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A RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED CROSSOVER TRIAL OF NIMODIPINE IN OLDER PERSONS WITH DETRUSOR INSTABILITY AND URGE INCONTINENCE
0022-5347/02/1672-0586/0 THE JOURNAL OF UROLOGY® Copyright © 2002 by AMERICAN UROLOGICAL ASSOCIATION, INC.®
Vol. 167, 586 –590, February 2002 Printed in U.S.A.
A RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED CROSSOVER TRIAL OF NIMODIPINE IN OLDER PERSONS WITH DETRUSOR INSTABILITY AND URGE INCONTINENCE GARY NAGLIE,* SIDNEY B. RADOMSKI,† CHRIS BRYMER, KAREN MATHIASEN, KEITH O’ROURKE AND GEORGE TOMLINSON From the Divisions of General Internal Medicine and Clinical Epidemiology and Urology, University Health Network, the Geriatrics Program, Toronto Rehabilitation Institute, the Clinical Epidemiology and Health Care Research Program (University Health Network Unit) and Departments of Medicine, Health Administration, Public Health Sciences and Urology, University of Toronto, Toronto, Division of Geriatrics, Parkwood Hospital and Department of Medicine, University of Western Ontario, London and the Loeb Research Unit, Ottawa Hospital and Department of Surgery, University of Ottawa, Ottawa, Ontario, Canada
ABSTRACT
Purpose: We evaluated the efficacy of nimodipine, a dihydropyridine calcium channel blocker that relaxes vascular and nonvascular smooth muscle, for geriatric urge incontinence. Materials and Methods: A randomized, double-blind, placebo controlled crossover trial of 30 mg. nimodipine twice daily for 3 weeks in older persons with detrusor instability and chronic urge incontinence was done. A total of 86 participants with a mean age of 73.4 years were randomized. The primary outcome was the number of incontinent episodes, as measured by the self completion of a 5-day voiding record. Secondary outcomes included the impact of urinary incontinence on quality of life measured with a modified incontinence impact questionnaire (mIIQ) and symptoms, as measured by the American Urological Association (AUA) symptom score. Results: A total of 76 (88.4%) participants completed the study. There was no significant difference in the number of incontinent episodes with nimodipine versus placebo, which included a difference of 0.03 incontinent episodes during a 5-day period (p ⫽0.98, 95% confidence interval ⫺2.7 to 2.8). Scores on the mIIQ and the AUA symptom score were not significantly different with nimodipine versus placebo (p ⫽ 0.07 and 0.22, respectively). Regardless of initial treatment, participants had improvement with time, that is a period effect, of incontinent episodes (p ⬍0.0001), mIIQ scores (p ⫽ 0.0002) and AUA symptom score values (p ⬍0.0001). Conclusions: Treatment of geriatric urge incontinence with 30 mg. nimodipine twice daily did not result in a significant improvement of incontinent episodes, mIIQ scores or AUA symptom scores. KEY WORDS: urinary incontinence, adult, aged, calcium channel blockers, double-blind method
Urinary incontinence is a common condition affecting an estimated 30% of all community dwelling older persons as well as 50% to 70% of nursing home residents.1 Urge incontinence is the most common cause of urinary incontinence in the elderly, and can result in decreased activity, social isolation, depression, diminished quality of life and long-term care placement.2 Behavioral and pharmacological interventions have been used for management of urge incontinence. Drugs, such as immediate release oxybutynin, propantheline and dicyclomine, have anticholinergic side effects that impact use in the elderly.3 The newer formulation of controlled release oxybutynin still has significant anticholinergic side effects.4 Although there are less anticholinergic side effects with tolterodine, they still exist, especially at higher doses.5 Behavioral therapy is a safe option for treatment of urge incontinence in the elderly. However, it is labor intensive, costly and requires a highly motivated patient.3 Furthermore, there is a lack of standardization of behavioral therapy programs, and results can be quite variable.3, 6 Nimodipine is a dihydropyridine calcium channel blocker
that relaxes vascular and nonvascular smooth muscle. There are 2 mechanisms whereby nimodipine may be effective for urge incontinence. It may enhance perfusion of the frontal cerebral inhibitory control center for bladder contraction, an area that has been shown to be hypoperfused in a large series of geriatric cases of urge incontinence,7 and/or it may act on bladder smooth muscle directly. Elliot et al have found that nimodipine is a far more potent inhibitor of detrusor contraction than either nifedipine or verapamil in rat and human bladder tissue.8 There is some evidence that intravesical therapy with verapamil can be beneficial to patients with neurogenic detrusor hyperreflexia.9 A small number of randomized trials have evaluated the effect of calcium channel blockers on patients with detrusor instability. A few studies have demonstrated the effectiveness of terodiline.10 –13 However, terodiline is not a pure calcium channel antagonist, as it also has anticholinergic properties. Furthermore, terodiline is no longer available because of serious ventricular arrhythmia side effects. A double-blind crossover study of flunarizine in 14 women with detrusor instability and urinary incontinence revealed a nonsignificant trend towards improvement of bladder capacity, volume at first sensation and flow rate, and a significant improvement of symptoms.14 The purpose of this randomized, controlled, double-blind crossover trial was to determine the efficacy of the calcium channel blocker nimodipine at a dose of 30 mg. twice daily for treating detrusor instability with urinary urge incontinence
Accepted for publication August 10, 2001. Supported by a research grant from the Physicians’ Services Incorporated Foundation of Ontario and a career award from the Physicians’ Services Incorporated Foundation (Arthur Bond Award). *Financial interest and/or other relationship with Astra Zeneca, Janssen-Ortho and ID Biomedical. †Financial interest and/or other relationship with Pfizer, Pharmacia Upjohn, Purdue and Geryx Medical. 586
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in a geriatric outpatient population. A cross-over design was chosen rather than a parallel group to control better for the large interindividual variability that exists in incontinent populations by allowing patients to act as their own controls. This effect in turn reduces the sample size needed to ensure adequate statistical power. METHODS
