Direct Oral Anticoagulants in Obesity: An Updated Literature Review.

OBJECTIVE: To review literature on the use of direct-acting oral anticoagulants (DOACs) in patients with high body weight (BW) and/or high body mass index (BMI) and to make recommendations regarding use in this patient population. DATA SOURCES: A search using PubMed was conducted (inception to April 13, 2020) using the term DOAC AND the terms obesity OR body weight. A separate search was also conducted with individual DOACs (dabigatran, apixaban, rivaroxaban, edoxaban) and the aforementioned terms. STUDY SELECTION AND DATA EXTRACTION: Studies included examined the effect of BW and/or BMI on DOAC pharmacokinetics, efficacy, or safety. Included studies had DOAC indications of prevention of stroke in nonvalvular atrial fibrillation, or treatment or long-term prevention of venous thromboembolism. DATA SYNTHESIS: The efficacy and safety of DOACs in patients with high BW/BMI has not yet been elucidated by randomized trials; however, 2016 international guidelines suggest avoiding their use in patients with a BW >120 kg or BMI >40 kg/m2. Since 2016, several studies have been published examining use of DOACs in this patient population. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This review thoroughly discusses the literature on DOACs in patients with a BW >120 kg or BMI >40 kg/m2 pre-2016 and post-2016 guidelines. CONCLUSIONS: Evidence indicates that each DOAC may have differences in outcomes when used in patients with a high BW/BMI. Currently, low-quality data are available that support avoiding dabigatran and considering apixaban or rivaroxaban; lack of sufficient data preclude a recommendation for edoxaban use in this patient population.

HIV Clinical Updates: New Single-Tablet Regimens.

OBJECTIVE: To review the pharmacokinetics, safety, common drug-drug interactions (DDIs), and advantages and disadvantages of new single-tablet regimens (STRs) approved since September 2016 for HIV-1 infection. DATA SOURCES: A search using PubMed was conducted (2004 through May 2018) using the following keywords: single tablet regimen AND HIV. Additionally, a PubMed search was conducted for each individual STR using the generic names of the agents. For specific STRs, additional search terms were added to narrow results. Articles were evaluated for content, and additional references were identified from a review of literature citations. Conference abstracts from national and international HIV conferences were also searched. STUDY SELECTION AND DATA EXTRACTION: Studies included were published randomized controlled trials and observational studies that evaluated STR approved since September 2016. Relevant conference abstracts were included if the study design was a randomized controlled trial or observational study pertaining to the STRs included. DATA SYNTHESIS: Four new STRs are available, including the first dual antiretroviral therapy (ART) regimen for virologically suppressed patients. Of the STRs, only 1 is a new molecular entity, and others include new combinations of existing agents that result in distinct advantages and disadvantages. Relevance to Patient Care and Clinical Practice: The treatment of HIV-1 continues to improve with new agents developed rapidly. These agents should be analyzed in regard to efficacy, safety, DDIs, and appropriateness for specific patients on an individual basis. CONCLUSIONS: STRs and agents in the pipeline continue to simplify ART regimens, increase medication adherence, and minimize toxicities.

Rapidity of Correction of Hyponatremia Due to Syndrome of Inappropriate Secretion of Antidiuretic Hormone Following Tolvaptan.

