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Introduction This study described patients hospitalized for acute heart failure (AHF) in Japan who received intravenous (IV) diuretics and/or vasodilators as the initial therapy. Methods The Japan Medical Data Vision database was used to identify adult patients hospitalized for AHF during 2013–2017, who were hemodynamically stable at presentation and treated with IV diuretics and/or IV vasodilators as initial therapy. Treatment patterns and use of cardiac rehabilitation, as well as outcomes (e.g., length of stay [LOS], in-hospital mortality, HF-readmission) were reported overall and by year of AHF hospitalization. Results Of 30,360 patients (mean age = 80.0 years; 52.2% male), 87.0% were treated during the hospitalization with IV diuretics, 63.9% with IV vasodilators, and 13.8% with intensified therapies. On average, the duration of IV therapy was 10.6 days. In-hospital cardiac rehabilitation was utilized by 51.7% of the patients for 11.7 days on average. Mean LOS was 23.3 days, while in-hospital mortality and 30-day HF readmission post-discharge were 13.2 and 9.5%, respectively. Hospitalization outcomes remained stable between 2013 and 2017 despite important changes in AHF management such as a decrease in carperitide use (55.9–40.0% in 2017), and increases in use of tolvaptan (from 14.2% in 2013 to 31.3% in 2017) and of cardiac rehabilitation (from 43.2% in 2013 to 56.1% in 2017). Patients with intensified therapies had the longest IV therapy duration (mean 23.8 days vs. 5.5–9.9 days), the highest cardiac rehabilitation services use (60.2 vs. 38.3–57.0%), the longest LOS (mean 36.7 vs. 16.3–22.2 days), and the highest in-hospital mortality (37.4 vs. 3.1–12.4%) compared to the other treatment groups. Conclusions Contemporary treatment for AHF hospitalization in Japan comprises a long duration of IV therapy followed by extended use of oral medications and in-hospital cardiac rehabilitation prior to discharge. Patients requiring intensified therapies had much longer LOS and higher in-hospital mortality. Supplementary Information The online version contains supplementary material available at 10.1007/s40119-021-00212-y.

Results There were 33,269 apixaban-warfarin, 9,345 dabigatran-warfarin, and 42,156 rivaroxaban-warfarin matched pairs, with a median follow-up of 4-5 months. Compared with warfarin, apixaban was associated with lower rates of stroke/systemic embolism (hazard ratio [HR] 0.52; 95% confidence interval [95% CI], 0.43-0.62), major bleeding (HR 0.60; 95% CI, 0.55-0.66) and stroke/myocardial infarction/all-cause mortality (HR 0.70; 95%CI, 0.66-0.74); dabigatran was associated with lower rates of major bleeding (HR: 0.73; 95% CI, 0.62-0.85); dabigatran and rivaroxaban were associated with lower rates of stroke/myocardial infarction/all-cause mortality (HR 0.77; 95% CI, 0.69-0.86 and HR 0.81; 95% CI, 0.77-0.85, respectively). Rivaroxaban was associated with a lower rate of stroke/systemic embolism (HR 0.61; 95% CI, 0.53-0.71) and a higher rate of major bleeding (HR 1.10; 95%CI, 1.03-1.18) versus warfarin.

Background There is limited evidence on the clinical and cost benefits of screening for atrial fibrillation (AF) with electrocardiogram (ECG) in asymptomatic adults. Methods We adapted a previously published Markov model to evaluate the clinical and economic impact of one-time screening for non-valvular AF (NVAF) with a single 12-lead ECG and a 14-day extended screening with a hand-held ECG device (Zenicor single-lead ECG, Z14) compared with no screening. Clinical events considered included ischemic stroke, systemic embolism, major bleeds, myocardial infarction, and death. Epidemiology and effectiveness data for extended screening were from the STROKESTOP study. Risks of clinical events in NVAF patients were derived from ARISTOTLE. Analyses were conducted from the perspective of a third-party payer, considering a population with undiagnosed NVAF, aged 75 years in the USA. Costs and utilities were discounted at a 3% annual rate. Parameter uncertainty was formally considered via deterministic and probabilistic sensitivity analyses (DSA and PSA). Structural uncertainty was assessed via scenario analyses. Results In a hypothetical cohort of 10,000 patients followed over their lifetimes, the number of additional AF diagnoses was 54 with 12-lead ECG and 255 with Z14 compared with no screening. Both screening strategies led to better health outcomes (ischemic strokes avoided: ECG 12-lead, 9.8 and Z14, 42.2; quality-adjusted life-years gained: ECG 12-lead, 31 and Z14, 131). Extended screening and one-time screening were cost effective compared with no screening at a willingness-to-pay (WTP) threshold of $100,000 per QALY gained ($58,728/QALY with ECG 12-lead and $47,949/QALY with Z14 in 2016 US dollars). ICERs remained below $100,000 per QALY in all DSA, most PSA runs, and in all scenario analyses except for a scenario assuming low anticoagulation persistence. Conclusions Our analysis suggests that, screening the general population at age 75 years for NVAF is cost effective at a WTP threshold of $100,000. Both extended screening and one-time screening for NVAF are expected to provide health benefits at an acceptable cost. Electronic supplementary material The online version of this article (10.1007/s40258-019-00542-y) contains supplementary material, which is available to authorized users.

