Effectiveness and Safety of Oral Anticoagulants Among Nonvalvular Atrial Fibrillation Patients.

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.

Current treatment practice and outcomes. Report of the hyponatremia registry.

Current management practices for hyponatremia (HN) are incompletely understood. The HN Registry has recorded diagnostic measures, utilization, efficacy, and outcomes of therapy for eu- or hypervolemic HN. To better understand current practices, we analyzed data from 3087 adjudicated adult patients in the registry with serum sodium concentration of 130 mEq/l or less from 225 sites in the United States and European Union. Common initial monotherapy treatments were fluid restriction (35%), administration of isotonic (15%) or hypertonic saline (2%), and tolvaptan (5%); 17% received no active agent. Median (interquartile range) mEq/l serum sodium increases during the first day were as follows: no treatment, 1.0 (0.0-4.0); fluid restriction, 2.0 (0.0-4.0); isotonic saline, 3.0 (0.0-5.0); hypertonic saline, 5.0 (1.0-9.0); and tolvaptan, 4.0 (2.0-9.0). Adjusting for initial serum sodium concentration with logistic regression, the relative likelihoods for correction by 5 mEq/l or more (referent, fluid restriction) were 1.60 for hypertonic saline and 2.55 for tolvaptan. At discharge, serum sodium concentration was under 135 mEq/l in 78% of patients and 130 mEq/l or less in 49%. Overly rapid correction occurred in 7.9%. Thus, initial HN treatment often uses maneuvers of limited efficacy. Despite an association with poor outcomes and availability of effective therapy, most patients with HN are discharged from hospital still hyponatremic. Studies to assess short- and long-term benefits of correction of HN with effective therapies are needed.

Predictors of autosomal dominant polycystic kidney disease progression.

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.

Cost-effectiveness of recombinant human hyaluronidase-facilitated subcutaneous versus intravenous rehydration in children with mild to moderate dehydration.

OBJECTIVE: To evaluate the cost-effectiveness of recombinant human hyaluronidase-facilitated subcutaneous (rHFSC) fluid administration compared to intravenous (IV) fluid administration in children with mild to moderate dehydration in the emergency department (ED). METHODS: A decision analytic model was created based on the results of a controlled clinical trial that compared the administration of isotonic fluids via rHFSC or IV for rehydration. The costs were determined from the hospital's perspective. The effectiveness unit was successful rehydration in the ED without the need for hospitalization for continued hydration. Mean estimates were determined for both the cost and effectiveness of each treatment. The incremental differences in costs and effectiveness were determined between treatments. Sensitivity analysis testing was also conducted. RESULTS: The treatment success rate was 93% with rHFSC fluids and 76% for IV fluids. Across all ages, the mean cost of rHFSC fluids was $722, compared to $889 for IV fluids. The difference in effectiveness was due to the larger number of patients for whom IV access could not be established, necessitating a rescue route of administration to deliver parenteral fluids. The difference in the overall cost was primarily due to the shorter time in the ED for patients receiving rHFSC fluids versus those treated with IV fluids. The cost-effectiveness of rHFSC compared to IV was most apparent in younger patients (<3 years of age), where IV access was more difficult to obtain. CONCLUSION: Analysis of this clinical trial data revealed that rHFSC fluid administration demonstrated greater treatment effectiveness and cost-effectiveness than traditional IV fluid administration in the ED. The primary reasons for this were the ease of obtaining parenteral access via rHFSC in young patients (especially those under 3) where IV access is difficult, and a shorter ED stay with rHFSC fluid administration.

Disease Management and Outcomes in Patients Hospitalized for Acute Heart Failure in Japan.

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.

Clinical and Economic Outcomes Among Nonvalvular Atrial Fibrillation Patients With Coronary Artery Disease and/or Peripheral Artery Disease.

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.

Cost-Effectiveness of Extended and One-Time Screening Versus No Screening for Non-Valvular Atrial Fibrillation in the USA.

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.

Corrigendum to "Effectiveness and Safety of Oral Anticoagulants in Adults with Non-valvular Atrial Fibrillation Patients and Concomitant Coronary/Peripheral Artery Disease" American Journal of Medicine 131:09 (2018): 1074-1085.e4.

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.

Effectiveness and safety of oral anticoagulants in older adults with non-valvular atrial fibrillation and heart failure.

Direct oral anticoagulants (DOACs) are at least as efficacious and safe as warfarin among non-valvular atrial fibrillation (NVAF) patients; limited evidence is available regarding NVAF patients with heart failure (HF). US Medicare enrollees with NVAF and HF initiating DOACs (apixaban, rivaroxaban, dabigatran) or warfarin were selected. Propensity score matching and Cox models were used to estimate the risk of stroke/systemic embolism (SE), major bleeding (MB), and major adverse cardiac events (MACE) comparing DOACs versus warfarin and DOACs versus DOACs. We identified 10,570 apixaban-warfarin, 4,297 dabigatran-warfarin, 15,712 rivaroxaban-warfarin, 4,263 apixaban-dabigatran, 10,477 apixaban-rivaroxaban, and 4,297 dabigatran-rivaroxaban matched pairs. Compared to warfarin, apixaban had lower rates of stroke/SE (hazard ratio = 0.64, 95% confidence interval = 0.48-0.85), MB (hazard ratio = 0.66, 0.58-0.76), and MACE (hazard ratio = 0.73,0.67-0.79); dabigatran and rivaroxaban had lower rates of MACE (hazard ratio = 0.87,0.77-0.99; hazard ratio = 0.84, 0.79-0.89, respectively). Rivaroxaban had a lower stroke/SE rate (hazard ratio = 0.65, 0.52-0.81) and higher MB rate (hazard ratio = 1.18, 1.08-1.30) versus warfarin. Compared to dabigatran and rivaroxaban, apixaban had lower MB (hazard ratio = 0.71, 0.57-0.89; hazard ratio = 0.55, 0.49-0.63) and MACE rates (hazard ratio = 0.80, 0.69-0.93; hazard ratio = 0.86, 0.79-0.94), respectively. All DOACs had lower MACE rates versus warfarin; differences were observed in stroke/SE and MB. Our findings provide insights about OAC therapy among NVAF patients with HF.