BACKGROUND: Tolvaptan effectively corrects hyponatremia due to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), but undesired overcorrection can occur. We hypothesized that pretherapy parameters can predict the rapidity of response to tolvaptan in SIADH. STUDY DESIGN: Multicenter historical cohort study. SETTING & PARTICIPANTS: Adults with SIADH or congestive heart failure (CHF) treated with tolvaptan for a serum sodium concentration ≤ 130 mEq/L at 5 US hospitals. PREDICTORS: Demographic and laboratory parameters. OUTCOMES: Rate of change in serum sodium concentration. MEASUREMENTS: Spearman correlations, analysis of variance, and multivariable linear mixed-effects models. RESULTS: 28 patients with SIADH and 39 patients with CHF treated with tolvaptan (mean baseline serum sodium, 120.6 and 122.4 mEq/L, respectively) were studied. Correction of serum sodium concentration > 12 mEq/L/d occurred in 25% of patients with SIADH compared to 3% of those with CHF (P<0.001). Among patients with SIADH, the increase in serum sodium over 24 hours was correlated with baseline serum sodium concentration (r=-0.78; P<0.001), serum urea nitrogen concentration (SUN; r=-0.76; P<0.001), and estimated glomerular filtration rate (r=0.58; P=0.01). Baseline serum sodium and SUN concentrations were identified as independent predictors of change in serum sodium concentration in multivariable analyses. When patients were grouped into 4 categories according to baseline serum sodium and SUN median values, those with both low baseline serum sodium (≤121 mEq/L) and low baseline SUN concentrations (≤10mg/dL) exhibited a significantly greater rate of increase in serum sodium concentration (mean 24-hour increase of 15.4 mEq/L) than the other 3 categories (P<0.05). Among patients with CHF, only baseline SUN concentration was identified as an independent predictor of change in serum sodium concentration over time. LIMITATIONS: Lack of uniformity in serial serum sodium concentration determinations and documentation of water intake. CONCLUSIONS: Baseline serum sodium and SUN values are predictive of the rapidity of hyponatremia correction following tolvaptan use in SIADH. We advise caution when dosing tolvaptan in patients with both low serum sodium and SUN concentrations.

Sofosbuvir/Velpatasvir/Voxilaprevir: A Pan-Genotypic Direct-Acting Antiviral Combination for Hepatitis C.

OBJECTIVES: To review the efficacy and safety of sofosbuvir/velpatasvir/voxilaprevir in the treatment of hepatitis C virus (HCV) infection. DATA SOURCES: A literature search through PubMed was conducted (August 2010 to August 2017) using the terms GS-9857, voxilaprevir, and NS3/4A protease inhibitor. STUDY SELECTION/DATA EXTRACTION: Studies of sofosbuvir/velpatasvir/voxilaprevir were identified. DATA SYNTHESIS: Sofosbuvir/velpatasvir/voxilaprevir is indicated for adult patients with chronic HCV without cirrhosis or with compensated cirrhosis who have (1) genotype 1 through 6 and have previously been treated with an NS5A inhibitor or (2) genotype 1a or 3 and have previously been treated with sofosbuvir without an NS5A inhibitor. POLARIS-1 demonstrated that sofosbuvir/velpatasvir/voxilaprevir for 12 weeks was highly effective in patients with HCV genotype 1 through 6 who had prior exposure to an NS5A inhibitor. POLARIS-2 failed to demonstrate that sofosbuvir/velpatasvir/voxilaprevir for 8 weeks was noninferior to sofosbuvir/velpatasvir for 12 weeks in patients with HCV genotype 1 through 6 who had no prior exposure to direct-acting antivirals (DAAs). POLARIS-3 demonstrated that sofosbuvir/velpatasvir/voxilaprevir for 8 weeks was as effective as sofosbuvir/velpatasvir for 12 weeks in patients with HCV genotype 3 and compensated cirrhosis who had no prior exposure to DAAs. POLARIS-4 demonstrated that sofosbuvir/velpatasvir/voxilaprevir was as effective as sofosbuvir/velpatasvir for 12 weeks in patients with HCV genotype 1 through 3 who had prior exposure to DAAs but not an NS5A inhibitor. The most common adverse reactions were headache, fatigue, diarrhea, and nausea. CONCLUSIONS: Sofosbuvir/velpatasvir/voxilaprevir is safe and effective to treat HCV in patients who have previously been treated with DAAs.

Safety and effectiveness of direct oral anticoagulants following ultrasound-assisted catheter directed thrombolysis for venous thromboembolism.

