Marisa Battistella

Systematic Review of the Risk of Adverse Outcomes Associated with Vascular Endothelial Growth Factor Inhibitors for the Treatment of Cancer

Background Anti-angiogenic therapy targeted at vascular endothelial growth factor (VEGF) is now used to treat several types of cancer. We did a systematic review of randomized controlled trials (RCTs) to summarize the adverse effects of vascular endothelial growth factor inhibitors (VEGFi), focusing on those with vascular pathogenesis. Methods and Findings We searched MEDLINE, EMBASE and Cochrane Library until April 19, 2012 to identify parallel RCTs comparing a VEGFi with a control among adults with any cancer. We pooled the risk of mortality, vascular events (myocardial infarction, stroke, heart failure, and thromboembolism), hypertension and new proteinuria using random-effects models and calculated unadjusted relative risk (RR). We also did meta-regression and assessed publication bias. We retrieved 83 comparisons from 72 studies (n = 38,078) on 11 different VEGFi from 7901 identified citations. The risk of mortality was significantly lower among VEGFi recipients than controls (pooled RR 0.96, 95% confidence interval [CI] 0.94 to 0.98, I2 = 0%, tau2 = 0; risk difference 2%). Compared to controls, VEGFi recipients had significantly higher risk of myocardial infarction (MI) (RR 3.54, 95% CI 1.61 to 7.80, I2 = 0%, tau2 = 0), arterial thrombotic events (RR 1.80, 95% CI 1.24 to 2.59, I2 = 0%, tau2 = 0); hypertension (RR 3.46, 95% CI 2.89 to 4.15, I2 = 58%, tau2 = 0.16), and new proteinuria (RR 2.51, 95% CI 1.60 to 3.94, I2 = 87%, tau2 = 0.65). The absolute risk difference was 0.8% for MI, 1% for arterial thrombotic events, 15% for hypertension and 12% for new proteinuria. Meta-regression did not suggest any statistically significant modifiers of the association between VEGFi treatment and any of the vascular events. Limitations include heterogeneity across the trials. Conclusions VEGFi increases the risk of MI, hypertension, arterial thromboembolism and proteinuria. The absolute magnitude of the excess risk appears clinically relevant, as the number needed to harm ranges from 7 to 125. These adverse events must be weighed against the lower mortality associated with VEGFi treatment.

Long-term Follow-up of the Hemodialysis Infection Prevention With Polysporin Ointment (HIPPO) Study: A Quality Improvement Report

BACKGROUND Infection is a common and serious complication in hemodialysis patients accessed using central venous catheters (CVCs). Previously, a randomized double-blinded trial (HIPPO [Hemodialysis Infection Prevention With Polysporin Ointment] Study) showed that application of a topical polyantibiotic ointment at the CVC exit site decreased CVC-related infections, including bacteremias and their adverse consequences. Based on this studys results, our institution implemented a policy of routine topical polyantibiotic ointment application for CVC-related infection prophylaxis. The main purpose of this prospective observational study was to determine whether the low rate of CVC-related infection achieved by topical polyantibiotic ointment use during a randomized controlled trial would be observed during long-term prophylaxis as part of routine clinical care. STUDY DESIGN Quality improvement report. SETTING & PARTICIPANTS All adult long-term hemodialysis patients using a tunneled cuffed CVC in a large university-affiliated outpatient hemodialysis program in 2004-2009 were included. QUALITY IMPROVEMENT PLAN To prospectively monitor the impact of a policy-wide strategy of topical polyantibiotic ointment application at CVC exit sites (1 time/wk) as infection prophylaxis. A multidisciplinary team approach to the surveillance, prospective tracking, and management of hemodialysis CVC-related infection was used. OUTCOMES & MEASUREMENTS Rates of CVC-related infections (exit-site infections and bacteremias), percentages of contributing organisms, and consequences of CVC-related infections. RESULTS After 6 years, CVC exit-site infection and bacteremia rates remained low (<1.0/1,000 catheter-days). Gram-positive organisms accounted for 61.2% of exit-site infections and 72.1% of bacteremias. LIMITATIONS A center effect of the same institution conducting the randomized trial and the quality improvement study may limit the studys generalizability to other centers. The impact of possible unmeasured cointerventions cannot be excluded. CONCLUSION Long-term use of topical antibiotic application at CVC exit sites resulted in a sustained decrease in all CVC-related infections. A multidisciplinary effort to monitor and track outcomes allowed safe and effective implementation of a new prophylactic strategy.

