Nonresponders, Partial Responders, and Complete Responders to PDE5 Inhibitors Therapy According to IIEF Criteria: Validation of an Anchor-Based Treatment Responder Classification
May Yang, MPH; Xiao Ni, PhD; Angelina Sontag, PhD; Heather J. Litman, PhD; Raymond C. Rosen, PhD
ONLINE: October 11, 2013 – The Journal of Sexual Medicine
The International Index of Erectile Function (IIEF) is considered the “gold standard” tool for assessing erectile dysfunction (ED). While categories of ED severity have been suggested based on the IIEF, there is currently no standard way to evaluate minimal clinically important difference (MCID) or define an ED treatment responder. As a result, there is no objective way to determine whether ED treatment is effective.
The authors of this study offer a new classification of treatment responder, which may be used in research and clinical care.
This definition will help researchers interpret results of clinical trials. It will also help physicians determine the proper dosing of phosphodiesterase type 5 (PDE5) inhibitors used to treat of ED.
Participants were men who had made at least four sexual intercourse attempts during a 4-week treatment-free run-in period. The men were randomly assigned to three groups for 12 weeks of treatment. One group received a placebo. The second received 10 mg of tadalafil. The third took 20 mg of tadalafil on an as-needed basis. The men were seen by the researchers every 4 weeks.
The men were over 18 years old, had had ED for at least three months, and had a regular female partner. Men who were unable to achieve an erection after radical prostatectomy or pelvic surgery were excluded. Men who had penile deformities or penile implants were also excluded, as were men who took nitrates, antiandrogens, or cancer chemotherapy drugs. The analysis data set included 3,252 men.
Main Outcome Measures
The IIEF was administered at baseline and after treatment. Two criteria were used to categorize subjects: whether or not their IIEF-EF domain score was ≥26 (considered normal function) at the end of the study and whether or not they had achieved MCID or greater at the end point. MCID was defined as a change in the IIEF-EF domain score of ≥ 4 points.
Ninety-seven percent of the subjects completed these assessments for the entire study period. The men were then assigned to one of three treatment groups based on the degree to which they responded to the study treatment.
The diary-based Sexual Encounter Profile (SEP) was also used.
The Global Assessment Question (GAQ) was “Has the treatment you have been taking over the past study interval improved your erections?” Men were asked this question at the end of the study or during the discontinuation visit.
The authors defined discriminant validity as “the extent to which the new classification successfully discriminates between active treatments and controls.” They hypothesized that more men in the 10/20 mg tadalafil treatment group would achieve complete treatment response, compared with fewer men in the control group who would be considered responders.
The authors defined convergent validity as “the extent to which the new outcome classification is correlated with conceptually related or similar measures.” They explained, “Our convergent validity assessment focused on the association between the new responder classification and measures of response as defined by SEP 3 (i.e., MCID+ or –) and GAQ (patient assessment of treatment improvement, yes/no).
Covariates included measures known or hypothesized to be associated with ED, such as coronary artery disease, depression, and diabetes. Medications, such as antidepressants, antipsychotics, SSRIs, and statins were part of the concomitant medication index.
Other covariates included:
• baseline ED severity
• duration of ED
• previous use of PDE5 inhibitors (yes/no) and treatment condition
• age at enrollment
• alcohol use
• body mass index (BMI)
Treatment responders were defined as:
• Complete. Erectile function ≥ 26
• Partial. Erectile function < 26, but meeting MCID criteria
• Nonresponder. Erectile function < 26, not meeting MCID criteria
When compared to partial responders and nonresponders, complete responders were younger, had milder ED at baseline, and had had ED for a shorter period of time. They also had slightly lower numbers of comorbidities and concomitant medication use.
When compared to the complete and partial responders, nonresponders tended to be older, had had ED for a longer period of time, had more comorbidities, and used more concomitant medications.
The partial responders fell in between these two groups in terms of the prevalence of comorbidities. However, they had the highest proportion of severe ED at baseline (43%) compared to the complete responders (22%) and the nonresponders (37%).
The treatment responder measure showed a high level of discriminant validity, especially in the complete responder group. Eighty-nine percent of men treated with 10/20 mg of tadalafil were complete responders compared to 11% of the men in the placebo group. Seventy-three percent of partial responders were in the tadalafil group; 27% were in the placebo group. For nonresponders, 54% were in the placebo group and 46% were in the tadalafil group.
Based on Cochran-Armitage trend tests, the classification measure was determined to have adequate convergent validity. The percentage of subjects who met the MCID criteria for SEP 3 increased from nonresponders to complete responders with percentages in the active group as follows: 26%, 75%, and 83%. The placebo group showed a similar trend with 10% of nonresponders meeting SEP 3 MCID criteria compared to 49% of the partial responders and 61% of the complete responders.
For the tadalafil group, according to GAQ, 99% the complete responders said that treatment improved their erections. This rate was 86% for partial responders and 44% for nonresponders. In the placebo group, improvement in erections was reported by 85% of the complete responders, 56% of the partial responders, and 17% of the nonresponders.
Men in the complete responders group were 19 times more likely to meet the SEP 3 MCID criteria when compared to the nonresponders group. Complete responders were also 78 times more likely to report improvement in treatment compared to the nonresponders.
Covariates that were significantly associated with SEP 3 MCID included age, baseline ED severity, BMI, and treatment condition.
Complete responders were 14 times more likely to have met MCID criteria for successful intercourse when compared to nonresponders. Partial responders were 7 times more likely to have this result.
Complete responders were 59 times more likely than nonresponders to report treatment-improved erections while partial responders were 10 times more likely.
The authors explained, “The new responder definition combines a validated diagnostic classification with MCID in a comprehensive and clinically meaningful way. Our responder definition was found to have a high level of discriminant and convergent validities.”
They suggested the following uses for the new definition:
• creation of a risk calculator or treatment planner for clinicians
• assessment of situations where the patient may be considering more invasive treatments
• compliance with FDA Guidance (2009) on Patient Reported Outcome for developing a transparent, evidence-based, validated definition
• use as a basis of comparative effectiveness outcomes research on new ED treatments
The authors noted that the strengths of their study include its foundation on prior research and the availability of a large database of randomized trials that included the IIEF, SEP and GAQ.
They acknowledged that quality of life measures were not used to assess convergent validity, a “minor limitation.”