Clinical Health Updates

Alpha-blocker or nifedipine may help pass kidney stones

Clinical Question:
Can drug treatment improve passage of ureteral stones?

Bottom Line:
This meta-analysis of low-quality studies shows that ureteral stone passage can be enhanced by treating patients with an alpha-blocker such as tamsulosin (Flomax) or the calcium channel blocker nifedipine (Procardia). Better studies may refute these findings, but for now either approach is an option.

Reference:
Singh A, Alter HJ, Littlepage A. A systematic review of medical therapy to facilitate passage of ureteral calculi. Ann Emerg Med 2007;50(5):552-563.

Study Design:
Meta-analysis (randomized controlled trials)

Synopsis:
The researchers conducting this study combined the results of small studies evaluating the effectiveness of alpha-blockers, a calcium channel blocker, or both, to increase the passage of ureteral calculi. The meta-analysis was well done. Two authors independently searched several databases, including the Cochrane database, to find randomized studies. They also conducted a hand search of urologic journals and conference proceedings. Two authors also independently abstracted data. They identified 22 studies. Only 1 study was considered to be of good quality with a Jadad score of 3 (out of a possible 5), with all the rest scoring 1 or 2. All but 1 of the studies was unblinded, and the researchers did not report on whether allocation was concealed in the studies. There was mild heterogeneity found among the alpha-blocker studies, as well as evidence of publication bias. Alpha-blockers, primarily tamsulosin, were studied in 16 trials enrolling 1235 men. Nine trials evaluated the time to stone expulsion in patients with stones of 3 mm to 18 mm in size and located in the distal portion of the ureter, with a 2-day to 6-day average improvement in time to stone passage. The calcium channel blocker was studied in 9 trials of 686 patients with an average stone size of greater than 5 mm located in all aspects of the ureter. The average reduction in time to stone expulsion was not reported, though stone passage was more likely, on average, with treatment (relative risk = 1.50; 95% CI, 1.34-1.68) over the various periods of follow-up.

Fesoterodine effective for treating overactive bladder syndrome

Clinical Question:
Is fesoterodine effective and safe in the treatment of overactive bladder syndrome?

Bottom Line:
Fesoterodine reduces urinary urgency incontinent episodes by an average of one per day compared with placebo. Whether this difference is clinically significant is best made on an individual patient basis. Dry mouth is the most common reason for discontinuing active treatment.

Reference:
Nitti VW, Dmochowski R, Sand PK, et al. Efficacy, safety and tolerability of fesoterodine for overactive bladder syndrome. J Urology 2007;178(6):2488-2494.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
The authors evaluated the efficacy, tolerability and safety of the new antimuscarinic agent fesoterodine relative to placebo for overactive bladder syndrome. This was a randomized, double-blind, placebo controlled, multicenter trial performed in the United States. Overall 836 subjects with urinary frequency, urinary urgency or urgency urinary incontinence were randomized to placebo (274), 4 mg fesoterodine (283) or 8 mg fesoterodine (279) once daily for 12 weeks. The primary efficacy end point was the change in the number of micturitions per 24 hours. Co-primary end points were the change in the number of urgency urinary incontinence episodes per 24 hours and the treatment response. Secondary efficacy end points were other bladder diary variables, such as the change in mean voided volume per micturition, number of continent days and number of urgency episodes per 24 hours. Tolerability and safety were assessed by evaluating adverse events, electrocardiograms, post-void residual urine volume, laboratory parameters and treatment withdrawals. Treatment with 4 or 8 mg fesoterodine resulted in statistically significant and clinically relevant improvements from baseline to end of treatment for the primary and co-primary end points compared with placebo (p <0.05). Results for most secondary end points, including mean voided volume per micturition, number of continent days and number of urgency episodes per 24 hours, were also significantly improved vs placebo. The adverse events reported more frequently with fesoterodine than with placebo were dry mouth, constipation and urinary tract infection.

Reducing homocysteine not beneficial in advanced chronic kidney disease

Clinical Question:
Does reducing homocysteine levels with supplemental folic acid and B vitamins reduce mortality or morbidity in patients with chronic kidney disease?

