Faculty Bibliography

OBJECTIVE:To review the role of the sodium-glucose cotransporter-2 (SGLT2) inhibitors in the management of type 2 diabetes (T2DM), including the effects on renal and cardiovascular (CV) outcomes. DATA SOURCES/METHODS:A literature search of MEDLINE databases (1964 through May 2018) was conducted utilizing key words sodium-glucose co-transporter-2 inhibitors, SGLT2 inhibitors, and diabetes; additional limits for drug names were added. STUDY SELECTION AND DATA EXTRACTION/METHODS:Available English-language data from reviews, abstracts, presentations, and clinical trials of use of SGLT2 therapy specifically detailing outcomes on CV and renal disease in humans were reviewed. DATA SYNTHESIS/RESULTS:This review will explore the role of the SGLT2 inhibitors on CV and renal outcomes in patients with T2DM. Relevance to Patient Care and Clinical Practice: A paradigm shift regarding the regulation of medications for the treatment of T2DM has resulted in the need for CV outcomes data as part of the drug approval process. Reduction of major CV events and progression of nephropathy in patients with T2DM represent major outcomes of clinical significance. Few medications have been able to establish a reduction in these end points; data for the use of SGLT2 inhibitors are favorable in this regard. CONCLUSION/CONCLUSIONS:The SGLT2 inhibitors represents a class of medications that reduce glucose levels via a novel and complementary mechanism. Emerging evidence suggests a plausible explanation for the observed reduction in adverse renal and CV outcomes in recent clinical trials. Questions remain whether these agents reduce renal disease risk greater than achievement of the same glycemic goals as other antidiabetics and whether CV and renal benefits are reproducible in high-risk patients with chronic kidney disease.

Idarucizumab, a fully humanized Fab antibody fragment, is indicated for reversal of dabigatran's anticoagulant activity. Idarucizumab neutralizes the anticoagulant effects of dabigatran by binding to dabigatran and its metabolite. In the full analysis of 503 patients, idarucizumab fully reversed the anticoagulant effect of dabigatran in more than 98% of patients. Real-world clinical experience with idarucizumab for dabigatran reversal remains limited. We report 11 real-world clinical cases in which idarucizumab was administered for dabigatran reversal in the setting of bleed (bleeding cohort n = 5) or emergent procedure (emergent procedure cohort, n = 6). Coagulation tests and clinical outcomes were assessed before and after idarucizumab administration. Clinical outcomes included thromboembolic events and hemostasis. The median (IQR) aPTT (seconds) before versus after idarucizumab was 40.4 (36.1) versus 27.3 (6.2) (bleeding cohort) and 50.1 (13.4) versus 26.5 (8.1) (emergent procedure cohort). The median (IQR) INR before and after idarucizumab was 2.0 (1.1) versus 1.2 (0.1) (bleeding cohort) and 1.1 (0.5) versus 1.1 (0.3) (emergent procedure cohort). Hemostasis was achieved in 4/5 patients in the bleeding cohort and 5/6 patients in the emergent procedure cohort. Thrombotic events occurred in four patients with a median time (IQR) from idarucizumab administration of 7.4 (4.3-14.7) days. Idarucizumab achieved adequate dabigatran reversal as evident by normalization of aPTT, INR, and achieving hemostasis. However, our data demonstrates a high thrombotic risk associated with dabigatran reversal with idarucizumab than previously reported.

Limited evidence is available to guide periprocedural management of oral anticoagulants in the setting of interventional radiology (IR) procedures. For direct oral anticoagulants, therapy interruption (TI) is based on medication half-life and procedural bleeding risk. Periprocedural management of warfarin includes INR monitoring, and possible bridging with parenteral anticoagulants. It is unknown if these recommendations apply to IR procedures. To evaluate bleeding complications and thromboembolic events following periprocedural management of the factor Xa (FXa) inhibitors or warfarin in patients undergoing IR procedures. We performed a retrospective, observational study at NYU Langone Health (NYULH) of all adult patients who underwent an IR procedure from January 2015 to July 2017 and were receiving apixaban, rivaroxaban, or warfarin. Patients who were pregnant or who had a mechanical heart valve were excluded. At NYULH, TI is not required for FXa inhibitors, and an INR < 3 is recommended for patients on warfarin undergoing low risk procedures. For moderate/high risk procedures, TI for 48 h or 72 h with reduced renal function, is recommended for FXa inhibitors, and an INR < 1.5 is recommended for patients on warfarin. We evaluated 350 IR procedures, with a total of 174 low bleeding risk and 176 moderate/high bleeding risk. The 30-day major bleeding rate was 0.9%, clinically relevant non-major bleeding rate was 3%, minor bleeding rate was 1% and thromboembolic event rate was 1%. The periprocedural oral anticoagulation management strategy at NYULH appears safe given the low 30-day incidence of bleeding and thromboembolic events.

