A comparative study of chronic spontaneous urticaria and chronic mast cell mediated angioedema.

Background: Mast cell-mediated angioedema (MC-AE) is considered a form of chronic spontaneous urticaria (CSU). Objective: To investigate the clinical and laboratory features that distinguish MC-AE from antihistamine-responsive CSU (CSU), and antihistamine-resistant CSU (R-CSU) with and without concomitant AE. Methods: A retrospective observational study using the electronic patient record data base of patients with MC-AE, CSU, R-CSU, and sex- and age-matched control group (control), with a case-control ratio of 1:2. Results: A total of 986 subjects in the CSU group, 148 in the R-CSU group, 64 in the MC-AE group, and 1198 in the control group were compared. The R-CSU group without AE was characterized by lower total IgE levels (118.5 ± 84.7 IU/mL) and higher High sensitivity-C reactive protein (hs-CRP) levels (138.9 ± 94.2 IU/mL, p = 0.027; and 7.4 ± 6.9 mg/L versus 5.1 ± 6.8 mg/L, p = 0.001) than the CSU without AE group. The R-CSU group with AE was characterized by lower total IgE levels (112.1 ± 81.3 IU/mL) than the CSU group with AE (141.7 ± 89.5 IU/mL; p < 0.001), higher hs-CRP levels (7.1 ± 6.1 mg/L versus 4.7 ± 5.9 mg/L; p < 0.001). There were fewer female subjects in the MC-AE group (31 [48.4%]) than in the CSU with AE and in the R-CSU with AE 223 (67.8%) and 18 (66.7%), respectively; p = 0.012). MC-AE group was characterized by less eyelid/perioral/facial involvement and more limb involvement than in the CSU with AE and R-CSU with AE groups (p < 0.001). Conclusion: Low IgE in MC-AE and higher IgE in CSU may signify two distinct types of immune dysregulation. Due to clinical and laboratory differences between MC-AE and CSU, we suggest questioning the assumption that MC-AE is a form of CSU.

[CHEMOTHERAPY FOR CANCER PATIENTS - ARE WE CHOOSING WISELY?]

INTRODUCTION: The American Society of Clinical Oncology has identified non-evidence-based chemotherapy as one of the 10 most prevalent examples of futile care and has identified chemotherapy at the last month of life as a quality indicator of oncology practice. OBJECTIVES: To characterize chemotherapy treatment and the use of palliative and other healthcare services during the last year of life among cancer patients in an Israeli Health Maintenance Organization (HMO). METHODS: A cross-sectional study was conducted of members of Leumit Health Services (LHS) who died of cancer between 2009 and 2013. Data captured from LHS databases included: diagnosis, target drugs prescribed, health services utilization, and demographic data. Patients were stratified by time that elapsed between their last chemotherapy treatment and the date of death. The groups were compared in terms of demographics, morbidity, health services utilization and palliative care referrals over the six months prior to death. RESULTS: The study included 2,617 patients who received chemotherapy during their last year of life. Of these patients, 18.8% received chemotherapy 0-14 days prior to death. Palliative care referrals were less frequent among patients who received their last chemotherapy treatment during the 14 days prior to death (15.8%) and highest among patients who received their last chemotherapy treatment ≥180 days prior to death (31.9%: P<0.0001(. CONCLUSIONS: Survival and the probability of administering palliative care at the end of life are inversely associated with the probability of administering chemotherapy. DISCUSSION: Efforts should be made to increase awareness amongst oncologists that aggressive treatment during the last weeks of life may be futile.

Hematologic parameters as biomarkers for antihistamine and omalizumab resistance in chronic spontaneous urticaria.