Participants were recruited by advertising the study in newspapers, on local radio and television stations, and circulating flyers to physician offices. Potential participants were initially screened by telephone, and those who met basic inclusion criteria were invited to the Toronto Western Hospital for further assessment, including a medical and incontinence history, physical examination, 5-day voiding record, urinalysis and urine culture, multichannel urodynamic testing (including stress maneuvers and determination of postvoid residual urine volume) and cystoscopy. Urodynamic testing was performed with a fill rate of 25 to 50 cc per minute with normal saline at room temperature. The Appendix lists the inclusion and exclusion15, 16 criteria for the study. Urge incontinence was defined as urinary leakage with documented detrusor instability on urodynamic testing, including an increase in detrusor pressure 15 cm. or greater of water during urodynamic testing, or documented instability at less than 15 cm. of water with symptoms of urgency.17 The study was a randomized, double-blind, placebo controlled crossover trial that was preceded by a 2-week run-in period. Voiding records, quality of life and symptom scores were collected twice, 1 week apart, during the run-in period. Participants who successfully completed the runin period were randomized to the order of treatment based on a computer generated randomization code available from the study biostatistician. Participants received a container of study medication containing either 45 capsules of 30 mg. nimodipine or placebo, matched for appearance and taste. The participant was instructed to take 1 capsule every morning with breakfast and every evening before bedtime for 3 weeks (period 1). The participant then returned the container with the unused capsules to the research assistant who performed a pill count to assess compliance. After a 2-week washout period the participant received a second container of study medication with similar instructions, again with a repeat pill count after 3 weeks (period 2). The primary outcome measure was the change from baseline in the number of incontinent episodes, as measured by a self-completed 5-day voiding record documenting the number, and timing of voluntary voiding and incontinent episodes. All other measures were considered secondary outcomes. Quality of life was measured with a modified version of the incontinence impact questionnaire (IIQ), a selfadministered urinary incontinence specific instrument developed by Wyman et al.18 We modified the IIQ by replacing the scaled response from “none/slightly/moderately/greatly” to “never/⬍ 1⁄2 the time/about 1⁄2 the time/⬎ 1⁄2 the time/always,” by reducing the total number of items from 26 to 16 and adding 1 item on sleep. Scoring of the modified IIQ (mIIQ) was based on a maximum score of 63, with higher scores representing a greater impact of incontinence on quality of life. Urinary symptoms were measured with the American Urological Association (AUA) benign prostatic hypertrophy symptom score, which is a 7 item self-administered questionnaire, with a total score of 35 and higher scores representing worse symptoms.19 Although used predominately for benign prostatic hypertrophy, the AUA symptom score has been shown to be reliable and valid in postmenopausal women with detrusor instability and urge incontinence, with improvement in scores after treatment.20, 21 The effect of treatment was also assessed by 3 questions that were asked after
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each treatment period to assess participant subjective perception of how treatment affected the number of incontinent events, amount of leakage and urgency to urinate (“much worse/a little worse/about the same/a little better/much better”). Medication adverse effects were measured at the end of each treatment period by a self-administered questionnaire that included a list of 17 possible symptoms that participants were asked to rate themselves on compared with before starting the study medication. A post-void residual urine volume was measured by an in-and-out catheterization to assess for urinary retention, and lying and standing blood pressure was recorded to assess for orthostatic hypotension at the end of treatment periods 1 and 2. Our study received ethics approval from the Toronto Hospital, which is now the University Health Network, and the University of Toronto. The study was suspended for 91⁄2 weeks in response to concerns about possible adverse drug events. An independent safety monitoring committee reviewed all adverse events with nimodipine and placebo, and reviewed the current literature on possible toxicity with calcium channel blockers. The committee did not find any evidence of more adverse events with nimodipine. Based on new publications suggesting possible adverse events with some calcium channel blockers in patients with underlying cardiovascular disease,22–24 the committee advised that the study be continued with the exclusion of patients with established coronary artery disease. The University and Hospital Ethics Committees approved the continuation of the study with the revised exclusion criteria and a revised consent form. Test-retest reliability of the outcome measures was established by comparing the results for each of the measures in week 1 with those of week 2 of the run-in period using Pearson’s correlation coefficient. Investigation of the possibility of a carry over effect was done according to the methods suggested by Senn.25 The primary analysis of the crossover data used paired t-tests and a random effects analysis of variance to examine changes with time in continuous outcomes. The primary analysis was also redone on the logarithm of the ratio of the number of incontinent episodes with nimodipine versus placebo, in which half was added to the counts to avoid zeroes. An intention to treat analysis was performed that assessed each of the following assumptions about the outcomes of participants who withdrew from the study: 1) all had an equal response to nimodipine and placebo, 2) all were cured of incontinence by nimodipine and 3) all were cured of incontinence by placebo. Responses to the 3 subjective questions about treatment effectiveness were analyzed with the signed rank test. McNemar’s chi-square test was used to analyze differences in adverse events and orthostatic hypotension. Data analysis was performed with commercial software. For the sample size calculation we defined a treatment response as a 30% reduction in the number of incontinent events compared with baseline. Assuming a 40% response rate with placebo, 60% with nimodipine, and a correlation of 0.25 between responses to nimodipine and placebo, a sample size of 72 was calculated to give 80% power when testing at an ␣ ⫽ 0.05.26 RESULTS
The figure shows the flow of study patients. Of the 187 patients who were screened 71 were ineligible for our study. An additional 29 patients were excluded from the study after the run-in period because they did not have 4 incontinent episodes on a 5-day voiding record, were unable to maintain a voiding record or did not want to continue with the study. A total of 86 patients were randomized, including 42 to group 1 (nimodipine first) and 44 to group 2 (placebo first). There were 6 patients in group 1 who did not complete the study, including 3 because of side effects, 1 to undergo surgery and
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Flow of study participants through selection and intervention protocols. R, randomization
2 because of temporary study suspension, and 4 in group 2, including 1 who died and 3 because of temporary study suspension. The randomized participants ranged from 65 to 88 years old, and baseline characteristics are shown in table 1. The 10 randomized participants who did not complete the study differed slightly from the 76 who did in regard to age, sex and number of incontinent episodes during the run-in period but none of these differences were statistically significant. Of the 76 patients who completed the study 40 (52.6%) had not received any prior medical therapy for urge incontinence, 25 (32.9%) had previously been treated with oxybutynin chloride, and 11 (14.5%) had previously been treated with oxybutynin chloride and at least 1 other medication. For the 82 randomized participants the test-retest reliability of the outcome measures was high, including 0.92 for the 5-day voiding record, 0.82 mIIQ and 0.77 AUA symptom score. TABLE 1. Mean baseline characteristics of randomized participants
