Tadalafil Once Daily for Erectile Dysfunction
This study (EDATE) represents the first observation of treatment continuation, effectiveness and tolerability in ED patients treated with tadalafil OaD in routine clinical practice. Time to discontinuation from start of tadalafil OaD treatment was chosen as primary outcome because this measure reflects satisfaction, which is the most important aspect for the patient, integrating compatibility with sexual activity patterns, effectiveness, psychosocial factors and tolerability, all of which may impact the treatment adherence of an individual patient.
While the median time to discontinuation of tadalafil OaD could not be estimated because of a lower than anticipated number of events, the 25th percentile was 31 weeks. After 2, 4 and 6 months, respectively, 94.0%, 88.3% and 86.3% of patients who had initiated or switched to tadalafil OaD at baseline were still continuing this treatment. In a previous RCT which assessed treatment adherence of 770 PDE5-inhibitor naïve patients who were randomised to tadalafil OaD, tadalafil PRN, or sildenafil PRN and were followed up for 24 weeks, median time to discontinuation of tadalafil OaD was 19 weeks, compared with 10 weeks for sildenafil PRN. At 2, 4 and 6 months respectively, 75.9%, 52.5% and 47.8% of randomised patients continued treatment with tadalafil OaD. Patients thus adhered longer to tadalafil OaD in the observational setting of EDATE. An important reason for this difference may be that patients in EDATE had chosen their preferred treatment at baseline, whereas patients in the RCT had been randomised to a particular drug or treatment regimen. Consistent with this interpretation, only 1.5% of all patients starting tadalafil OaD discontinued because they did not want to take an ED medication every day in EDATE, as opposed to 10.5% of patients randomised to tadalafil OaD. This may also explain the low percentage of patients switching to PRN treatment.
For patients treated previously with PDE5-inhibitors, lack of efficacy of their previous treatment, patient preference for OaD treatment (after discussing treatment options with the physician and/or preference based on prior information), the feeling that their previous medication controlled their sexual life, and partner request were the most important reasons for choice of tadalafil OaD (Table 2). For PDE5-inhibitor naïve patients, clinical experience of the investigator (i.e. physicians' advice to the patient guiding patient choice) and patient preference were the most frequently recorded reasons for initiating tadalafil OaD treatment. Another key difference between the two studies assessing treatment adherence was that patients had to pay for their PDE5-inhibitor treatment in EDATE (ED treatment with PDE5-inhibitors is not reimbursed in the participating countries), while they were supplied with study drug for free during the RCT. Nevertheless, only 2.1% of all patients on tadalafil OaD reported "costs of medication" as reason for discontinuation in the observational EDATE study. It may be assumed that the participating patients were well informed regarding potential benefits and medication costs prior to the decision to start treatment. This may suggest a positive cost-benefit for the large majority of patients who continued treatment. The main reason for discontinuation of tadalafil OaD was lack of efficacy (hardness of erection), reported by 4.2% of all patients starting tadalafil OaD. As expected, this proportion was much lower when compared with the RCT, where 21.4% of PDE5-inhibitor naïve patients randomised to tadalafil OaD stated this reason.
Patients with ED diagnosed by their general practitioner on average adhered longer to OaD treatment than patients with ED diagnosed by an urologist (p < 0.001). We can only speculate about the reasons. General practitioners who agreed to participate in EDATE may primarily have been those with a special interest in sexual medicine, and therefore experienced in dealing with patients reporting sexual complaints. Also, general practitioners frequently have a long-standing relationship with their patients. This might have led to a more individual discussion with the patient on available treatment options and therefore to a higher probability of choosing the treatment suited best for the particular patients' needs and expectations, thus resulting in a higher adherence.
Tadalafil OaD was confirmed to be effective in the large majority of patients, as demonstrated by significant improvements in IIEF-EF. LSmean scores increased by 7.1 points from baseline to 4–6 months (T3) after initiation of tadalafil OaD, exceeding the minimally clinically important difference (MCID) of four points, and were consistent with the 9.4-point increase observed with tadalafil OaD in the previous RCT. Overall, 86% of patients reported improvements in their ability to engage in sexual activity, consistent with 84% observed with tadalafil OaD in the RCT.