Background: Biomarkers of resistance to H1-antihistamines (AH) and omalizumab in chronic spontaneous urticaria (CSU) are still a matter of debate. Objective: To identify clinical and laboratory attributes of the patient that may be predictive of AH and omalizumab resistance in CSU. Methods: We conducted a retrospective observational study by using the electronic patient record data base of patients with CSU and of sex- and age-matched controls. Patients with CSU were divided into three study groups: the CSU group, patients who responded to AHs; the antihistamine-resistant CSU (AH-CSU) group, patients refractory to a fourfold AH dose; and the control group, composed of a random sample of age- and sex-matched subjects, with a case-control ratio of 1:2. The patients in the AH-CSU group treated with omalizumab were compared according to the response or resistance to omalizumab. Results: A total of 106 subjects in the AH-CSU group, 483 in the CSU group, and 1198 in the control group were compared. Both AH-CSU (112.7 ± 43.1 kU/mL) and CSU (129.5 ± 52.4 kU/mL) groups were associated with higher plasma total IgE levels than control group (103.2 ± 49.5 kU/mL; p < 0.001). The AH-CSU group was characterized by a higher plasma high-sensitivity C-reactive protein level (6.4 ± 3.7 mg/L) than the CSU group (4.3 ± 1.4 mg/L; p < 0.001) and the control group (3.1 ± 1.8 mg/L; p < 0.001). The AH-CSU and CSU groups were characterized by a lower mean ± standard deviation basophil counts (0.18 ± 0.16 cells ×109/L and 0.19 ± 0.11 cells ×109/L, respectively) than the control group (0.22 ± 0.09 cells ×109/L; p < 0.001). The mean platelet volume was higher in the AH-CSU group (11.2 ± 0.3 fL) than in the CSU group (11.1 ± 0.4 fL; p = 0.002) and in the control group (10.3 ± 0.4 fL; p < 0.001). There were no significant differences in the mean levels of lymphocytes, monocytes, eosinophils, basophils, and platelets, and the rates of eosinopenia and basopenia between the patients in the AH-CSU group who responded to and those who were resistant to omalizumab. Conclusion: This study provided additional data of interest to examine the pathophysiologic role of low-grade inflammation and basopenia in patients with CSU and resistant to AHs and omalizumab.

Factors related to omalizumab resistance in chronic spontaneous urticaria.

Background: Omalizumab resistance (OmR) in chronic spontaneous urticaria (CSU) remains poorly understood. Objective: To identify clinical and laboratory attributes of patients that may be predictive of OmR in CSU. Methods: We conducted a retrospective observational study by using an electronic patient record data base of patients with severe CSU refractory to a fourfold H1-antihistamine dose, treated with omalizumab 300 mg every 4 weeks for at least 24 weeks. Complete response (CR) was defined as the reduction of baseline urticaria activity score by ≥ 90%, partial response (PR) by ≥ 30% to <90%, and OmR by <30% at 24 weeks. The patient characteristics of the CR, PR, and OmR groups were compared. Results: Sixty-three patients (58.9%) had a complete remission at 24 weeks of omalizumab therapy, and 16 patients (14.9%) had OmR. The patients who were OmR were characterized by a higher rate of arterial hypertension 7 (43.8%), higher mean ± standard deviation (SD) high-sensitivity C-reactive protein (hs-CRP) level (10.3 ± 8.2 mg/L), mean ± SD white blood cell (WBC) count (9.1 ± 2.8 × 10³ cells/mL), and higher mean ± SD C3 level (164.3 ± 45.4 mg/dL) at baseline than the patients with CR (arterial hypertension, 9 [13.1%], p = 0.009; mean ± SD hs-CRP, 3.4 ± 10.1, p = 0.014; mean ± SD WBC count, 6.5 ± 3.8 × 10³ cells/mL, p = 0.012; and mean ± SD C3 level, 121.8 ± 42.1 m/dL, p < 0.001). In multivariable analysis adjusted for age, sex, and body mass index, OmR was associated with an hs-CRP level of >3.0 mg/L (odds ratio 1.94 [95% confidence interval, 1.28-3.15], p = 0.009) and with C3 > 160 mg/dL (odds ratio 1.54 [95% confidence interval, 1.05-2.36], p = .017). Conclusion: Obesity, arterial hypertension, high plasma C3 level, and high-CRP level were associated with OmR in severe CSU.

Association of alopecia areata with atopic dermatitis and chronic spontaneous urticaria.

BACKGROUND: Epidemiologic studies report that alopecia areata (AA) is related to various atopic and autoimmune diseases. The purpose of this study was to identify clinical characteristics and the prevalence of comorbid conditions in Israeli patients with AA. METHODS: This retrospective, matched, case-control study was based on data from an electronic patient record data base. The patients with an electronically documented diagnosis of AA were included in the AA group. The control group was randomly sampled from the remaining subjects, with a case-to-control ratio of two controls for each case. Comorbidity was compared between the study groups. RESULTS: A total of 1751 subjects (49.4% men and 50.6% women), ages 34.9 ± 17.8 years old, were identified. The control group consisted of 3502 age- and sex-matched subjects. The AA group was characterized by a higher blood eosinophil count (0.39 ± 0.12 cells/mm3) than the control group (0.31 ± 0.14 cells/mm3; p < 0.001). In the AA group, there was a higher prevalence of allergic rhinitis (odds ratio [OR] 2.15 [1.85-2.49]; p < 0.001), asthma (OR 1.57 [1.28-1.93]; p < 0.001), atopic dermatitis (AD) (OR 4.17 [3.18-5.47]; p < 0.001), and food allergy (OR 2.79 [1.58-4.91]; p < 0.001) than in the control group. The prevalence of organ-specific and systemic autoimmune diseases was significantly higher in the AA group than in the control group, with the OR of having any autoimmune disease calculated to be 4.72 (3.99-5.57; p < 0.001). The OR of having chronic spontaneous urticaria (CSU) with AA was 6.15 (4.06-9.32; p < 0.001). In patients with concomitant AA and CSU, allergic rhinitis and AD were more prevalent than in patients with CSU in the control group. CONCLUSION: An estimated prevalence of AA among an Israeli population was ∼0.8%. The novel finding of our study was the high prevalence of food allergy and CSU in patients with AA.