To address literature gaps on treatment with real-world evidence, this study compared effectiveness, safety, and cost outcomes in NVAF patients with coronary or peripheral artery disease (CAD, PAD) prescribed apixaban versus other oral anticoagulants. NVAF patients aged ≥65 years co-diagnosed with CAD/PAD initiating warfarin, apixaban, dabigatran, or rivaroxaban were selected from the US Medicare population (January 1, 2013 to September 30, 2015). Propensity score matching was used to match apixaban versus warfarin, dabigatran, and rivaroxaban cohorts. Cox models were used to evaluate the risk of stroke/systemic embolism (SE), major bleeding (MB), all-cause mortality, and a composite of stroke/myocardial infarction/all-cause mortality. Generalized linear and two-part models were used to compare stroke/SE, MB, and all-cause costs between cohorts. A total of 33,269 warfarin-apixaban, 9,335 dabigatran-apixaban, and 33,633 rivaroxaban-apixaban pairs were identified after matching. Compared with apixaban, stroke/SE risk was higher in warfarin (hazard ratio [HR]: 1.93; 95% confidence interval [CI]: 1.61 to 2.31), dabigatran (HR: 1.69; 95% CI: 1.18 to 2.43), and rivaroxaban (HR: 1.24; 95% CI: 1.01 to 1.51) patients. MB risk was higher in warfarin (HR: 1.67; 95% CI: 1.52 to 1.83), dabigatran (HR: 1.37; 95% CI: 1.13 to 1.68), and rivaroxaban (HR: 1.87; 95% CI: 1.71 to 2.05) patients vs apixaban. Stroke/SE- and MB-related medical costs per-patient per-month were higher in warfarin, dabigatran, and rivaroxaban patients versus apixaban. Total all-cause health care costs were higher in warfarin and rivaroxaban patients compared with apixaban patients. In conclusion, compared with apixaban, patients on dabigatran, rivaroxaban, or warfarin had a higher risk of stroke/SE, MB, and event-related costs.

SummaryThe ARISTOTLE trial showed a risk reduction of stroke/systemic embolism (SE) and major bleeding in non-valvular atrial fibrillation (NVAF) patients treated with apixaban compared to warfarin. This retrospective study used four large US claims databases (MarketScan, PharMetrics, Optum, and Humana) of NVAF patients newly initiating apixaban or warfarin from January 1, 2013 to September 30, 2015. After 1:1 warfarin-apixaban propensity score matching (PSM) within each database, the resulting patient records were pooled. Kaplan-Meier curves and Cox proportional hazards models were used to estimate the cumulative incidence and hazard ratios (HRs) of stroke/SE and major bleeding (identified using the first listed diagnosis of inpatient claims) within one year of therapy initiation. The study included a total of 76,940 (38,470 warfarin and 38,470 apixaban) patients. Among the 38,470 matched pairs, 14,563 were from MarketScan, 7,683 were from PharMetrics, 7,894 were from Optum, and 8,330 were from Humana. Baseline characteristics were balanced between the two cohorts with a mean (standard deviation [SD]) age of 71 (12) years and a mean (SD) CHA2DS2-VASc score of 3.2 (1.7). Apixaban initiators had a significantly lower risk of stroke/SE (HR: 0.67, 95 % CI: 0.59–0.76) and major bleeding (HR: 0.60, 95 % CI: 0.54–0.65) than warfarin initiators. Different types of stroke/SE and major bleeding – including ischaemic stroke, haemorrhagic stroke, SE, intracranial haemorrhage, gastrointestinal bleeding, and other major bleeding – were all significantly lower for apixaban compared to warfarin treatment. Subgroup analyses (apixaban dosage, age strata, CHA2DS2-VASc or HAS-BLED score strata, or dataset source) all show consistently lower risks of stroke/SE and major bleeding associated with apixaban as compared to warfarin treatment. This is the largest “real-world” study on apixaban effectiveness and safety to date, showing that apixaban initiation was associated with significant risk reductions in stroke/SE and major bleeding compared to warfarin initiation after PSM. These benefits were consistent across various high-risk subgroups and both the standard-and low-dose apixaban dose regimens.Note: The review process for this manuscript was fully handled by Christian Weber, Editor in Chief.Supplementary Material to this article is available online at www.thrombosis-online.com.