Bottom Line:
Supplemental folic acid and B vitamins in patients with chronic kidney disease does not reduce mortality or the incidence of cardiovascular events.

Reference:
Jamison RL, Hartigan P, Kaufman JS, et al, for the Veterans Affairs Site Investigators. Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease. A randomized controlled trial. JAMA 2007;298(10):1163-1170.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
Supplemental folic acid and B vitamins is not beneficial in high-risk cardiovascular patients. Whether this is also true for patients with chronic renal disease is unknown. These investigators identified 2056 adults, 21 years or older, with advanced or end-stage chronic kidney disease and elevated homocysteine levels (>= 15 umol/L). Patients randomly received, in double-blind fashion (concealed allocation assignment), a once-daily capsule containing folic acid (40 mg), pyridoxine (100 mg), and cyanocobalamin (2mg), or an identical placebo. Individuals assessing outcomes remained masked to treatment group assignment. Complete follow-up occurred for more than 96% of patients for a median length of 3.2 years. Analyses were by intention to treat. Although plasma homocysteine levels were significantly lower in the intervention group, treatment had no effect on all-cause mortality or the incidence of any secondary outcomes, including myocardial infarction, stroke, or amputation. The study was 80% powered to detect a 17% relative risk reduction in mortality in the intervention group compared with the placebo group.

Trospium chloride (Sanctura) effective for overactive bladder symptoms

Clinical Question:
Is trospium chloride effective and safe in the treatment of overactive bladder?

Bottom Line:
Trospium chloride (Sanctura) once daily provided significant improvements in overactive bladder symptoms (frequency, urgency urinary incontinence and urgency). Efficacy was similar to that seen previously with trospium chloride twice daily, while class effect anticholinergic adverse events occurred at comparatively low levels. Dry mouth was elicited at the lowest reported rate in the oral antimuscarinic drug class.

Reference:
Staskin D, Sand P, Zinner N, Dmochowski R; Trospium Study Group. Once daily trospium chloride is effective and well tolerated for the treatment of overactive bladder: Results from a multicenter phase III trial. J Urology 2007;178:978-984.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
These investigators enrolled 601 patients meeting standard criteria for overactive bladder (frequency, urgency, and urinary incontinence). Patients randomly received (uncertain allocation concealment) 60 mg trospium chloride once daily or matched placebo. Study participants masked to treatment group assignment self-reported outcomes using a validated urinary urgency severity scale. Complete follow-up occurred for 98% of patients at 12 weeks. Using intention-to-treat analysis, patients assigned to the trospium group were more likely to achieve “normalization” (no urgency urinary incontinence episodes and a daily void frequency of 8 or less) than the placebo group (20.5% vs 11.3 %; number needed to treat = 11; 95% CI, 7-29). Although it is uncertain if the difference is clinically relevant, trospium-treated patients also reported significantly fewer urgency urinary incontinence episodes daily than the placebo group (mean = 1.6 vs 2.2). Adverse events occurring more often in the trospium group included dry mouth (8.7%) and constipation (9.4%).

Antibiotic prophylaxis may not decrease risk of recurrent UTI in children

Clinical Question:
Does antibiotic prophylaxis reduce the risk of recurrent urinary tract infection in children?

Bottom Line:
In a cohort of otherwise healthy children with a first urinary tract infection (UTI), antibiotic prophylaxis exposure was not associated with a reduced risk of recurrent UTI. Antibiotic exposure did, however, increase the risk of treatment-resistant pathogens.

Reference:
Conway PH, Cnaan A, Zaoutis T, Henry BV, Grundmeier RW, Keren R. Recurrent urinary tract infections in children. Risk factors and association with prophylactic antimicrobials. JAMA 2007;298:179-186.

