Factors affecting decisions of an HMO Drug Exemptions Committee on individual patient requests for coverage of non-formulary drugs.

BACKGROUND: In Israel, coverage of health needs is delivered by four health maintenance organizations (HMOs), which are budgeted by the government according to the recommendations of the National Drug Formulary (NDF) Committee. For medications not listed in the NDF, individuals may request to cover the costs by the HMO Exemptions Committee (DEC). The objectives of the current study, a first of its kind, are to document the DEC decision process, to identify its components and to determine the decisions' clinical outcome. METHODS: This retrospective cohort study included all members (≥ age 18) of the Maccabi Healthcare Service (MHS) who submitted a request to the DEC between June 2017 and December 2018. Collected data include patient demographics, clinical information and components of the decision process. Decision success (i.e., clinical outcome correlated with DEC decision) was determined by clinical outcome over at least one-year follow-up. RESULTS: A total of 335 requests were included. Strong evidence and rare disease were positively associated with approvals, while the availability of alternative treatments and costs were negatively associated. The majority of decisions (75%) met predicted clinical outcomes. Only estimated costs were found to be associated with decision success. CONCLUSIONS: Factors that reduce the potential costs of a requested drug are significantly associated with higher odds for drug approval, but only when the evidence supports potential benefit.

Effects of imatinib on glycemic and lipid profiles: a retrospective cohort study.

Despite a favorable effect of imatinib on glucose metabolism in animal models, human reports are inconsistent. We retrospectively studied the long-term effect of imatinib on fasting plasma glucose (FPG), glycated hemoglobin (HbA1C), LDL-cholesterol (LDL), and triglycerides (TGs) in a large HMO cohort of patients initiating therapy. In patients with diabetes (n = 118), significant reductions in HbA1c (0.53%, IQR 0.09, 1.19; p < .001) and FPG (10.2 mg/dL, IQR -3.5, 32.2; p < .001), independent of demographics and of glucose-lowering drugs utilization, were observed during the first year of imatinib treatment. Significant reductions in LDL (17.8 mg/dL, IQR -1.3, 34.0; p < .001) and TG (25.0 mg/dL, IQR -2.3, 58.3; p < .001), also independent of demographics and of statin utilization, were evident in the entire cohort (n = 611) during the first imatinib year. All reductions persisted during the second treatment year. To conclude, imatinib is associated with durable metabolic benefits, which may guide TKI choice in patients with cardiovascular co-morbidities.

Pregnancy outcomes following gestational exposure to papaverine: An observational comparative study.

AIMS: Papaverine is indicated for abdominal pain of various aetiologies. However, data on maternal and foetal safety following gestational exposure are lacking. The aim was to examine whether first trimester exposure to papaverine is associated with increased risk for major malformation and whether gestational exposure at any stage is associated with increased risk for preterm delivery, lower birthweight, small for gestational age, caesarean section (CS), lower Apgar score and perinatal death. METHODS: A retrospective comparative study consisted of pregnant women treated with papaverine between February 2010 and October 2019 at a large tertiary center. The control group comprised of livebirth deliveries randomly selected from the institutional obstetric database. RESULTS: The study group consisted of 498 pregnancies, which resulted in 537/544 (98.7%) live births, of whom 46/537 (8.6%) were exposed during the first trimester. The control group consisted of 498 pregnancies and 514 live births. Rate of major malformations did not differ between study group (2/46, 4.3%) and control (25/315, 4.9%, P = .67). Papaverine exposure was associated with higher rate of preterm delivery (22.3 vs. 10.3%, P < .001), CS (35.9 vs. 24.1%, P < .001) and lower birth weight (3207 vs. 3246 g, P = .02). Adjustment for treatment indication demonstrated that these remained significant only when given for obstetrical/surgical aetiologies. Comparable rates were observed for the remaining outcomes. CONCLUSIONS: Short-term gestational exposure to papaverine adjusted for indication was not associated with preterm deliveries, CS, lower birthweight, small for gestational age or perinatal death. Rate of major malformations among 46 first trimester exposures was comparable to controls.

Concomitant oral potassium chloride and anticholinergic therapy is associated with upper gastrointestinal bleeding: A cohort study.