Background and Purpose- This ARISTOPHANES study (Anticoagulants for Reduction in Stroke: Observational Pooled Analysis on Health Outcomes and Experience of Patients) used multiple data sources to compare stroke/systemic embolism (SE) and major bleeding (MB) among a large number of nonvalvular atrial fibrillation patients on non-vitamin K antagonist oral anticoagulants (NOACs) or warfarin. Methods- A retrospective observational study of nonvalvular atrial fibrillation patients initiating apixaban, dabigatran, rivaroxaban, or warfarin from January 1, 2013, to September 30, 2015, was conducted pooling Centers for Medicare and Medicaid Services Medicare data and 4 US commercial claims databases. After 1:1 NOAC-warfarin and NOAC-NOAC propensity score matching in each database, the resulting patient records were pooled. Cox models were used to evaluate the risk of stroke/SE and MB across matched cohorts. Results- A total of 285 292 patients were included in the 6 matched cohorts: 57 929 apixaban-warfarin, 26 838 dabigatran-warfarin, 83 007 rivaroxaban-warfarin, 27 096 apixaban-dabigatran, 62 619 apixaban-rivaroxaban, and 27 538 dabigatran-rivaroxaban patient pairs. Apixaban (hazard ratio [HR], 0.61; 95% CI, 0.54-0.69), dabigatran (HR, 0.80; 95% CI, 0.68-0.94), and rivaroxaban (HR, 0.75; 95% CI, 0.69-0.82) were associated with lower rates of stroke/SE compared with warfarin. Apixaban (HR, 0.58; 95% CI, 0.54-0.62) and dabigatran (HR, 0.73; 95% CI, 0.66-0.81) had lower rates of MB, and rivaroxaban (HR, 1.07; 95% CI, 1.02-1.13) had a higher rate of MB compared with warfarin. Differences exist in rates of stroke/SE and MB across NOACs. Conclusions- In this largest observational study to date on NOACs and warfarin, the NOACs had lower rates of stroke/SE and variable comparative rates of MB versus warfarin. The findings from this study may help inform the discussion on benefit and risk in the shared decision-making process for stroke prevention between healthcare providers and nonvalvular atrial fibrillation patients. Clinical Trial Registration- URL: https://www.clinicaltrials.gov/ . Unique identifier: NCT03087487.

Background Direct oral anticoagulants (DOAC) are at least non-inferior to warfarin in efficacy and safety among patients with nonvalvular atrial fibrillation. Limited evidence is available regarding outcomes for nonvalvular atrial fibrillation patients with coronary/peripheral artery disease. Methods Non-valvular atrial fibrillation patients aged ≥65 years diagnosed with coronary/peripheral artery disease in the US Medicare population, newly initiating DOACs (apixaban, rivaroxaban, dabigatran) or warfarin were selected from January 1, 2013 to September 30, 2015. Propensity score matching was used to compare DOACs vs warfarin. Cox proportional hazards models were used to estimate the risk of stroke/systemic embolism, major bleeding, and composite of stroke/myocardial infarction/all-cause mortality. Results There were 15,527 apixaban-warfarin, 6,962 dabigatran-warfarin, and 25,903 rivaroxaban-warfarin–matched pairs, with a mean follow-up of 5-6 months. Compared with warfarin, apixaban was associated with lower rates of stroke/systemic embolism (hazard ratio [HR] 0.48; 95% confidence interval [CI], 0.37-0.62), major bleeding (HR 0.66; 95% CI, 0.58-0.75), and stroke/myocardial infarction/all-cause mortality (HR 0.63; 95% CI, 0.58-0.69); dabigatran and rivaroxaban were associated with lower rates of stroke/myocardial infarction/all-cause mortality (HR 0.79; 95% CI, 0.70-0.90 and HR 0.87; 95% CI, 0.81-0.92, respectively). Rivaroxaban was associated with a lower rate of stroke/systemic embolism (HR 0.72; 95% CI, 0.60-0.89) and a higher rate of major bleeding (HR 1.14; 95% CI, 1.05-1.23) vs warfarin. Conclusions All DOACs were associated with lower stroke/myocardial infarction/all-cause mortality rates compared with warfarin; differences were observed in rates of stroke/systemic embolism and major bleeding. Findings from this observational analysis provide important insights about oral anticoagulation therapy among non-valvular atrial fibrillation patients with coronary/peripheral artery disease and may help physicians in the decision-making process when treating this high-risk group of patients.