No apparent association between bipolar disorder and cancer in a large epidemiological study of outpatients in a managed care population.

An association between bipolar disorder (BD) and cancer risk has been reported. The purpose of this study was to investigate this association through linkage analysis of a national HMO database and a national cancer registry. All members of the Leumit Health Services (LHS) HMO of Israel from 2000 to 2012 were included. Members with a recorded diagnosis of BD and a record of at least one written or dispensed prescription for pharmacotherapy for treatment of BD were classified as patients with BD. We linked the LHS population with the Israel National Cancer Registry database to capture all cases of cancer reported. Standardized incidence ratios (SIRs) for cancer in the BD population as compared with non-BD LHS members were calculated. A total of 870 323 LHS members were included in the analysis; 3304 of whom met the criteria for inclusion in the BD arm. We identified 24 515 and 110 cancer cases among members without BD and with BD, respectively. Persons with BD were no more likely than other HMO members to be diagnosed with cancer during the follow-up period [SIR, males=0.91, 95% confidence interval (CI): 0.66-1.22; SIR, females=1.15, 95% CI: 0.89-1.47]. Sensitivity analysis using different criteria for positive BD classification (lithium treatment alone or registered physician diagnosis) had no effect on the estimate of cancer risk. A nonstatistically significant association between breast cancer and BD among women was observed (SIR=1.24, 95% CI: 0.79-1.86). These findings do not corroborate previously reported associations between BD and elevated cancer risk.

Prevalence of dermatologic diseases among patients with selective immunoglobulin A deficiency.

BACKGROUND: There are no published large-scale epidemiologic studies regarding the prevalence of skin diseases in patients with selective immunoglobulin A (IgA) deficiency (sIgAD). The purpose of this study was to investigate the prevalence of dermatological diseases in patients with sIgAD. METHODS: This retrospective matched case-control study was based on data from the Leumit Healthcare Services data base (approximately 725,000 residents of Israel), which was searched for all subjects aged ≥12 years who had undergone serum total IgA measurements during 2004-14 for any reason. The case group included subjects with sIgAD. The control A group was randomly sampled from those subjects in whom an IgA was drawn (n ≈ 725,000), with a ratio of 10 controls for every case (1:10). The control A group was randomly sampled from those subjects in whom an IgA was drawn (n = 104,729) and the control B group was randomly sampled from the full study population (n ≈ 725,000), with a ratio of 10 controls for every case (1:10). Comorbidity was compared between the study groups. RESULTS: The sIgAD group was characterized: 1) By a higher prevalence of atopic dermatitis (AD) (16 [4.6 %]) than the control A group (76 [2.1 %]; p = 0.004 and the control B group (64 [1.9 %]; p = 0.002). 2) By higher prevalence of acne (69 [19.9 %]) than the control A group (516 [13.8 %]; p = 0.013) and control B group (494 [14.2 %]; p < 0.001). 3) By higher rate of chronic spontaneous urticaria (CSU) (17 [4.9 %)] than in the control A group (31 [0.9 %], with odds ratio 5.54 [3.04-10.13]; p < 0.001) and the control B group (28 [0.8 %]; p < 0.001). CONCLUSIONS: sIgAD is characterized by a higher prevalence of AD, CSU and acne.

Revealed Opportunism: How Physicians "Game" Prior Authorization Protocols Until They Are Rescinded.

