Monthly Archives: April 2015

In children with vesicoureteral reflux and at least one febrile urinary tract infection, do prophylactic antibiotics prevent recurrences or other adverse events?

Prophylactic antibiotics reduce recurrent UTI in kids with VUR (RIVUR)

Bottom Line

Antibiotic prophylaxis reduces the likelihood of recurrent urinary tract infections (UTIs) over a 2-year period (number needed to treat [NNT] = 8), but does not change the likelihood of renal scarring, at least over the medium term. This findings may lead to greater use of imaging to detect vesicoureteral reflux (VUR) in children, something that should be considered with care given the associated radiation exposure and modest benefits of prophylaxis. (LOE = 1b)Bottom Line


The RIVUR Trial Investigators, Hoberman A, Greenfield SP, et al. Antimicrobial prophylaxis for children with vesicoureteral reflux. N Engl J Med 2014;370(25):2367-2376.

Study Design Randomized controlled trial (double-blinded) Funding Government
Setting Outpatient (specialty) Allocation Concealed


Approximately one third of children with febrile UTI have VUR, and antibiotic prophylaxis is commonly recommended to prevent recurrent infections and renal scarring and dysfunction. These investigators enrolled 607 children between the ages of 2 months and 71 months from 19 US sites. All the children had confirmed VUR (grade I to IV) and a febrile UTI within 112 days of randomization. Groups were balanced at the start of the study and the analysis was by intention to treat. The children’s median age was 12 months, with an interquartile range of 6 to 31 months; 92% of participants were female and 81% were white. The severity of VUR was grade II or III for 80% of participants. Children were randomized to receive prophylaxis with trimethoprim-sulfamethoxazole (3 mg/15 mg per kg) or matching placebo, and were followed up for 2 years. Adherence to the study medication was similar between groups. The likelihood of recurrent febrile or symptomatic UTI was significantly lower in the active treatment group (absolute risk reduction = 12%; NNT = 8). The authors calculated the results first by assuming that kids with missing data had a UTI, then by assuming that they did not, and a third time just omitting the missing data; the results were the same. There was no difference in the likelihood of renal scarring (11.9% for prophylaxis and 10.2% for placebo) or renal cortical defects. Children with grade III or IV reflux at baseline were more likely to have febrile or symptomatic recurrences than children with grade I or II reflux (22.9% vs 14.3%; P = .003). Adverse events were similar between groups.

Mark H. Ebell, MD, MS
Associate Professor
University of Georgia
Athens, GA

Is citalopram useful in the management of agitation in patients with Alzheimer disease?

Citalopram reduces agitation but may worsen cognitive impairment in Alzheimer disease

Bottom Line

Citalopram (Celexa; up to 30 mg daily, as tolerated) significantly reduces symptoms of agitation in patients with Alzheimer disease. However, the use of rescue lorazepam for agitation was not significantly reduced with the use of citalopram so the clinical significance of this improvement may be minimal. In addition, patients given citalopram showed significantly worsening cognitive impairment than patients given placebo. (LOE = 1b)


Porsteinsson AP, Drye LT, Pollock BG, et al, for the CitAD Research Group. Effect of citalopram on agitation in Alzheimer disease. The CitAD randomized clinical trial. JAMA 2014;311(7):682-691.

Study Design Randomized controlled trial (double-blinded) Funding Government
Setting Outpatient (specialty) Allocation Concealed