Outcomes associated with warfarin time in therapeutic range among US veterans with nonvalvular atrial fibrillation.

BACKGROUND: 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. METHODS AND RESULTS: 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 TTR <65% 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. TTR <65% was observed in 65% of patients. Mean CHA2DS2-VASC score (SD) was 2.9 (1.5) in the low TTR cohort and 2.7 (1.4) in the high TTR cohort. Patients with TTR <65% had a higher risk for any stroke/SE (HR: 1.57; 95% CI: 1.41-1.75), major bleeding (HR: 2.78; 95% CI: 2.55-3.03) and all-cause mortality (HR: 1.73; 95% CI: 1.67-1.79). CONCLUSIONS: The observed quality of warfarin control in VA EMR suggests room for improvement given the association with elevated risk of adverse clinical outcomes.

Apixaban 5 and 2.5 mg twice-daily versus warfarin for stroke prevention in nonvalvular atrial fibrillation patients: Comparative effectiveness and safety evaluated using a propensity-score-matched approach.

Prior real-world studies have shown that apixaban is associated with a reduced risk of stroke/systemic embolism (stroke/SE) and major bleeding versus warfarin. However, few studies evaluated the effectiveness and safety of apixaban according to its dosage, and most studies contained limited numbers of patients prescribed 2.5 mg twice-daily (BID) apixaban. Using pooled data from 4 American claims database sources, baseline characteristics and outcomes for patients prescribed 5 mg BID and 2.5 mg BID apixaban versus warfarin were compared. After 1:1 propensity-score matching, 31,827 5 mg BID apixaban-matched warfarin patients and 6600 2.5 mg BID apixaban-matched warfarin patients were identified. Patients prescribed 2.5 mg BID apixaban were older, had clinically more severe comorbidities, and were more likely to have a history of stroke and bleeding compared with 5 mg BID apixaban patients. Compared with warfarin, 5 mg BID apixaban was associated with a lower risk of stroke/SE (hazard ratio [HR]: 0.70, 95% confidence interval [CI]: 0.60-0.81) and major bleeding (HR: 0.59, 95% CI: 0.53-0.66). Compared with warfarin, 2.5 mg BID apixaban was also associated with a lower risk of stroke/SE (HR: 0.63, 95% CI: 0.49-0.81) and major bleeding (HR: 0.59, 95% CI: 0.49-0.71). In this real-world study, both apixaban doses were assessed in 2 patient groups differing in age and clinical characteristics. Each apixaban dose was associated with a lower risk of stroke/SE and major bleeding compared with warfarin in the distinct population for which it is being prescribed in United States clinical practice. TRIAL REGISTRATION: Clinicaltrials.Gov Identifier: NCT03087487.

Effectiveness and Safety of Anticoagulants in Adults with Non-valvular Atrial Fibrillation and Concomitant Coronary/Peripheral Artery Disease.

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.

Effectiveness and safety of apixaban versus warfarin in non-valvular atrial fibrillation patients in "real-world" clinical practice. A propensity-matched analysis of 76,940 patients.

The 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.

Modeling of serum C-telopeptide levels with daily and monthly oral ibandronate in humans.

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.

Treatment effect, adherence, and safety of high fluid intake for the prevention of incident and recurrent kidney stones: a systematic review and meta-analysis.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Health care utilization, costs, and readmission rates associated with hyponatremia.

PURPOSE: 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. METHODS: 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. RESULTS: Hospital length of stay (LOS) (± standard deviation) (3.78 ± 3.19 vs 3.54 ± 3.26 days; P < 0.001) and cost ($5396 ± $6500 vs $4979 ± $6152; P < 0.001 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%; P < 0.001), as well as the 30-day readmission rate (12.1% vs 2.9%; P < 0.001) 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; P < 0.001) and 30-day hospital readmission for hyponatremia (odds ratio, 4.76; confidence limits, 4.31, 5.26; P < 0.001). CONCLUSION: 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.

Hyponatremia-associated healthcare burden among US patients hospitalized for cirrhosis.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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; P < 0.001), hospital cost ($13,842 ± $20,702 vs. $11,140 ± $20,562; P < 0.001), intensive care unit (ICU) LOS (4.58 ± 4.7 vs. 3.59 ± 4.4 days; P < 0.001), and ICU cost ($7,038 ± $7,781 vs. $5,360 ± $7,557; P < 0.001) were greater for the HN cohort, as was the 30-day re-admission rate (all cause: 31.1% vs. 24.8%; P < 0.001; hyponatremia related: 25.1% vs. 11.0%; P < 0.001). 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; P < 0.001; hyponatremia related: OR 2.68; CI 2.48-2.90; P < 0.001). CONCLUSION: 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.

Healthcare resource burden associated with hyponatremia among patients hospitalized for heart failure in the US.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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). LIMITATIONS: 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. CONCLUSIONS: Hyponatremia in HF patients is a predictor of increased hospital resource use and represents a potential target for intervention to reduce healthcare expenditures.

Update on tolvaptan for the treatment of hyponatremia.

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.