BACKGROUND: Prior authorization (PA) is a management technique that has been implemented to manage the utilization of expensive drugs and to improve the precision of drug prescribing. PA requirements may incentivize physicians to document adverse effects, sometimes falsely, to meet the eligibility requirements. OBJECTIVES: To identify documentation patterns that may facilitate the quantitative analysis of physician gaming and underreporting behaviors associated with the prescribing of angiotensin-converting enzyme (ACE) inhibitors in a primary care setting, and to evaluate the effect of a PA requirement on the documentation of adverse events as a way to receive approval for more expensive drugs. METHODS: We conducted a retrospective analysis of physician electronic reporting of adverse effects associated with ACE inhibitors before and after the revocation of a PA requirement for angiotensin receptor blockers (ARBs) between 2004 and 2013 in an Israeli HMO. The data were stratified into 2 groups-patients who were newly prescribed an ACE inhibitor or those who had been receiving an ACE inhibitor for at least 1 year. The annual rate of adverse events related to ACE inhibitors (ie, the number of reported cases of adverse events per 1000 patients receiving an ACE inhibitor) was calculated from data captured on the date the events were first reported for the 5 years before and 5 years after the revocation of the PA constraint. RESULTS: A total of 151,845 patients treated with ACE inhibitors were identified during the 10-year study period. The reported adverse events among patients newly treated with an ACE inhibitor peaked in 2007 to 10 cases per 1000 patients, and gradually decreased to 4.6 cases in 2012, which was the year after the PA requirements for the ARBs valsartan and candesartan were rescinded by the HMO. Among previously treated patients, adverse events rates decreased from a high of 5.4 per 1000 patients in 2008 to 1.9 in 1000 patients in 2012, the year after the PA restraints for the last 2 ARBs with a requirement were revoked. CONCLUSIONS: The PA requirement influenced physician propensity for reporting drug side effects, possibly encouraging reporting inaccuracies. The decline in the incidence of reported side effects, in both subpopulations in the study, with the revocation of the PA requirement confirms our hypothesis that physicians were incentivized to document the side effects related to ACE inhibitors to meet the eligibility requirements for the approval of an ARB by the HMO.

Clinical-laboratory characteristics of ANA-positive chronic idiopathic urticaria.

Despite the established association between chronic idiopathic/spontaneous urticaria (CIU) and presence of antinuclear antibodies (ANAs), the prevalence of autoimmune comorbidities in this population has not been analyzed. Here, we aim to identify clinical and laboratory manifestations associated with ANA-positive CIU. ANA-positive patients were identified via electronic data capture from the electronic patient record database of Leumit Health care Services (LHS) of Israel. Patient characteristics, medical histories, and details of diagnostic workup, medical treatment, and follow-up were retrieved by performing a chart review of electronic patient records (EPRs). The prevalence of target diseases among ANA(+) CIU(+), ANA(+) CIU(-), and ANA(-) CIU(+) patients was calculated. A total of 91 ANA(+) CIU(+), 3131 ANA(+) CIU(-), and 478 ANA(-) CIU(+) patients were identified. The ANA(+) CIU(+) group was characterized by higher prevalence of Sjögren's syndrome (SS)-A 52 antibodies (Ab) (7.7% versus 2.4%; p = 0.008), SS-A 60 Ab (11% versus 2.8%; p = < 0.001), and SS-B Ab (14.3% versus 3.2%; p < 0.001), compared with ANA(-) CIU(+) group. Additionally, ANA(+) CIU(+) patients were more likely to be diagnosed with thyroid autoimmune diseases, higher C-reactive protein (6.4 ± 10.3 versus 4.1 ± 8.8 mg/L; p = 0.027), and more profound basopenia (0.04 ± 0.09 versus 0.15 ± 0.11 cell/mm(3); p < 0.001) than ANA(-) CIU patients. More ANA(+) CIU(+) patients were resistant to four-fold standard licensed doses of antihistamines than ANA(-) CIU(+) patients [11 (12.1%) versus 29 (6.1%); p = 0.046]. ANA-positive CIU is characterized by higher prevalence of SS-A 52, SS-A 60, and SS-B antibodies and poorer clinical response to antihistamine medications.

A natural experiment in mass media modulated pharmacokinetics after a change in tablet formulation.