The percentage of patients who discontinued tadalafil OaD treatment because of adverse events reported in EDATE (2.8%) was close to that reported in the RCT (3.9%). Headache was the most frequently reported adverse events in both studies. No new or unexpected safety signals associated with tadalafil OaD treatment in routine practice were detected.
Potential baseline factors which may contribute to treatment discontinuation (identified using the modelling approach) included age and duration of living arrangement, which may be related to the frequency of sexual activity.
EDATE not only provides the first results on tadalafil OaD treatment in routine practice, but also extends the knowledge on PDE5-inhibitor treatment in general gained from previous prospective observational studies. Comparing different PDE5-inhibitor regimen across different observational studies may be criticised because design and patient populations as well as definitions of continuation, persistence and adherence are different. Nevertheless, the comparison of continuation rates observed in a number of previous studies with different PDE5 inhibitors PRN may provide useful information.
In the European Erectile Dysfunction Observational Study (EDOS), 57.7% of all patients prescribed tadalafil PRN at baseline (regardless if naïve or previously treated) and followed up for 6 months remained on this treatment for 6 months; the corresponding rates in treatment-naïve patients only was 89% (tadalafil PRN), compared with 63–64% (sildenafil or vardenafil). The corresponding values for the tadalafil OaD cohort of the current study EDATE were 78.3% (609 of 778 patients starting the observation) and 94.8% (398 of 420 naïve patients completing the study). In another European observational study (DETECT), 84% of patients reported continued tadalafil PRN use at 12 months. Persistence of tadalafil PRN use at Month 6 was 71.6% and 68.8%, respectively, in two observational studies conducted in Latin America and Middle East/North Africa.
Although based on different studies, these data suggest that continuation rates after treatment with tadalafil OaD may at least be non-inferior compared with PRN regimens. This could result from a true advantage of the OaD regimen, but also from shared decision-making and more comprehensive patient information. Before starting OaD treatment, physicians might have taken more time to discuss the possible benefits and pitfalls of the various ED treatment approaches to identify the most appropriate regimen for each individual patient. Patients who made an informed decision together with their physicians and choose the most suitable treatment with respect to their preferences and needs (regarding dosing, duration of action and spontaneity of sexual activity) may be more likely to continue their treatment. This hypothesis would need confirmation by an interventional trial with standardised comprehensive patient information regarding the different treatment regimen, followed by either free patient choice of the PDE5 inhibitor regimen, or randomised treatment assignment.
Limitations of this study include bias caused by routine practice and preference of participating investigators, as suggested by the high proportion of patients starting with tadalafil OaD at baseline. To increase the external validity of our data, we aimed to minimise this potential source of bias by randomly selecting sites from a list of investigators expressing interest in participation and by asking sites to enrol patients consecutively. This site selection and enrolment process was a particular strength of the study. We cannot exclude that results were still biased because only sites and investigators with an interest to participate could be selected. In addition, patients who had chosen tadalafil OaD may have decided to participate in the study more frequently than patients starting PRN treatment because only patients starting with tadalafil OaD received additional postbaseline evaluations. As patients had to pay their treatment during the observational period, this might have biased the tadalafil OaD cohort towards patients with higher education and economic status.
In conclusion, 86.3% of men who started/switched to tadalafil OaD at baseline continued tadalafil OaD treatment for ≥ 6 months. IIEF-EF scores improved significantly, exceeding the MCID, with 91% of patients reporting improved erections and 86% reporting improved ability to engage in sexual activity at T3. The majority of study completers (91%) continued tadalafil OaD after the study. No new or unexpected safety signals associated with tadalafil OaD treatment in routine practice were detected.
If patients receive adequate information about the respective properties of treatments available and their appropriate use and are given the opportunity to choose an ED treatment suited to their individual needs and preferences, they may experience clinically relevant EF improvement and may likely be satisfied with their medication in routine practice. Detailed patient information, expectation-management and participative decision-making at the time of prescription might improve treatment adherence compared with an RCT setting.