Ultrasound-assisted catheter-directed thrombolysis (USAT) is a novel approach for the treatment of venous thromboembolism (VTE) that is thought to be associated with a decreased risk of bleeding. Direct oral anticoagulants (DOACs) are approved for the treatment of VTE but have not been studied in a post-fibrinolysis setting. The intention of this retrospective observational study was to determine the safety and effectiveness of DOACs compared to the vitamin-K-antagonist (VKA) warfarin following USAT in patients with documented VTE. Included patients were aged 18 years or older who had documented VTE and received oral anticoagulation with either a DOAC or VKA following USAT. The primary outcome of this study was to compare the 90-day composite incidence of major and minor bleeding and recurrent VTE between patients receiving DOACs after USAT to those receiving VKA after USAT. Similar rates of bleeding and recurrent VTE were observed (4/42; 9.5% in the DOAC group versus 2/34; 5.9% in the VKA group). The use of DOAC therapy post-USAT for VTE was not associated with higher rates of 90-day major or minor bleeding or 90-day recurrent VTE.

Single-Tablet Regimens for the Treatment of HIV-1 Infection.

OBJECTIVE: To review the pharmacokinetics, safety, drug-drug interactions, and advantages and disadvantages of currently available single-tablet regimens (STRs) for HIV-1 infection. DATA SOURCES: A search using PubMed was conducted (up to September 2016) using the following keywords: single tablet regimen AND HIV. Additionally, a PubMed search was conducted for each individual STR using the generic names of the agents. Articles were evaluated for content, and additional references were identified from a review of literature citations. STUDY SELECTION AND DATA EXTRACTION: Studies included were predominantly phase III clinical trials with the exception of tenofovir alafenamide because phase I and phase II trials were also relevant for this new antiretroviral agent. DATA SYNTHESIS: Six STRs are currently available for the treatment of HIV-1. Each agent has unique pharmacokinetic, safety, and drug-drug interaction profiles that result in distinct advantages and disadvantages. Three of these agents are first-line recommended therapies per national guidelines because of high virological efficacy and tolerability. CONCLUSIONS: STRs have significantly advanced HIV management by minimizing pill burden and improving patient compliance. It is important to consider the nuances of each STR in regard to renal and hepatic function, drug interactions, and tolerability, to ensure safe and effective use.

Evaluating the safety and effectiveness of venous thromboembolism prophylaxis in patients with sickle cell disease.

Nearly every component of hemostasis is altered in sickle cell disease (SCD), yet little evidence exists to guide utilization of venous thromboembolism prophylaxis (VTEP) in this population. This retrospective cohort study included 135 adult patients admitted with a diagnosis of SCD vaso-occlusive crisis to the general medicine service at a tertiary care academic medical center from August 1, 2011 to August 1, 2013. If VTEP was discontinued, the medical record was reviewed for suspicion of VTE, hemorrhage, heparin-induced thrombocytopenia (HIT), or other adverse events. The primary objective was to characterize the safety and effectiveness of VTEP in SCD. The secondary objective was to assess the correlation of VTE with risk factors documented in the general medical population. Most patients (116/135, 85.9%) were prescribed VTEP upon admission, with early discontinuation in 23 patients (19.8%). Reasons for discontinuation included suspicion of VTE (10/116, 8.6%), hemorrhage (5/116, 4.3%), and/or HIT (4/116, 3.4%). Since patients with SCD receiving standard VTEP regimens appear to have similar outcomes compared to medically ill patients in prospective studies, using these regimens appears to be safe when indicated in the opinion of the provider. Once daily injections may be preferred in order to optimize adherence.

Factors associated with bleeding after ultrasound-assisted catheter-directed thrombolysis for the treatment of pulmonary embolism.

