Arteriovenous Fistulae for Haemodialysis: A Systematic Review and Meta-analysis of Efficacy and Safety Outcomes.

BACKGROUND: Arteriovenous fistulae are the currently recommended gold standard vascular access modality for haemodialysis because of their prolonged patency, improved durability, and low risk of infection for those that mature. However, notable disadvantages are observed in terms of protracted maturation time, associated high rates of catheter use, and substantial abandonment rates. The aim of this study was to quantitatively summarize the outcomes of fistula patency, infection, maturation, and abandonment published in the scientific literature. METHODS: This was a systematic review and meta-analyses of studies evaluating fistula outcomes. Literature searches were conducted in multiple databases to identify observational and interventional studies of mean fistula patency rates at 1 year, infection risk, maturation time, and abandonment. Digitisation software was used to simulate individual patient level data from Kaplan-Meier survival plots. RESULTS: Over 8000 studies were reviewed, and from these, 318 studies were included comprising 62,712 accesses. For fistulas the primary unassisted, primary assisted, and secondary patency rates at one year were 64%, 73% and 79% respectively, however not all fistulas reported as patent could be confirmed as being clinically useful for dialysis (i.e. functional patency). For fistulas that were reported as mature, mean time to maturation was 3.5 months, however only 26% of created fistulas were reported as mature at 6 months and 21% of fistulas were abandoned without use. Overall risk of infection in fistula patients was 4.1% and the overall rate per 100 access days was 0.018. CONCLUSIONS: Reported fistula patency rates may overstate their potential clinical utility when time to maturation, maturation rate, abandonment and infection are considered. Protracted maturation times, abandonment and infection all have a significant impact on evaluating the clinical utility of fistula creation. A rigorous and consistent set of outcomes definitions for hemodialysis access are necessary to clarify factors contributing to fistula success and the clinical consequence of fistula failure.

Recombinant human tumor necrosis factor receptor (p75) Fc fusion protein (TNFR:Fc) in rheumatoid arthritis.

BACKGROUND: Tumor necrosis factor (TNF) is the dominant mediator of the cytokine cascade that causes inflammation and joint destruction in rheumatoid arthritis. A new class of agents under investigation, the biologic TNF inhibitors, inhibits the activity of TNF. Recombinant human TNF receptor p75 Fc fusion protein (TNFR:Fc; Enbrel) blocks the activity of the cytokine TNF. The preclinical, Phase I, and Phase II data of TNFR:Fc in rheumatoid arthritis are reviewed in this article. METHODS: All available data on TNFR:Fc in rheumatoid arthritis were reviewed. These data included published literature and data on file at the manufacturer. RESULTS: TNFR:Fc has been effective in many models of inflammation, including animal models of rheumatoid arthritis and in clinical rheumatoid arthritis trials. Conclusions from a study with TNFR "knockout" mice (genetically altered mice incapable of producing TNFR proteins) demonstrated that p75 TNFR is a natural antagonist of TNF-mediated inflammation. A placebo-controlled, dose-escalation, Phase I trial evaluated the safety and efficacy of TNFR:Fc in patients with rheumatoid arthritis. There were no serious adverse effects reported. A Phase II, randomized, double-blind, placebo-controlled trial evaluated 180 patients with active rheumatoid arthritis whose previous therapy had failed. A dose-response relationship was observed in the number of tender and swollen joints; patients who received the highest dose (16 mg/m2) of TNFR:Fc had the greatest improvement. Treatment was generally well tolerated. TNFR:Fc is nonimmunogenic; no antibodies to TNFR:Fc have been detected thus far in human studies. CONCLUSIONS: Preliminary data indicate that TNFR:Fc is an excellent candidate for future long-term studies in the treatment of rheumatoid arthritis.

Advances and issues in the pharmacotherapy of rheumatoid arthritis.