AIM: To determine whether oral potassium chloride (KCI) therapy with concomitant anticholinergic exposure among hospitalized patients is associated with an excess risk for upper gastrointestinal bleeding (UGIB). METHODS: A retrospective controlled study among hospitalized patients between January 2007 and April 2019 who were treated with oral KCI. Patients were divided into two groups: with or without concomitant exposure to agents with anticholinergic activity. Outcome was defined as any UGIB. RESULTS: The final sample included 13 728 subjects who received oral KCI treatment, of them 3542 (25.8%) had at least one documented overlap with an anticholinergic agent. Mean age was 67.6 (±17.2) and 6893 (50.2%) were females. Median KCI dose was 2.4 g (interquartile range [IQR] 1.2-5.4, n = 9416) with the majority (90.4%) being treated with the wax-matrix form (Slow-K). Twenty-six (0.2%) patients experienced an UGIB event. Univariate analysis demonstrated a significantly higher rate of UGIB among patients concomitantly treated with oral KCI and anticholinergics (0.3%) compared to those without anticholinergic exposure (0.1%, P = 0.018), with median 7 days (IQR 3-16.8) from first KCI dose to bleeding event. Multivariate analysis demonstrated that concomitant anticholinergic exposure (Odds Ratio 2.48, 95% Confidence Interval 1.11-6.51, P = 0.022) and anticoagulation treatment among patients with hemato-oncologic disease (OR 6.61, 95% CI 1.96-22.25, P = 0.002) were significantly associated with UGIB. CONCLUSION: Hospitalized patients treated concomitantly with oral KCI and anticholinergic agents have significantly increased risk for UGIB.

Uninterrupted direct oral anticoagulant treatment during acute illness: Impact on clinical outcomes.

BACKGROUND: Uninterrupted drug therapy during acute illness is often associated with pharmacokinetic and pharmacodynamic variations. Among warfarin treated patients, these changes are reflected in the INR. However, in the case of direct oral anticoagulants (DOACs), given that routine laboratory monitoring is not recommended, these changes may result in unforeseen thromboembolic or bleeding events. OBJECTIVES: To determine the rate of thromboembolic (TEE) and bleeding events associated with uninterrupted DOAC compared to warfarin treatment during acute illness. METHODS: A retrospective cohort study of patients treated with DOACs or warfarin, both at steady state, who were hospitalized for acute illness. Primary outcome was any TEE or major bleeding requiring re-hospitalization within one month from discharge. Secondary outcome was a composite of major bleeding and clinically relevant non-major bleeding (CRNMB) events. RESULTS: A total of 410 patients continued oral anticoagulant treatment during their hospitalization, of whom 191 (46.6%) were on DOACs and 219 (53.4%) on warfarin, with a total of 18 (4.4%) events. Rates of TEE and major bleeding events did not differ between DOACs and warfarin treated patients (0.9% vs. 0.5% and 0.5% vs. 1%, respectively). Similarly, rate of secondary outcome was comparable between DOACs (4.7%) and warfarin (2.7%, p = 0.29). Sub-analyses demonstrated significantly higher rates among rivaroxaban (10.4%) treated patients compared to warfarin (p = 0.03). CONCLUSION: Uninterrupted treatment with DOACs during acute illness is not associated with increased risk for re-hospitalizations due to bleeding or thromboembolic events compared to warfarin. Our results suggest a higher bleeding rate among rivaroxaban treated patients at high bleeding risk.

Publisher Correction: Pyroglutamic acidosis as a cause for high anion gap metabolic acidosis: a prospective study.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Is Pyroglutamic Acid a Prognostic Factor Among Patients with Suspected Infection? A Prospective Cohort Study.