Mean pt. age % Female Data from run-in period: Mean No. incontinent episodes Mean mIIQ score Mean AUA symptom score Data from urodynamic tests: Mean vol. infused (ml.) Mean max. flow rate (ml./sec.) Mean detrusor pressure at instability (cm. H2O) Mean max. voiding pressure (cm. H2O)
Complete Data
Incomplete Data
73.9 84.2
69.5 90.0
19.5 22.2 14.9
14.3 21.4 9.9
307.6 18.8 48.2
283.0 19.6 49.9
31.0
25.6
For the 76 participants who received nimodipine and placebo there were an average of 0.03 fewer incontinent episodes during a 5-day period on placebo (p ⫽ 0.98, 95% confidence interval [CI]-2.7 to 2.8 incontinent episodes). A paired test analysis of the logarithm of the number of incontinent episodes also yielded a nonsignificant difference between nimodipine and placebo. Transformed back to the original scale, the mean number of incontinent episodes with placebo was 0.85 times that with nimodipine (p ⫽ 0.08, 95% CI 0.70 to 1.02). The intention to treat analysis did not yield any significant differences in the number of incontinent episodes between nimodipine and placebo. The results were unchanged when only those patients randomized before the temporary study suspension (74 of 76 who completed the study) were included in the analysis. The total number of incontinent episodes, mIIQ scores and AUA symptom scores during each period for the 76 participants who completed the study are shown in table 2. There was a significant decrease in the number of incontinent episodes with time in both groups, suggesting a period effect (p ⬍0.0001). Within subjects comparison of mIIQ scores in periods 1 and 2 revealed a 1.4 point lower score with nimodipine versus placebo (p ⫽ 0.07). The mIIQ scores decreased with time in both groups, suggesting a period effect (p ⫽ 0.0002). Within subjects comparison of AUA symptom scores in periods 1 and 2 revealed a 0.63 point lower score with nimodipine versus placebo (p ⫽ 0.22). These scores also decreased with time in both groups, suggesting a period effect (p ⬍0.0001). No significant differences were found between nimodipine and placebo in regard to the participant subjective perception of treatment effect on the number of incontinent episodes (p ⫽ 0.62), amount of urine leakage (p ⫽ 0.94) or symptomatic urinary urgency (p ⫽ 0.84). No statistically significant difference was noted in adverse effects between nimodipine and placebo (table 3). There were 2 participants who withdrew from the study for side effects while taking nimodipine, including 1 for shortness of breath and 1 death due to a myocardial infarction, and 2 withdrawals for side effects while taking placebo (both for dizziness). Post-void residual urine volumes were measured for 79 participants at the end of periods 1 and 2. Mean residual volume was 29.5 ml. for placebo and 28.7 for nimodipine (p ⫽ 0.80). In all cases residual urine volume was less than 150 ml. Mean systolic blood pressure was 3.6 mm. Hg lower with nimodipine versus placebo (p ⫽ 0.03), and mean diastolic blood pressure was 1.6 mm. Hg lower with nimodipine (p ⫽ 0.07). The range of the difference in systolic blood pressure between nimodipine and placebo was from 42 mm. Hg lower TABLE 2. Incontinent episodes on 5-day voiding record, mIIQ scores and AUA symptom scores Mean ⫾ SD Group 1*
Group 2†
Incontinent episodes Run-in period Period 1 Washout period Period 2
15.40 ⫾ 12.40 10.97 ⫾ 10.75 13.06 ⫾ 12.33 8.36 ⫾ 10.69
Run-in period Period 1 Washout period Period 2
21.26 ⫾ 12.45 15.00 ⫾ 13.29 17.58 ⫾ 13.40 16.11 ⫾ 14.94
23.12 ⫾ 20.95 18.68 ⫾ 20.29 19.45 ⫾ 19.71 16.38 ⫾ 17.62 mIIQ scores 22.99 ⫾ 14.67 19.38 ⫾ 14.82 20.72 ⫾ 17.19 18.38 ⫾ 15.76
AUA symptom scores Run-in period 13.99 ⫾ 5.12 15.78 ⫾ 5.47 Period 1 11.44 ⫾ 5.62 13.75 ⫾ 6.46 Washout period 12.03 ⫾ 5.40 14.02 ⫾ 6.64 Period 2 11.57 ⫾ 6.20 12.58 ⫾ 6.48 * Nimodipine was received during period 1 and placebo period 2. † Placebo was received during period 1 and nimodipine period 2.
RANDOMIZED TRIAL OF NIMODIPINE FOR URGE INCONTINENCE TABLE 3. Adverse symptoms by treatment group % Worse With Nimodipine Dizziness Light-headedness Fatigue Nausea Diarrhea Abdominal pain Constipation Drowsiness Insomnia Headache Confusion Rash Vision change Joint pain Muscle pain Chest pain Palpitations
7.7 13.0 28.6 5.2 7.8 7.8 5.2 13.2 6.7 9.3 5.3 7.8 6.6 13.2 14.5 9.2 1.3
% Worse % No p With Placebo Difference Value 9.0 7.8 18.2 7.8 5.2 7.8 10.4 13.2 4.0 10.7 2.6 9.1 7.9 15.8 15.8 2.6 2.6
83.3 79.2 53.2 87.0 87.0 84.4 84.4 73.6 89.3 80.0 92.1 83.1 85.5 71.0 69.7 88.2 96.1
0.71 0.23 0.12 0.83 0.38 0.61 0.93 0.59 0.36 0.70 0.34 0.71 0.73 0.74 0.66 0.09 0.88
to 30 mm. Hg higher with nimodipine. The range of the difference in diastolic blood pressure between nimodipine and placebo was from 17 mm. Hg lower to 17 mm. Hg higher with nimodipine. There was no significant difference in the occurrence of orthostatic hypotension with nimodipine versus placebo (p ⫽ 0.57). The pill count revealed that participants took 95% of the nimodipine and 96% of the placebo (p ⫽ 0.65). DISCUSSION
In this randomized, double-blind, placebo controlled crossover trial for geriatric urge incontinence nimodipine did not result in a significant reduction in incontinent episodes. It is unlikely that we missed a clinically significant improvement with nimodipine since the upper limit of the 95% CI was a reduction of 2.7 incontinent episodes during a 5-day period, representing less than a 15% reduction in total incontinent episodes. The borderline statistically significant reduction in the mIIQ score of 1.4 points with nimodipine is not likely to be clinically important since this difference is less than the average intra-individual difference noted on the test-retest measurements during the run-in period. The small change in the AUA symptom score was neither clinically nor statistically significant. There was a reduction in incontinent episodes, mIIQ scores and AUA symptom scores with time, which occurred regardless of treatment order, that is a period effect (table 2). This result likely represents the “placebo effect” of participating in a study and interacting closely with a research assistant. This finding emphasizes the need for placebo controlled studies when evaluating treatment of urge incontinence. The lack of improvement with nimodipine may have been due to the use of too low a dose or too short a treatment period, or an inadequate washout period with a carry over effect. In a study that compared older (mean age 65.3 years) with younger patients (25.2) mean elimination half-life for nimodipine was prolonged in the older group (22.2 versus 2.8 hours, respectively).27 Based on this information and our concern about possible hypotensive side effects, a dose schedule of 30 mg. twice daily rather than 3 times daily was chosen. The significantly lower systolic blood pressure that we observed in study participants while on nimodipine suggests that there was sufficient drug available to result in systemic effects. Even considering a potentially prolonged nimodipine half-life in the elderly, study patients should have had a steady state concentration of nimodipine by week
