Infusion-related reactions with pegloticase, a recombinant uricase for the treatment of chronic gout refractory to conventional therapy.

BACKGROUND: In clinical trials of pegloticase, a PEGylated uricase developed for treatment of gout refractory to conventional therapy, infusion-related reactions (IRs) were the second most frequent adverse event reported. OBJECTIVE: The objective of this study was to provide a detailed account of IRs with pegloticase therapy. METHODS: Data from 2 replicate, 6-month randomized trials and an open-label extension study were pooled. Infusions of pegloticase (8 mg) were administered biweekly or monthly; all patients received prophylaxis (antihistamine, acetaminophen, and corticosteroid) and were tested for urate levels prior to each infusion. An IR was defined by protocol as any otherwise unexplained adverse event or cluster of temporally related events occurring during or within 2 hours of infusion. RESULTS: Infusion-related reactions occurred in 94 (45%) of 208 patients receiving pegloticase; 10 patients reported IRs at first infusion and 84 during subsequent infusions. Chest discomfort (15%), flushing (12%), and dyspnea (11%) were the most common symptoms. Most IRs were rated mild or moderate; 7% were rated severe. All IRs resolved with slowing, interrupting, or stopping the infusion. No patient required blood pressure or ventilatory support. Infusion-related reactions were associated with loss of pegloticase urate-lowering efficacy: 91% of all IRs occurred in patients with preinfusion serum uric acid concentrations (sUA) greater than 6 mg/dL. For patients sustaining preinfusion sUA of less than 6 mg/dL, IRs occurred in fewer than 1 per 100 infusions. CONCLUSIONS: Phase 3 trial data combined with post hoc analyses demonstrated that knowledge of sUA preceding each pegloticase infusion and cessation of therapy when urate-lowering efficacy is lost provide a means to optimize the safety of pegloticase in clinical practice.

Long-term safety of pegloticase in chronic gout refractory to conventional treatment.

OBJECTIVE: To evaluate the long-term safety (up to 3 years) of treatment with pegloticase in patients with refractory chronic gout. METHODS: This open-label extension (OLE) study was conducted at 46 sites in the USA, Canada and Mexico. Patients completing either of two replicate randomised placebo-controlled 6-month trials received pegloticase 8 mg every 2 weeks (biweekly) or every 4 weeks (monthly). Safety was evaluated as the primary outcome, with special interest in gout flares and infusion-related reactions (IRs). Secondary outcomes included urate-lowering and clinical efficacy. RESULTS: Patients (n=149) received a mean±SD of 28±18 pegloticase infusions and were followed for a mean of 25±11 months. Gout flares and IRs were the most frequently reported adverse events; these were least common in patients with a sustained urate-lowering response to treatment and those receiving biweekly treatment. In 10 of the 11 patients with a serious IR, the event occurred when uric acid exceeded 6 mg/dl. Plasma and serum uric acid levels remained <6 mg/dl in most randomised controlled trial (RCT)-defined pegloticase responders throughout the OLE study and were accompanied by sustained and progressive improvements in tophus resolution and flare incidence. CONCLUSIONS: The safety profile of long-term pegloticase treatment was consistent with that observed during 6 months of RCT treatment; no new safety signals were identified. Improvements in clinical status, in the form of flare and tophus reduction initiated during RCT pegloticase treatment in patients maintaining goal range urate-lowering responses were sustained or advanced during up to 2.5 years of additional treatment.

Primary care providers' knowledge, beliefs and treatment practices for gout: results of a physician questionnaire.

OBJECTIVE: We sought to examine primary care providers' gout knowledge and reported treatment patterns in comparison with current treatment recommendations. METHODS: We conducted a national survey of a random sample of US primary care physicians to assess their treatment of acute, intercritical and tophaceous gout using published European and American gout treatment recommendations and guidelines as a gold standard. RESULTS: There were 838 respondents (response rate of 41%), most of whom worked in private practice (63%) with >16 years experience (52%). Inappropriate dosing of medications in the setting of renal disease and lack of prophylaxis when initiating urate-lowering therapy (ULT) accounted for much of the lack of compliance with treatment recommendations. Specifically for acute podagra, 53% reported avoidance of anti-inflammatory drugs in the setting of renal insufficiency, use of colchicine at a dose of ≤2.4 mg/day and no initiation of a ULT during an acute attack. For intercritical gout in the setting of renal disease, 3% would provide care consistent with the recommendations, including initiating a ULT at the appropriate dose with dosing titration to a serum urate level of ≤6 mg/dl and providing prophylaxis. For tophaceous gout, 17% reported care consistent with the recommendations, including ULT use with dosing titration to a serum urate level of ≤6 mg/dl and prophylaxis. CONCLUSION: Only half of primary care providers reported optimal treatment practices for the management of acute gout and <20% for intercritical or tophaceous gout, suggesting that care deficiencies are common.