Study Design:
Cohort (retrospective)

Synopsis:
The evidence regarding risk factors for recurrent urinary tract infection (UTI) and the risks and benefits of antimicrobial prophylaxis in children is scant. The authors identified the risk factors for recurrent UTI in a pediatric primary care cohort, to determine the association between antimicrobial prophylaxis and recurrent UTI, and to identify the risk factors for resistance among recurrent UTIs. From a network of 27 primary care pediatric practices in urban, suburban, and semirural areas spanning 3 states, a cohort of children aged 6 years or younger who were diagnosed with first UTI between July 1, 2001, and May 31, 2006, was assembled. Time-to-event analysis was used to determine risk factors for recurrent UTI and the association between antimicrobial prophylaxis and recurrent UTI, and a nested case-control study was performed among children with recurrent UTI to identify risk factors for resistant infections. Time to recurrent UTI and antimicrobial resistance of recurrent UTI pathogens. Among 74 974 children in the network, 611 (0.007 per person-year) had a first UTI and 83 (0.12 per person-year after first UTI) had a recurrent UTI. In multivariable Cox time-to-event models, factors associated with increased risk of recurrent UTI included white race (0.17 per person-year; hazard ratio [HR], 1.97; 95% confidence interval [CI], 1.22-3.16), age 3 to 4 years (0.22 per person-year; HR, 2.75; 95% CI, 1.37-5.51), age 4 to 5 years (0.19 per person-year; HR, 2.47; 95% CI, 1.19-5.12), and grade 4 to 5 vesicoureteral reflux (0.60 per person-year; HR, 4.38; 95% CI, 1.26-15.29). Sex and grade 1 to 3 vesicoureteral reflux were not associated with risk of recurrence. Antimicrobial prophylaxis was not associated with decreased risk of recurrent UTI (HR, 1.01; 95% CI, 0.50-2.02), even after adjusting for propensity to receive prophylaxis, but was a risk factor for antibimicrobial resistance among children with recurrent UTI (HR, 7.50; 95% CI, 1.60-35.17).

PSA every 4 years as good as annual

Clinical Question:
Is a 4-year screening interval as effective as annual screening for prostate cancer?

Bottom Line:
The interval cancer rate with a 4-year screening interval was low, confirming that the screening procedure has a high sensitivity and that the 4-year screening interval is reasonable. Although this study can’t tell us whether men are better or worse off as a result of screening, it suggests that for those men who choose to be screened, annual screening isn’t necessary. Other, smaller studies have similarly found that men with low prostate-specific antigen (PSA) levels don’t need annual screening.

Reference:
van der Cruijsen-Koeter IW, van der Kwast TH, Schröder FH. Interval carcinomas in the European Randomized Study of Screening for Prostate Cancer (ERSPC)-Rotterdam. J Natl Cancer Inst 2003; 95:1462-466.

Study Design:
Randomized controlled trial (nonblinded)

Synopsis:
The interval cancer rate is an important parameter for determining the sensitivity of a screening procedure and the screening interval. The authors evaluated the time and mechanism of detection and the stage distribution of interval prostate cancers diagnosed during a 4-year screening interval. They determined the rate of interval cancers and the sensitivity of the screening protocol (involving prostate-specific antigen, digital rectal and transrectal ultrasound examinations) in a cohort of 17 226 men (8350 on the screened arm, 8876 on the control arm) enrolled consecutively on the European Randomized Study of Screening for Prostate Cancer-Rotterdam. Men on the screened arm received a first screen between October 1993 and December 1996 and a scheduled second screen 4 years later. Prostate cancers detected in men enrolled on the control arm over the same 4-year period and, between screens, in men on the screened arm, were identified by linkage to the Dutch national cancer registry. During the first screen, 412 prostate cancers were detected. During the subsequent 4-year period, 135 cancers were diagnosed in men in the control arm and 25 cancers were diagnosed in men in the screened arm. Seven of the 25 cancers were diagnosed in men who had refused a recommended biopsy at their initial screen. Of the remaining 18 cancers, all were classified as stage T1A-C or T2A and none were poorly differentiated or metastatic. The rate of interval cancers relative to the number of cancers in the control group was 18.5% (25/135), or 13.3% (18/135), if the seven who refused an initial biopsy were excluded. The sensitivity of the screening protocol was 79.8% when considering all 25 interval cancers and 85.5% when considering 18 interval cancers.

