Sensitivity analyses comparing time-to-event outcomes only existing in a subset selected postrandomization and relaxing monotonicity.

In randomized studies researchers may be interested in the effect of treatment assignment on a time-to-event outcome that only exists in a subset selected after randomization. For example, in preventative HIV vaccine trials, it is of interest to determine whether randomization to vaccine affects the time from infection diagnosis until initiation of antiretroviral therapy. Earlier work assessed the effect of treatment on outcome among the principal stratum of individuals who would have been selected regardless of treatment assignment. These studies assumed monotonicity, that one of the principal strata was empty (e.g., every person infected in the vaccine arm would have been infected if randomized to placebo). Here, we present a sensitivity analysis approach for relaxing monotonicity with a time-to-event outcome. We also consider scenarios where selection is unknown for some subjects because of noninformative censoring (e.g., infection status k years after randomization is unknown for some because of staggered study entry). We illustrate our method using data from an HIV vaccine trial.

Finasteride monotherapy maintains stable lower urinary tract symptoms in men with benign prostatic hyperplasia following cessation of alpha blockers.

OBJECTIVE: Our Canadian multicentre open-label study sought to evaluate, in patients with moderate/severe lower urinary symptoms (LUTS) secondary to benign prostatic hyperplasia, the effect on symptoms of 9 months of monotherapy with finasteride 5 mg following 9 months of combination treatment (finasteride with an alpha-blocker) as quantified according to the International Prostate Symptom Score (IPSS). METHODS: The primary outcome measure for efficacy was the maintenance of IPSS response after cessation of the alpha-blocker. Subjects were treated with a combination of finasteride and an alpha-blocker for 9 months and then with finasteride alone for 3 or 9 months. RESULTS: Results showed that the IPSS scores after 3 months of monotherapy were within the criteria for equivalence to those after 9 months of combination therapy. Symptom control equivalence was also found after 9 months of monotherapy. The IPSS response rate was also similar for combination and monotherapy. The safety profile was similar and as expected with these medications. CONCLUSION: Control of LUTS associated with BPH thus appears to be maintained for at least 9 months with finasteride alone, following a 9-month course of combination therapy with finasteride and an alpha-blocker, with similar safety profiles.

Predictive value of maximum urethral closure pressure, urethral hypermobility and urethral incompetence in the diagnosis of clinically significant female genuine stress incontinence.

PURPOSE: We determined the value of urethral hypermobility, maximum urethral closure pressure (MUCP) and urethral incompetence in the diagnosis of stress urinary incontinence (SUI). MATERIALS AND METHODS: In this study 369 women with clinical symptoms suggestive of SUI without symptoms of bladder overactivity were evaluated in regard to urethral incompetence, urethral hypermobility and mean MUCP. The cohort was divided into 2 groups according to continence/incontinence status. ROC curves were used to test the performance of the various predicting factors. These factors were combined in forward stepwise logistic regression to find the cutoff point that simultaneously optimized sensitivity and specificity. RESULTS: Continent and incontinent patients differed with regards to urethral incompetence and hypermobility (each p <0.0001). Incontinent patients had a greater probability of a higher grade of each factor. Even after adjusting for the older age of incontinent patients by ANCOVA. MUCP was significantly lower in the incontinent group (p <0.001). The best univariate optimized cutoff point for discriminating continence from incontinence was obtained with urethral incompetence greater than grade I. CONCLUSIONS: The best single predictor of clinically significant SUI is urethral incompetence, followed by urethral hypermobility and MUCP. When combining several factors, namely grade II urethral incompetence with grade III hypermobility, grade III urethral incompetence with grades I to III hypermobility and grade IV urethral incompetence with or without urethral hypermobility, all indicated more than a 90% probability of clinically significant SUI.

Observations on the function of the female urethra: II: Relation between maximum urethral closure pressure at rest and the degree of urethral incompetence.

AIMS: To study the relation between maximum urethral closure pressure (MUCP) at rest and the degree of urethral incompetence in the female. PATIENTS AND METHODS: Two hundred fifty five patients aged 20 years or older, with stable bladders on multichannel urodynamics, without known neurological pathology, and with no previous history of pelvic or anti-incontinence surgery were included in the study. Resting urethral pressure profile (UPP) and the grade of urethral incompetence was registered. RESULTS: Mean age of the group was 45.6+/-12.7 years; mean MUCP was 62.7+/-28.5 cm of water. There was a statistically significant difference in the MUCP when the different grades of urethral incompetence were compared to each other, the higher grades being associated with a lower maximal closure pressure. CONCLUSIONS: This study demonstrates that there is a highly significant relationship between MUCP and between all grades of urethral incompetence. This supports previous observations that MUCP decreases when abdominal leak point pressure (ALPP) is low and that this might be secondary to some mechanical failure in the pressure transmission from the abdominal cavity to the urethra. Studies should never compare continent to incontinent cohorts without considering their ALPP because in doing so they are comparing groups that are functionally heterogeneous.