Patients' knowledge and beliefs concerning gout and its treatment: a population based study.

BACKGROUND: For patients to effectively manage gout, they need to be aware of the impact of diet, alcohol use, and medications on their condition. We sought to examine patients' knowledge and beliefs concerning gout and its treatment in order to identify barriers to optimal patient self-management. METHODS: We identified patients (≥18 years of age) cared for in the setting of a multispecialty group practice with documentation of at least one health care encounter associated with a gout diagnosis during the period 2008-2009 (n = 1346). Patients were sent a questionnaire assessing knowledge with regard to gout, beliefs about prescription medications used to treat gout, and trust in the physician. Administrative electronic health records were used to identify prescription drug use and health care utilization. RESULTS: Two hundred and forty patients returned surveys out of the 500 contacted for participation. Most were male (80%), white (94%), and aged 65 and older (66%). Only 14 (6%) patients were treated by a rheumatologist. Only a minority of patients were aware of common foods known to trigger gout (e.g., seafood [23%], beef [22%], pork [7%], and beer [43%]). Of those receiving a urate-lowering medication, only 12% were aware of the short-term risks of worsening gout with initiation. These deficits were more common in those with active as compared to inactive gout. CONCLUSION: Knowledge deficits about dietary triggers and chronic medications were common, but worse in those with active gout. More attention is needed on patient education on gout and self-management training.

Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: two randomized controlled trials.

CONTEXT: Patients with chronic disabling gout refractory to conventional urate-lowering therapy need timely treatment to control disease manifestations related to tissue urate crystal deposition. Pegloticase, monomethoxypoly(ethylene glycol)-conjugated mammalian recombinant uricase, was developed to fulfill this need. OBJECTIVE: To assess the efficacy and tolerability of pegloticase in managing refractory chronic gout. DESIGN, SETTING, AND PATIENTS: Two replicate, randomized, double-blind, placebo-controlled trials (C0405 and C0406) were conducted between June 2006 and October 2007 at 56 rheumatology practices in the United States, Canada, and Mexico in patients with severe gout, allopurinol intolerance or refractoriness, and serum uric acid concentration of 8.0 mg/dL or greater. A total of 225 patients participated: 109 in trial C0405 and 116 in trial C0406. INTERVENTION: Twelve biweekly intravenous infusions containing either pegloticase 8 mg at each infusion (biweekly treatment group), pegloticase alternating with placebo at successive infusions (monthly treatment group), or placebo (placebo group). MAIN OUTCOME MEASURE: Primary end point was plasma uric acid levels of less than 6.0 mg/dL in months 3 and 6. RESULTS: In trial C0405 the primary end point was reached in 20 of 43 patients in the biweekly group (47%; 95% CI, 31%-62%), 8 of 41 patients in the monthly group (20%; 95% CI, 9%-35%), and in 0 patients treated with placebo (0/20; 95% CI, 0%-17%; P < .001 and <.04 for comparisons between biweekly and monthly groups vs placebo, respectively). Among patients treated with pegloticase in trial C0406, 16 of 42 in the biweekly group (38%; 95% CI, 24%-54%) and 21 of 43 in the monthly group (49%; 95% CI, 33%-65%) achieved the primary end point; no placebo-treated patients reached the primary end point (0/23; 95% CI, 0%-15%; P = .001 and < .001, respectively). When data in the 2 trials were pooled, the primary end point was achieved in 36 of 85 patients in the biweekly group (42%; 95% CI, 32%-54%), 29 of 84 patients in the monthly group (35%; 95% CI, 24%-46%), and 0 of 43 patients in the placebo group (0%; 95% CI, 0%-8%; P < .001 for each comparison). Seven deaths (4 in patients receiving pegloticase and 3 in the placebo group) occurred between randomization and closure of the study database (February 15, 2008). CONCLUSION: Among patients with chronic gout, elevated serum uric acid level, and allopurinol intolerance or refractoriness, the use of pegloticase 8 mg either every 2 weeks or every 4 weeks for 6 months resulted in lower uric acid levels compared with placebo. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00325195.