Prostate CA relatively common even with PSA < 4.0

Clinical Question:
How common is prostate cancer among men with a prostate-specific antigen level of less than or equal to 4.0 ng/mL?

Bottom Line:
Prostate cancer, even high-grade disease, is found in older men with a so-called normal prostate-specific antigen (PSA) result. Biopsy-detected prostate cancer, including high-grade cancers, is not rare among men with PSA levels of 4.0 ng per milliliter or less–levels generally thought to be in the normal range. It is wise to remember that although prostate cancer occurs in 17% of men, it only kills approximately 3% of them. It is wise to be cautious about working up “abnormal” PSA tests, and very hesitant about biopsying men with a PSA <= 4.0 ng/mL.

Reference:
Thompson IM, Pauler DK, Goodman PJ, et al. Prevalence of prostate cancer among men with a prostate-specific antigen level <= 4.0 ng per milliliter. N Engl J Med 2004; 350:2239-246.

Study Design:
Cohort (prospective)

Synopsis:
The optimal upper limit of the normal range for prostate-specific antigen (PSA) is unknown. The authors investigated the prevalence of prostate cancer among men in the Prostate Cancer Prevention Trial who had a PSA level of 4.0 ng per milliliter or less. Of 18,882 men enrolled in the prevention trial, 9459 were randomly assigned to receive placebo and had an annual measurement of PSA and a digital rectal examination. Among these 9459 men, 2950 men never had a PSA level of more than 4.0 ng per milliliter or an abnormal digital rectal examination, had a final PSA determination, and underwent a prostate biopsy after being in the study for seven years. Among the 2950 men (age range, 62 to 91 years), prostate cancer was diagnosed in 449 (15.2 percent); 67 of these 449 cancers (14.9 percent) had a Gleason score of 7 or higher. The prevalence of prostate cancer was 6.6 percent among men with a PSA level of up to 0.5 ng per milliliter, 10.1 percent among those with values of 0.6 to 1.0 ng per milliliter, 17.0 percent among those with values of 1.1 to 2.0 ng per milliliter, 23.9 percent among those with values of 2.1 to 3.0 ng per milliliter, and 26.9 percent among those with values of 3.1 to 4.0 ng per milliliter. The prevalence of high-grade cancers increased from 12.5 percent of cancers associated with a PSA level of 0.5 ng per milliliter or less to 25.0 percent of cancers associated with a PSA level of 3.1 to 4.0 ng per milliliter.

PSA velocity predicts post-treatment prostate CA outcome

Clinical Question:
Does the rate of rise of prostate specific antigen predict the outcome following radical prostatectomy for men with prostate cancer?

Bottom Line:
Men whose PSA level increases by more than 2.0 ng per milliliter during the year before the diagnosis of prostate cancer may have a relatively high risk of death from prostate cancer despite undergoing radical prostatectomy.

Reference:
D’Amico AV, Chen M-H, Roehl KA, and Catalona WJ. Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy. N Engl J Med 2004; 351: 125-35.

Study Design:
Cohort (prospective)

Synopsis:
The investigators evaluated whether men at risk for death from prostate cancer after radical prostatectomy can be identified using information available at diagnosis. They studied 1095 men with localized prostate cancer to assess whether the rate of rise in the prostate-specific antigen (PSA) level–the PSA velocity–during the year before diagnosis, the PSA level at diagnosis, the Gleason score, and the clinical tumor stage could predict the time to death from prostate cancer and death from any cause after radical prostatectomy. As compared with an annual PSA velocity of 2.0 ng per milliliter or less, an annual PSA velocity of more than 2.0 ng per milliliter was associated with a significantly shorter time to death from prostate cancer (P<0.001) and death from any cause (P=0.01). An increasing PSA level at diagnosis (P=0.01), a Gleason score of 8, 9, or 10 (P=0.02), and a clinical tumor stage of T2 (P<0.001) also predicted the time to death from prostate cancer. For men with an annual PSA velocity of more than 2.0 ng per milliliter, estimates of the risk of death from prostate cancer and death from any cause seven years after radical prostatectomy were also influenced by the PSA level, tumor stage, and Gleason score at diagnosis.