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3 when the voiding records were completed. Nevertheless, the low dose and/or short treatment duration may have contributed to the negative study results. Given the evidence of delayed drug elimination of nimodipine in the elderly,27 we used a 2-week washout period to ensure complete elimination of the active drug. Statistical analysis that looked for a carry over effect failed to demonstrate any.25 Therefore, it seems unlikely that the lack of response to nimodipine that was noted in this trial was due to an inadequate washout period. Several factors suggest that our patient population had relatively severe urge incontinence, limiting the generalizability of our results to less severely affected individuals. Our study inclusion criteria required that patients had documented detrusor instability on urodynamics testing in addition to having urge incontinence, and mean detrusor pressure at instability for the study patients was relatively high (48.2 cm. water). Furthermore, just under half the patients who completed the study had received at least 1 prior medication for urge incontinence. The 3 major outcome measures used in this trial, including voiding record, AUA symptom score and mIIQ, represent 3 important constructs, specifically the number of incontinent episodes (voiding record), more general urinary symptoms (AUA symptom score), and the impact of incontinence and urinary symptoms on function (mIIQ). Although the symptoms score has not been used extensively in urge incontinence populations and this study represents the first use of the mIIQ, our study results provide supportive evidence of the reliability and construct validity of these measures in an older population with urge incontinence. The test-retest reliability of the AUA symptom score and mIIQ were 0.77 and 0.82, respectively. The consistency of the symptom score and mIIQ findings with the voiding record results, showing a significant period effect but no significant treatment effect, provides construct validation for these measures. We did not find any significant differences in adverse effects between nimodipine and placebo. However, the sample size in our trial was not adequate to exclude all potentially important side effects. A nonsignificant increase in lightheadedness, fatigue and chest pain was reported by patients taking nimodipine. These adverse events may be clinically important in light of the significant reduction in blood pressure that we observed with nimodipine and concerns raised in the literature about possible adverse events associated with calcium channel blockers. Some studies have suggested that short acting calcium channel blockers may be associated with an increased risk of cardiac events in patients with underlying cardiovascular disease.22–24 None of these studies evaluated nimodipine, so it remains unclear if these adverse effects can occur with nimodipine. CONCLUSIONS
Nimodipine did not result in a significant improvement of the number of incontinent episodes, incontinence-specific quality of life score, urinary symptom score or subjective perception of treatment effects. Therefore, we conclude that 30 mg. nimodipine twice daily is not effective for treatment of urge incontinence in older persons. Studies of higher doses of nimodipine in this population should proceed with caution, given the reduction in blood pressure noted with low dose nimodipine in our study and concerns raised in the literature about possible adverse events with some calcium channel blockers in patients with underlying coronary artery disease. The study medication, matched placebo and money to reimburse participant travel expenses were provided by Miles Canada.
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RANDOMIZED TRIAL OF NIMODIPINE FOR URGE INCONTINENCE APPENDIX: STUDY INCLUSION AND EXCLUSION CRITERIA
Inclusion Criteria ● 65 years or older ● a history, physical exam and urodynamic findings consistent with urge incontinence ● at least 4 documented episodes of urinary incontinence on a 5-day voiding record
Exclusion Criteria ● requiring an indwelling or condom catheter, or intermittent catheterization ● a clinical history of stress urinary incontinence ● a history of ⬎2 urinary tract infections per year, insulin dependent diabetes, spinal cord pathology, symptomatic orthostatic hypotension, congestive heart failure or ventricular arrhythmia ● taking any calcium channel blocker ● cognitive impairment* ● evidence of prostate or bladder cancer ● cystoscopic or urodynamic evidence of outlet obstruction† ● post-void residual urine volume greater than 100 cc or more than trivial urinary leakage occurring with coughing/straining in the sitting or standing position ● unable to complete a 5-day voiding record during the run-in period
* As demonstrated by a score of ⬍24/30 on a Folstein Mini-Mental State Examination.15 † Based on the Abrams-Griffiths nomogram.16 REFERENCES
1. Busby-Whitehead, J. and Johnson, T. M.: Urinary incontinence. Clin Geriatr Med, 14: 285, 1998 2. Fantl, J. A., Newman, D. K., Colling, J. et al: Management of acute and chronic urinary incontinence in adults. Guideline Technical Report No, 2, 1996 Update. Rockville: Department of Health and Human Services. Public Health Service, Agency for Health Care Policy and Research. AHCPR Publication No. 96 –N017, September 1996 3. Burgio, K. L., Locher, J. L., Goode, P. S. et al: Behavioral versus drug treatment for urge urinary incontinence in older women: a randomized controlled trial. JAMA, 280: 1995, 1998 4. Anderson, R. U., Mobley, D., Blank, B. et al: Once daily controlled versus immediate release oxybutynin chloride for urge urinary incontinence. OROS Oxybutynin Study Group. J Urol, 161: 1809, 1999 5. Chapple, C. R.: Muscarinic receptor antagonists in the treatment of overactive bladder. Urology, suppl., 55: 33, 2000 6. Payne, C. K.: Behavioral therapy for overactive bladder. Urology, suppl., 55: 3, 2000 7. Griffiths, D. J., McCracken, P. N., Harrison, G. M. et al: Cerebral aetiology of urinary urge incontinence in elderly people. Age Ageing, 23: 246, 1994 8. Elliot, R. A., Norman, R. I. and Parker, S. G.: Effect of treatment with calcium antagonists in vitro and in vivo on the contractile response of isolated rat and human detrusor muscle. Clin Sci, 91: 467, 1996 9. Mattiasson, A., Ekstrom, B. and Andersson, K. E.: Effects of intravesical installation of verapamil in patients with detrusor hyperactivity. J Urol, 141: 174, 1989 10. Ekman, G., Andersson, K. E., Rud, T. et al: A double-blind crossover study of the effects of terodiline in women with unstable bladder. Acta Pharmacol Toxicol (Copenh), suppl., 46: 39, 1980 11. Peters, D.: Terodiline in the treatment of urinary frequency and motor urge incontinence. A controlled multicentre trial. Scand J Urol Nephrol Suppl, 87: 21, 1984 12. Tapp, A., Fall, M., Norgaard, J. et al: Terodiline: a dose titrated, multicentre study of the treatment of idiopathic detrusor instability in women. J Urol, 142: 1027, 1989 13. Norton, P., Karram, M., Wall, L. L. et al: Randomized doubleblind trial of terodiline in the treatment of urge incontinence in women. Obstet Gynecol, 84: 386, 1994 14. Palmer, J. H., Worth, P. H. L. and Exton-Smith, A. N.: Flunar-
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Vol. 167, 586 –590, February 2002 Printed in U.S.A.
A RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED CROSSOVER TRIAL OF NIMODIPINE IN OLDER PERSONS WITH DETRUSOR INSTABILITY AND URGE INCONTINENCE GARY NAGLIE,* SIDNEY B. RADOMSKI,† CHRIS BRYMER, KAREN MATHIASEN, KEITH O’ROURKE AND GEORGE TOMLINSON From the Divisions of General Internal Medicine and Clinical Epidemiology and Urology, University Health Network, the Geriatrics Program, Toronto Rehabilitation Institute, the Clinical Epidemiology and Health Care Research Program (University Health Network Unit) and Departments of Medicine, Health Administration, Public Health Sciences and Urology, University of Toronto, Toronto, Division of Geriatrics, Parkwood Hospital and Department of Medicine, University of Western Ontario, London and the Loeb Research Unit, Ottawa Hospital and Department of Surgery, University of Ottawa, Ottawa, Ontario, Canada
ABSTRACT
Purpose: We evaluated the efficacy of nimodipine, a dihydropyridine calcium channel blocker that relaxes vascular and nonvascular smooth muscle, for geriatric urge incontinence. Materials and Methods: A randomized, double-blind, placebo controlled crossover trial of 30 mg. nimodipine twice daily for 3 weeks in older persons with detrusor instability and chronic urge incontinence was done. A total of 86 participants with a mean age of 73.4 years were randomized. The primary outcome was the number of incontinent episodes, as measured by the self completion of a 5-day voiding record. Secondary outcomes included the impact of urinary incontinence on quality of life measured with a modified incontinence impact questionnaire (mIIQ) and symptoms, as measured by the American Urological Association (AUA) symptom score. Results: A total of 76 (88.4%) participants completed the study. There was no significant difference in the number of incontinent episodes with nimodipine versus placebo, which included a difference of 0.03 incontinent episodes during a 5-day period (p ⫽0.98, 95% confidence interval ⫺2.7 to 2.8). Scores on the mIIQ and the AUA symptom score were not significantly different with nimodipine versus placebo (p ⫽ 0.07 and 0.22, respectively). Regardless of initial treatment, participants had improvement with time, that is a period effect, of incontinent episodes (p ⬍0.0001), mIIQ scores (p ⫽ 0.0002) and AUA symptom score values (p ⬍0.0001). Conclusions: Treatment of geriatric urge incontinence with 30 mg. nimodipine twice daily did not result in a significant improvement of incontinent episodes, mIIQ scores or AUA symptom scores. KEY WORDS: urinary incontinence, adult, aged, calcium channel blockers, double-blind method
Urinary incontinence is a common condition affecting an estimated 30% of all community dwelling older persons as well as 50% to 70% of nursing home residents.1 Urge incontinence is the most common cause of urinary incontinence in the elderly, and can result in decreased activity, social isolation, depression, diminished quality of life and long-term care placement.2 Behavioral and pharmacological interventions have been used for management of urge incontinence. Drugs, such as immediate release oxybutynin, propantheline and dicyclomine, have anticholinergic side effects that impact use in the elderly.3 The newer formulation of controlled release oxybutynin still has significant anticholinergic side effects.4 Although there are less anticholinergic side effects with tolterodine, they still exist, especially at higher doses.5 Behavioral therapy is a safe option for treatment of urge incontinence in the elderly. However, it is labor intensive, costly and requires a highly motivated patient.3 Furthermore, there is a lack of standardization of behavioral therapy programs, and results can be quite variable.3, 6 Nimodipine is a dihydropyridine calcium channel blocker
that relaxes vascular and nonvascular smooth muscle. There are 2 mechanisms whereby nimodipine may be effective for urge incontinence. It may enhance perfusion of the frontal cerebral inhibitory control center for bladder contraction, an area that has been shown to be hypoperfused in a large series of geriatric cases of urge incontinence,7 and/or it may act on bladder smooth muscle directly. Elliot et al have found that nimodipine is a far more potent inhibitor of detrusor contraction than either nifedipine or verapamil in rat and human bladder tissue.8 There is some evidence that intravesical therapy with verapamil can be beneficial to patients with neurogenic detrusor hyperreflexia.9 A small number of randomized trials have evaluated the effect of calcium channel blockers on patients with detrusor instability. A few studies have demonstrated the effectiveness of terodiline.10 –13 However, terodiline is not a pure calcium channel antagonist, as it also has anticholinergic properties. Furthermore, terodiline is no longer available because of serious ventricular arrhythmia side effects. A double-blind crossover study of flunarizine in 14 women with detrusor instability and urinary incontinence revealed a nonsignificant trend towards improvement of bladder capacity, volume at first sensation and flow rate, and a significant improvement of symptoms.14 The purpose of this randomized, controlled, double-blind crossover trial was to determine the efficacy of the calcium channel blocker nimodipine at a dose of 30 mg. twice daily for treating detrusor instability with urinary urge incontinence
Accepted for publication August 10, 2001. Supported by a research grant from the Physicians’ Services Incorporated Foundation of Ontario and a career award from the Physicians’ Services Incorporated Foundation (Arthur Bond Award). *Financial interest and/or other relationship with Astra Zeneca, Janssen-Ortho and ID Biomedical. †Financial interest and/or other relationship with Pfizer, Pharmacia Upjohn, Purdue and Geryx Medical. 586
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in a geriatric outpatient population. A cross-over design was chosen rather than a parallel group to control better for the large interindividual variability that exists in incontinent populations by allowing patients to act as their own controls. This effect in turn reduces the sample size needed to ensure adequate statistical power. METHODS