Adherence and occurrence of fractures after switching to once-monthly oral bisphophonates.

PURPOSE: Reducing dosing demands of medications generally increases adherence, although this relationship has not been demonstrated with the once-monthly oral bisphosphonates (BP). The study aim is to test whether switching from once-weekly BPs to once-monthly BPs improves adherence and fracture risk. METHODS: This is an interrupted times-series analysis of new users of once-weekly BPs in a nationwide administrative health database from 2003 to 2007. Participants include 1835 individuals who switched to once-monthly BPs and two propensity-matched comparator groups: 1835 individuals who switched to a different once-weekly BP, and 1835 who did not switch. We measured changes in adequate adherence pre- and post-switch as monthly medication possession ratio >0.80, and calculated incidence rate ratios (IRR) of osteoporotic fractures. RESULTS: All study groups experienced major adherence failure in the first year of therapy: the proportion of adequate adherers was 42% among once-monthly switchers, 47% among once-weekly switchers, and 37% among nonswitchers. However, the once-monthly switch was associated with less adherence failure (4% fewer adherers per month pre-switch vs. 1% fewer adherers per month post-switch, p<0.000). There was no statistically significant change in adherence rates for the other groups. We did not detect significantly reduced fracture risk with once-monthly switch: 1 year post-switch, the fracture incidence risk ratios for once-monthly switchers relative to once-weekly switchers were IRR 0.83, 95% CI: 0.50-1.36, and IRR 0.90, 95% CI: 0.54-1.49, relative to nonswitchers). CONCLUSIONS: Reducing the dosing demands of oral bisphosphonates from once-weekly to once-monthly decreased adherence failure but had an uncertain impact on fracture risk.

Patient decision to initiate therapy for osteoporosis: the influence of knowledge and beliefs.

BACKGROUND: There are effective treatments to prevent osteoporotic fractures, but these treatments are underutilized. OBJECTIVE: To evaluate the influence of patient characteristics, perceptions, knowledge and beliefs about osteoporosis on the decision to initiate osteoporotic treatment. PARTICIPANTS: We identified female members of a managed care plan who had a dual energy x-ray absorptiometry (DXA) bone density test and fulfilled World Health Organization criteria for osteoporosis. Patients were excluded if they received osteoporotic medications in the prior 6 months. MEASUREMENTS: Patients were sent a questionnaire that included items assessing satisfaction with physician-patient communication, trust in the physician, osteoporosis knowledge and beliefs, beliefs about prescription medications, and perceptions of barriers to medication use. Administrative electronic health records were used to identify prescription drug use and health care utilization. RESULTS: Two hundred and thirty-six women returned surveys and research authorization forms out of 465 contacted for participation. One hundred and thirty-five (57.2%) filled a prescription for an osteoporotic drug in the first 3 months after the DXA exam. The largest differences between initiators and non-initiators were in beliefs in the benefits of medications, and distrust of medications, with initiators believing more strongly in the benefits and effectiveness of medications (p < .001), and non-initiators reporting more distrust of medications (p < .001). Osteoporosis knowledge and the belief that osteoporosis is a serious disease were also related to therapy initiation in bivariate analysis. CONCLUSIONS: Only 57% of patients initiated osteoporotic medication within 3 months of diagnosis. The decision to start osteoporosis treatment appeared to be related to a patient's beliefs in the effectiveness of osteoporosis medications and distrust of medications.

Identification of patients with arthritis and arthritis-related functional limitation using administrative data.

OBJECTIVE: To develop algorithms on the basis of administrative data to identify patients with arthritis and arthritis-related functional limitation (AFL). STUDY DESIGN AND SETTING: In this retrospective study, 361 enrollees of a health plan underwent a clinical examination to confirm arthritis and assessment of functional limitation on the basis of responses to the health assessment questionnaire. Administrative data were obtained on these subjects and included arthritis drugs dispensed, as well as outpatient and emergency department diagnoses and procedures (including radiographic studies, arthritis procedures, and laboratory tests). Composite risk scores for arthritis and AFL were created on the basis of the association of arthritis-related healthcare utilization with confirmed arthritis and AFL. Algorithms were then developed on the basis of the composite risk scores using logistic regression models. RESULTS: The algorithm using the arthritis composite score to identify arthritis patients had an area under the ROC curve (AUC) of 0.74, sensitivity of 75 percent and specificity of 57 percent. Similarly, the algorithm using the AFL composite score to identify patients with AFL had an AUC of 0.73, sensitivity of 62 percent, and specificity of 75 percent. CONCLUSION: The developed algorithms will enable health plans to screen their enrollees for persons with arthritis and AFL. This will facilitate enrollment of patients with arthritis and AFL in disease management programs and/or targeted interventions.