Poor quality of warfarin control (time in therapeutic range [TTR] 65%) can lead to increased risk of adverse events. The objective of this study was to examine the overall quality of international normalized ratio (INR) control and the association of TTR with clinical outcomes including stroke, major bleeding, and all-cause mortality among US warfarin users.This retrospective observational cohort study utilized the US Veterans Affairs electronic medical records database (VA EMR). Patients with NVAF who newly initiated warfarin from 1 January 2005 to 31 December 2015 were grouped into two cohorts based on TTR65% or ≥65%. TTR was computed from INR test results. Clinical outcomes assessed were stroke/systemic embolism (SE), hemorrhagic stroke, ischemic stroke, and major bleeding, defined based on hospitalization with those conditions as primary diagnosis, as well as all-cause mortality. Patients were followed from warfarin initiation to the first occurrence of an outcome or censoring. Propensity score weighted time-varying Cox regression was used to evaluate the risk of the clinical events. A total of 127,385 NVAF patients with mean TTR of 51% were included. TTR65% was observed in 65% of patients. Mean CHAThe observed quality of warfarin control in VA EMR suggests room for improvement given the association with elevated risk of adverse clinical outcomes.

Autosomal dominant polycystic kidney disease is a genetic disorder associated with substantial variability in its natural course within and between affected families. Understanding predictors for rapid progression of this disease has become increasingly important with the emergence of potential new treatments. This systematic review of the literature since 1988 evaluates factors that may predict and/or effect autosomal dominant polycystic kidney disease progression. Predicting factors associated with early adverse structural and/or functional outcomes are considered. These factors include PKD1 mutation (particularly truncating mutation), men, early onset of hypertension, early and frequent gross hematuria, and among women, three or more pregnancies. Increases in total kidney volume and decreases in GFR and renal blood flow greater than expected for a given age also signify rapid disease progression. Concerning laboratory markers include overt proteinuria, macroalbuminuria, and perhaps, elevated serum copeptin levels in affected adults. These factors and others may help to identify patients with autosomal dominant polycystic kidney disease who are most likely to benefit from early intervention with novel treatments.

To evaluate the burden of hyponatremia in terms of hospital resource utilization, costs, and 30-day hospital readmission among patients hospitalized for heart failure (HF) in routine clinical practice.Hyponatremic (HN) patients (≥18 years of age) with HF discharged between January 2, 2007 and March 31, 2010 were selected from the Premier Hospital Database and matched to non-HN HF patients using exact and propensity score matching. Univariate and multivariate statistics were utilized to compare hospital resource utilization (total and intensive care unit (ICU)) and associated costs and 30-day hospital readmission among cohorts.The study population included 51,710 subjects (HN = 25,855, non-HN = 25,855). In comparison to the non-HN cohort, length of stay (LOS) (7.7 ± 8.3 vs 6.3 ± 7.6 days, p 0.001), hospitalization cost ($13,339 ± $19,273 vs $10,475 ± 15,157, p 0.001), ICU LOS (4.9 ± 5.4 vs 4.2 ± 5.4 days, p 0.001) and ICU cost ($7195 ± $9522 vs $5618 ± 10,919, p 0.001) as well as rate of 30-day readmission (all cause: 25.3% vs 22.2%, p 0.001; hyponatremia-related: 21.4% vs 5.0%, p 0.001) were greater for the HN cohort. After adjustment, hyponatremia was associated with a 21.5% increase in hospital LOS, a 25.6% increase in hospital cost, a 13.7% increase in ICU LOS and a 24.6% increase in ICU cost. Additionally, hyponatremia was associated with increased risk of ICU admission (Odds Ratio (OR) = 1.58, [CI = 1.37, 1.84], p 0.001) and 30-day hospital readmission (all cause: OR = 1.19, [CI = 1.14, 1.24], p 0.001; hyponatremia-related: 5.10 [CI = 4.77, 5.46], p 0.001).Laboratory data for serum sodium level are not available in the Premier database and the severity of hyponatremia could not be established, although several patient variables were controlled for in this study by exact and propensity score matching techniques.Hyponatremia in HF patients is a predictor of increased hospital resource use and represents a potential target for intervention to reduce healthcare expenditures.

