi‑square test revealed no significant differences in
the distribution of the proportion of preference between Spanish and non‑Spanish
patients (p>0.05).
Likewise, in the evaluation of
preference for the dosing instructions in the cohort of 13 patients who
received tadalafil with the instructions
corresponding to the latter drug or to sildenafil,
the majority of Spanish subjects (72.7%) preferred the dosing instructions
corresponding to tadalafil, though the limited sample
size of this cohort does not allow the generation of statistical significance
(p>0.05). The percentage preference for treatment with tadalafil
analyzed by subgroups did not vary according to the baseline concomitant
illnesses, the prior use of sildenafil, or the
sequence of treatment or dose adjustment received. Likewise, no variations were
seen in relation to age or the origin and degree of severity of ED at baseline
– though the Spanish population showed a more marked difference in the subgroup
of patients aged <50 years, in those with ED of moderate intensity, or
with ED of organic or mixed origin. It is important to indicate that the preference
for tadalafil was maintained in both the patients
with prior exposure to sildenafil before the study
(66.7%) and in those who had never used the drug (73.1%). On the other hand,
with tadalafil the number of sexual intercourses was
greater, and a longer time elapsed from administration of the drug to the first
attempted coitus than with sildenafil. In this
context, approximately half of the attempts among the patients who received tadalafil took place more than four hours after dosing.
This behavior is undoubtedly explained by the fact
that the unique response period of tadalafil allows
patients to start sexual activity at different times after dosing and in the
subsequent 36 hours – not necessarily in the first four hours after
administration as expected when using shorter action drugs.
Nevertheless, despite more
restrictive dosing instructions in terms of the drug response period, almost
one‑quarter of the patients who received sildenafil
had intercourse at least once 12 or more hours after dosing – thus reflecting
the beneficial effect perceived among many patients by the fact that sexual
activity can be postponed as long as possible after actual dosing.
In general, the tolerability of both
drugs was good and similar, and consistent with the observations corresponding
to the global study population (except for flu syndrome, which was more
frequently reported in the Spanish series) and with the general adverse events
profile reported for tadalafil and sildenafil8,9,11-14. Only three patients (4.7%) abandoned treatment due to
adverse events (2 with tadalafil and 1 with
sildenafil).
Although the results of this study
are clear and consistent with the findings of most preference studies
contrasting the two drugs recorded in the literature to date20-24, a number of factors must be taken into consideration
when interpreting the data of the study:
The restriction to 35% in terms of
the proportion of patients allowed to receive sildenafil
100 mg could exert some influence upon the end results of the study, since
although the medical literature supports this practice25-27, there is no absolute certainty that it precisely
reflects the proportion of patients who use sildenafil
50 or 100 mg in actual clinical practice. Moreover, a non‑negligible
percentage of patients who requested a change in dose were denied the petition
because the aforementioned limit had been reached. Nevertheless, the global
result in terms of preference for tadalafil is
supported by the fact that a significant preference for tadalafil
was observed in the group of patients who did not request dose adjustment, and
because all the patients who requested and were granted dose adjustment also
preferred tadalafil. Only in the 5 Spanish
patients who requested but were denied a dose increment did preference favor sildenafil – though the
difference failed to reach statistical significance due to the small size of
this subgroup.
It must also be pointed out that the
study only made use of the tadalafil 20 mg dose,
since at the time of the trial the latter was considered the recommended
starting dose. At present, while this recommended starting dose has not changed
in some countries, in
Likewise, the dosing instructions
used could have introduced some bias in favor of tadalafil in the interpretation of the information supplied
to the patient. In effect, these were only proposed instructions (since the
drug was not yet marketed at the time) that introduced certain terms suggesting
dosing flexibility and the possibility of spontaneity in relation to sexual
intercourse. In contrast, the instructions corresponding to sildenafil
were those of the manufacturer that had already been approved by the regulatory
authorities. On the other hand, the patients treated with sildenafil
only received the dosing instructions for sildenafil,
and not those corresponding to tadalafil.
Nevertheless, this was done to avoid efficacy bias in detriment of sildenafil, represented by encouraging use of the drug
outside its maximum efficacy time interval.
Despite all the above
considerations, these results show that under double blind conditions, the
majority of patients preferred tadalafil for the
treatment of erectile dysfunction. In the study, no specific evaluation was
made of the reasons for such preference, though this subject has been addressed
by other studies25,26. In this sense, the longer response period was found
to be the main reason for choosing the drug.
In conclusion, 69.6% of the Spanish
patients who participated in the evaluation of treatment preference preferred tadalafil over sildenafil for the
treatment of their erectile dysfunction. Likewise, 72.7% of the patients in
whom preference for the dosing instructions was evaluated preferred to take tadalafil with the instructions corresponding to this same drug,
instead of with the instructions for sildenafil.
Potential limitations of the study
include restriction to 35% in the proportion of patients with access to the
dose increment (to 100 mg) of sildenafil, and
the provision of more detailed instructions for tadalafil
– though it is questionable whether these aspects have an impact on the
results. Both tadalafil and sildenafil
were generally well tolerated.
The data obtained reinforce the need
to implicate as far as possible both the patient and his couple in the decision
taking process relating to the management of erectile dysfunction, with the
individualization of treatment after implementing an adequate strategy for
informing on the benefits and characteristics of the different treatments, and
for identifying the sociological, psychological, cultural and sexual behavioral factors of the patients and their couples. In
this way it will be possible to guarantee that the ultimate treatment option is
effectively the option best adapted to the needs and expectations of the
patient and his couple.
Acknowledgements. This clinical
study has been conducted under the sponsorship of Lilly ICOS LLC. The authors
thank Prof. Remigio Vela‑Navarrete,
Dr. José M. Martínez‑Sagarra, Dr. Alberto Gonzalvo, Dr. Juan Vicente Cardoso,
Dr. Carlos Llorente, and Dr. Javier Estébanez for their participation in the study and the
contribution of scientific data for carrying out the trial. Thanks are also due
to Beatriz Sanz, María Costi, and Elena Bolaños for
their work, dedication and help in conducting the study.
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Dr. A. Cassinello
Hervas
Dr.
A. Cassinello‑Hervas
Laboratorios
Lilly, S.A.
Avda. De la
Industria, 30
28108 Alcobendas (Madrid), Spain
(Article received on