Discussion
This study (EDATE) represents the first observation of treatment continuation, effectiveness and tolerability in ED patients treated with tadalafil OaD in routine clinical practice. Time to discontinuation from start of tadalafil OaD treatment was chosen as primary outcome because this measure reflects satisfaction, which is the most important aspect for the patient, integrating compatibility with sexual activity patterns, effectiveness, psychosocial factors and tolerability, all of which may impact the treatment adherence of an individual patient.
While the median time to discontinuation of tadalafil OaD could not be estimated because of a lower than anticipated number of events, the 25th percentile was 31 weeks. After 2, 4 and 6 months, respectively, 94.0%, 88.3% and 86.3% of patients who had initiated or switched to tadalafil OaD at baseline were still continuing this treatment. In a previous RCT which assessed treatment adherence of 770 PDE5-inhibitor naïve patients who were randomised to tadalafil OaD, tadalafil PRN, or sildenafil PRN and were followed up for 24 weeks, median time to discontinuation of tadalafil OaD was 19 weeks, compared with 10 weeks for sildenafil PRN. At 2, 4 and 6 months respectively, 75.9%, 52.5% and 47.8% of randomised patients continued treatment with tadalafil OaD. Patients thus adhered longer to tadalafil OaD in the observational setting of EDATE. An important reason for this difference may be that patients in EDATE had chosen their preferred treatment at baseline, whereas patients in the RCT had been randomised to a particular drug or treatment regimen. Consistent with this interpretation, only 1.5% of all patients starting tadalafil OaD discontinued because they did not want to take an ED medication every day in EDATE, as opposed to 10.5% of patients randomised to tadalafil OaD. This may also explain the low percentage of patients switching to PRN treatment.
For patients treated previously with PDE5-inhibitors, lack of efficacy of their previous treatment, patient preference for OaD treatment (after discussing treatment options with the physician and/or preference based on prior information), the feeling that their previous medication controlled their sexual life, and partner request were the most important reasons for choice of tadalafil OaD (Table 2). For PDE5-inhibitor naïve patients, clinical experience of the investigator (i.e. physicians' advice to the patient guiding patient choice) and patient preference were the most frequently recorded reasons for initiating tadalafil OaD treatment. Another key difference between the two studies assessing treatment adherence was that patients had to pay for their PDE5-inhibitor treatment in EDATE (ED treatment with PDE5-inhibitors is not reimbursed in the participating countries), while they were supplied with study drug for free during the RCT. Nevertheless, only 2.1% of all patients on tadalafil OaD reported "costs of medication" as reason for discontinuation in the observational EDATE study. It may be assumed that the participating patients were well informed regarding potential benefits and medication costs prior to the decision to start treatment. This may suggest a positive cost-benefit for the large majority of patients who continued treatment. The main reason for discontinuation of tadalafil OaD was lack of efficacy (hardness of erection), reported by 4.2% of all patients starting tadalafil OaD. As expected, this proportion was much lower when compared with the RCT, where 21.4% of PDE5-inhibitor naïve patients randomised to tadalafil OaD stated this reason.
Patients with ED diagnosed by their general practitioner on average adhered longer to OaD treatment than patients with ED diagnosed by an urologist (p < 0.001). We can only speculate about the reasons. General practitioners who agreed to participate in EDATE may primarily have been those with a special interest in sexual medicine, and therefore experienced in dealing with patients reporting sexual complaints. Also, general practitioners frequently have a long-standing relationship with their patients. This might have led to a more individual discussion with the patient on available treatment options and therefore to a higher probability of choosing the treatment suited best for the particular patients' needs and expectations, thus resulting in a higher adherence.
Tadalafil OaD was confirmed to be effective in the large majority of patients, as demonstrated by significant improvements in IIEF-EF. LSmean scores increased by 7.1 points from baseline to 4–6 months (T3) after initiation of tadalafil OaD, exceeding the minimally clinically important difference (MCID) of four points, and were consistent with the 9.4-point increase observed with tadalafil OaD in the previous RCT. Overall, 86% of patients reported improvements in their ability to engage in sexual activity, consistent with 84% observed with tadalafil OaD in the RCT.
