Using Vignettes to Compare the Quality of Clinical Care Variation in Economically Divergent Countries

Objective. To determine whether clinical vignettes can measure variations in the quality of clinical care in two economically divergent countries.
Data Source/Study Setting. Primary data collected between February 1997 and February 1998 at two Veterans Affairs facilities in the United States and four government-run outpatient facilities in Macedonia.
Study Design. Randomly selected, eligible Macedonian and U.S. physicians (>97 percent participation rate) completed vignettes for four common outpatient conditions. Responses were judged against a master list of explicit quality criteria and scored as percent correct.
Data Collection/ Extraction. An ANOVA model and two-tailed t-tests were used to compare overall scores by case, study site, and country.
Principal Findings. The mean score for U.S. physicians was 67 percent (+/−11 percent) compared to 48 percent (+/−11 percent) for Macedonian physicians. The quality of clinical practice, which emphasizes basic skills, varied greatly in both sites, but more so in Macedonia. However, the top Macedonian physicians in all sites approached or—in one case—exceeded the median score in the U.S. sites.
Conclusions. Vignettes are a useful method for making cross-national comparisons of the quality of care provided in very different settings. The vignette measurements revealed that some physicians in Macedonia performed at a standard comparable to that of their counterparts in the United States, despite the disparity of the two health systems. We infer that in poorer countries, policy that promotes improvements in the quality of clinical practice—not just structural inputs—could lead to rapid improvements in health.     

Epidemic parenteral exposure to volatile sulfur-containing compounds at a hemodialysis center.

OBJECTIVE: To determine the cause of acute illness on August 30, 2000, among patients at an outpatient dialysis center (center A). DESIGN: We performed a cohort study of all patients receiving dialysis on August 30, 2000; reviewed dialysis procedures; and analyzed dialysis water samples using microbiologic and chemical assays. SETTING: Dialysis center (center A). PATIENTS: A case-patient was defined as a patient who developed chills within 5 hours after starting hemodialysis at center A on August 30, 2000. RESULTS: Sixteen (36%) of 44 patients at center A met the case definition. All case-patients were hospitalized; 2 died. Besides chills, 15 (94%) of the case-patients experienced nausea; 12 (75%), vomiting; and 4 (25%), fever. Illness was more frequent on the second than the first dialysis shift (16 of 20 vs 0 of 24, P < .001); no other risk factors were identified. The center's water treatment system had received inadequate maintenance and disinfection and a sulfurous odor was noted during sampling of the water from the reverse osmosis (RO) unit. The water had elevated bacterial counts. Volatile sulfur-containing compounds (ie, methanethiol, carbon disulfide, dimethyldisulfide, and sulfur dioxide) were detected by gas chromatography and mass spectrometry in 8 of 12 water samples from the RO unit and in 0 of 28 samples from other areas (P < .001). Results of tests for heavy metals and chloramines were within normal limits. CONCLUSIONS: Parenteral exposure to volatile sulfur-containing compounds, produced under anaerobic conditions in the RO unit, could have caused the outbreak. This investigation demonstrates the importance of appropriate disinfection and maintenance of water treatment systems in hemodialysis centers.     

Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer.

PURPOSE: We determined the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLT) of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when infused on days 1, 8, and 15 of a 28-day cycle in advanced solid tumor patients. We also characterized the pharmacokinetics of 17-AAG, its effect on chaperone and client proteins, and whether cytochrome P450 (CYP) 3A5 and NAD(P)H:quinone oxidoreductase 1 (NQO1) polymorphisms affected 17-AAG disposition or toxicity. PATIENTS AND METHODS: An accelerated titration design was used. Biomarkers were measured in peripheral-blood mononuclear cells (PBMCs) at baseline and on days 1 and 15, and pharmacokinetic analysis was performed on day 1 of cycle 1. CYP3A5*3 and NQO1*2 genotypes were determined and correlated with pharmacokinetics and toxicity. RESULTS: Twenty-one patients received 52 courses at 11 dose levels. DLTs at 431 mg/m(2) were grade 3 bilirubin (n = 1), AST (n = 1), anemia (n = 1), nausea (n = 1), vomiting (n = 1), and myalgias (n = 1). No tumor responses were seen. 17-AAG consistently increased heat shock protein (Hsp) 70 levels in PBMCs. At the MTD, the clearance and half-life (t(1/2)) of 17-AAG were 11.6 L/h/m(2) and 4.15 hours, respectively; whereas the active metabolite 17-aminogeldanamycin had a t(1/2) of 7.63 hours. The CYP3A5*3 and NQO1*2 polymorphisms were not associated with 17-AAG toxicity. The CYP3A5*3 polymorphism was associated with higher 17-AAG clearance. CONCLUSION: The MTD of weekly 17-AAG is 308 mg/m(2). 17-AAG induced Hsp70 in PBMCs, indicating that Hsp90 has been affected. Further evaluation of 17-AAG is ongoing using a twice-weekly regimen, and this schedule of 17-AAG is being tested in combination with chemotherapy.     