Consequences of poor compliance with bisphosphonates.

BACKGROUND: Prior research on the ability of bisphosphonates to prevent fractures and related health care utilization has been based on high levels of compliance achievable in clinical trial settings. This study was undertaken to assess rates of osteoporotic fractures and health care utilization as a function of bisphosphonate compliance in usual clinical practice. METHODS: This retrospective cohort study used 2000-2004 pharmacy and medical claims data from 45 large U.S. employers. Our sample included persons diagnosed with osteoporosis, aged 40 years or older, and who initiated use of either alendronate or risedronate. Main outcome measures were medication compliance, rates of osteoporotic fracture, and costs for inpatient care, outpatient services, and prescription drugs. RESULTS: We identified 17,988 new users of bisphosphonate therapy. After 1 to 3 years of follow-up, only 30.6% to 42.9% of patients could achieve high compliance (80%-100%), 17.4%-23.0% moderate compliance (79%-40%), and 33.8%-52.0% had low compliance (0%-39%). Multivariate models of fracture risk showed benefits (p<10) with compliance levels of at least 60%, after which no risk benefit could be detected. Multivariate models of health care costs showed statistically significant (p<.05) total costs savings of $859 to $366 per year with high to moderate compliance levels. However, individuals achieving less than 40% compliance had no detectable decrease in inpatient or outpatient costs to offset the increase in drug costs. CONCLUSIONS: Reductions in fracture risk and overall health costs can be detected in individuals achieving as little as 60% to 40% compliance with bisphosphonates. However, as many as 34% of patients in the first year of therapy and 52% by the third year will not reach even the minimal compliance levels required to receive benefits.

Effects of conjugated equine estrogen on risk of fractures and BMD in postmenopausal women with hysterectomy: results from the women's health initiative randomized trial.

UNLABELLED: Further analyses from the Women's Health Initiative estrogen trial shows that CEE reduced fracture risk. The fracture reduction at the hip did not differ appreciably among risk strata. These data do not support overall benefit over risk, even in women at highest risk for fracture. INTRODUCTION: The Women's Health Initiative provided evidence that conjugated equine estrogen (CEE) can significantly reduce fracture risk in postmenopausal women. Additional analysis of the effects of CEE on BMD and fracture are presented. MATERIALS AND METHODS: Postmenopausal women 50-79 years of age with hysterectomy were randomized to CEE 0.625 mg daily (n = 5310) or placebo (n = 5429) and followed for an average 7.1 years. Fracture incidence was assessed by semiannual questionnaire and verified by adjudication of radiology reports. BMD was measured in a subset of women (N = 938) at baseline and years 1, 3, and 6. A global index was used to examine whether the balance of risks and benefits differed by baseline fracture risk. RESULTS: CEE reduced the risk of hip (hazard ratio [HR], 0.65; 95% CI, 0.45-0.94), clinical vertebral (HR, 0.64; 95% CI, 0.44-0.93), wrist/lower arm (HR, 0.58; 95% CI, 0.47-0.72), and total fracture (HR, 0.71; 95% CI, 0.64-0.80). This effect did not differ among strata according to age, oophorectomy status, past hormone use, race/ethnicity, fall frequency, physical activity, or fracture history. Total fracture reduction was less in women at the lowest predicted fracture risk in both absolute and relative terms (HR, 0.86; 95% CI, 0.68-1.08). CEE also provided modest but consistent positive effects on BMD. The HRs of the global index for CEE were relatively balanced across tertiles of summary fracture risk (lowest risk: HR, 0.81; 95% CI, 0.62-1.05; mid risk: HR, 1.09; 95% CI, 0.92-1.30; highest risk: HR, 1.04; 95% CI, 0.88-1.23; interaction, p = 0.42). CONCLUSIONS: CEE reduces the risk of fracture and increases BMD in hysterectomized postmenopausal women. Even among the women with the highest risk for fractures, when considering the effects of estrogen on other important health outcomes, a summary of the burden of monitored effects does not indicate a significant net benefit.