Ultrasound-assisted catheter directed thrombolysis (US-CDT) is frequently used for the treatment of pulmonary embolism. Due to the variety of thrombolytic and anticoagulant dosing utilized in practice, patients with pulmonary embolism who undergo US-CDT may be at an increased risk of bleeding. The primary objective of this study was to determine factors associated with major bleeding occurring with US-CDT. Secondary outcomes included in-hospital mortality and ventilator-free days. This multicentre retrospective cohort study evaluated inpatients diagnosed with pulmonary embolism and treated with US-CDT and systemic anticoagulation. A total of 173 patients were included. Most patients receiving US-CDT had a submassive pulmonary embolism with a median Pulmonary Embolism Severity Index (PESI) score of 85. Major bleeding events occurred in 37 of the 173 patients (21%). In-hospital mortality occurred in four (11%) of the patients who experienced major bleeding and three (2%) patients who did not experience major bleeding (P = 0.04). Factors associated with a higher risk of major bleeding included female sex and anticoagulation strategy. The odds of major bleeding were 3.3 times higher for women than for men (odds ratio = 3.32, 95% confidence interval 1.29-8.54). In addition, for each second increase in goal aPTT the odds of major bleeding increased by 5% (odds ratio = 1.05, 95% confidence interval 1.02-1.09). In patients with pulmonary embolism treated with US-CDT, major bleeding may be underestimated. In this analysis, major bleeding was associated with female sex and higher goal aPTT levels. In addition, bleeding with US-CDT was associated with a higher risk of in-hospital mortality.

Multi-center retrospective study evaluating the efficacy and safety of apixaban versus warfarin for treatment of venous thromboembolism in patients with severe obesity.

STUDY OBJECTIVE: Direct oral anticoagulants are the standard of care for venous thromboembolism (VTE) treatment. These agents are recommended regardless of patient weight and body mass index (BMI). However, there remains limited evidence supporting the use of apixaban in patients with severe obesity with a BMI ≥40 kg/m2 or weight ≥120 kg. The purpose of this study was to evaluate the efficacy and safety of apixaban for VTE in patients with a BMI ≥40 kg/m2 or weight ≥120 kg. DESIGN: This multi-center, retrospective study compared the use of apixaban versus warfarin in patients with severe obesity for the treatment of VTE between January 1, 2012, and December 31, 2019. Patients were identified by diagnosis codes for acute VTE and a weight ≥120 kg or BMI ≥40 kg/m2 . The primary efficacy outcome was time to recurrence of VTE within 12 months, and the primary safety outcome was time to major bleeding within 12 months. Secondary outcomes included incidence of recurrent VTE, major bleeding, clinically relevant non-major bleeding (CRNMB), all-cause mortality, number of total hospital encounters, and switch in anticoagulant. MAIN RESULTS: A total of 1099 patients were included in the study. Of these, 314 patients received apixaban and 785 received warfarin. The mean weight and BMI were 137 kg and 46 kg/m2 , respectively. Time to recurrent VTE was significantly longer in those treated with apixaban compared to warfarin (p = 0.018). After controlling for confounding factors, apixaban use was associated with a reduced risk of recurrent VTE compared to warfarin (hazard ratio [HR] = 0.54, 95% confidence interval [CI]: 0.29-0.97, p = 0.04). There were no significant differences in major bleeding, CRNMB, or all-cause mortality between groups. CONCLUSION: In patients with a BMI ≥40 kg/m2 or weight ≥120 kg, apixaban appears to be effective and safe for the treatment of VTE.

An immunohistochemical comparison between MiTF and MART-1 with Azure blue counterstaining in the setting of solar lentigo and melanoma in situ.

BACKGROUND: Evaluation of cutaneous pigmented lesions can be diagnostically challenging and represents an activity often supplemented by immunohistochemistry. Immunohistochemical studies typically employ 3,3'-diaminobenzidine (DAB) resulting in brown staining of both melanocytes and melanin. Difficulty may thus arise in distinguishing different cell types in heavily melanized lesions. Azure blue counterstaining has been used in conjunction with melanoma antigen recognized by T-cells (MART-1) to differentiate melanocytes from melanin by highlighting the latter blue-green. Microphthalmia transcription factor (MiTF) represents an alternative immunomarker that shows nuclear reactivity, which facilitates ease of interpretation. METHODS: Twenty examples of solar lentigo and melanoma in situ (MIS) were independently evaluated utilizing MiTF and MART-1/Azure blue for melanocyte quantification. Melanocyte counts were averaged over five high-power fields (×400) to obtain a mean melanocytic count. RESULTS: There was no significant difference in the mean melanocytic count between MART-1/Azure blue and MiTF as assessed in the solar lentigo group and as assessed independently in the MIS group. MiTF nuclear staining facilitated interpretation and required less laboratory preparation, as an additional counterstain was not necessary. CONCLUSIONS: MiTF is as effective as MART-1/Azure blue in identifying melanocytes in the context of solar lentigo or MIS. On the basis of our results, we favor expanding the use of MiTF as an immunohistochemical marker, as it provides an efficient alternative to MART-1 with Azure blue counterstaining in the evaluation of cutaneous pigmented lesions.

