Erez Battat

Natural History of Thyroid Function Tests over 5 Years in a Large Pediatric Cohort

CONTEXT Because clinical manifestations of thyroid disorders are variable and subtle in children and adolescents, thyroid function tests are often repeated in patients with nonspecific symptoms. OBJECTIVES The objective of the study was to determine the natural history of initial abnormal TSH and define populations at greater risk for developing a subsequent thyroid dysfunction. METHODS A total of 121,052 of 1.043 million outpatients aged 0.5-16 yr insured by the Clalit Health Medical Organization had a TSH determination in 2002 and follow-up to 2007. Extracted from the Clalit Health Medical Organization database were their demographic data, referral diagnoses, and laboratory results (TSH, free T(4), thyroid antibodies). Excluded were patients with overt hypothyroidism or hyperthyroidism on initial testing. RESULTS Results of 96.5% of initial serum TSH concentrations were normal (0.35-5.5 mIU/liter), 0.2% were low (<0.35 mIU/liter), 2.9% elevated (>5.5 to <or=10 mIU/liter), and 0.4% highly elevated (>10 mIU/liter). The frequency of TSH testing increased with age and female gender. During follow-up, repeated (two to more than four) TSH tests were performed in 45.7% of the patients. In the second TSH determination, normal TSH was documented in 40, 73.6, and 78.9% of those whose initial serum TSH was highly elevated, elevated, and low, respectively, and in 97% of those with normal initial TSH. Predictive factors for a sustained highly elevated TSH were initial TSH greater than 7.5 mIU/liter (P = 0.014) and female gender (P = 0.047). CONCLUSIONS In the pediatric population, initial normal or slightly elevated TSH levels are likely to remain normal or spontaneously normalize without treatment. Patients with initial levels greater than 7.5 mIU/liter, particularly girls, are at a greater risk for sustained abnormal TSH levels.

The association between continuity of care in the community and health outcomes: a population- based study

BackgroundThe study goal was to assess indices of continuity of care in the primary care setting and their association with health outcomes and healthcare services utilization, given the reported importance of continuity regarding quality of care and healthcare utilization.MethodsThe study included a random sample of enrollees from Clalit Health Services 19 years-of-age or older who visited their primary care clinic at least three times in 2009. Indices of continuity of care were computed, including the Usual Provider Index (UPC), Modified Modified Continuity Index (MMCI), Continuity of Care Index (COC), and Sequential Continuity (SECON). Quality measures of preventive medicine and healthcare services utilization and their costs were assessed as outcomes.Results1,713 randomly sampled patients were included in the study (mean age: 48.9 ± 19.2, 42% males). Continuity of care indices were: UPC: 0.75; MMCI: 0.81; COC: 0.67; SECON: 0.70. After controlling for patient characteristics in a multivariate analysis, a statistically significant association was found between higher values of UPC, COC, and SECON and a decrease in the number and cost of ED visits. Higher MMCI values were associated with a greater number and higher costs of medical consultation visits. Continuity of care indices were associated with BMI measurements, and inversely associated with blood pressure measurements. No association was found with other quality indicators, e.g., screening tests for cancer.ConclusionsSeveral continuity of care indices were associated with decreased number and costs of ED visits. There were both positive and negative associations of continuity of care indices with different aspects of healthcare utilization. The relatively small effects of continuity might be due to the consistently high levels of continuity in Clalit Health Services.

Opioid Use in an Israeli Health Maintenance Organization: 2000–2006

OBJECTIVE The objective of this study was to assess opioid use during 7 years (2000-2006) among Clalit Health Services (CHS) members. DESIGN Purchasing data of opioids authorized for use in Israel were obtained from the computerized databases of CHS. Patient demographics and cancer morbidity were also extracted. The data were analyzed by converting the purchased opioids to oral morphine equivalents (OMEs). SETTING CHS is the largest health maintenance organization in Israel (3,774,600) and insures almost 54% of the Israeli population. PATIENTS All CHS members who purchased an opioid at least once during the 7-year study period (2000-2006). INTERVENTION There were no interventions in this study. OUTCOME MEASURES The outcome measures of this study were total OME purchased per year, OME (mg) per capita/per year, and OME (mg) daily dose. RESULTS There were 119,562 patients who purchased an opioid at least once (3.2% of CHS population). Of them, 57.4% were women, 69.0% aged 65 years and above (average age 56.05 years +/- 26.7), 7.7% purchased opioids for more than 12 months, and 81.3% purchased opioids for only 1-4 months. A 96% increase in total OME purchased was found between 2000 and 2006 (from 56.4 kg to 110.6 kg). The annual OME purchased per capita increased from 15.7 mg in the year 2000 to 29.3 mg in 2006. The total number of patients who received at least one opioid prescription increased by 60%, while the growth in total number of CHS members was smaller (4.8%). CONCLUSIONS There is a growing use of opioids at CHS during the 7-year period, a potential indicator of the progress made in improving accessibility and availability of opioids in our health care organization in Israel.