The optimal management of agitation in patients with Alzheimer disease remains uncertain. These investigators identified 186 adults with probable Alzheimer disease based on standard international criteria and Mini-Mental State Examination (MMSE) scores from 5 to 28 with physician-determined clinically significant agitation. The average age of the patients was 78.5 years and all had dementia for at least 5 years. Approximately two-thirds of the patients also took cholinesterase inhibitors and approximately 40% took memantine. Exclusion criteria included major depressive disorder or psychosis requiring antipsychotic treatment. Patients randomly received (concealed allocation assignment) citalopram (starting dose = 10 mg per day, with titration as tolerated to a target dose of 30 mg per day over 3 weeks) or matched placebo. Lorazepam and trazodone served as rescue medications for significant agitation or sleep disturbance. Individuals masked to treatment group assignment assessed outcomes using validated neurobehavioral rating scales and scoring tools. Complete follow-up occurred for 90% of patients at 9 weeks. Of these, 80% remained on treatment. Using intention-to-treat analysis, patients taking citalopram showed significantly improved scores (correlating with fewer signs and symptoms of agitation) than those taking placebo (mean score for the citalopram group = 4.1 vs mean score for the placebo group = 5.4; range = 0-18, with higher scores indicating more severe symptoms). Results from a scoring tool that evaluates overall clinician impression of global function showed that 40% of citalopram-treated patients had moderate or marked improvement from baseline severity compared with 26% of patients taking the placebo (number needed to treat = 7; 95% CI, 4-127). No differences occurred between the 2 treatments groups in the use of rescue lorazepam. Regarding adverse effects, MMSE results showed significant cognitive worsening in patients taking citalopram, and both falls and upper respiratory tract infections were also noted more often in the citalopram group.

David Slawson, MD
Director of Information Sciences
University of Virginia Health System
Charlottesville, VA

Viscosupplementation: Is there evidence that viscosupplementation is effective for osteoarthritis of the knee?

Teaching Topic from the New England Journal of Medicine

March 12, 2015

Viscosupplementation for Osteoarthritis of the Knee D.J. Hunter

Clinical Pearls

Recent estimates suggest that knee osteoarthritis affects approximately 250 million people worldwide. Typically, knee pain limits activity and impairs quality of life. The risk of mobility disability (defined as the need for help with walking or climbing stairs) attributable to knee osteoarthritis alone is greater than that associated with any other medical condition in people 65 years of age or older.

What is the rationale for treating osteoarthritis of the knee with intraarticular injections of hyaluronic acid (viscosupplementation)?

Hyaluronate is a naturally occurring component of the cartilage and the synovial fluid. Within the normal adult knee, there is approximately 2 ml of synovial fluid, with a hyaluronate concentration of 2.5 to 4.0 mg per milliliter. Hyaluronate is responsible for the rheologic properties of synovial fluid, enabling it to act as a lubricant or shock absorber, depending on the forces exerted on it. In osteoarthritis, synovial hyaluronate is depolymerized and cleared at higher rates than normal. These changes reduce the viscoelasticity of the synovial fluid. The therapeutic goal of administration of intraarticular hyaluronate is to provide and maintain intraarticular lubrication, which increases the viscoelastic properties of synovial fluid; this form of therapy is therefore sometimes termed “viscosupplementation.”

Is there evidence that viscosupplementation is effective for osteoarthritis of the knee?

Despite numerous trials and meta-analyses, the efficacy of hyaluronate-related agents in patients with knee osteoarthritis remains debated and uncertain. Meta-analyses assessing the efficacy of this form of therapy have had discordant findings, possibly because each review used different search strategies and selection criteria to identify trials for inclusion in the analysis. There is also controversy over whether the molecular mass of hyaluronate influences efficacy. The effectiveness of intraarticular hyaluronate is at best modest and at worst, in some of the aforementioned meta-analyses, indistinguishable from that of placebo. Although there are some data suggesting that younger patients and patients with less-severe disease may have greater benefit from this treatment than do older patients and those with more advanced disease, further evidence is required to support this claim. The effect of intraarticular hyaluronate on the structural progression of osteoarthritis, especially after repeat administration over longer intervals, remains an open question, with some pilot evidence suggesting positive effects.

Morning Report Questions

Q. What side effects are associated with the procedure?

A. Minor side effects include pain at the injection site (which occurs in 1 to 33% of patients), local joint pain and swelling (in <1 to 30%), and local skin reactions (in 3 to 21%). More serious side effects can occur. Pseudoseptic reactions (occurring in 1 to 3% of patients), which are characterized by inflammation and swelling of the joint that are not caused by infection, can be severe and may require further medical treatment. These reactions usually occur after sensitization with the second or third injection of a series or with a repeat treatment course. True joint infections have also been reported, but these appear to be rare.