Hyponatremia is a frequent comorbid condition of patients hospitalized for cirrhosis and a predictor of disease severity and mortality. This study evaluated the healthcare burden of hyponatremia among patients hospitalized for cirrhosis in the real world.Hyponatremic (HN) patients (-18 years of age) with cirrhosis were identified using the Premier Hospital Database (January 1, 2007 to March 31, 2010) and matched to non-HN patients with cirrhosis using a combination of exact patient characteristics and propensity score matching. Univariate and multivariate statistics were utilized to compare hospital resource utilization, cost, and 30-day hospital re-admission among patient cohorts.The study population included 21,864 subjects (HN 10,932; non-HN 10,932). The hospital length of stay (LOS) (7.63 ± 7.4 vs. 5.89 ± 6.2 days; P0.001), hospital cost ($13,842 ± $20,702 vs. $11,140 ± $20,562; P0.001), intensive care unit (ICU) LOS (4.58 ± 4.7 vs. 3.59 ± 4.4 days; P0.001), and ICU cost ($7,038 ± $7,781 vs. $5,360 ± $7,557; P0.001) were greater for the HN cohort, as was the 30-day re-admission rate (all cause: 31.1% vs. 24.8%; P0.001; hyponatremia related: 25.1% vs. 11.0%; P0.001). Multivariate analysis showed that hyponatremia was associated with a 29.5% increase in hospital LOS, a 26.6% increase in overall hospital cost, a 23.2% increase in S. ICU LOS, and a 28.6% increase in ICU cost. Additionally, hyponatremia was associated with an increased risk of 30-day hospital re-admission (all cause: odds ratio [OR] 1.37; confidence interval [CI] 1.28-1.46; P0.001; hyponatremia related: OR 2.68; CI 2.48-2.90; P0.001).Hyponatremia in patients with cirrhosis is a predictor of increased hospital resource use and 30-day hospital re-admission, and represents a potential target for intervention to reduce healthcare expenditures for patients hospitalized for cirrhosis.

BackgroundAlternative treatment of dehydration is needed when intravenous (IV) or oral rehydration therapy fails. Subcutaneous (SC) hydration facilitated by recombinant human hyaluronidase offers an alternative treatment for dehydration. This clinical trial is the first to compare recombinant human hyaluronidase-facilitated SC (rHFSC) rehydration with standard IV rehydration for use in dehydrated children.ObjectiveThis Phase IV noninferiority trial evaluated whether rHFSC fluid administration can be given safely and effectively, with volumes similar to those delivered intravenously, to children who have mild to moderate dehydration.MethodsThe study included mild to moderately dehydrated children (Gorelick dehydration score) aged 1 month to 10 years. They were randomized to receive 20 mL/kg of isotonic fluids using rHFSC or IV therapy over 1 hour and then as needed until clinically rehydrated. The primary outcome was total volume of fluid administered (emergency department [ED] plus inpatient hospitalization). Secondary outcomes included mean volume infused in the ED alone, postinfusion dehydration scores and weight changes, line placement success and time, safety, and provider and parent/guardian questionnaire.Results148 patients (mean age, 2.3 [1.91] years]; white, 53.4%; black, 31.8%) were enrolled in the intention-to-treat population (73 rHFSC; 75 IV). The primary outcome, mean total volume infused, was 365.0 (324.6) mL in the rHFSC group over 3.1 hours versus 455.8 (597.4) mL in the IV group over 6.6 hours (P = 0.51). The secondary outcome of mean volume infused in the ED alone was 334.3 (226.40) mL in the rHFSC group versus 299.6 (252.33) mL in the IV group (P = 0.03). Dehydration scores and weight changes postinfusion were similar. Successful line placement occurred in all 73 rHFSC-treated patients and 59 of 75 (78.7%) IV-treated patients (P < 0.0001). All IV failures occurred in patients aged

BACKGROUND: Hyponatremia is a prevalent electrolyte disorder in hospitalized patients indicative of greater morbidity and mortality. A large-scale retrospective analysis was conducted to evaluate the incremental burden of hospitalized hyponatremic (HN) versus non-HN patients in terms of hospital resource utilization, costs, and hospital readmissions in the real-world setting. METHODS: HN patients (≥18 years) were selected from the Premier Hospital Database between January 1, 2007 and March 31, 2010 and matched to a non-HN control cohort using propensity score matching. Bivariate and multivariate statistics were employed to evaluate the differences in healthcare resource utilization, costs, and hospital readmissions between patient cohorts. RESULTS: Among the matched patient cohorts, length of stay (LOS) (8.8 ± 10.3 vs 7.7 ± 8.5 days, P < 0.001), hospital admission costs ($15,281 ± $24,054 vs $13,439 ± $22,198, P < 0.001), intensive care unit (ICU) LOS (5.5 ± 7.9 vs 4.9 ± 7.1 days, P < 0.001), and ICU costs ($8525 ± $13,342 vs $7597 ± $12,695, P < 0.001) were greater for the HN versus non-HN cohort, as were hospital readmission rates 30 days postdischarge. Multivariate regressions further demonstrated that hyponatremia was associated with an increase of 10.9% for LOS, 8.2% for total hospitalization costs, 10.2% for ICU LOS, and 8.9% for ICU costs. Additionally, after multivariate adjustment, hyponatremia was associated with a 15.0% increased chance for hospital readmission 30 days postdischarge (P < 0.0001). CONCLUSIONS: Hyponatremia is an independent predictor of increased hospitalization LOS and cost, ICU admission and cost, and 30-day hospital readmission, and therefore represents a potential target for intervention to reduce healthcare expenditures for a large population of hospitalized hyponatremic patients. Journal of Hospital Medicine 2012; © 2012 Society of Hospital Medicine