BACKGROUND: After a new formulation of levothyroxine was distributed in Israel, side effects were reported to the Ministry of Health generating extensive media coverage. The purpose of this study was to determine whether the new formulation was associated with a change in thyroid-stimulating hormone (TSH) levels of treated patients and to evaluate the effect of the extensive media coverage on the incidence of laboratory test performance. STUDY DESIGN: Retrospective-cohort and crosssectional analysis. METHODS: All patients from the Leumit Health Services of Israel treated with levothyroxine between October 2009 and February 2012 were included in the study. A retrospective cohort was constructed of patients treated and maintained within the desired target range (0.35-5 mIU/L) from January to July 2010. A longitudinal analysis was conducted to calculate the monthly distribution of TSH levels from laboratory tests during routine care over 26 months. Data were stratified by cohort and noncohort patients. RESULTS: Data were captured for 18,106 levothyroxine-treated patients; 1140 were included into the retrospective cohort. In both subpopulations a sharp rise in the number of tests performed monthly is observed at the peak of media coverage during October and November 2011. In the retrospective cohort the proportion of TSH results within target range fell to a low of 67.5% during December 2011, with 25.3% between 5.01 and 20 mIU/L. Results>20 mIU/L then peaked at 3.8% indicating an increase in patients who stopped taking levothyroxine. CONCLUSIONS: These results demonstrate the power of mass media to influence patient behavior and to foment a public health scare.

Modifying prescribing behaviour of angiotensin receptor blockers by selectively rescinding managerial prior authorization requirements for losartan.

AIMS: To evaluate whether rescinding the prior authorization (PA) requirement (managerial pre-approval) for losartan in an health maintenance organization (HMO) could reduce prescribing of the more expensive angiotensin receptor blockers (ARBs). METHODS: HMO physicians were notified that losartan would no longer require PA, and appropriate changes were made to the electronic prescribing computer program. The monthly distribution by drug of the number of prescriptions for ARBs dispensed for new patients was calculated before and after the policy change from data captured from electronic records. The proportion of patients (percentage and 95% confidence interval) treated with losartan who met the criteria for treatment with ARBs (hypertension or cardiac insufficiency in patients who have developed adverse effects in response to angiotensin-converting enzyme inhibitors or macroproteinuria) during the first month after the PA requirement was rescinded was calculated. RESULTS: The total number of PA requests for ARBs declined by 48.6% from 961 in December 2008, the month before the policy change, to 494 the following January, rising again to 651 during January 2010. Prescription incidence changed from 121 to 255 patients treated per month (114% increase) for losartan, from 15 to 16 (6.7% increase) for candesartan, and from 89 to 71 (20.2% decrease) for valsartan. The duration of effect for decrease in ARB requests for the more expensive drugs was approximately 1 year. Only 23.3% (95% confidence interval 18.1-28.4) of patients receiving losartan met the criteria for receiving ARBs. CONCLUSIONS: Rescinding the PA requirement for this drug alone was an effective limited-duration strategy for reduction of prescription of relatively expensive drugs.

Drug use evaluation of tamoxifen focusing on off-label use in a managed care population in Israel.

BACKGROUND: Policy development to manage new off-label uses of medications is an issue relevant to health policy stakeholders internationally. Retrospective drug utilization analyses may be useful to identify practice trends in the use of drugs for unapproved (off-label) uses. Since drug use evaluations (DUE) are generally performed for expensive medications or when safety concerns warrant increased scrutiny, patterns of off-label use of inexpensive drugs will probably be undetected. Tamoxifen citrate, an estrogen receptor antagonist, is indicated in Israel exclusively for palliative [sic: meaning adjuvant] treatment of breast cancer. This DUE was motivated by observations that tamoxifen may be used off-label for indications without evidence of safety or efficacy. OBJECTIVES: To assess the extent of off-label prescribing of tamoxifen and ascertain what evidence is available supporting the use of the drug for the off-label indications observed. METHODS: A retrospective DUE of tamoxifen was performed for the 12 months of calendar year 2008 in a 650,000-member HMO in Israel for patients who received at least 1 prescription for tamoxifen. All patients for whom tamoxifen was dispensed in 2008 were identified from pharmacy claims data. The HMO's electronic patient record (EPR) was subsequently queried to identify the diagnoses of patients who received tamoxifen and exclude those patients who had a diagnosis code (ICD-9-CM 174.x or 175.x) for breast cancer. An EPR chart review was also performed to identify and exclude patients who had a diagnosis or treatment of breast cancer that was recorded in free text. For the patients who did not have a diagnosis code or free-text description of breast cancer, the recorded off-label diagnoses and ICD-9-CM codes in the EPR during the visit when tamoxifen was first prescribed were tabulated. A literature search was conducted to collect information supporting the use of tamoxifen for the observed off-label indications. We defined the use as "supported" if studies were found in PubMed, Cochrane database, or Micromedex that supported the clinical decision to use the drug for the off-label indication. RESULTS: 877 patients were treated with tamoxifen in 2008 of whom 826 (94.2%) had a diagnosis of breast cancer, and 51 patients (5.8%) received the drug from 41 physicians in 7 medical specialty categories for 25 different off-label diagnoses. Of these 25 diagnoses, 33 patients (64.7% of 51 patients with off-label use) received tamoxifen for 8 diagnoses that were associated with some evidence to support their off-label use. Malignant neoplasm of ovary (n = 13) and female infertility (n = 13) were the most commonly recorded indications with some evidence to support off-label use. Of the 13 women treated for infertility, 9 (69.2%) had been treated with clomiphene citrate prior to being treated with tamoxifen, suggesting that some physicians may be experimenting with tamoxifen as second-line treatment. CONCLUSIONS: Tamoxifen was found to be used off-label in only 5.8% of the patients who received the drug in 2008 in this HMO, and only 18 patients (2.1%) received tamoxifen for a diagnosis that did not have some supporting evidence of efficacy. Since off-label prescribing of tamoxifen was found to be relatively rare, this HMO did not impose a prior authorization requirement for this drug and instead added an edit in the EPR to block off-label prescribing by requiring the physician to register a diagnosis of breast cancer.