Rheumatoid arthritis (RA) is an unremitting and progressive disease despite the use of second-line drugs in the majority of patients. In addition, a shortened life-span directly attributable to RA is now recognized. The additions of methotrexate and sulfasalazine to the therapeutic armamentarium represent important treatment advances during the past decade. To improve the effectiveness of second-line drug therapy, earlier intervention and use of these newer drugs in combination with older second-line drugs is being advocated. Several proposed strategies for intervening earlier, combining second-line drugs, and/or improving patient selection for second-line drug therapy are reviewed. Systematic evaluation of these strategies is needed. Controlled studies to date have not demonstrated combining second-line drugs is superior to using individual second-line agents. Future advances in optimizing patient outcomes with these drugs will require systematic screening for potentially superior treatment strategies followed by supportive proof of effectiveness in the form of large-scale studies.

Nabumetone: a "nonacidic" nonsteroidal antiinflammatory drug.

OBJECTIVE: To review the pharmacology, pharmacokinetic disposition, dosage recommendations, adverse effects, drug interactions, and efficacy of nabumetone in patients with selected rheumatic disorders and soft-tissue injuries. DATA SOURCES: Data from scientific literature were extracted, evaluated, and summarized for presentation. A MEDLINE search was conducted using the following indexing terms: antiinflammatory agents, nonsteroidal, nabumetone, rheumatoid arthritis (RA), and osteoarthritis (OA). Studies evaluating nabumetone reported in articles, abstracts, or proceedings involving human subjects were considered for inclusion. STUDY SELECTION: Special consideration was given to clinical studies using double-blind, randomized, parallel, controlled designs. Studies comparing the effectiveness and safety of nabumetone with placebo and other nonsteroidal antiinflammatory drugs (NSAIDs) were included. DATA EXTRACTION: Data from human studies published in the English language were evaluated. Trials were assessed according to study design, sample size, and description of outcomes. DATA SYNTHESIS: Nabumetone is a nonacidic prodrug that is metabolized to an active nonsteroidal antiinflammatory moiety, 6-methoxy-2-naphthylacetic acid (6-MNA). 6-MNA is a structural analog of naproxen. Like naproxen and other NSAIDs, 6-MNA possesses analgesic, antipyretic, and antiinflammatory activity, 6-MNA has a prolonged elimination half-life, ranging from 17 to 74 hours, which allows for once-daily dosing. The efficacy of nabumetone for treating symptoms of RA and OA has been established in controlled clinical trials. Nabumetone also has been studied in ankylosing spondylitis and soft-tissue injuries. Adverse effects associated with nabumetone are similar to those associated with other NSAIDs. Gastrointestinal reactions occur most frequently in the form of abdominal pain or indigestion, nausea, or vomiting. Central nervous system adverse effects occur less frequently, and are followed in order of occurrence by rashes. CONCLUSIONS: Nabumetone is a prodrug metabolized to an active metabolite structurally related to naproxen. Studies have demonstrated the efficacy of nabumetone, but no advantages over the many other NSAIDs now available.

Impact of voluntary vs enforced compliance of third-generation cephalosporin use in a teaching hospital.

STUDY OBJECTIVE: The purpose of this study was to assess and compare the impact of voluntary compliance and enforced compliance with institutional guidelines for initiating third-generation cephalosporin therapy. DESIGN: An audit of third-generation cephalosporin use during a 6-month period shortly after ceftriaxone and ceftazidime were added to the hospital formulary already containing cefotaxime was performed. During this period, compliance to institutional guidelines for initiating therapy was voluntary. A follow-up audit during a similar 6-month period was performed to assess compliance with institutional guidelines shortly after an enforcement policy was placed in effect. The results of these two audits were compared to assess usage patterns of these cephalosporins, compliance rates with institutional guidelines for initiating therapy, use of susceptibility testing to guide therapy, effect of use of these drugs on susceptibility patterns within the hospital, and third-generation cephalosporin costs during periods when institutional policy was unenforced and enforced. RESULTS: Only 24.2% of 66 courses of third-generation cephalosporins were initiated in compliance with institutional guidelines during the initial audit period. Susceptibility testing revealed an organism susceptible to a first-generation cephalosporin in 13 courses but in only six instances was a switch to the more narrow-spectrum antibiotic performed. At the time routine susceptibility testing to ceftazidime and ceftriaxone was instituted, 92% of Enterobacter cloacae were sensitive to ceftriaxone and 89% of Pseudomonas aeruginosa were sensitive to ceftazidime. Fifteen months later, when voluntary compliance to institutional policy was terminated, 70% of E cloacae were sensitive to ceftriaxone and 73% of P aeruginosa were sensitive to ceftazidime. During the last 6 months of this period, pharmacy expenditures totaled $50,000. The second audit revealed 85.4% of 48 courses of treatment complied with guidelines for initiating therapy. Since enforcement was instituted, sensitivity of E cloacae to ceftriaxone has risen to 88% and sensitivity of P aeruginosa to ceftazidime has increased to 80%. Pharmacy expenditures decreased to $23,000.