Disclosure of medical errors: what factors influence how patients respond?

BACKGROUND: Disclosure of medical errors is encouraged, but research on how patients respond to specific practices is limited. OBJECTIVE: This study sought to determine whether full disclosure, an existing positive physician-patient relationship, an offer to waive associated costs, and the severity of the clinical outcome influenced patients' responses to medical errors. PARTICIPANTS: Four hundred and seven health plan members participated in a randomized experiment in which they viewed video depictions of medical error and disclosure. DESIGN: Subjects were randomly assigned to experimental condition. Conditions varied in type of medication error, level of disclosure, reference to a prior positive physician-patient relationship, an offer to waive costs, and clinical outcome. MEASURES: Self-reported likelihood of changing physicians and of seeking legal advice; satisfaction, trust, and emotional response. RESULTS: Nondisclosure increased the likelihood of changing physicians, and reduced satisfaction and trust in both error conditions. Nondisclosure increased the likelihood of seeking legal advice and was associated with a more negative emotional response in the missed allergy error condition, but did not have a statistically significant impact on seeking legal advice or emotional response in the monitoring error condition. Neither the existence of a positive relationship nor an offer to waive costs had a statistically significant impact. CONCLUSIONS: This study provides evidence that full disclosure is likely to have a positive effect or no effect on how patients respond to medical errors. The clinical outcome also influences patients' responses. The impact of an existing positive physician-patient relationship, or of waiving costs associated with the error remains uncertain.

Identifying unrecognized peripheral arterial disease among asymptomatic patients in the primary care setting.

National initiatives to enhance recognition of the detrimental impact of peripheral arterial disease on the health of adult Americans have been advocated. The objective of this study was to evaluate a strategy for identifying patients with unrecognized peripheral arterial disease from among persons without known atherosclerotic disease in the primary care setting. A cross-sectional design was used. Participants were patients receiving care from a multispecialty group practice in Massachusetts between July 2002 and July 2003, with a scheduled appointment with a primary care physician. Persons 70 years of age or older who were not already known to have atherosclerotic disease were enrolled. In addition, persons aged 50-69 with a diagnosis of diabetes mellitus, dyslipidemia, hypertension, and/or smoking based on information derived from administrative databases, and not known to have atherosclerotic disease, were enrolled. Before the scheduled appointment, potential study participants completed a telephone interview to ascertain their medical history. The ankle-brachial index (ABI) of eligible patients was measured at the time of the scheduled primary care office visit. Peripheral arterial disease was diagnosed if 1 or both legs had an ABI of or=70 years, 45 (12.5%) were diagnosed with peripheral arterial disease. Nine (2.5%) of 358 subjects aged 50-69 years were diagnosed with peripheral arterial disease. The average total time (n = 52) for ABI testing was 13.7 (SD: +/-3.3) minutes. Patients aged >or=70 years required more time for ABI testing compared to those aged 50-69 (mean: 15.0 vs 13.0 minutes, p=0.04). Unrecognized asymptomatic peripheral arterial disease can be commonly detected among patients in the primary care setting who are not already known to have atherosclerotic disease. The yield from screening is substantially greater among unselected older patients compared with younger patients specifically identified as having risk factors for PAD. These findings should help inform the development and implementation of new initiatives to enhance the early detection of peripheral arterial disease among asymptomatic patients in the primary care setting.

A multi-modal intervention for Activating Patients at Risk for Osteoporosis (APROPOS): Rationale, design, and uptake of online study intervention material.