Participants were recruited by advertising the study in newspapers, on local radio and television stations, and circulating flyers to physician offices. Potential participants were initially screened by telephone, and those who met basic inclusion criteria were invited to the Toronto Western Hospital for further assessment, including a medical and incontinence history, physical examination, 5-day voiding record, urinalysis and urine culture, multichannel urodynamic testing (including stress maneuvers and determination of postvoid residual urine volume) and cystoscopy. Urodynamic testing was performed with a fill rate of 25 to 50 cc per minute with normal saline at room temperature. The Appendix lists the inclusion and exclusion15, 16 criteria for the study. Urge incontinence was defined as urinary leakage with documented detrusor instability on urodynamic testing, including an increase in detrusor pressure 15 cm. or greater of water during urodynamic testing, or documented instability at less than 15 cm. of water with symptoms of urgency.17 The study was a randomized, double-blind, placebo controlled crossover trial that was preceded by a 2-week run-in period. Voiding records, quality of life and symptom scores were collected twice, 1 week apart, during the run-in period. Participants who successfully completed the runin period were randomized to the order of treatment based on a computer generated randomization code available from the study biostatistician. Participants received a container of study medication containing either 45 capsules of 30 mg. nimodipine or placebo, matched for appearance and taste. The participant was instructed to take 1 capsule every morning with breakfast and every evening before bedtime for 3 weeks (period 1). The participant then returned the container with the unused capsules to the research assistant who performed a pill count to assess compliance. After a 2-week washout period the participant received a second container of study medication with similar instructions, again with a repeat pill count after 3 weeks (period 2). The primary outcome measure was the change from baseline in the number of incontinent episodes, as measured by a self-completed 5-day voiding record documenting the number, and timing of voluntary voiding and incontinent episodes. All other measures were considered secondary outcomes. Quality of life was measured with a modified version of the incontinence impact questionnaire (IIQ), a selfadministered urinary incontinence specific instrument developed by Wyman et al.18 We modified the IIQ by replacing the scaled response from “none/slightly/moderately/greatly” to “never/⬍ 1⁄2 the time/about 1⁄2 the time/⬎ 1⁄2 the time/always,” by reducing the total number of items from 26 to 16 and adding 1 item on sleep. Scoring of the modified IIQ (mIIQ) was based on a maximum score of 63, with higher scores representing a greater impact of incontinence on quality of life. Urinary symptoms were measured with the American Urological Association (AUA) benign prostatic hypertrophy symptom score, which is a 7 item self-administered questionnaire, with a total score of 35 and higher scores representing worse symptoms.19 Although used predominately for benign prostatic hypertrophy, the AUA symptom score has been shown to be reliable and valid in postmenopausal women with detrusor instability and urge incontinence, with improvement in scores after treatment.20, 21 The effect of treatment was also assessed by 3 questions that were asked after
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each treatment period to assess participant subjective perception of how treatment affected the number of incontinent events, amount of leakage and urgency to urinate (“much worse/a little worse/about the same/a little better/much better”). Medication adverse effects were measured at the end of each treatment period by a self-administered questionnaire that included a list of 17 possible symptoms that participants were asked to rate themselves on compared with before starting the study medication. A post-void residual urine volume was measured by an in-and-out catheterization to assess for urinary retention, and lying and standing blood pressure was recorded to assess for orthostatic hypotension at the end of treatment periods 1 and 2. Our study received ethics approval from the Toronto Hospital, which is now the University Health Network, and the University of Toronto. The study was suspended for 91⁄2 weeks in response to concerns about possible adverse drug events. An independent safety monitoring committee reviewed all adverse events with nimodipine and placebo, and reviewed the current literature on possible toxicity with calcium channel blockers. The committee did not find any evidence of more adverse events with nimodipine. Based on new publications suggesting possible adverse events with some calcium channel blockers in patients with underlying cardiovascular disease,22–24 the committee advised that the study be continued with the exclusion of patients with established coronary artery disease. The University and Hospital Ethics Committees approved the continuation of the study with the revised exclusion criteria and a revised consent form. Test-retest reliability of the outcome measures was established by comparing the results for each of the measures in week 1 with those of week 2 of the run-in period using Pearson’s correlation coefficient. Investigation of the possibility of a carry over effect was done according to the methods suggested by Senn.25 The primary analysis of the crossover data used paired t-tests and a random effects analysis of variance to examine changes with time in continuous outcomes. The primary analysis was also redone on the logarithm of the ratio of the number of incontinent episodes with nimodipine versus placebo, in which half was added to the counts to avoid zeroes. An intention to treat analysis was performed that assessed each of the following assumptions about the outcomes of participants who withdrew from the study: 1) all had an equal response to nimodipine and placebo, 2) all were cured of incontinence by nimodipine and 3) all were cured of incontinence by placebo. Responses to the 3 subjective questions about treatment effectiveness were analyzed with the signed rank test. McNemar’s chi-square test was used to analyze differences in adverse events and orthostatic hypotension. Data analysis was performed with commercial software. For the sample size calculation we defined a treatment response as a 30% reduction in the number of incontinent events compared with baseline. Assuming a 40% response rate with placebo, 60% with nimodipine, and a correlation of 0.25 between responses to nimodipine and placebo, a sample size of 72 was calculated to give 80% power when testing at an ␣ ⫽ 0.05.26 RESULTS
The figure shows the flow of study patients. Of the 187 patients who were screened 71 were ineligible for our study. An additional 29 patients were excluded from the study after the run-in period because they did not have 4 incontinent episodes on a 5-day voiding record, were unable to maintain a voiding record or did not want to continue with the study. A total of 86 patients were randomized, including 42 to group 1 (nimodipine first) and 44 to group 2 (placebo first). There were 6 patients in group 1 who did not complete the study, including 3 because of side effects, 1 to undergo surgery and
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Flow of study participants through selection and intervention protocols. R, randomization
2 because of temporary study suspension, and 4 in group 2, including 1 who died and 3 because of temporary study suspension. The randomized participants ranged from 65 to 88 years old, and baseline characteristics are shown in table 1. The 10 randomized participants who did not complete the study differed slightly from the 76 who did in regard to age, sex and number of incontinent episodes during the run-in period but none of these differences were statistically significant. Of the 76 patients who completed the study 40 (52.6%) had not received any prior medical therapy for urge incontinence, 25 (32.9%) had previously been treated with oxybutynin chloride, and 11 (14.5%) had previously been treated with oxybutynin chloride and at least 1 other medication. For the 82 randomized participants the test-retest reliability of the outcome measures was high, including 0.92 for the 5-day voiding record, 0.82 mIIQ and 0.77 AUA symptom score. TABLE 1. Mean baseline characteristics of randomized participants