The percentage of patients who discontinued tadalafil OaD treatment because of adverse events reported in EDATE (2.8%) was close to that reported in the RCT (3.9%). Headache was the most frequently reported adverse events in both studies. No new or unexpected safety signals associated with tadalafil OaD treatment in routine practice were detected.
Potential baseline factors which may contribute to treatment discontinuation (identified using the modelling approach) included age and duration of living arrangement, which may be related to the frequency of sexual activity.
EDATE not only provides the first results on tadalafil OaD treatment in routine practice, but also extends the knowledge on PDE5-inhibitor treatment in general gained from previous prospective observational studies. Comparing different PDE5-inhibitor regimen across different observational studies may be criticised because design and patient populations as well as definitions of continuation, persistence and adherence are different. Nevertheless, the comparison of continuation rates observed in a number of previous studies with different PDE5 inhibitors PRN may provide useful information.
In the European Erectile Dysfunction Observational Study (EDOS), 57.7% of all patients prescribed tadalafil PRN at baseline (regardless if naïve or previously treated) and followed up for 6 months remained on this treatment for 6 months; the corresponding rates in treatment-naïve patients only was 89% (tadalafil PRN), compared with 63–64% (sildenafil or vardenafil). The corresponding values for the tadalafil OaD cohort of the current study EDATE were 78.3% (609 of 778 patients starting the observation) and 94.8% (398 of 420 naïve patients completing the study). In another European observational study (DETECT), 84% of patients reported continued tadalafil PRN use at 12 months. Persistence of tadalafil PRN use at Month 6 was 71.6% and 68.8%, respectively, in two observational studies conducted in Latin America and Middle East/North Africa.
Although based on different studies, these data suggest that continuation rates after treatment with tadalafil OaD may at least be non-inferior compared with PRN regimens. This could result from a true advantage of the OaD regimen, but also from shared decision-making and more comprehensive patient information. Before starting OaD treatment, physicians might have taken more time to discuss the possible benefits and pitfalls of the various ED treatment approaches to identify the most appropriate regimen for each individual patient. Patients who made an informed decision together with their physicians and choose the most suitable treatment with respect to their preferences and needs (regarding dosing, duration of action and spontaneity of sexual activity) may be more likely to continue their treatment. This hypothesis would need confirmation by an interventional trial with standardised comprehensive patient information regarding the different treatment regimen, followed by either free patient choice of the PDE5 inhibitor regimen, or randomised treatment assignment.
Limitations of this study include bias caused by routine practice and preference of participating investigators, as suggested by the high proportion of patients starting with tadalafil OaD at baseline. To increase the external validity of our data, we aimed to minimise this potential source of bias by randomly selecting sites from a list of investigators expressing interest in participation and by asking sites to enrol patients consecutively. This site selection and enrolment process was a particular strength of the study. We cannot exclude that results were still biased because only sites and investigators with an interest to participate could be selected. In addition, patients who had chosen tadalafil OaD may have decided to participate in the study more frequently than patients starting PRN treatment because only patients starting with tadalafil OaD received additional postbaseline evaluations. As patients had to pay their treatment during the observational period, this might have biased the tadalafil OaD cohort towards patients with higher education and economic status.
In conclusion, 86.3% of men who started/switched to tadalafil OaD at baseline continued tadalafil OaD treatment for ≥ 6 months. IIEF-EF scores improved significantly, exceeding the MCID, with 91% of patients reporting improved erections and 86% reporting improved ability to engage in sexual activity at T3. The majority of study completers (91%) continued tadalafil OaD after the study. No new or unexpected safety signals associated with tadalafil OaD treatment in routine practice were detected.
If patients receive adequate information about the respective properties of treatments available and their appropriate use and are given the opportunity to choose an ED treatment suited to their individual needs and preferences, they may experience clinically relevant EF improvement and may likely be satisfied with their medication in routine practice. Detailed patient information, expectation-management and participative decision-making at the time of prescription might improve treatment adherence compared with an RCT setting.