OBJECTIVE: To develop an innovative and effective educational intervention to inform patients about the need for osteoporosis treatment and to determine factors associated with its online uptake. METHODS: Postmenopausal women with a prior fracture and not currently using osteoporosis therapy were eligible to be included in the Activating Patients at Risk for OsteoPOroSis (APROPOS). Four nominal groups with a total of 18 racially/ethnically diverse women identified osteoporosis treatment barriers. We used the Information, Motivation, Behavior Skills conceptual model to develop a direct-to-patient intervention to mitigate potentially modifiable barriers to osteoporosis therapy. The intervention included videos tailored by participants' race/ethnicity and their survey responses: ranked barriers to osteoporosis treatment, deduced barriers to treatment, readiness to behavior change, and osteoporosis treatment history. Videos consisted of "storytelling" narratives, based on osteoporosis patient experiences and portrayed by actresses of patient-identified race/ethnicity. We also delivered personalized brief phone calls followed by an interactive voice-response phone messages aimed to promote uptake of the videos. RESULTS: To address the factors associated with online intervention uptake, we focused on participants assigned to the intervention arm (n = 1342). These participants were 92.9% Caucasian, with a mean (SD) age 74.9 (8.0) years and the majority (77.7%) had some college education. Preference for natural treatments was the barrier ranked #1 by most (n = 130; 27%), while concern about osteonecrosis of the jaw was the most frequently reported barrier (at any level; n = 322; 67%). Overall, 28.1% (n = 377) of participants in the intervention group accessed the videos online. After adjusting for relevant covariates, the participants who provided an email address had 6.07 (95% CI 4.53-8.14) higher adjusted odds of accessing their online videos compared to those who did not. CONCLUSION: We developed and implemented a novel tailored multi-modal intervention to improve initiation of osteoporosis therapy. An email address provided on the survey was the most important factor independently associated with accessing the intervention online. The design and uptake of this intervention may have implications for future studies in osteoporosis or other chronic diseases.

Health plan members' views on forgiving medical errors.

BACKGROUND: How patients respond to medical errors may influence how physicians approach disclosure of medical errors, but information on patients' responses is limited. Research is needed on how the circumstances that surround a medical error affect how patients respond. OBJECTIVE: To investigate whether patients' tendency to forgive a physician following a medical error varied under different circumstances. STUDY DESIGN: Cross-sectional survey. METHODS: We mailed a questionnaire to 1500 randomly selected health plan members; the response rate was 66%. Questionnaire items assessed the likelihood of forgiveness following a medical error under 12 circumstances drawn from a review of the literature. RESULTS: Respondents were most likely to forgive a physician if the patient failed to provide complete information (93% would or might forgive) and least likely to forgive if the error was due to efforts to keep costs down (11% would or might forgive). Most respondents would not forgive a physician when the physician was tired or distracted (68%), was incomplete in data collection (76%), lacked knowledge (78%), or failed to follow up (85%). Men were more likely to forgive than women; the most educated respondents were most likely to forgive. CONCLUSIONS: Our findings suggest that patients are not likely to forgive a physician in circumstances in which they suspect incompetence, inattention, or a lack of caring on the part of the physician involved. A more comprehensive understanding of forgiveness and the effect of forgiveness on the physician-patient relationship following a medical error is needed.

Health plan members' views about disclosure of medical errors.

BACKGROUND: Various authorities and national organizations encourage disclosing medical errors, but there is little information on how patients respond to disclosure. OBJECTIVE: To examine how the type of error, severity of adverse clinical outcome, and level of disclosure affect patients' responses to error and disclosure. DESIGN: Mail questionnaire survey (8 versions were developed) varying 3 factors in a completely crossed, randomized, factorial design. Each questionnaire included a vignette describing 1) a medical error (failure to check for penicillin allergy or inadequate monitoring of antiepileptic medication); 2) an associated clinical outcome (life-threatening or less serious); and 3) a physician-patient dialogue, with either full disclosure (acceptance of responsibility and an apology) or nondisclosure (expression of regret without acceptance of responsibility or an apology). SETTING: New England-based health plan. PARTICIPANTS: Random sample of 1500 adult members received the questionnaire, with a 66% response rate. MEASUREMENTS: Likelihood of changing physicians, likelihood of seeking legal advice, ratings of patient satisfaction, trust and emotional reaction in response to a vignette and dialogue, and views on medical error and disclosure. RESULTS: Full disclosure reduced the reported likelihood of changing physicians and increased patient satisfaction, trust, and positive emotional response. Full disclosure reduced the reported likelihood of seeking legal advice in only 1 error-and-outcome vignette. In the other vignettes, the percentage of patients indicating that they would seek legal advice was relatively high even with full disclosure. Almost all respondents (98.8%) wanted to be told of errors, most (83%) favored financial compensation if harm occurred, and few (12.7%) favored compensation if no harm occurred. LIMITATIONS: Since the study was done in the context of a managed care plan in one geographic area, it could not assess whether the results are generalizable to other populations. In addition, it could not determine whether responses to the simulated situations used predict responses to real situations. CONCLUSIONS: Patients will probably respond more favorably to physicians who fully disclose medical errors than to physicians who are less forthright, but the specifics of the case and the severity of the clinical outcome also affect patients' responses. In some circumstances, the desire to seek legal advice may not diminish despite full disclosure.