The cyclin-dependent kinase inhibitor UCN-01 plus cisplatin in advanced solid tumors: a California cancer consortium phase I pharmacokinetic and molecular correlative trial.

BACKGROUND: UCN-01 (7-hydroxy-staurosporine) is a novel antineoplastic agent targeting cyclin-dependent kinases, which shows potent in vitro and in vivo activity against a broad range of tumor types. Our group has previously shown that UCN-01 potentiates the apoptotic response of agents such as cisplatin in vitro by preventing sequence-specific abrogation of G2 arrest caused by DNA-damaging chemotherapies. PATIENTS AND METHODS: This National Cancer Institute-sponsored phase I trial was designed to determine the safety, maximum tolerated dose, and pharmacokinetics of escalating doses of cisplatin in combination with UCN-01 in patients with advanced malignant solid tumors, as well as to do molecular correlative studies on tumor specimens. Cisplatin was infused over 1 hour before UCN-01 (45 mg/m2/d) given as a 72-hour continuous infusion. Escalation of cisplatin was planned through five dose levels at 20, 30, 45, 60, and 75 mg/m2. RESULTS: Ten patients were accrued. Accrual was halted at dose level 2 (cisplatin, 30 mg/m2) due to dose-limiting toxicities consisting of grade 5 sepsis with respiratory failure associated with grade 3 creatinine (one patient) and grade 3 atrial fibrillation (one patient). Plasma and salivary pharmacokinetics of UCN-01 were unaffected by cisplatin. Pretreatment and posttreatment tumor biopsies showed that UCN-01 was active against a key molecular target, the checkpoint kinase Chk1.CONCLUSIONS: This phase I trial failed to achieve targeted therapeutic dose levels of cisplatin when combined with prolonged infusion UCN-01. However, because preclinical data indicate that UCN-01 potentiates response to platinum, further studies with alternative dose schedules of the combination, or with other platinum analogues, are warranted.     

Phase III, randomized, double-blind study of epoetin alfa compared with placebo in anemic patients receiving chemotherapy.

PURPOSE: To determine whether weekly epoetin alfa could improve hemoglobin (HgB) levels, reduce RBC transfusions, and improve quality of life (QOL) in patients with advanced cancer and with anemia after receiving myelosuppressive chemotherapy. PATIENTS AND METHODS: This double-blind, placebo-controlled study randomly assigned patients to placebo or epoetin alfa (Ortho Biotech, Bridgewater, NJ) 40,000 U subcutaneous weekly for 16 weeks. QOL, HgB, and RBC transfusions were measured pretreatment and monthly. RESULTS: The study accrued 344 patients; 330 were assessable for efficacy and 305 were assessable for QOL. Placebo-treated patients had a mean increase in HgB of 0.9 g/dL (range, -3.8 to +5.3) compared with 2.8 g/dL (range, -2.2 to +7.5) for epoetin-treated patients (P < .0001). During the study, 31.7% of placebo-treated patients achieved a > or = 2 g/dL HgB increase compared with 72.7% of epoetin-treated patients (P < .0001). The incidence of RBC transfusion for placebo and epoetin treatment arms was 39.6% and 25.3% (P = .005), respectively. The placebo group received 256 units of RBCs compared with 127 units in the epoetin group (P < .0001). The incidence of toxicity in the groups was similar. Changes in the average QOL scores from baseline to the end of the study were similar in the two groups (P = not significant). The HgB responders (irrespective of treatment arm) had a mean change in Functional Assessment of Cancer Therapy (FACT) fatigue score from a baseline of +5.1 compared with -2.1 for the nonresponders (P = .006). CONCLUSION: Epoetin alfa significantly improved HgB and reduced transfusions in this patient population. These results support the use of weekly epoetin alfa as an ameliorative agent for cancer-related anemia.     