Hyperammonemia in azotemic cats.

OBJECTIVES: Hyperammonemia occurs in cats with hepatobiliary and nutritional (cobalamin and arginine deficiency) disorders, and has also been documented in four cats with renal azotemia. We hypothesized that in cats with renal azotemia, fasting hyperammonemia would correlate with indices of worsening kidney function, and would be independent of cobalamin, potassium, systemic inflammation or urinary tract infection (UTI) with urease-producing bacteria. METHODS: A fasted blood sample was prospectively collected for ammonia and cobalamin analysis from 18 client-owned cats with renal azotemia (creatinine [Cr] ⩾1.6 mg/dl, urine specific gravity <1.030 or documentation of historical chronic kidney disease [CKD]). Correlations between blood ammonia and selected biochemical parameters were analyzed using Pearson's correlation coefficient. RESULTS: Seven castrated males and 11 spayed females with a median age of 12 years (range 4-19 years) were enrolled. Ten of 18 (56%) cats presented for acute kidney injury (AKI) or acute on chronic kidney disease (AoCKD), and 8/18 (44%) presented for progressive CKD. The median Cr was 5.9 mg/dl (range 1.9-24.7 mg/dl). Hyperammonemia was documented in 4/18 (22%) cats, with a median of 95 µmol/dl (range 85-98 µmol/dl), and all four of these cats were classified as AKI/AoCKD. Blood ammonia concentrations had a significant moderate positive correlation between blood urea nitrogen (BUN) (r = 0.645, P = 0.003), Cr (r = 0.578, P = 0.012) and serum phosphorus (r = 0.714, P = 0.0009) but not with cobalamin, potassium or white blood cell count. No cats had UTIs with urease-producing bacteria. CONCLUSIONS AND RELEVANCE: A correlation exists between blood ammonia and BUN, Cr and phosphorus in cats with renal azotemia. Future studies are warranted in a larger population of cats to determine the true prevalence, etiology and potential therapeutic effect of medical management of hyperammonemia on long-term prognosis in cats with kidney disease.

Therapeutic plasma exchange to mitigate flunixin meglumine overdose in a cria.

OBJECTIVE: To describe the use of therapeutic plasma exchange (TPE) in the treatment of flunixin meglumine overdose in a cria. CASE SUMMARY: A 3-day-old alpaca cria was diagnosed with ureteral obstruction and agenesis resulting in severe bilateral hydronephrosis. During hospitalization, the cria inadvertently received a flunixin meglumine overdose of >65 mg/kg. Here, we report the use of lipid emulsion and TPE to mitigate flunixin meglumine toxicosis. TPE appeared to prevent any flunixin-induced kidney or gastrointestinal injury, even in a patient with congenital defects of the urinary tract. NEW INFORMATION PROVIDED: This is the first report of the use of TPE in a cria.

Evaluation of an antimicrobial stewardship approach to minimize overuse of antibiotics in patients with asymptomatic bacteriuria.

An antimicrobial stewardship educational initiative provided to physicians and pharmacists was evaluated at an academic medical center to minimize inappropriate treatment of asymptomatic bacteriuria (ASB). A significant decrease in empirical antimicrobial use for ASB was observed after education. Multifaceted educational initiatives can reduce inappropriate antimicrobial treatment of ASB.