Second-line antirheumatic drugs in the elderly with rheumatoid arthritis: a post hoc analysis of three controlled trials.

This study assessed the relative efficacy and toxicity of second-line antirheumatic drugs in patients 65 years of age or older compared to younger counterparts. The results of three prospective, double-blind, parallel, randomized, multicenter trials were reanalyzed, stratifying outcomes by intervention and patient age. Efficacy was assessed by categorizing patient responses as follows: important improvement, no meaningful change, or progressive disease. Toxicity was analyzed by comparing withdrawal rates due to adverse effects. The three trials compared the following treatments: (1) D-penicillamine 10-12 mg/day versus azathioprine 1.25-1.5 mg/kg/day; (2) gold sodium thiomalate 50 mg intramuscularly weekly versus auranofin 6 mg/day versus placebo; and (3) pulse oral methotrexate 7.5-15.0 mg weekly versus placebo. At baseline, 103 patients age 65 or older were similar to 485 patients less than 65 years of age, with the exception of disease duration in all studies and erythrocyte sedimentation rate in one study. For patients completing each study, efficacy outcomes based on age were not significantly different. Withdrawal rates due to adverse drug reactions were also not significantly different.

A controlled trial comparing sulfasalazine, gold sodium thiomalate, and placebo in rheumatoid arthritis.

One hundred eight-six patients with active rheumatoid arthritis were evaluated in a double-blind, randomized study that compared treatment with sulfasalazine (SSZ) (2 mg/day), gold sodium thiomalate (GST) (50 mg/week), and placebo (PBO). The 37-week course of therapy was completed by 109 patients. While marked improvement was seen in all 3 treatment groups, the only statistically significant differences between SSZ or GST and PBO were in a decreased erythrocyte sedimentation rate and increased grip strength in the right hand. GST is known to be superior to PBO, and the response of the GST-treated group was similar to that seen in other trials. The response of the PBO group, however, was much greater than in other placebo groups we have studied. SSZ was similar in efficacy to injectable gold, but was better tolerated. Because of adverse drug reactions (most commonly, rash, stomatitis, and proteinuria), 41% of patients were withdrawn from the GST treatment. Untoward drug effects (most frequently, rash and gastrointestinal distress) caused 16% of patients to be withdrawn from SSZ therapy.

One-year experience in patients treated with auranofin following completion of a parallel, controlled trial comparing auranofin, gold sodium thiomalate, and placebo.

Following a 21-week double-blind trial that compared the effects of treatment with auranofin (AUR), gold sodium thiomalate, and placebo in 193 patients, 147 patients entered a 1-year, open-label study of treatment with AUR (6 mg/day). Results of this open-label study suggest that AUR has a long-term use profile similar to that of other slow-acting antirheumatic drugs. AUR appears to be capable of sustaining an initial response to gold sodium thiomalate. The withdrawal rate remains relatively high: Nearly half of the study patients had discontinued AUR by the end of 1 year.

The effect of cimetidine on serum concentrations of piroxicam.