Phase I and pharmacologic study of infusional topotecan and Carboplatin in relapsed and refractory acute leukemia.

PURPOSE: To assess the maximum tolerated dose, toxicities, pharmacokinetics, and antileukemic activity of topotecan and carboplatin in adults with recurrent or refractory acute leukemias. EXPERIMENTAL DESIGN: Patients received topotecan and carboplatin by 5-day continuous infusion at nine dose levels. Patients achieving a complete remission received up to two additional courses for consolidation. Plasma topotecan and ultrafilterable platinum were assayed on days 1 to 5. In addition, pretreatment levels of various polypeptides in leukemic cells were examined by immunoblotting to assess possible correlations with response. RESULTS: Fifty-one patients received a total of 69 courses of therapy. Dose-limiting toxicity consisted of grade 4/5 typhlitis and grade 3/4 mucositis after one course of therapy or grade 4 neutropenia and thrombocytopenia lasting >50 days when a second course was administered on day 21. Among 45 evaluable patients, there were 7 complete remissions, 2 partial remissions, 1 incomplete complete remission, and 1 reversion to chronic-phase chronic myelogenous leukemia. Topotecan steady-state plasma concentrations increased with dose. No accumulation of topotecan or ultrafilterable platinum occurred between days 1 and 5 of therapy. Leukemic cell levels of topoisomerase I, checkpoint kinase 1, checkpoint kinase 2, and Mcl-1 correlated with proliferating cell nuclear antigen but not with response. In contrast, low Bcl-2 expression correlated with response (P = 0.014, Mann-Whitney U test). CONCLUSIONS: The maximum tolerated dose was 1.6 mg/m(2)/d topotecan plus 150 mg/m(2)/d carboplatin. The complete remission rate in a heavily pretreated population was 16% (33% at the highest three dose levels). Responses seem to correlate with low pretreatment blast cell Bcl-2 expression.     

PREFERENCES FOR THE NORMATIVE BASIS OF HEALTH CARE PRIORITY SETTING: SOME EVIDENCE FROM TWO COUNTRIES

The present paper concerns the criteria people would prefer for prioritising health programmes. It differs from most empirical studies as subjects were not asked about their personal preferences for programmes per se. Rather, they were asked about the principles that should guide the choice of programmes. Four different principles were framed as arguments for alternative programmes. The results from population surveys in Australia and Norway suggest that people are least supportive of the principle that decision makers should follow the stated preferences of the public. Rather, respondents expressed more support for decisions based upon health maximisation, equality and urgency. Copyright © 2012 John Wiley & Sons, Ltd.     

TD-1792 versus Vancomycin for Treatment of Complicated Skin and Skin Structure Infections

TD-1792 is a first-in-class glycopeptide-cephalosporin heterodimer that exhibits bactericidal activity against Gram-positive pathogens. We conducted a randomized, double-blind, active-control, phase II trial in patients with complicated skin and skin structure infections caused by suspected or confirmed Gram-positive organisms. Patients 18 to 65 years old were randomized to receive 7 to 14 days of either TD-1792 (2 mg/kg of body weight intravenously [i.v.] every 24 h [q24h]) or vancomycin (1 g i.v. q12h, with dosage regimens adjusted per site-specific procedures). A total of 197 patients were randomized and received at least one dose of study medication. Rates of clinical success at the test-of-cure evaluation were similar in all analysis populations. Among 170 clinically evaluable patients, cure rates were 91.7% and 90.7% in the TD-1792 and vancomycin groups, respectively (95% confidence interval [CI] of −7.9 to 9.7 for the difference). In microbiologically evaluable patients with methicillin-resistant Staphylococcus aureus at baseline (n = 75), cure rates were 94.7% in the TD-1792 group and 91.9% in the vancomycin group. Microbiological eradication of Gram-positive pathogens (n = 126) was achieved in 93.7% and 92.1% of patients in the TD-1792 and vancomycin groups, respectively. Seven patients were discontinued from study medication due to an adverse event (AE): 2 and 5 in the TD-1792 and vancomycin groups, respectively. AEs were of similar types and severities between the two groups, other than pruritus, which was more common in patients who received vancomycin. No patients in the TD-1792 group experienced a serious AE. This study supports further clinical development of TD-1792 in patients with Gram-positive infection.