Tolvaptan is a member of a new class of drugs, called the vaptans, that antagonize receptors of the neurohormone arginine vasopressin. From a clinical perspective, tolvaptan has been shown to be efficacious in the treatment of hyponatremia, whether it is idiopathic or disease related, and it may have a more favorable benefit/risk profile than other treatment modalities. From an economic perspective, tolvaptan is an expensive drug for treating hyponatremia, but recent economic cost-offset models provide evidence that tolvaptan can be cost effective. The cost-effectiveness of tolvaptan is driven by reduced healthcare resource usage and hospitalization costs. More comparative research of tolvaptan versus other pharmacotherapies and analyses of patients treated with tolvaptan in the real world are needed to better determine the benefits of tolvaptan usage to patient outcome, and more accurately assess its value in the treatment of hyponatremia, an independent predictor of morbidity, mortality and cost.

Purpose This subgroup analysis of ARISTOPHANES study used multiple datasources to compare S/SE, MB, and their respective components among NVAF patients (pts) prescribed NOACs stratified by index dosage. Methods A retrospective observational study of NVAF pts initiating api, dabi, riva or warfarin from 01/01/2013–09/30/2015 was conducted using CMS Medicare data and four other US commercial claims databases, covering > 180 million beneficiaries. After propensity score matching (PSM) in each database between standard-dose NOACs (5 mg BID api–150 mg BID dabi, 5 mg BID api–20 mg QD riva, and 150 mg BID dabi–20 mg QD riva) and lower-dose NOACs (2.5 mg BID api-75 mg BID dabi, 2.5 mg BID api–10 or 15 mg QD riva, and 75 mg BID dabi–10 or 15 mg QD riva), the resulting patient records were pooled. Cox models were used to estimate hazard ratios of S/SE and MB. S/SE included ischemic stroke, hemorrhagic stroke, and SE; MB included gastrointestinal (GI) bleeding, intracranial hemorrhage (ICH), and other MB. Results Standard-dose api pts had a similar rate of S/SE but a lower rate of MB vs. standard-dose dabi; lower-dose api pts had a lower rate of S/SE and MB versus lower-dose dabi. In both standard and lower dose analyses, api was associated with a lower rate of S/SE and MB compared to riva. Compared to standard-dose riva, standard-dose dabi was associated with a similar rate of S/SE and lower rate of MB. Lower-dose dabi was associated with a higher rate of S/SE and similar rate of MB compared to lower-dose riva. Conclusions Among NVAF pts, both standard- and lower-dose api pts had lower rates of MB compared to corresponding doses of dabi and riva, respectively; both doses of api demonstrated lower rates of S/SE vs. corresponding doses of riva. The comparisons between dabi and riva showed varying results for S/SE and MB across dosage levels. Dose selection criteria cannot be ascertained from the current data sources. Future studies of pts who were appropriately dosed are warranted.

Background Limited real-world evidence exists on comparative effectiveness and safety of NOACs vs warf by NOAC dosage. Methods A retrospective observational study of NVAF patients (pts) newly initiating apixaban, dabigatran, rivaroxaban, or warfarin from 01 January 2013–30 September 2015 was conducted using CMS Medicare data and four other US commercial claims databases, covering > 180 million beneficiaries annually (∼56% of US population). After propensity score matching in each database between each standard NOAC dose and warfarin (5 mg BID api-warf, 150 mg BID dabi-warf, 20 mg QD riva-warf), as well as each lower NOAC dose and warf (2.5 mg BID api-warf, 75 mg BID dabi-warf, and 10 or 15 mg QD riva-warf), the resulting pts records were pooled. Cox models were used to estimate S/SE and MB hazard ratios. S/SE included ischemic stroke, hemorrhagic stroke, and SE; MB included gastrointestinal (GI) bleeding, intracranial hemorrhage (ICH), and other MB. Results Pts initiating lower and standard NOAC doses had different baseline characteristics, such as age and renal disease. Pts data were assessed for a mean of 7–8 months. Standard- and lower-dose api pts were each associated with lower rates of S/SE and MB vs warf. Standard and lower-dose dabi pts each had similar rates of S/SE compared to warf. Standard-dose dabi pts had a lower rate of MB and lower-dose dabi pts had a similar rate of MB vs warf. Standard-dose riva pts were associated with a lower S/SE rate, and lower-dose riva pts had a similar rate of S/SE compared to warf. Standard- and lower-dose riva pts were each associated with higher MB rates compared to warf. All doses of NOACs were associated with lower rates of ICH compared to warf. Conclusions In this large observational study, api was the only NOAC associated with lower rates of S/SE and MB for both doses compared to warf. Dose selection criteria cannot be ascertained from current data sources. Future studies of pts who were appropriately dosed should be warranted.