Pyroglutamic acid (PGA) is a compound that accumulates during oxidative stress and hence, elevated levels may be associated with poor prognosis in patients with infection or sepsis. To examine this hypothesis, patients presenting with acute infection were recruited in the emergency department and prospectively followed for 30 days. Sport urine samples were quantified for PGA. Outcomes were mortality and composite outcome of death or organ failure. Thirty two (32%) patients had qSOFA≥2. Median urine PGA was 22.9 (IQR 17.64, 33.53) µmol/mmol creatinine. Four patients demonstrated PGA values ≥ 63 µmol/mmol creatinine. Univariate analysis showed that PGA concentration ≥ 75th percentile (i.e. 33.53 µmol/mmol creatinine) was associated with higher rates of in-hospital mortality (p = 0.041) with similar trend for PGA ≥ 63 µmol/mmol creatinine (p = 0.04). However, multivariate analysis showed that PGA was not associated with worse outcomes, whereas heart rate was associated with both composite outcomes (HR 1.0, p = 0.008 and HR 1.02, p = 0.001 for composite outcome with 30 days and in-hospital mortality, respectively). Among low risk patients, high PGA levels were consistently associated with worse outcomes. In conclusion, urine PGA concentration was not associated with worse outcomes among septic patients. Nevertheless, future studies should evaluate this association in larger cohorts.

Clinically significant incidental QTc prolongation is subject to within-individual variability.

BACKGROUND: Prolonged QTc interval observed in daily practice is often deemed to be drug induced and might result in drug discontinuation, with possible therapeutic consequences. However, whether clinically significant prolonged QTc may be due to within-individual variability occurs has yet to be described. METHODS: A retrospective cohort study documenting within-individual QTc variability in subjects attending annual routine medical evaluation. At each visit, QT interval was measured and corrected for heart rate using Bazett and three other commonly used formulae. Outcome measures were rates of ΔQTc ≥60 msec, absolute QTc ≥500 msec and QTc ≥25% from baseline. RESULTS: A total of 188 subjects [54 (29%)] females were recruited. Mean age at first ECG was 54 ± 12.8 years with mean time interval of 12.2 ± 1.1 months between measurements. Mean Bazett QTc was higher compared to the other 3 formulae: 412 ± 20 vs. 400 ± 16 msec. Using Bazett formula, 18/188 (9.6%) and 5/188 (2.7%) subjects showed at least one measurement with ΔQTc ≥60 msec and QTc ≥500 msec, respectively. Of the former, 5/18 (27.8%) showed QTc ≥25% prolongation. In multivariate analysis, QTc ≥500 msec was significantly associated with number of measurements (HR: 5.01, 95%CI: 1.21-20.78, p = .026) with no effect of other known confounders. Lower rates were demonstrated with the other three formulae. CONCLUSION: In clinical practice, significant prolonged QTc may be attributed to within-individual variability, particularly when adjusting the QT interval with Bazett correction. This should be taken into consideration when decisions on changing current drug regimens are to be made.

Pyroglutamic acidosis as a cause for high anion gap metabolic acidosis: a prospective study.

5-oxoprolinemia (pyroglutamic acid, PGA) in the absence of acetaminophen use has been rarely reported as a cause for high anion gap metabolic acidosis. We investigated the prevalence and risk factors for elevated PGA concentrations among hospitalized patients with high anion gap metabolic acidosis: We prospectively enrolled patients with high anion gap metabolic acidosis hospitalized in the department of medicine. For each patient we collected the main diagnosis, concurrent medications and laboratory parameters. Spot urine samples were tested for PGA concentration. Levels ≥63 µmol/mmol creatinine were considered elevated. Overall, forty patients were prospectively followed. Mean age was 66.9 (17.9) years. Four (6.3%) patients had a high urine PGA level and demonstrated also lower blood pH (7.2 vs 7.3, p = 0.05) and lower serum lactate concentration (17.5 mg/dl vs 23.0 mg/dl, p = 0.04). Additionally, the high PGA level group consisted of more patients with septic shock [2/4 (50%) vs 3/36 (8.3%)] with a trend towards significance (p = 0.07). In conclusion, PGA might have a role in patients with septic shock and acidosis. Being a treatable condition, PGA should be taken into consideration particularly when no other cause for high anion gap is identified.

Pharmacokinetics and Immune Reconstitution Following Discontinuation of Thiopurine Analogues: Implications for Drug Withdrawal Strategies.