Evaluating time in therapeutic range for hemodialysis patients taking warfarin.

Warfarin is frequently used in the hemodialysis (HD) population for atrial fibrillation (AF) and venous thromboembolism (VTE); however, there is insufficient evidence to support this practice. Given that HD patients have 3 - 10 times the risk for both stroke and bleeding than the general population, anticoagulation in these patients is controversial. Time in therapeutic range (TTR) is accepted as a surrogate outcome of clinical effectiveness and safety of warfarin. The primary objective of this study was to evaluate TTR in an HD population. A 6-year retrospective chart review was performed in 46 HD patients on warfarin (target international normaized ratio (INR)=2-3). One year of patient data was collected, which included weekly INRs, demographics and clinical outcomes. TTR was calculated using the Rosendaal and fraction of INRs in range methods. The mean TTR using the Rosendaal and fraction of INRs in range method was 49.2±14.6% and 44.2±13.5%, respectively. Patients were 3 times more likely to be below target than above it, suggesting they were more often at risk of inadequate efficacy rather than toxicity. There were 9 serious bleeding and 9 thrombotic events; these occurred in patients with a TTR<60%. For the 9 serious bleeding events, the median INR on the day of the event was 2.1 (IQR 1.81-2.75). In conclusion, this HD unit is not meeting the TTR goal established in the literature and patients are often subtherapeutic. Further studies to investigate ways to improve TTR are warranted. Ultimately, a prospective study evaluating the safety and efficacy of warfarin in HD patients is needed.

Targeted Deprescribing in an Outpatient Hemodialysis Unit: A Quality Improvement Study to Decrease Polypharmacy

BACKGROUND Polypharmacy in hemodialysis patients can result in adverse patient outcomes. Deprescribing tools can reduce polypharmacy, yet no method exists for an outpatient hemodialysis population. DESIGN Quality improvement study. SETTING & PARTICIPANTS 240 patients in a tertiary-care outpatient hemodialysis unit. QUALITY IMPROVEMENT PLAN We aimed to: (1) develop a deprescribing tool for target medications with poor evidence for efficacy and safety, (2) determine its effectiveness in decreasing polypharmacy, and (3) monitor patient safety and satisfaction. OUTCOMES The primary outcome was the proportion of target medications completely deprescribed after 4 weeks. Secondary outcomes were the proportion of target medications completely deprescribed after 6 months, average number of medications per patient before and after deprescription, and proportion of successful deprescriptions for each target medication. MEASUREMENTS Number of medications deprescribed at 4 weeks and 6 months. Patient safety and satisfaction were monitored using drug-specific monitoring parameters. RESULTS A deprescribing tool for specific medications was developed and implemented in the hemodialysis unit. 5 medication classes were selected: quinine, diuretics, α1-blockers, proton pump inhibitors, and 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins). All 240 patients in the unit were screened using the deprescribing tool. There were 171 of 240 (71%) patients prescribed at least 1 of the 5 target medications, and after applying the tool, 35 of 40 (88%) eligible patients had the medications deprescribed. There were 31 of 40 (78%) target medications completely deprescribed. 6 months after the study, only 5 of 31 (16%) medications discontinued were represcribed. At the end of the study, 57% of patients were taking fewer medications than at baseline. No adverse events were observed. LIMITATIONS Single-center study that relied on patient self-reporting of medication use and adherence to our recommendations. CONCLUSIONS Deprescribing tools can be applied successfully in an outpatient hemodialysis unit to reduce polypharmacy while maintaining patient safety and satisfaction.