Mean pt. age % Female Data from run-in period: Mean No. incontinent episodes Mean mIIQ score Mean AUA symptom score Data from urodynamic tests: Mean vol. infused (ml.) Mean max. flow rate (ml./sec.) Mean detrusor pressure at instability (cm. H2O) Mean max. voiding pressure (cm. H2O)
Complete Data
Incomplete Data
73.9 84.2
69.5 90.0
19.5 22.2 14.9
14.3 21.4 9.9
307.6 18.8 48.2
283.0 19.6 49.9
31.0
25.6
For the 76 participants who received nimodipine and placebo there were an average of 0.03 fewer incontinent episodes during a 5-day period on placebo (p ⫽ 0.98, 95% confidence interval [CI]-2.7 to 2.8 incontinent episodes). A paired test analysis of the logarithm of the number of incontinent episodes also yielded a nonsignificant difference between nimodipine and placebo. Transformed back to the original scale, the mean number of incontinent episodes with placebo was 0.85 times that with nimodipine (p ⫽ 0.08, 95% CI 0.70 to 1.02). The intention to treat analysis did not yield any significant differences in the number of incontinent episodes between nimodipine and placebo. The results were unchanged when only those patients randomized before the temporary study suspension (74 of 76 who completed the study) were included in the analysis. The total number of incontinent episodes, mIIQ scores and AUA symptom scores during each period for the 76 participants who completed the study are shown in table 2. There was a significant decrease in the number of incontinent episodes with time in both groups, suggesting a period effect (p ⬍0.0001). Within subjects comparison of mIIQ scores in periods 1 and 2 revealed a 1.4 point lower score with nimodipine versus placebo (p ⫽ 0.07). The mIIQ scores decreased with time in both groups, suggesting a period effect (p ⫽ 0.0002). Within subjects comparison of AUA symptom scores in periods 1 and 2 revealed a 0.63 point lower score with nimodipine versus placebo (p ⫽ 0.22). These scores also decreased with time in both groups, suggesting a period effect (p ⬍0.0001). No significant differences were found between nimodipine and placebo in regard to the participant subjective perception of treatment effect on the number of incontinent episodes (p ⫽ 0.62), amount of urine leakage (p ⫽ 0.94) or symptomatic urinary urgency (p ⫽ 0.84). No statistically significant difference was noted in adverse effects between nimodipine and placebo (table 3). There were 2 participants who withdrew from the study for side effects while taking nimodipine, including 1 for shortness of breath and 1 death due to a myocardial infarction, and 2 withdrawals for side effects while taking placebo (both for dizziness). Post-void residual urine volumes were measured for 79 participants at the end of periods 1 and 2. Mean residual volume was 29.5 ml. for placebo and 28.7 for nimodipine (p ⫽ 0.80). In all cases residual urine volume was less than 150 ml. Mean systolic blood pressure was 3.6 mm. Hg lower with nimodipine versus placebo (p ⫽ 0.03), and mean diastolic blood pressure was 1.6 mm. Hg lower with nimodipine (p ⫽ 0.07). The range of the difference in systolic blood pressure between nimodipine and placebo was from 42 mm. Hg lower TABLE 2. Incontinent episodes on 5-day voiding record, mIIQ scores and AUA symptom scores Mean ⫾ SD Group 1*
Group 2†
Incontinent episodes Run-in period Period 1 Washout period Period 2
15.40 ⫾ 12.40 10.97 ⫾ 10.75 13.06 ⫾ 12.33 8.36 ⫾ 10.69
Run-in period Period 1 Washout period Period 2
21.26 ⫾ 12.45 15.00 ⫾ 13.29 17.58 ⫾ 13.40 16.11 ⫾ 14.94
23.12 ⫾ 20.95 18.68 ⫾ 20.29 19.45 ⫾ 19.71 16.38 ⫾ 17.62 mIIQ scores 22.99 ⫾ 14.67 19.38 ⫾ 14.82 20.72 ⫾ 17.19 18.38 ⫾ 15.76
AUA symptom scores Run-in period 13.99 ⫾ 5.12 15.78 ⫾ 5.47 Period 1 11.44 ⫾ 5.62 13.75 ⫾ 6.46 Washout period 12.03 ⫾ 5.40 14.02 ⫾ 6.64 Period 2 11.57 ⫾ 6.20 12.58 ⫾ 6.48 * Nimodipine was received during period 1 and placebo period 2. † Placebo was received during period 1 and nimodipine period 2.
RANDOMIZED TRIAL OF NIMODIPINE FOR URGE INCONTINENCE TABLE 3. Adverse symptoms by treatment group % Worse With Nimodipine Dizziness Light-headedness Fatigue Nausea Diarrhea Abdominal pain Constipation Drowsiness Insomnia Headache Confusion Rash Vision change Joint pain Muscle pain Chest pain Palpitations
7.7 13.0 28.6 5.2 7.8 7.8 5.2 13.2 6.7 9.3 5.3 7.8 6.6 13.2 14.5 9.2 1.3
% Worse % No p With Placebo Difference Value 9.0 7.8 18.2 7.8 5.2 7.8 10.4 13.2 4.0 10.7 2.6 9.1 7.9 15.8 15.8 2.6 2.6
83.3 79.2 53.2 87.0 87.0 84.4 84.4 73.6 89.3 80.0 92.1 83.1 85.5 71.0 69.7 88.2 96.1
0.71 0.23 0.12 0.83 0.38 0.61 0.93 0.59 0.36 0.70 0.34 0.71 0.73 0.74 0.66 0.09 0.88
to 30 mm. Hg higher with nimodipine. The range of the difference in diastolic blood pressure between nimodipine and placebo was from 17 mm. Hg lower to 17 mm. Hg higher with nimodipine. There was no significant difference in the occurrence of orthostatic hypotension with nimodipine versus placebo (p ⫽ 0.57). The pill count revealed that participants took 95% of the nimodipine and 96% of the placebo (p ⫽ 0.65). DISCUSSION
In this randomized, double-blind, placebo controlled crossover trial for geriatric urge incontinence nimodipine did not result in a significant reduction in incontinent episodes. It is unlikely that we missed a clinically significant improvement with nimodipine since the upper limit of the 95% CI was a reduction of 2.7 incontinent episodes during a 5-day period, representing less than a 15% reduction in total incontinent episodes. The borderline statistically significant reduction in the mIIQ score of 1.4 points with nimodipine is not likely to be clinically important since this difference is less than the average intra-individual difference noted on the test-retest measurements during the run-in period. The small change in the AUA symptom score was neither clinically nor statistically significant. There was a reduction in incontinent episodes, mIIQ scores and AUA symptom scores with time, which occurred regardless of treatment order, that is a period effect (table 2). This result likely represents the “placebo effect” of participating in a study and interacting closely with a research assistant. This finding emphasizes the need for placebo controlled studies when evaluating treatment of urge incontinence. The lack of improvement with nimodipine may have been due to the use of too low a dose or too short a treatment period, or an inadequate washout period with a carry over effect. In a study that compared older (mean age 65.3 years) with younger patients (25.2) mean elimination half-life for nimodipine was prolonged in the older group (22.2 versus 2.8 hours, respectively).27 Based on this information and our concern about possible hypotensive side effects, a dose schedule of 30 mg. twice daily rather than 3 times daily was chosen. The significantly lower systolic blood pressure that we observed in study participants while on nimodipine suggests that there was sufficient drug available to result in systemic effects. Even considering a potentially prolonged nimodipine half-life in the elderly, study patients should have had a steady state concentration of nimodipine by week