A demonstration of the impact of response bias on the results of patient satisfaction surveys.

OBJECTIVES: The purposes of the present study were to examine patient satisfaction survey data for evidence of response bias, and to demonstrate, using simulated data, how response bias may impact interpretation of results. DATA SOURCES: Patient satisfaction ratings of primary care providers (family practitioners and general internists) practicing in the context of a group-model health maintenance organization and simulated data generated to be comparable to the actual data. STUDY DESIGN: Correlational analysis of actual patient satisfaction data, followed by a simulation study where response bias was modeled, with comparison of results from biased and unbiased samples. PRINCIPAL FINDINGS: A positive correlation was found between mean patient satisfaction rating and response rate in the actual patient satisfaction data. Simulation results suggest response bias could lead to overestimation of patient satisfaction overall, with this effect greatest for physicians with the lowest satisfaction scores. CONCLUSIONS: Findings suggest that response bias may significantly impact the results of patient satisfaction surveys, leading to overestimation of the level of satisfaction in the patient population overall. Estimates of satisfaction may be most inflated for providers with the least satisfied patients, thereby threatening the validity of provider-level comparisons.

Effect of pegloticase on renal function in patients with chronic kidney disease: a post hoc subgroup analysis of 2 randomized, placebo-controlled, phase 3 clinical trials.

BACKGROUND: Pegloticase is approved in the US for treatment of refractory chronic gout. Since chronic kidney disease (CKD) is common in these patients, we conducted a post-hoc analysis of 2 replicate phase 3 trials and the subsequent open-label extension study to determine the effects of pegloticase on renal function in patients with CKD stages 3 and 4, as well as the effects of renal dysfunction on pegloticase efficacy and safety. FINDINGS: Patients with renal insufficiency were randomized to pegloticase 8 mg every 2 weeks (n = 42), pegloticase 8 mg every 4 weeks (n = 41), or placebo (n = 20) for 6 months as defined by the study protocols. Renal function was assessed by estimated glomerular filtration rate (eGFR). All patients completing the randomized trials could participate in an open-label extension study for a further 2.5 years. Uric acid response, the primary end point in the trials, was plasma uric acid <6.0 mg/dl for 80% of months 3 and 6.Mean eGFR in both pegloticase dosing cohorts remained constant over the randomized treatment phase and long-term open-label extension study. The number of patients achieving uric acid response was similar across CKD stages (32% stage 1, 23% stage 2, 35% stage 3, and 39% stage 4, respectively, P = 0.3). There was no difference in the pegloticase safety profile based on CKD stage. CONCLUSIONS: Pegloticase treatment does not impact eGFR in CKD patients and response to pegloticase is independent of CKD stage. TRIAL REGISTRATION: Clinical trial identifier: NCT00325195.

Tophus burden reduction with pegloticase: results from phase 3 randomized trials and open-label extension in patients with chronic gout refractory to conventional therapy.

INTRODUCTION: Two replicate randomized, placebo-controlled six-month trials (RCTs) and an open-label treatment extension (OLE) comprised the pegloticase development program in patients with gout refractory to conventional therapy. In the RCTs, approximately 40% of patients treated with the approved dose saw complete response (CR) of at least one tophus. Here we describe the temporal course of tophus resolution, total tophus burden in patients with multiple tophi, tophus size at baseline, and the relationship between tophus response and urate-lowering efficacy. METHODS: Baseline subcutaneous tophi were analyzed quantitatively using computer-assisted digital images in patients receiving pegloticase (8 mg biweekly or monthly) or placebo in the RCTs, and pegloticase in the OLE. Tophus response, a secondary endpoint in the trials, was evaluated two ways. Overall tophus CR was the proportion of patients achieving a best response of CR (without any new/enlarging tophi) and target tophus complete response (TT-CR) was the proportion of all tophi with CR. RESULTS: Among 212 patients randomized in the RCTs, 155 (73%) had ≥ 1 tophus and 547 visible tophi were recorded at baseline. Overall tophus CR was recorded in 45% of patients in the biweekly group (P = 0.002 versus placebo), 26% in the monthly group, and 8% in the placebo group after six months of RCT therapy. TT-CR rates at six months were 28%, 19%, and 2% of tophi, respectively. Patients meeting the primary endpoint of sustained urate-lowering response to therapy (responders) were more likely than nonresponders to have an overall tophus CR at six months (54% vs 20%, respectively and 8% with placebo). CONCLUSIONS: Pegloticase reduced tophus burden in patients with refractory tophaceous gout, especially those achieving sustained urate-lowering. Complete resolution of tophi occurred in some patients by 13 weeks and in others with longer-term therapy. TRIAL REGISTRATIONS: NCT00325195, NCT01356498.