Antibiotic lock: In vitro stability of vancomycin and four percent sodium citrate stored in dialysis catheters at 37°C

Catheter‐related bacteremia (CRB) is a major cause of morbidity and mortality especially among patients receiving hemodialysis (HD). Antibiotic lock therapy represents a promising technique in the treatment of CRB. Several studies have evaluated antibiotics in combination with heparin as an interdialytic locking solution as adjunctive therapy for CRB. The objective of this study was to evaluate the chemical stability of the vancomycin in 4% sodium citrate in HD catheters as an interdialytic lock. Vancomycin was prepared and diluted with sodium citrate 4% and stored in polyvinyl chloride syringes, 2 carbothane dialysis catheters (Hemostar®) and 2 dual floating HD catheters (CardioMed®). Syringes were stored at 4 °C or 23 °C and the catheters were stored in an incubator at 37 °C for 72 hours. Samples underwent daily chromatographic analysis and the luminal concentration of vancomycn was determined on study days 0, 1, and 3. When vancomycin is reconstituted with normal saline to achieve a concentration of 50 mg/mL, and then further diluted in 4% sodium citrate, to achieve concentrations of either 1 or 3 mg/mL, and then stored at 4 °C, room temperature, or 37 °C, solutions were observed to retain >92% of the initial concentration for the study period of 3 days. Based on the fastest degradation rate determined with 95% confidence interval, >90% is retained for 6.53 days. We conclude that vancomycin—4% citrate solutions stored in polyvinyl chloride syringes or HD catheters are not significantly affected by temperature or concentration within the 72 hours storage period. Therefore, these solutions can be anticipated to be suitable as a HD interdialytic antibiotic lock in standard HD catheters.

A FORMAL MEDICATION RECONCILIATION PROGRAMME IN A HAEMODIALYSIS UNIT CAN IDENTIFY MEDICATION DISCREPANCIES AND POTENTIALLY PREVENT ADVERSE DRUG EVENTS

BACKGROUND Patients on haemodialysis have been identified as high-risk for medication discrepancies and adverse drug events. Medication reconciliation is an important patient safety initiative to prevent adverse drug events. The primary objective of our study was to determine the number and types of medication discrepancies and drug therapy problems (DTPs) identified in patients on haemodialysis. Our second objective was to assess the potential clinical impact and severity of all unintentional medication discrepancies identified. METHODS Patients in an academic haemodialysis unit were interviewed to obtain a best possible medication history (BPMH) between May and August 2010. The BPMH was documented and discrepancies were identified, classified and resolved with the interprofessional team. An interprofessional panel conducted a discrepancy clinical impact assessment for potential adverse drug events. RESULTS Two hundred and twenty-eight patients on haemodialysis were interviewed and 512 discrepancies were identified for 151 patients (3.4 discrepancies per patient). Of these, 174 (34%) were undocumented intentional discrepancies and 338 (66%) were unintentional discrepancies. The unintentional discrepancies were classified as 21% omissions, 36% commissions and 43% incorrect dose/frequency. Most drug therapy problems were related to patient taking a medication that was not indicated (25%), medication required but patient not taking (25%), patient not willing to take the medication as prescribed (28%) or incorrect dosing of a drug (20%). Overall, 6% of discrepancies were classified as clinically significant potential adverse drug events. CONCLUSION Medication discrepancies appear to be common in patients on haemodialysis. Formal interprofessional medication reconciliation practice models are essential to identify discrepancies and prevent patients from experiencing adverse drug events.