Observations on the function of the female urethra: III: An overview with special reference to the relation between urethral hypermobility and urethral incompetence.

AIMS: To analyze the relation between urethral hypermobility and urethral incompetence, and to summarize the interdependence between maximum urethral closure pressure (MUCP), urethral hypermobility, and urethral incompetence. PATIENTS AND METHODS: A group of 255 patients was selected from a large bank of cases. Inclusion criteria were age 20 years or above, no neurological disease, stable bladder, and no previous incontinence surgery or hysterectomy. The degree of hypermobility (cysto-urethrocele) and the degree of urethral incompetence (abdominal leak point pressure (ALPP)) were determined. Statistical analyses between urethral hypermobility and incompetence were performed with Spearman's correlation and the Jonckherre-Terpstra test. RESULTS: The Spearman's rank correlation test showed a statistically significant relation between urethral hypermobility and the degree of urethral incompetence (P = 0.0049). CONCLUSIONS: The statistically significant relation between urethral incompetence and hypermobility suggests that urethral incompetence will increase as the degree of urethral hypermobility does. Optimal conditions for urinary continence include a high maximum urethral closure pressure, absence of hypermobility, and a low degree of urethral incompetence. This last factor is assured by a strong support underneath the urethra permitting compression of the latter during straining. Failure of the urethral closure mechanism is highly probable with a diminished maximum closure pressure accompanied by urethral hypermobility often associated with a high degree of urethral incompetence. Clinically significant urinary incontinence may appear in many intermediate circumstances between these two extreme states, but stress urinary incontinence is essentially an activity-related phenomenon.

Observations on the function of the female urethra: I: relation between maximum urethral closure pressure at rest and urethral hypermobility.

AIMS: To study the relation between maximum urethral closure pressure at rest and urethral hypermobility in female patients. PATIENTS AND METHODS: We selected 255 patients aged 20 years and older, with a stable bladder on multichannel urodynamics, without known neurological pathology, and without a history of pelvic or anti-incontinence surgery. A resting urethral pressure profile and the degree of urethral hypermobility were registered. Two-tailed analyses of variance (ANOVA) with Fisher's post-hoc tests were used to detect any statistically significant difference (P < 0.05) in urethral closure pressure between groups with varying degrees of urethral hypermobility. RESULTS: Mean age was 45.6 +/- 12.7 (range 20-77) years. Mean maximum urethral closure pressure for the entire group was 62.7 +/- 29 (range 10-150) cm of water. A statistically significant inverse relationship was found between age and maximum urethral closure pressure (r = 0.489, P < 0.0001) when both analyzed as continuous variables, and with age categorized in 10-year increments (P < 0.0001). When comparing mean urethral closure pressure in each group examined for urethral hypermobility, a statistically significant difference was noted when grades I, II, and III were compared to grade 0 hypermobility. No significant difference was observed when grades I, II, and III were compared to each other. Even if statistically non-significant, there exists an inverse relationship between the degree of urethral hypermobility and the maximum urethral closure pressure: a higher hypermobility is associated with a lesser urethral closure pressure. CONCLUSIONS: Urethral closure pressure falls significantly when urethral hypermobility is present. This decrease is not related to patient's age or parity. Our observations demonstrate an inverse relation between urethral closure pressure and the degree of cysto-urethrocele. As hypermobility increases, closure pressure decreases, even if this decrease does not reach the level of statistical significance.

Frequency-volume chart: the minimum number of days required to obtain reliable results.

AIMS: There is wide variation in the number of days necessary to maintain a diary and still furnish reliable data on which to base a sound clinical assessment. Estimates range from 1 day to 2 weeks, 7 days probably being the criterion standard. The goal of this retrospective study was to evaluate how much the 7-day period could be shortened without compromising the reliability of data. METHODS: Various lengths of frequency-volume (FV) charts (from 1 day to 6 days) were compared with the standard 7-day charts on 14 FV parameters. RESULTS: Overall results show that a 4-day dairy is nearly identical to the 7-day chart (most r > or = 0.95). Results of the 1-, 2-, and 3-day charts were frequently different statistically from the 7-day chart, whereas comparison of the 4-day chart with the 7-day chart showed no statistically significant differences. In addition, results of 4-day FV charts from a new control cohort showed no significant differences from the 7-day charts of the main cohort. CONCLUSIONS: In conclusion, our study indicates that the 4-day chart is as reliable as the 7-day chart. This reduction in the length of time, although easier for the patients, does not compromise the diagnostic value of the FV charts.