Identifying patients with osteoporosis or at risk for osteoporotic fractures.

OBJECTIVES: To test the validity of using administrative data to identify patients with osteoporosis or low bone mineral density (BMD) and high risk for osteoporotic fractures. STUDY DESIGN: We conducted a retrospective cohort study. METHODS: We analyzed data from a managed care plan in Massachusetts. We developed 6 case-identification algorithms based on number of osteoporosis (OP) diagnoses, clinical setting of the OP diagnosis, timing of the OP diagnosis relative to BMD test, and clinical fracture risk factors adapted from the World Health Organization Fracture Risk Assessment Tool. We validated the algorithms against BMD results and calculated sensitivity, specificity, and positive predictive value (PPV) against 2 diagnostic criteria (T-score ≤--2.5 and T-score ≤--2.0). RESULTS: When compared against the first criterion (T-score ≤--2.5), the sensitivity of algorithm (35% to 80%), specificity (65% to 93%), PPV (44% to 63%), and adding fracture risk factors did not improve case identification. When compared against the expanded criterion (T-score ≤--2.0), we found the sensitivity of the algorithms ranged from 23% to 63%, specificity from 72% to 95%, and PPV from 67% to 83%. Including fracture risk in the expanded OP criterion improved case identification, and the algorithms achieved the highest PPV: 70% to 85%. CONCLUSIONS: Identifying patients with OP or low BMD and high risk for osteoporotic fractures is possible in administrative data if using information about both OP diagnoses and fracture risk profile.

Serum procalcitonin in systemic autoimmune diseases--where are we now?

OBJECTIVES: To review the current evidence regarding the value of measuring procalcitonin (PCT) levels in patients with systemic autoimmune diseases, with a focus on the evidence for diagnostic and analytical performance of this biomarker. A brief description of the pathophysiological basis of this biomarker is also included. METHODS: Using PubMed from the National Library of Medicine, relevant English literature on PCT in patients with different systemic autoimmune diseases, from 1990 to 2009, was reviewed. The search used keywords referring to procalcitonin and systemic lupus erythematosus, antineutrophil cytoplasmic antibody-associated systemic vasculitis, Goodpasture syndrome, rheumatoid arthritis, and giant cell arteritis. RESULTS: When used in the appropriate clinical setting, the measurement of serum PCT levels is valuable as a marker of severe systemic bacterial and fungal infections and sepsis. Information regarding plasma PCT levels in patients with active underlying systemic autoimmune diseases is limited, primarily from observational studies and case series, with considerable variability of patient characteristics and clinical settings. In the detection of systemic infection concomitant with autoimmune diseases, PCT had a diagnostic sensitivity of 53 to 100% and a specificity of 84 to 97% (depending on the selection criteria) and was superior to other inflammatory markers tested. Most of the studies used a semiquantitative test for PCT measurement (functional assay sensitivity <0.5 ng/mL), which can explain the low sensitivity of the test. PCT levels were not significantly affected by renal function abnormalities or immunosuppressive agents. Although high PCT levels commonly occurred with infection, elevated levels of PCT could be found in patients with vasculitis without evidence of infection, often correlated with high disease activity scores. CONCLUSIONS: Significantly elevated PCT levels offer good specificity and sensitivity for systemic infection in patients with systemic autoimmune diseases, regardless of the use of corticosteroids or immunosuppressive agents. PCT measurement may add to diagnostic accuracy in patients with systemic autoimmune diseases who present with a febrile illness, especially when highly sensitive PCT assays and specific PCT cutoff ranges are used in a predefined clinical setting (reflecting the likelihood of infection versus an autoimmune disease flare). However, there are limitations when using this biomarker in patients with systemic autoimmune diseases. PCT levels should not replace the necessary extensive diagnostic workup, which should include a thorough history and physical examination, combined with appropriate immunological, microbiological, radiological, and histological data.