Bleeding in patients with atrial fibrillation treated with dabigatran, rivaroxaban or warfarin: A retrospective population-based cohort study

BACKGOUND Randomized controlled trials (RCTs) have shown that dabigatran, rivaroxaban and warfarin cause similar bleeding rates. METHODS We performed a retrospective population-based cohort study to determine the incidence of bleeding in patients with atrial fibrillation (AF) beginning dabigatran, rivaroxaban or warfarin. Consecutive patients initiating anticoagulation for AF during a 3year period were identified using a computerized database. Patients who bled and required hospitalization underwent chart review. Bleeding incidences were calculated per 100 patient-years of treatment. RESULTS 18,249 patients were included: 9564 (52.4%) received warfarin, 5976 (32.7%) dabigatran, and 2709 (14.8%) rivaroxaban. Bleeding incidences were 3.9 (95% CI, 3.6-4.4) in warfarin-treated patients, 4.2 (95% CI, 3.7-4.7) in dabigatran patients, and 4.1 (95% CI, 3.0-5.3) in rivaroxaban patients. Intracranial hemorrhage (ICH) rates were 0.71 (95% CI, 0.56-0.90) for warfarin, 0.4 (95% CI, 0.18-0.87) for dabigatran, and 0.27 (95%CI, 0.10-0.80) for rivaroxaban. GI hemorrhage rates were 1.88 (95%CI, 1.62-2.20) for warfarin, 2.98 (95% CI, 2.4-3.5) for dabigatran and 2.39 (95%CI, 1.6-3.5) for rivaroxaban. CONCLUSIONS We demonstrate similar bleeding rates with both dabigatran 150mg and 110mg and rivaroxaban compared to warfarin.

The 'real-life' impact of adding bevacizumab to first-line therapy in metastatic colorectal cancer patients: a large Israeli retrospective cohort study.

Abstract Background. After a decade of extensive use, the actual contribution of bevacizumab in first-line treatment of metastatic colorectal cancer (mCRC) is still unclear. Objective. To evaluate ‘real-life’ outcomes of patients with mCRC before and after the introduction of bevacizumab to standard mCRC first-line practice. Methods. Using the computerized administrative database of Clalit Health Services’ (CHS), Israels largest health care provider, we retrospectively compared two cohorts (n = 1739): (A) all CHS’ patients diagnosed with mCRC between January 2000 and December 2004 that received first-line irinotecan or oxaliplatin-based combination chemotherapy (before bevacizumab was introduced) (n = 1052), and (B) all patients that started first-line irinotecan or oxaliplatin combination chemotherapy together with bevacizumab between September 2006 and December 2009 (after bevacizumab was fully reimbursed in Israel for mCRC first-line therapy) (n = 687). The primary endpoint was overall survival (OS) and secondary endpoints were first-line progression-free survival (PFS) and metastatectomy rates. Results. Median OS was longer in Cohort B than in Cohort A [23.0 months vs.15.0, adjusted hazard ratio (HR), 0.75]. Secondary outcomes were also better; PFS of 14.0 months vs. 9.8 in the earlier period (HR, 0.75) and metastatectomy rate of 8.1% versus 3.9%. The longer OS in Cohort B was preserved even after controlling for latter-line epidermal growth factor receptor (EGFR) inhibitor use (HR = 0.77). Conclusion. In this analysis, OS, PFS and metastatectomy rates of first-line treatment of mCRC were significantly higher in the later period of the study. These results, derived from ‘real-life’ practice, suggest that the use of bevacizumab, among other alterations in the clinical management of mCRC between the two periods, might have had a significant contribution to these outcomes, and may therefore support the current practice of adding bevacizumab to first-line treatment of mCRC.