The use of enoxaparin in specialty populations-including those with renal dysfunction, extremeness of body weight, pregnant patients, and pediatric patients-has not been studied in clinical trials. Monitoring anti-factor Xa activity (antiXa) as a surrogate to measure the activity of enoxaparin may be of interest. A case series of patients admitted to New York University Langone Health between December 2012 and July 2014 who received at least three consecutive doses of enoxaparin for the treatment of VTE and had a peak antiXa level drawn at steady state were evaluated. Patients were included if they were ≤ 18 years of age or if they were > 18 years of age and met one of the following criteria: pregnant, creatinine clearance (CrCl) ≤ 50 ml/min at the time of initiation of enoxaparin, or had a body weight ≤ 50 kg or ≥ 120 kg. A total of 31 patients were included in the analysis. The percentage of patients who achieved a therapeutic antiXa level (0.5-1.2 IU/mL for twice daily enoxaparin or 1-2 IU/mL for once daily enoxaparin) at the time of the first antiXa level drawn was greatest for the adult patients; however, the patients with renal impairment and low body weight were more likely to be sub-therapeutic at first antiXa level check. In addition, neonates and young children required increased enoxaparin doses to achieve therapeutic antiXa. Optimal dosing of enoxaparin in specialty populations has not been established. Furthermore, higher initial doses of enoxaparin may be needed in pediatric patients to attain therapeutic antiXa levels.

Background: Novoseven is a recombinant preparation of human factor VIIa (rFVIIa) indicated for the treatment of bleeding episodes and perioperative management. Aims: To evaluate the cost and utilization of rFVIIa at a large academic medical center. Methods: We performed a retrospective review. Data collection included baseline characteristics, past medical history, and antithrombotic use. Utilization of rVIIa included indication for use, number of doses, and blood product administration within 24 hours. Incidence of venous thromboembolism (VTE), stroke, transient ischemic attack (TIA), death from systemic embolism, myocardial infarction (MI), hypersensitivity, and disseminated intravascular coagulation (DIC) were also collected. The primary outcome was utilization and cost of rVIIa at NYULH. Secondary outcomes included compliance to NYULH off-label dosing guideline, blood product administration, adverse effects, and thromboembolic events. Results: The majority of rFVIIa use was for refractory bleeding after cardiac surgery. Dosing was according to NYULH guideline, lower, and higher than recommended in 76.5%, 3.9% and 17.6% of cases respectively. The costs of rVIIa decreased after development of the off-label dosing guideline and transition from blood bank to pharmacy. The total incidence of thromboembolic events within 30 days was 19.6%; 17.6% arterial and 2% venous. Seventy percent of patients with an adverse event were over 70 years of age. Use of rFVIIa reduced the median number of units of blood products administered. Conclusions: Administration of rFVIIa for cardiac surgery appears to be effective for hemostasis. Transitioning rFVIIa from the blood bank to pharmacy and implementation of a dosing guideline appears to have reduced costs. Patients receiving rFVIIa should be monitored for thromboembolic events. Elderly patients may be at higher risk for thromboembolic events and further literature is needed to determine the optimal use of rFVIIa or if other hemostatic agents may be warranted in this population

Cancer is a known hypercoagulable state that leads to an increased risk of venous thromboembolism (VTE). Low molecular weight heparin remains the preferred anticoagulant for VTE in patients with cancer over vitamin K antagonist. However, the preferred anticoagulant in prevention of stroke and systemic embolism in atrial fibrillation (AF) in patients with cancer has yet to be determined. The direct oral anticoagulants (DOACs) are increasingly being utilized; however their role in cancer has only recently been investigated. The objective of this retrospective cohort was to describe real-world anticoagulation prescribing patterns in cancer patients at a large academic medical center between January 1, 2013 and October 31, 2016. We sought to assess the safety, tolerability, and efficacy of DOACs in patients with cancer for either VTE and/or AF. Patient demographic, clinical characteristics, as well as bleeding and thrombotic events were collected. There were 214 patients in our analysis, of which 71 patients (33%) received a DOAC [apixaban (n = 22), dabigatran (n = 17), and rivaroxaban (n = 32)]. There were fewer bleeding events and/or discontinuations in the DOAC group compared to enoxaparin (13 vs. 27, p = 0.022). There was no difference in major or minor bleeds or thromboembolic events in comparing DOAC to enoxaparin or DOAC to warfarin. This was a retrospective, single-institution study assessing the safety and efficacy of DOACs compared to warfarin or enoxaparin in patients with cancer. DOACs may represent an alternative to warfarin or enoxaparin in patients with cancer for VTE and/or stroke reduction in AF.