To evaluate the effect of cimetidine on serum concentrations of piroxicam, we administered a single 20-mg oral dose of piroxicam to 10 healthy male volunteers on 2 occasions. The first was given on day 1 of the study and the second on day 15, 7 days after starting cimetidine 300 mg orally 4 times a day. Nineteen blood samples were drawn for 7 days after each piroxicam dose to characterize its pharmacokinetics. Piroxicam was analyzed by high-performance liquid chromatography. The mean piroxicam elimination rate constants (Kel), elimination half-lives, and area under the serum concentration-time curves (AUC) were as follows (mean +/- standard deviation): (formula; see text) Data were analyzed with a Wilcoxon matched-pairs, signed-ranks, two-tailed statistical test. Although the increase in AUC was statistically significant, it was of low amplitude (mean 15%) and is probably not clinically significant. The results of this study suggest that cimetidine does not significantly alter the elimination kinetics of a single dose of piroxicam in young healthy males. Additional investigation is needed to confirm these findings in other patient populations.

Lack of correlation between blood gold concentrations and clinical response in patients with definite or classic rheumatoid arthritis receiving auranofin or gold sodium thiomalate.

We investigated the correlation between whole blood gold concentrations and clinical outcomes in 59 auranofin-treated patients and 51 gold sodium thiomalate-treated patients who completed a 21-week, placebo-controlled, multicenter parallel trial. Whole blood gold concentrations did not correlate with clinical outcome, as assessed by changes in joint tenderness, joint swelling, or Westergren erythrocyte sedimentation rate. They also did not correlate with toxic reactions necessitating withdrawal from the study.

Double-blind, multicenter controlled trial comparing topical dimethyl sulfoxide and normal saline for treatment of hand ulcers in patients with systemic sclerosis.

A prospective, randomized, double-blind trial compared topical therapy with 0.85% normal saline, 2% dimethyl sulfoxide (DMSO), and 70% DMSO for treatment of digital ulcers in 84 patients with systemic sclerosis. There were no statistically significant differences among the 3 treatment groups in the improvement in the total number of open ulcers, total surface area of open ulcers, average surface area per open ulcer, number of infected ulcers, number of inflamed ulcers, or patient pain assessment. While some patients improved during the study, improvement could not be attributed to a specific treatment. Over one-quarter of the patients treated with 70% DMSO were withdrawn for significant skin toxicity.

Pharmacology, clinical efficacy, and adverse effects of the nonsteroidal anti-inflammatory agent benoxaprofen.

Benoxaprofen is a nonsteroidal anti-inflammatory agent that belongs to the arylalkanoic acid class of antirheumatic drugs. Animal studies have demonstrated that it has analgesic, antipyretic, and anti-inflammatory properties. Although benoxaprofen is a relatively weak inhibitor of cyclo-oxygenase in in vitro systems, inhibits lipoxygenase in other systems, and inhibits monocyte migration in some animal models of inflammation, it has not been established that it is unique with regard to these actions. Benoxaprofen undergoes hepatic metabolism via glucuronidation as the primary route of elimination and has a half-life of 28-35 hr. Clinical trials have demonstrated that its analgesic and anti-inflammatory properties are useful in the management of the signs and symptoms of rheumatoid arthritis and osteoarthritis. Once daily dosing of 300-600 mg is effective for many patients. In addition to gastrointestinal intolerance, photosensitivity and onycholysis are the most frequent adverse effects encountered. Recent reports of fatal cholestatic jaundice often associated with nephrotoxicity led to the withdrawal of benoxaprofen from world markets. It is uncertain whether it will once again be available for clinical use.

Pharmacology, clinical efficacy, and adverse effects of piroxicam, a new nonsteroidal anti-inflammatory agent.

Piroxicam, a new non-steroidal anti-inflammatory drug, possesses analgesic, antipyretic, and anti-inflammatory properties and inhibits platelet aggregation in animal models. Its elimination half-life is 38 hours, and hepatic metabolism to inactive metabolites is the primary route of elimination. Less than 10% of a dose appears unchanged in the urine. Clinical studies demonstrate that piroxicam's analgesic and anti-inflammatory properties are useful in the management of rheumatoid arthritis and osteoarthritis. Limited clinical studies suggest that piroxicam may be useful in the management of acute gouty arthritis, ankylosing spondylitis, acute musculoskeletal disorders, and as an analgesic. The gastrointestinal system is the major site of adverse effects. Piroxicam is currently marketed in 20 mg capsules and once daily dosing has proven effective for many patients.