Appropriateness of non-vitamin K antagonist oral anticoagulant dose in patients with atrial fibrillation in Israel: A population-based study

The non-vitamin K oral antagonists (NOACs) are at least as effective as warfarin in the prevention of stroke in non valvular atrial fibrillation (NVAF) and are associated with less intracranial hemorrhage. Many patients with NVAF inappropriately do not receive anticoagulants often because of the inconvenience associated with warfarin administration. NOACs have the potential to increase anticoagulation use because they are safer and easier to administer than warfarin. Indeed, the use of anticoagulation in patients with newly diagnosed AF in many countries is increasing as a result of the use of NOACs in preference to warfarin [1]. However, as recently demonstrated in a large population based study in the United States, uptake of NOACs may not be as rapid as initially predicted and many AF patients with an indication for anticoagulation remain untreated [2]. Reasons for this may relate to an ongoing concern of physicians and patients related to the fact that a risk of hemorrhage associated with NOACs remains. This is borne out by the fact that a number of studies have shown a considerable overuse of lower rather than standard or “higher” doses of the NOACs, often not in compliance with clinical guidelines [3, 4]. We have previously reported on the rapid uptake of NAOCs among AF patients in Israel [5]. In this study we examine the extent, appropriateness and factors associated with low versus standard dose NOAC use. Patients starting anticoagulant treatment for NVAF for the first time between January 2011 and December 2014 were identified using the Clalit Health Services computerized clinical database using ICD-9 codes. This database includes current and previous drug prescription records thus first-time anticoagulant use could be established. Patients were categorized by age (< 60, 60–80,> 80 years), renal function (serum creatinine< 1.5, ≥1.5mg/dL) and weight (< 60, 60–100,> 100 kg) reflecting parameters used to determine the appropriate dose of dabigatran, rivaroxaban and apixaban, the NOACs that were available in Israel during the study period. They were licensed and reimbursed sequentially as follows: dabigatran January 1, 2011, rivaroxaban -January 1, 2012 and apixaban January 1, 2013. The CHADS2 score used in Israel during the study period and the Charlson co-morbidity index were recorded. The number and proportion of patients receiving each NOAC and each dose was determined. The dose assignment was according to the first dose prescribed for each patient. Data for patients changing doses or drugs during the study period were censored at the time of treatment change. The odds ratio (OR) for choosing the lower versus higher dose of each NOAC was calculated for each of the following parameters: age, renal function and weight. The proportion of patients receiving appropriate NOAC doses was calculated for each of the drugs using the manufacturers recommendations and the Clalit Health Services drug formulary which recommends reducing dabigatran dose from 150mg to 110mg bid for age > 80 years, age 75–80 years together with physician perception of increased bleeding risk based on the presence of gastrointestinal reflux, concomitant medications (aspirin or non steroidal anti-inflammatories or verapamil) or creatinine clearance 30–50mL/min. Rivaroxaban 15mg rather than 20mg daily is recommended for creatinine clearance 15–50mL/min and apixaban 2.5mg rather than 5mg bid is recommended if two or more of the following criteria are met: age≥ 75 years, weight≤ 60 kg or serum creatinine ≥1.5mg/dL. Statistical analysis was performed using GraphPad Prism© version 7.03 software. The study was approved by the Helsinki committee of Clalit Health Services. During the study period 26,183 patients initiated anticoagulation. Of these 14,257 (54.4%) received a VKA and are not further analyzed in this study. 1410 (5.4%) received dabigatran 150mg, 3777 (14.5%) dabigatran 110mg, 2140 (8.2%) received rivaroxaban 20mg, 2570 (9.8%) rivaroxaban 15mg and 802 (3%) received apixaban 5mg and 1227 (4.7%) 2.5mg (Table 1 and Fig. 1). The median age was 77 (range=25–102) years. Median CHADS2 score ranged from 3 to 4 for all the patients with a tendency to higher scores among the patients receiving lower dose NOACs. Patients receiving lower dose NOACs were more likely to have a serum creatinine 1.5 mg/dL than patients receiving standard dose NOACs. The median Charlson co-morbidity index ranged from 2 to 4 for all the patients with a tendency to higher scores among the patients receiving lower dose NOACs. The use of lower dose NOAC according to the Clalit Health Services drug formulary guidance for NOAC prescription was appropriate in only 16% (CI= 12–20) of patients receiving dabigatran 110mg, 21.5% (CI= 16–24) of patients receiving rivaroxaban 15mg and 32% (CI= 27–35) of patients receiving apixaban 2.5mg. Adjusted odds ratios were calculated to assess the factors predicting inappropriate use of lower dose versus standard dose NOACs. Age > 80 years (OR=4.9, CI= 4.0–6.2) was the strongest predictor