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3 when the voiding records were completed. Nevertheless, the low dose and/or short treatment duration may have contributed to the negative study results. Given the evidence of delayed drug elimination of nimodipine in the elderly,27 we used a 2-week washout period to ensure complete elimination of the active drug. Statistical analysis that looked for a carry over effect failed to demonstrate any.25 Therefore, it seems unlikely that the lack of response to nimodipine that was noted in this trial was due to an inadequate washout period. Several factors suggest that our patient population had relatively severe urge incontinence, limiting the generalizability of our results to less severely affected individuals. Our study inclusion criteria required that patients had documented detrusor instability on urodynamics testing in addition to having urge incontinence, and mean detrusor pressure at instability for the study patients was relatively high (48.2 cm. water). Furthermore, just under half the patients who completed the study had received at least 1 prior medication for urge incontinence. The 3 major outcome measures used in this trial, including voiding record, AUA symptom score and mIIQ, represent 3 important constructs, specifically the number of incontinent episodes (voiding record), more general urinary symptoms (AUA symptom score), and the impact of incontinence and urinary symptoms on function (mIIQ). Although the symptoms score has not been used extensively in urge incontinence populations and this study represents the first use of the mIIQ, our study results provide supportive evidence of the reliability and construct validity of these measures in an older population with urge incontinence. The test-retest reliability of the AUA symptom score and mIIQ were 0.77 and 0.82, respectively. The consistency of the symptom score and mIIQ findings with the voiding record results, showing a significant period effect but no significant treatment effect, provides construct validation for these measures. We did not find any significant differences in adverse effects between nimodipine and placebo. However, the sample size in our trial was not adequate to exclude all potentially important side effects. A nonsignificant increase in lightheadedness, fatigue and chest pain was reported by patients taking nimodipine. These adverse events may be clinically important in light of the significant reduction in blood pressure that we observed with nimodipine and concerns raised in the literature about possible adverse events associated with calcium channel blockers. Some studies have suggested that short acting calcium channel blockers may be associated with an increased risk of cardiac events in patients with underlying cardiovascular disease.22–24 None of these studies evaluated nimodipine, so it remains unclear if these adverse effects can occur with nimodipine. CONCLUSIONS
Nimodipine did not result in a significant improvement of the number of incontinent episodes, incontinence-specific quality of life score, urinary symptom score or subjective perception of treatment effects. Therefore, we conclude that 30 mg. nimodipine twice daily is not effective for treatment of urge incontinence in older persons. Studies of higher doses of nimodipine in this population should proceed with caution, given the reduction in blood pressure noted with low dose nimodipine in our study and concerns raised in the literature about possible adverse events with some calcium channel blockers in patients with underlying coronary artery disease. The study medication, matched placebo and money to reimburse participant travel expenses were provided by Miles Canada.
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RANDOMIZED TRIAL OF NIMODIPINE FOR URGE INCONTINENCE APPENDIX: STUDY INCLUSION AND EXCLUSION CRITERIA
Inclusion Criteria ● 65 years or older ● a history, physical exam and urodynamic findings consistent with urge incontinence ● at least 4 documented episodes of urinary incontinence on a 5-day voiding record
Exclusion Criteria ● requiring an indwelling or condom catheter, or intermittent catheterization ● a clinical history of stress urinary incontinence ● a history of ⬎2 urinary tract infections per year, insulin dependent diabetes, spinal cord pathology, symptomatic orthostatic hypotension, congestive heart failure or ventricular arrhythmia ● taking any calcium channel blocker ● cognitive impairment* ● evidence of prostate or bladder cancer ● cystoscopic or urodynamic evidence of outlet obstruction† ● post-void residual urine volume greater than 100 cc or more than trivial urinary leakage occurring with coughing/straining in the sitting or standing position ● unable to complete a 5-day voiding record during the run-in period
* As demonstrated by a score of ⬍24/30 on a Folstein Mini-Mental State Examination.15 † Based on the Abrams-Griffiths nomogram.16 REFERENCES
1. Busby-Whitehead, J. and Johnson, T. M.: Urinary incontinence. Clin Geriatr Med, 14: 285, 1998 2. Fantl, J. A., Newman, D. K., Colling, J. et al: Management of acute and chronic urinary incontinence in adults. Guideline Technical Report No, 2, 1996 Update. Rockville: Department of Health and Human Services. Public Health Service, Agency for Health Care Policy and Research. AHCPR Publication No. 96 –N017, September 1996 3. Burgio, K. L., Locher, J. L., Goode, P. S. et al: Behavioral versus drug treatment for urge urinary incontinence in older women: a randomized controlled trial. JAMA, 280: 1995, 1998 4. Anderson, R. U., Mobley, D., Blank, B. et al: Once daily controlled versus immediate release oxybutynin chloride for urge urinary incontinence. OROS Oxybutynin Study Group. J Urol, 161: 1809, 1999 5. Chapple, C. R.: Muscarinic receptor antagonists in the treatment of overactive bladder. Urology, suppl., 55: 33, 2000 6. Payne, C. K.: Behavioral therapy for overactive bladder. Urology, suppl., 55: 3, 2000 7. Griffiths, D. J., McCracken, P. N., Harrison, G. M. et al: Cerebral aetiology of urinary urge incontinence in elderly people. Age Ageing, 23: 246, 1994 8. Elliot, R. A., Norman, R. I. and Parker, S. G.: Effect of treatment with calcium antagonists in vitro and in vivo on the contractile response of isolated rat and human detrusor muscle. Clin Sci, 91: 467, 1996 9. Mattiasson, A., Ekstrom, B. and Andersson, K. E.: Effects of intravesical installation of verapamil in patients with detrusor hyperactivity. J Urol, 141: 174, 1989 10. Ekman, G., Andersson, K. E., Rud, T. et al: A double-blind crossover study of the effects of terodiline in women with unstable bladder. Acta Pharmacol Toxicol (Copenh), suppl., 46: 39, 1980 11. Peters, D.: Terodiline in the treatment of urinary frequency and motor urge incontinence. A controlled multicentre trial. Scand J Urol Nephrol Suppl, 87: 21, 1984 12. Tapp, A., Fall, M., Norgaard, J. et al: Terodiline: a dose titrated, multicentre study of the treatment of idiopathic detrusor instability in women. J Urol, 142: 1027, 1989 13. Norton, P., Karram, M., Wall, L. L. et al: Randomized doubleblind trial of terodiline in the treatment of urge incontinence in women. Obstet Gynecol, 84: 386, 1994 14. Palmer, J. H., Worth, P. H. L. and Exton-Smith, A. N.: Flunar-
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