Most observational studies on direct oral anticoagulants (DOACs) used single data sources with limited generalizability. This ARISTOPHANES (Anticoagulants for Reduction In STroke: Observational Pooled analysis on Health outcomes ANd Experience of patientS) study aimed to use multiple data sources to

Atrial fibrillation (AF) is a common arrhythmia, contributing to ≥15% of strokes in the United States (US). Its often asymptomatic nature makes finding cases challenging, and 24.6% of AF cases remain undiagnosed. Research has focused on screening for AF to prevent stroke via timely intervention.

The objective of this systematic review and meta-analysis were to evaluate the effectiveness of high fluid intake for the prevention of incident and recurrent kidney stones, as well as its adherence and safety. A literature search was performed encompassing 1980 through July 2014. Studies that reported relative risks, odds ratios, or hazard ratios comparing the risk of kidney stone events in patients with high vs inadequate fluid intake were included. Pooled risk ratios (RRs) and 95 % confidence intervals (CIs) were calculated using a random-effect, generic inverse variance method. Nine studies [2 randomized controlled trials (RCTs) with 269 patients; 7 observational studies with 273,685 individuals] were included in the meta-analysis. Pooled RRs of kidney stones in individuals with high-fluid intake were 0.40 (95 % CI 0.20–0.79) and 0.49 (0.34–0.71) in RCTs and observational studies, respectively. High fluid intake was significantly associated with reduced risk of recurrent kidney stones: RRs 0.40 (95 % CI 0.20–0.79) and 0.20 (0.09–0.44) in RCTs and observational studies, respectively. Adherence and safety data on high fluid intake treatment were limited; 1 RCT reported no withdrawals due to adverse events. This analysis demonstrated a significantly reduced risk of incident kidney stones among individuals with high fluid consumption. High fluid consumption also reduced the risk of recurrent kidney stones. Furthermore, the magnitude of risk reduction was high. Although increased water intake appears to be safe, future studies on its safety in patients with high risk of volume overload or hyponatremia may be indicated.

A previously validated kinetic-pharmacodynamic model was applied to changes in a marker of bone resorption (serum C-telopeptide cross-links of type I collagen [sCTX]) using data from a large-scale clinical trial of ibandronate (Monthly Oral iBandronate In LadiEs [MOBILE]). The model showed rapid and significant suppression of sCTX compared to baseline with daily and monthly ibandronate, and gradual recovery of sCTX levels between monthly doses. This modeled, post-dose oscillatory pattern of sCTX paralleled significant increases in BMD and was associated with an acceptable safety profile for patients in MOBILE, suggesting that the between-dose recovery of sCTX does not negatively affect the efficacy of once-monthly ibandronate.

Hyponatremia is associated with higher morbidity and mortality rates among hospitalized patients. Our study evaluated health care utilization and associated costs of patients hospitalized with a primary diagnosis of hyponatremia.Hospitalized patients with a primary discharge diagnosis of hyponatremia (aged ≥ 18 years) were identified from the Premier Perspective™ database (January 1, 2007-March 31, 2010) and matched to non-hyponatremic (non-HN) patients using a combination of exact patient characteristic matching and propensity score matching. Univariate and multivariate statistics were used to compare hospital resource usage, costs, and 30-day readmission rates between cohorts.Hospital length of stay (LOS) (± standard deviation) (3.78 ± 3.19 vs 3.54 ± 3.26 days; P0.001) and cost ($5396 ± $6500 vs $4979 ± $6152; P0.001 for the hyponatremic [HN] and non-HN patient cohorts, respectively) were greater for the HN cohort, but intensive care unit (ICU) costs ($3554 ± $6463 vs $3484 ± $8510; P = 0.828) and ICU LOS (2.37 ± 3.47 vs 2.52 ± 3.87; P = 0.345) did not differ between cohorts. The ICU admission rate (7.9% vs 4.4%; P0.001), as well as the 30-day readmission rate (12.1% vs 2.9%; P0.001) were greater for the HN cohort. After adjustment for key patient characteristics, hyponatremia was associated with a 7.6% increase in hospital LOS, an 8.9% increase in hospital costs, and a 9% increase in ICU costs. Hyponatremia was associated with an increased risk of ICU admission (odds ratio, 1.89, confidence limits, 1.72, 2.07; P0.001) and 30-day hospital readmission for hyponatremia (odds ratio, 4.76; confidence limits, 4.31, 5.26; P0.001).Compared with non-HN patients, patients with a primary diagnosis of hyponatremia use a greater amount of hospital resources and represent a challenge to hospital profitability due to the increased likelihood of 30-day readmission.