Prior authorization to improve testing of glycosylated hemoglobin in a managed care setting.

OBJECTIVE: To ascertain whether revocation of a prior authorization (PA) requirement by the Leumit Health Fund of Israel resulted in inferior rates of glycosylated hemoglobin (A1C) testing among new users of expensive diabetes medications. STUDY DESIGN: Electronic patient record (EPR) database study. METHODS: Data on new users of the target drugs and on A1C testing in these patients were extracted from EPR databases for the 6-month period after the revocation. The proportion (95% confidence interval [CI]) of patients who obtained at least 1 A1C test during the 4 months before initiation of treatment was calculated. The data were stratified by month to detect possible trends in rates of testing during the period after the policy change. RESULTS: After the PA requirement was rescinded, A1C testing among incident users of the target drugs dropped from 100% during the PA period to rates ranging from 85.6% (95% CI, 79.7%-91.5%) to 94.4% (95% CI, 90.8%-97.9%). Statistically significant variance in monthly rates of testing was not observed. CONCLUSIONS: Prior authorization has been successfully implemented in the managed care setting studied to obtain 100% performance of a laboratory test necessary to monitor drug therapy outcomes in patients with diabetes mellitus. When PA is implemented as a quality assurance strategy, its revocation should be accompanied by continuing education efforts designed to maintain optimal adherence to recommendations for appropriate care.

The tools of an evidence-based culture: implementing clinical-practice guidelines in an Israeli HMO.

PURPOSE: Although clinical-practice guidelines (CPGs) are implemented on the assumption that they will improve the quality, efficiency, and consistency of health care, they generally have limited effect in changing physicians' behavior. The purpose of this study was to design and implement an effective program for formulating, promulgating, and implementing CPGs to foster the development of an evidence-based culture in an Israeli HMO. METHOD: The authors implemented a four-stage program of stepwise collaborative efforts with academic institutions composed of developing quantitative tools to evaluate prescribing patterns, updating CPGs, collecting MDs' input via focus groups and quantitative surveys, and conducting a randomized controlled trial of a two-stage, multipronged intervention. The test case for this study was the development, dissemination, and implementation of CPG for the treatment of acute uncomplicated cystitis in adult women. Interventions in the form of a lecture at a conference and a letter with personalized feedback were implemented, both individually and combined, to improve physicians' rates of prescribing the first-line drug, nitrofurantoin, and, in the absence of nitrofurantoin, adhering to the recommended duration of three days of treatment with ofloxacin. RESULTS: The tools and data-generating capabilities designed and constructed in Stage I of the project were integral components of all subsequent stages of the program. Personalized feedback alone was sufficient to improve the rate of adherence to the guidelines by 19.4% (95% CI = 16.7, 22.1). CONCLUSIONS: This study provides a template for introducing the component of experimentation essential for cultivating an evidence-based culture. This process, composed of collaborative efforts between academic institutions and a managed care organization, may be beneficial to other health care systems.

Altered thermoregulation in ambulatory schizophrenia patients: a naturalistic study.