BACKGROUND AND AIMS: Discontinuation of thiopurine analogues is common prior to live vaccines, during infection or when de-escalating therapy. Data regarding clearance of active metabolites and immune re-constitution is scant. We aimed to determine drug elimination and immune re-constitution following thiopurine cessation. METHODS: The elimination kinetics of 6-thioguanine nucleotides (6-TGN) were determined in nine inflammatory bowel disease [IBD] patients discontinuing thiopurines. Immune reconstitution was evaluated by toxic shock syndrome toxin 1 [TSST1] or anti-CD3 [OKT3]-induced CD4+ T-cell proliferation, following an initial exposure to TSST1 and 6-mercaptopurine [6MP], separately or combined. RESULTS: All patients discontinuing thiopurines displayed first-order elimination kinetics of 6-TGN, with a median elimination half-life of 6.8 days [interquartile range 5.9-8.4]. Resting CD4+ T-cells exposed to 6MP preserved their response to subsequent polyclonal or Vß2+-preferential stimulation. By contrast, exposure of TSST1-activated CD4+ T-cells to 6MP inhibited their subsequent Vß2+clonal response to further stimulation [p = 0.008], whereas overall response to further non-Vß2-selective stimulation with OKT3 was unaltered [p = 0.9]. CONCLUSIONS: Upon 6MP/azathioprine discontinuation, a 6-TGN elimination half-life of less than 10 days is expected in most patients. Immune reconstitution, however, may take longer for T-cell clones exposed to stimulation during thiopurine treatment. These findings may be useful when considering thiopurine cessation.

High tacrolimus trough level variability is associated with rejections after heart transplant.

Tacrolimus, the major immunosuppressant after heart transplant (HTx) therapy, is a narrow therapeutic index drug. Hence, achieving stable therapeutic steady state plasma concentrations is essential to ensure efficacy while avoiding toxicity. Whether high variability in steady state concentrations is associated with poor outcomes is unknown. We investigated the association between tacrolimus trough level variability during the first year post-HTx and outcomes during and beyond the first postoperative year. Overall, 72 patients were analyzed for mortality, of whom 65 and 61 were available for rejection analysis during and beyond the first year post-HTx, respectively. Patients were divided into high (median >28.8%) and low tacrolimus level variability (<28.8%) groups. Mean tacrolimus levels did not differ between the groups (12.7 ± 3.4 ng/mL vs 12.8 ± 2.4 ng/mL, P = .930). Patients in the high variability group exhibited higher long-term rejection rate (median total rejection score: 0.33 vs 0, P = .04) with no difference in rejection scores within the first year post-HTx. Multivariate analysis showed that high tacrolimus trough level variability was associated with >8-fold increased risk for any rejection beyond the first year post-HTx (P = .011). Mortality was associated only with cardiovascular complications (P = .018), with no effect of tacrolimus through level variability.

Prescriber response to computerized drug alerts for electronic prescriptions among hospitalized patients.

BACKGROUND: Clinical decision support systems (CDSS) reduce prescription errors, but their effectiveness is reduced by high alert rates, "alert fatigue", and indiscriminate rejection. OBJECTIVES: To compare acceptance rates of alerts generated by the SafeRx® prescription CDSS among different alert types and departments in a tertiary care hospital, identify factors associated with alert acceptance, and determine whether alert overrides were justified. METHODS: In a retrospective study, we compared acceptance rates of all prescription alerts generated in 2013 in 18 departments of Israel's largest tertiary care center. In a prospective study in 2 internal medicine departments, we collected data on factors potentially associated with alert override, and an expert panel evaluated the justification for each overridden alert. We used multivariate analyses to examine the association between patient and physician-related factors and alert acceptance. RESULTS: In the retrospective study, of 390,841 prescriptions, 37.1% triggered at least one alert, 5.3% of which were accepted. Acceptance rates ranged from 7.9% for excessive dose alerts to 4.0% for duplicate drug and major drug-drug interactions alerts (p<0.001). In the prospective study, common reasons for alert overriding included "irrelevance to the specific condition" and "medication previously tolerated by the patient". Weekend shifts (incident rate ratio [IRR]=1.50 [95% CI, 1.01-2.22]) and a specific department (IRR=1.87 [1.23-2.87]) were associated with higher alert acceptance, while night shift (IRR=0.47 [0.26-0.85]) was associated with alert override. Most alert overrides (88.6%) were judged justified. CONCLUSIONS: The vast majority of SafeRx® alerts are overridden, and overriding is justified in most cases. Minimizing the number of alerts is essential to reduce the likelihood of developing "alert fatigue". Our findings may inform a rational, department-specific approach for alert silencing.