Q. What are the formal guidelines regarding viscosupplementation for treatment of osteoarthritis of the knee?

A. Consistent with the contradictory meta-analyses, available guidelines also have conflicting recommendations, despite being based on the same research evidence. A recent update of the evidence from the OARSI [Osteoarthritis Research Society International] suggested that the data from the more rigorous trials did not show a significant difference between the effect of hyaluronate and that of placebo; as a result, it was not recommended for the treatment of either knee or multiple-joint osteoarthritis. In the American Academy of Orthopaedic Surgeons clinical practice guideline, it was determined that the evidence was inconclusive and a recommendation could not be made for or against the use of intraarticular hyaluronate. Similarly, the 2012 American College of Rheumatology recommendations do not advocate the use of intraarticular hyaluronate for the initial management of knee osteoarthritis. However, if a patient does not have a satisfactory response to acetaminophen or nonsteroidal antiinflammatory drugs, then the use of tramadol, duloxetine, or intraarticular hyaluronate is conditionally recommended.

How effective is varenicline (Chantix) for smoking cessation?

Ebbert JO, Hughes JR, West RJ, et al. Effect of varenicline on smoking cessation through smoking reduction: a randomized clinical trial. JAMA. 2015 Feb 17;313(7):687-94. doi: 10.1001/jama.2015.280. (Original) PMID: 25688780

IMPORTANCE: Some cigarette smokers may not be ready to quit immediately but may be willing to reduce cigarette consumption with the goal of quitting.

OBJECTIVE: To determine the efficacy and safety of varenicline for increasing smoking abstinence rates through smoking reduction.
DESIGN, SETTING AND PARTICIPANTS: Randomized, double-blind, placebo-controlled, multinational clinical trial with a 24-week treatment period and 28-week follow-up conducted between July 2011 and July 2013 at 61 centers in 10 countries. The 1510 participants were cigarette smokers who were not willing or able to quit smoking within the next month but willing to reduce smoking and make a quit attempt within the next 3 months. Participants were recruited through advertising.
INTERVENTIONS: Twenty-four weeks of varenicline titrated to 1 mg twice daily or placebo with a reduction target of 50% or more in number of cigarettes smoked by 4 weeks, 75% or more by 8 weeks, and a quit attempt by 12 weeks. MAIN OUTCOMES AND MEASURES: Primary efficacy end point was carbon monoxide-confirmed self-reported abstinence during weeks 15 through 24. Secondary outcomes were carbon monoxide-confirmed self-reported abstinence for weeks 21 through 24 and weeks 21 through 52.
RESULTS: The varenicline group (n = 760) had significantly higher continuous abstinence rates during weeks 15 through 24 vs the placebo group (n = 750) (32.1% for the varenicline group vs 6.9% for the placebo group; risk difference (RD), 25.2% [95% CI, 21.4%-29.0%]; relative risk (RR), 4.6 [95% CI, 3.5-6.1]). The varenicline group had significantly higher continuous abstinence rates vs the placebo group during weeks 21 through 24 (37.8% for the varenicline group vs 12.5% for the placebo group; RD, 25.2% [95% CI, 21.1%-29.4%]; RR, 3.0 [95% CI, 2.4-3.7]) and weeks 21 through 52 (27.0% for the varenicline group vs 9.9% for the placebo group; RD, 17.1% [95% CI, 13.3%-20.9%]; RR, 2.7 [95% CI, 2.1-3.5]). Serious adverse events occurred in 3.7% of the varenicline group and 2.2% of the placebo group (P = .07).
CONCLUSIONS AND RELEVANCE: Among cigarette smokers not willing or able to quit within the next month but willing to reduce cigarette consumption and make a quit attempt at 3 months, use of varenicline for 24 weeks compared with placebo significantly increased smoking cessation rates at the end of treatment, and also at 1 year. Varenicline offers a treatment option for smokers whose needs are not addressed by clinical guidelines recommending abrupt smoking cessation.
TRIAL REGISTRATION(S): Identifier: NCT01370356.