False-positive PSA associated with increased worry, fears

Clinical Question:
Do men who receive a positive prostate specific antigen (PSA) test result subsequently shown to be wrong worry more about prostate cancer than men who receive a negative result?

Bottom Line:
False positive results of screening tests are not benign but carry with them a psychological cost. As with women receiving false-positive mammogram results, men receiving false-positive prostate specific antigen (PSA) test results report having thought and worried more about prostate cancer despite receiving a negative follow-up test (prostate biopsy) result. They also think, like women, that the false-positive result makes them more likely to develop prostate cancer. Screening can be bad for our patients’ mental health.

Reference:
McNaughton -Collins M, Fowler FJ, Caubet JF, et al. Psychological effects of a suspicious prostate cancer screening test followed by a benign biopsy result. Am J Med 2004;117:719-25.

Study Design:
Cohort (prospective)

Synopsis:
The authors evaluated the psychological implications of an apparently false-positive screening result for prostate cancer. The sample comprised 167 men with a benign biopsy result in response to a suspicious screening test result (biopsy group) and 233 men with a normal prostate-specific antigen (PSA) test result (control group). The men responded to a questionnaire within about 6 weeks of their biopsy or PSA results. They were asked about demographic characteristics, medical history, psychological effects, biopsy experience, and prostate cancer knowledge. The survey response rate was 85% (400/471). The mean (+/- SD) age of respondents was 60 +/- 9 years (range, 40 to 88 years); 88% (n = 350) were white. Forty-nine percent (81/167) of men in the biopsy group reported having thought about prostate cancer either “a lot” or “some of the time”, compared with 18% (42/230) in the control group (P < 0.001). In addition, 40% (67/167) in the biopsy group reported having worried “a lot” or “some of the time” that they may develop prostate cancer, compared with 8% (18/231) in the control group (P < 0.001).

Ureteral stents not effective, increase symptoms

Clinical Question:
Following treatment of ureteral stones, is stent placement safe and effective?

Bottom Line:
Patients with stents after ureteroscopy have significantly higher morbidity in the form of irritative lower urinary symptoms with no influence on stone free rate, rate of urinary tract infection, requirement for analgesia, or long term ureteric stricture formation. Because of the marked heterogeneity and poor quality of reporting of the included trials, the place of stenting in the management of patients after uncomplicated ureteroscopy remains unclear.

Reference:
Nabi G, Cook J, N’Dow J, McClinton S. Outcomes of stenting after uncomplicated ureteroscopy: systematic review and meta-analysis. BMJ 2007;334:572.

Study Design:
Meta-analysis (randomized controlled trials)

Synopsis:
The authors investigated the potential beneficial and adverse effects of routine ureteric stent placement after ureteroscopy. They did a systematic review and meta-analysis of randomised controlled trials. Data gathered from Cochrane controlled trials register (2006 issue 2), Embase, and Medline (1966 to 31 March 2006), without language restrictions. Review methods We included all randomised controlled trials that reported various outcomes with or without stenting after ureteroscopy. Two reviewers independently extracted data and assessed quality. Meta-analyses used both fixed and random effects models with dichotomous data reported as relative risk and continuous data as a weighted mean difference with 95% confidence intervals. Nine randomised controlled trials (reporting 831 participants) were identified. The incidence of lower urinary tract symptoms was significantly higher in participants who had a stent inserted (relative risk 2.25, 95% confidence interval 1.14 to 4.43, for dysuria; 2.00, 1.11 to 3.62, for frequency or urgency) after ureteroscopy. There was no significant difference in postoperative requirement for analgesia, urinary tract infections, stone free rate, and ureteric strictures in the two groups. Because of marked heterogeneity, formal pooling of data was not possible for some outcomes such as flank pain. A pooled analysis showed a reduced likelihood of unplanned medical visits or admission to hospital in the group with stents (0.53, 0.17 to 1.60), although this difference was not significant. None of the trials reported on health related quality of life. Cost reported in three randomised controlled trials favoured the group without stents. The overall quality of trials was poor and reporting of outcomes inconsistent.