Immune-mediated syndromes following intravenous bisphosphonate therapy.

OBJECTIVES: Intravenous (IV) infusion of aminobisphosphonates (ABP) induces cytokine release by peripheral blood Vγ9δ2 T cells, resulting in an immediate short-term inflammatory response in up to 50% of patients. We evaluated possible long-term pro-inflammatory effects of IV ABP. METHODS: Retrospective case-series study from one rheumatology specialist's clinic. 2261 electronic charts were reviewed for administration of 'zoledronate' or different brand names of zoledronic acid, and relevant clinical data was retrieved for patients who had received the infusion. RESULTS: Thirteen patients had recieved zoledronate. In six, new-onset or exacerbation of a previous inflammatory/autoimmune disorder was diagnosed within 3 months following infusion. Of these, one patient developed new-onset rheumatoid arthritis (RA), two polymyalgia rheumatica (PMR), two suffered a flare of Crohn's disease-related and aromatase inhibitor-induced arthralgias, and one patient acquired autoimmune hemophilia. Pre-existing malignancy and immediate inflammatory response following zoledronate were more frequent in patients experiencing new or worsening immunologic manifestations (3/6 vs. 0/7, and 5/6 vs. 2/7, respectively). CONCLUSIONS: Intravenous ABP may trigger induction of persistent autoimmune syndromes, especially when accompanied by an immediate adverse reaction or pre-existing malignancy.

Anti-fibrotic characteristics of Vγ9+ γδ T cells in systemic sclerosis.

OBJECTIVES: γδ T cells of the Vγ9Vδ2 subtype secrete anti-fibrotic cytokines upon isopentenyl pyrophosphate (IPP) stimulation. In this study, we sought to compare IPP and Zoledronate, an up-regulator of IPP, effects on proliferation and cytokine secretion of Vγ9+ T cells from systemic sclerosis (SSc) patients and healthy controls (HCs). We also examined the effect of IPP-triggered peripheral blood mononuclear cells (PBMC) on fibroblast procolla- gen secretion. METHODS: PBMC from SSc patients and HCs were stimulated by increasing concentrations of Zoledronate, with or without IPP, and Vγ9+ T cell percentages were calculated using FACScan analysis. Subsequently, PBMC were cultured with IPP or toxic shock syndrome toxin-1 (TSST-1), and contents of the anti-fibrotic cytokines tumour necrosis factor (TNF)-α and interferon (IFN)-γ were measured by ELISA kits. Finally, supernatants of IPP-triggered Vγ9+ T cells from SSc patients were added to fibroblast cultures, and relative intensities of procollagen α1 chains were determined by densinometry. RESULTS: Higher concentrations of Zoledronate were required for maximal proliferation of Vγ9+ T cells in 9 SSc patients compared to 9 HCs, irrespective of exogenous IPP. When compared to stimulation by TSST-1, a non-Vγ9+ selective reagent, secretion of the anti-fibrotic cytokines TNF-α and IFN-γ in response to IPP was relatively diminished in SSc but not in HCs. Reduction of procollagen secretion by fibroblasts cultured with supernatants of IPP-stimulated PBMC was observed only in some SSc patients. CONCLUSIONS: Activated Vγ9+ T cells could act as anti-fibrotic mediators in SSc, although decreased responsiveness to IPP may play a role in the pathological fibrosis of this disease.

Database evaluation of the association between serum magnesium levels and the risk of atrial fibrillation in the community.