BACKGROUND: Schizophrenia patients may exhibit alterations in core/body temperature. Hence, we intended to examine the potential existence of thermoregulatory abnormalities in ambulatory schizophrenia patients. METHODS: Anonymous electronic patient record data of the Leumit Health Fund (Israel) were screened for all schizophrenia patients who have no other apparent chronic co-morbidity (mental or non-mental) and had their oral temperature assessed during routine follow-ups (Schiz-rFUs) or for various transitory infectious/inflammatory processes (Schiz-Infect) during the years 1999-2005 (n = 535). The comparison group consisted of a comparable sample (n = 560) of healthy subjects (Control-rFUs and Control-Infect). RESULTS: The sub-group of Schiz-rFUs (n = 216) exhibited significantly lower mean oral temperature compared to the matched group of Control-rFUs (n = 140) (36.72 +/- 0.54 vs. 36.94 +/- 0.64C, respectively; P<0.05). There was no significant difference in mean oral temperatures between the Schiz-Infect (n = 319) and the Control-Infect (n = 420) (37.32 +/- 0.92 vs. 37.28 +/- 0.98C, respectively; NS). CONCLUSIONS: Ambulatory schizophrenia patients without a concomitant infectious/inflammatory process exhibit altered thermoregulation manifested by a substantial (about 0.2 C) and significantly lower oral temperature compared to healthy comparison subjects as well as a potential exaggerated increase in oral temperature during transitory infectious/inflammatory processes. The relevance of these phenomena to the pathophysiology of schizophrenia as well as the potential immune-mediated pathologies in schizophrenia merit further investigation.

Curtailing laboratory test ordering in a managed care setting through redesign of a computerized order form.

OBJECTIVE: To increase appropriate use of blood tests for folic acid and vitamin B12 ordered by primary care physicians in a managed care organization in Israel through redesign of a computerized order form. STUDY DESIGN: Pre-post intervention. METHODS: A new version of the computerized order form was launched. Utilization patterns were calculated for tests of vitamin B12, folic acid, and ferritin, which were previously grouped together. Concomitant utilization patterns for tests of hemoglobin and iron were evaluated as controls. RESULTS: Tests ordered for the 3 targets decreased by 31% to 41% relative to the preintervention month, with a further decrease to 36% to 53% the following month. Negligible changes in utilization patterns were observed for the controls (-2% to 3%) during the postintervention period. CONCLUSIONS: Simple restructuring of a computerized order form significantly reduced the number of laboratory tests suspected of being unnecessary or redundant. When overutilization of laboratory resources is suspected, managers should evaluate the efficiency of the organization's current ordering procedures before implementing resource-intensive interventions.

Prescription of ocular beta-blockers in patients with obstructive pulmonary disease: Does a central electronic medical record make a difference?

OBJECTIVES: Topical beta-blockers are contraindicated in obstructive pulmonary diseases (OPDs). In this study we aimed to evaluate through central or local electronic medical records (EMRs) the prescription patterns for topical ocular beta-blockers for patients with glaucoma and OPD treated by ophthalmologists. METHODS: The study was carried out at the Leumit Health Maintenance Organisation (HMO) in Israel. The physicians at the HMO all work with an EMR, either a central EMR incorporating data from primary-care physicians and consultants, or a local one. The study population included all HMO members who filled at least one prescription for antiglaucoma medications in 2004. The patients were divided into two groups: those with a previous diagnosis of OPD (ICD-9 codes 493) and those with no known diagnosis of OPD. RESULTS: 7481 patients consumed topical antiglaucoma medications during the study period, and 14.5% had a diagnosis of OPD. 798 OPD patients were treated by ophthalmologists, and of the 61.8% who were treated with topical beta-blockers, only 38 received betaxolol. In comparison with glaucoma patients without OPD, OPD patients received fewer beta-blockers (p < 0.001), more selective beta-blockers (p < 0.0001) and less timolol (p < 0.001). Of the OPD patients treated by ophthalmologists with a central EMR, 59.5% received beta-blockers in comparison with 66.4% treated by ophthalmologists with a local EMR (p = 0.06). OPD patients treated by ophthalmologists with a central EMR received more non-beta-blockers in comparison with patients treated by ophthalmologists with a local EMR (p = 0.02). CONCLUSION: Most patients with OPD and glaucoma continued to receive topical beta-blockers, mostly noncardioselective beta-blockers. A central EMR with a comprehensive and highly available medical history reduced the prescription of beta-blockers to OPD patients, but rates remained unacceptably high.

Empiric treatment of uncomplicated urinary tract infection with fluoroquinolones in older women in Israel: another lost treatment option?