With the tourism market climbing gradually out of recession, one might expect the ski operators to be looking forward to their first good winter in years. The signs are, however, that there will be little to celebrate this season. Although the winter holiday market grew by about 5 per cent in 1994, the ski holiday market shows little sign of a major recovery. In this paper the structure of the UK ski holiday market and the problems faced by operators in their marketing effort are analysed.

Growth hormone (GH) release from the anterior pituitary gland is predominantly regulated by the two antagonistic hypothalamic peptides, growth hormone-releasing hormone (GHRH) and somatostatin. Appraising endogenous GHRH action is thus made difficult by the confounding effects of (variable) hypothalamic somatostatin inhibitory tone. Accordingly, to evaluate endogenous GHRH actions, we used a clinical model of presumptively acute endogenous somatostatin withdrawal with concomitant GHRH release. To this end, we administered in randomized order placebo or the indirect cholinergic agonist, pyridostigmine, for 48 h to 13 healthy men of varying ages (29-77 years) and body mass indices (21-47 kg/m2). We sampled blood at 10-min intervals for 48 h during both placebo and pyridostigmine (60 mg orally every 6 h) administration, and used an ultrasensitive GH chemiluminescence assay (sensitivity 0.0002-0.005 microgram/l) to capture GH pulse profiles. Multiparameter deconvolution analysis was applied to quantitate the number, amplitude, mass, and duration of significant underlying GH secretory bursts, and simultaneously estimate the GH half-life and concurrent basal GH secretion. Approximate entropy was utilized as a novel regularity statistic to quantify the relative orderliness of the hormone release process. All measures of GH secretion/half-life and orderliness were statistically invariant across the two consecutive 24-h placebo sessions. In contrast, pyridostigmine treatment significantly increased the mean serum GH concentration from 0.23 +/- 0.054 microgram/l during placebo to 0.45 +/- 0.072 microgram/l during the first day of treatment (P < 0.01). There was also a significant rise in the calculated 24-h pulsatile GH production rate from 8.9 +/- 1.7 micrograms/l/day on placebo to 27 +/- 5.6 micrograms/l/day during active drug treatment (P < 0.01). Pyridostigmine significantly and selectively amplified GH secretory burst mass to 1.5 +/- 0.35 micrograms/l compared with 0.74 +/- 0.19 microgram/l on placebo (P < 0.01). This was attributable to stimulation of GH secretory burst amplitude (maximal rate of GH secretion attained within the release episode) with no prolongation of estimated burst duration. Basal GH secretion and approximate entropy were not altered by pyridostigmine. However, age was strongly related to more disorderly GH release during both days of pyridostigmine treatment (r = +0.79, P = 0.0013). During the second 24-h of continued pyridostigmine treatment, most GH secretory parameters decreased by 15-50%, but in several instances remained significantly elevated above placebo. Body mass index, but not age, was a significantly negative correlate of the pyridostigmine-stimulated increase in GH secretion (r = -0.65, P = 0.017). In summary, assuming that somatostatin is withdrawn and (rebound) GHRH release is stimulated via pyridostigmine administration, we infer that relatively unopposed GHRH action principally controls GH secretory burst mass and amplitude, rather than apparent GH secretory pulse duration, the basal GH secretion rate, or the serial regularity/orderliness of the GH release process in the human. Moreover, we infer that increasing age is accompanied by greater disorderliness of somatostatin-withdrawn GHRH, and hence rebound GH, release. The strongly negative correlation between pyridostigmine-stimulated GH secretion and body mass index (but not age) further indicates that increased relative adiposity may result in decreased effective (somatostatin-withdrawn) endogenous GHRH stimulus strength.

242 HYPONATREMIA IN HOSPITALIZED PATIENTS WITH CIRRHOSIS: INTERIM DATA FROM AN OBSERVATIONAL, PROSPECTIVE, MULTI-CENTER, GLOBAL HYPONATREMIA REGISTRY S. Sigal, A. Amin, J. Chiong, J. Dasta, A. Greenberg, J. Verbalis, J. Chiodo, K. Friend. New York University School of Medicine, New York, NY, University of California, Irvine, Loma Linda University, Loma Linda, CA, University of Texas College of Pharmacy, Austin, TX, Duke University Medical Center, Durham, NC, Georgetown University Medical Center, Washington, DC, Otsuka America Pharmaceutical, Inc., Princeton, NJ, USA E-mail: samuel.sigal@nyumc.org