BACKGROUND: In population studies, mild hypomagnesemia, determined by a single measurement, was associated with incident atrial fibrillation, over ~20 years of follow-up. We sought to determine whether mild (≤ 1.7 mg/dL) and moderate (≤ 1.5mg/dL) hypomagnesemia are temporally associated with increased incidence of atrial fibrillation (AF) in the community. METHODS: Health Maintenance Organization (HMO) database cohort study including beneficiaries with ≥ 1 serum magnesium measurement between 2004 and 2013. The follow-up period was defined from the first magnesium measurement to first listing in an AF registry (for cases) and December 2013 or date of death or loss to follow-up (for controls). We analyzed the association between serum magnesium quintiles, as well as the above clinically relevant hypomagnesemia thresholds, and incident AF using Cox proportional hazard regression analysis, adjusting for confounders. The association between serum magnesium and AF occurring within 3 months was also examined. RESULTS: Among 162,162 subjects, 2228 (1.4%) developed AF over a median follow-up of 25.3 months. Compared to the middle quintile the lowest magnesium quintile (≤ 1.9 mg/dL) had a significantly higher risk of AF (HR, 1.21; 95% CI: 1.07-1.37). Increased AF risk was also associated with mild (HR, 1.44; 95% CI: 1.20-1.73) and moderate hypomagnesemia (HR, 1.57; 95% CI: 1.14-2.15). No association was found when limiting the follow-up period to 3 months. CONCLUSIONS: In our study, hypomagnesemia was associated with incident AF over prolonged but not short-term follow-up periods, suggesting that this association may not be causal.

Implementation of a clinical decision support system for computerized drug prescription entries in a large tertiary care hospital.

BACKGROUND: Prescription errors are common in hospitalized patients and result in significant morbidity, mortality and costs. Electronic prescriptions with computerized physician order entry systems (CPOE) and integrated computerized decision support systems (CDSS providing online alerts) reduce prescription errors by approximately 50%. However, the introduction of CDSS is often met by opposition due to the flood of alerts, and most prescribers eventually ignore even crucial alerts ("alert fatigue"). OBJECTIVES: To describe the implementation and customization of a commercial CDSS (SafeRx) for electronic prescribing in Internal Medicine departments at a tertiary care center, with the purpose of improving comprehensibility and substantially reducing the number of alerts to minimize alert fatigue. METHODS: A multidisciplinary expert committee was authorized by the hospital administration to customize the CDSS according to the needs of six internal medicine departments at Sheba Medical Center. We assessed volume of prescriptions and alert types during the period February-August 2012 using the statistical functions provided by the CDSS. RESULTS: A mean of 339 +/- 13 patients per month per department received 11.2 +/- 0.5 prescriptions per patient, 30.1% of which triggered one or more CDSS alerts, most commonly drug-drug interactions (43.2%) and dosing alerts (38.3%). The review committee silenced or modified 3981 alerts, enhancing comprehensibility, and providing dosing instructions adjusted to the patient's renal function and recommendations for follow-up. CONCLUSIONS: The large volume of drug prescriptions in internal medicine departments is associated with a significant rate of potential prescription errors. To ensure its effectiveness and minimize alert fatigue, continuous customization of the CDSS to the specific needs of particular departments is required.

The association of proton pump inhibitors and hypomagnesemia in the community setting.

Evidence for the association between hypomagnesemia and proton pump inhibitors (PPIs), highlighted by the 2011 FDA Drug Safety Communication, rests mainly on studies in hospitalized patients. Our objectives were to determine the prevalence of hypomagnesemia and its association with PPIs in the community setting. We performed a retrospective cross-sectional analysis of a large health maintenance organization administrative database, including ambulatory patients with ≥1 serum magnesium concentrations between 2008 and 2011, the lowest referred to as "index magnesium." In cases with any (index magnesium ≤0.7 mmol/L) or severe (≤0.55 mmol/L) hypomagnesemia, we analyzed (vs. controls, >0.7 mmol/L) the association with PPI or H2 -blocker use during the 4-12 months preceding the index magnesium by logistic regression analysis, adjusting for confounders. Among 95,205 subjects, 5,696 (6.0%) had any hypomagnesemia, which was severe in 454 (0.5%), with twofold higher prevalences in those with established risk factors. PPI use during the 4 months preceding the index magnesium was more common in cases of any hypomagnesemia (adjusted OR = 1.66; 95% CI, 1.55-1.78) and severe hypomagnesemia (adjusted OR = 3.79; 2.99-4.82) than in controls without acid suppression. Hypomagnesemia remained significantly associated with PPI use when using H2 -blocker-users as reference (adjusted OR = 1.25 [P = 0.003] and 2.65 [P < 0.001] for any and severe hypomagnesemia, respectively). We conclude that hypomagnesemia is associated with PPI use in ambulatory patients.