BACKGROUND: Current guidelines for the treatment of uncomplicated urinary tract infection (UTI) in women recommend empiric therapy with antibiotics for which local resistance rates do not exceed 10-20%. We hypothesized that resistance rates of Escherichia coli to fluoroquinolones may have surpassed this level in older women in the Israeli community setting. OBJECTIVES: To identify age groups of women in which fluoroquinolones may no longer be appropriate for empiric treatment of UTI. METHODS: Resistance rates for ofloxacin were calculated for all cases of uncomplicated UTI diagnosed during the first 5 months of 2005 in a managed care organization (MCO) in Israel, in community-dwelling women aged 41-75 years. The women were without risk factors for fluoroquinolone resistance. Uncomplicated UTI was diagnosed with a urine culture positive for E. coli. The data set was stratified for age, using 5 year intervals, and stratum-specific resistance rates (% and 95% CI) were calculated. These data were analyzed to identify age groups in which resistance rates have surpassed 10%. RESULTS: The data from 1291 urine cultures were included. The crude resistance rate to ofloxacin was 8.7% (95% CI 7.4 to 10.2). Resistance was lowest among the youngest (aged 41-50 y) women (3.2%; 95% CI 1.11 to 5.18), approached 10% in women aged 51-55 years (7.1%; 95% CI 3.4 to 10.9), and reached 19.86% (95% CI 13.2 to 26.5) among the oldest women (aged 56-75 y). CONCLUSIONS: Physicians who opt to treat UTI in postmenopausal women empirically should consider prescribing drugs other than fluoroquinolones. Concomitant longitudinal surveillance of both antibiotic utilization patterns and uropathogen resistance rates should become routine practice in this managed-care organization.

Suboptimal pneumococcal pneumonia vaccination rates among patients at risk in a managed care organization in Israel.

OBJECTIVE: Pneumococcal pneumonia is a vaccine-preventable disease that poses a significant threat to immunocompromised patients. Vaccination rates tend to be low despite recommendations for vaccination in several groups of high-risk patients including any person aged 65 years or older. The purpose of this study was to (a) evaluate the vaccination rates among high-risk patients in a managed care setting in Israel and (b) gain a better understanding of the factors associated with suboptimal use of this vaccine. METHODS: Data were extracted from the electronic medical records of the managed care organization for patients with dates of service from January 2000 to December 2004 for whom the vaccine is recommended. Patients were identified via diagnosis codes according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). Vaccination rates were calculated for patients in each disease category. These high-risk patients were contacted to participate in a telephone survey to evaluate the variance in knowledge and awareness levels of the disease between the vaccinated and unvaccinated patients. RESULTS: A total of 672 patients were identified by the ICD-9-CM codes; 140 (20.8%) had been vaccinated and 532 (79.2%) were unvaccinated. Vaccination rates were highest among patients with solid organ transplants (33.3%), followed by nephrotic syndrome (29.4%), bone marrow transplants (10.2%), and human immunodeficiency virus (HIV, 9%), for an overall rate of 20.8%. Of these patients, survey responses were obtained from 364 (54.2%). Respondents who were unvaccinated tended to be less well informed about which patient populations are at risk for the disease and the availability of the vaccine. CONCLUSION: The pneumococcal vaccination rate among immunocompromised patients in this managed care organization was found to be inadequate, at just 20.8% of the target population. Approaches based on direct contact with the patient, such as by a case manager, may be more successful in the future.

When gatekeepers meet the sentinel: the impact of a prior authorization requirement for cefuroxime on the prescribing behaviour of community-based physicians.

AIMS: Prior authorization (PA), the requirement of physicians to obtain pre-approval as a prerequisite for coverage, may decrease drug utilization via a 'sentinel effect', a decrease in utilization caused by external review of prescribing. The purpose of this study was to assess the affect a PA restriction had on the utilization patterns of cefuroxime tablets in a managed care organization (MCO) in Israel. METHODS: Physician prescribing patterns were evaluated by conducting a retrospective drug utilization analysis. Data were derived from the electronic patient records of the MCO studied. All prescriptions for solid state antibiotics for patients diagnosed with an infectious disease written during three parallel 3-month segments, before, during and after a PA restriction for cefuroxime was enforced, were included. Frequency and proportion of antibiotic prescriptions for cefuroxime tablets, distribution of infectious diseases treated with cefuroxime, and the request rejection rate when PA was required were calculated. RESULTS: Prescriptions for cefuroxime declined from 5538 prescriptions (8.0% of eligible antibiotic prescriptions, 95% CI 7.8, 8.2) in the initial period to 1036 (1.2%, 95% CI 1.1, 1.3) during the PA period, rising to 3961 (4.3%, 95% CI 4.2, 4.4) in the post-PA period. Changes in the distribution of diseases treated with cefuroxime during the PA stage tended to regress after revocation to those observed in the pre-PA period. The rejection rate was found to be 8.5% (95% CI=6.9, 10.1). CONCLUSIONS: The implementation of a prior authorization requirement for cefuroxime tablets markedly reduced the use of this drug, probably due to a 'sentinel effect'.