Cost Savings Using a Protocol Approach to Manage Anemia in a Hemodialysis Unit

Background: National guidelines recommend using anemia management protocols to guide treatment. The objective of this study was to determine if an anemia management protocol would improve hemoglobin (Hgb) indices in hemodialysis patients and to measure whether the protocol would reduce the use and cost of darbepoetin alfa (DBO) and intravenous (IV) iron in hemodialysis patients. Methods: An anemia management protocol was created and implemented for hemodialysis patients at our institution. A retrospective observational review of the use of DBO and IV iron as well as changes in Hgb, transferrin saturation and ferritin in 174 patients was conducted 6 months before and after implementation of the anemia protocol. Results: The number of Hgb measurements in the target range increased from 44.3 to 46.0% (p = 0.48) after protocol implementation. The mean weekly dose of DBO was reduced from 34.56 ± 31.12 to 31.11 ± 28.64 μg post-protocol implementation (p = 0.011), which translated to a cost savings of USD 41,649 over 6 months. The mean monthly IV iron dose also decreased from 139.56 ± 98.83 to 97.65 ± 79.05 mg (p < 0.005), a cost savings of USD 18,594 over the same time period. Conclusion: The use of an anemia management protocol resulted in the deprescribing of DBO and iron agents while increasing the number of patients in the target Hgb range, which led to significant cost savings in the treatment of anemia.

Antibiotic lock: In vitro stability of gentamicin and sodium citrate stored in dialysis catheters at 37 °C

Catheter‐related bacteremia (CRB) is a major cause of morbidity and mortality especially among patients receiving hemodialysis. Antibiotic lock therapy represents a promising technique in the treatment of CRB. Several studies have evaluated antibiotics in combination with heparin as an interdialytic locking solution for prophylaxis of CRB. The objective of this study was to evaluate the stability of gentamicin and sodium citrate in hemodialysis catheters as an interdialytic lock. Solutions containing gentamicin 2.5 mg/mL and sodium citrate 40 mg/mL (4%) were prepared individually and in combination. The solutions were instilled into dialysis catheters and stored at 37 °C for 96 h. Samples were withdrawn randomly from catheter lumens at 24‐hour intervals for 4 days and stored at −20 °C until analysis. The samples were analyzed with validated, stability‐indicating HPLC assays. The luminal concentration of gentamicin 2.5 mg/mL, sodium citrate 40 mg/mL (4%), and the combination was determined on study days 0, 1, 2, 3, and 4. When gentamicin was combined with sodium citrate and stored at 37 °C in dialysis catheters, the solution showed no decrease in either the gentamicin or the sodium citrate concentrations over the 96‐hour study period. The percent of the original concentration at 96 h was 102.4±1.03 for gentamicin and 102.9±1.25 for citrate (P=0.5556). The combination of gentamicin 2.5 mg/mL and sodium citrate 40 mg/mL (4%) can be retained in hemodialysis catheters for at least 96 h at 37 °C with no evidence of degradation.

A systematic review of direct oral anticoagulant use in chronic kidney disease and dialysis patients with atrial fibrillation

Background There is a lack of clear benefit and a potential risk of bleeding with direct oral anticoagulant (DOAC) use in chronic kidney disease (CKD) and dialysis patients with atrial fibrillation. The objective of this study was to evaluate how treatment with DOACs affects stroke and bleeding outcomes compared with warfarin or aspirin. Methods We conducted a systematic review of randomized controlled trials, cohort studies and case series, and searched electronic databases from 1946 to 2017. Studies evaluating stroke and bleeding outcomes with DOAC use in CKD and dialysis patients were included. Results From 8008 studies, 10 met the inclusion criteria. For moderate CKD patients (estimated glomerular filtration rate  <60 mL/min/1.73 m2), there was no difference in stroke outcomes between dabigatran 110 mg [hazard ratio (HR) 0.78, 95% confidence interval (95% CI) 0.51-1.21], rivaroxaban (HR 0.82-0.84, 95% CI 0.25-2.69) and edoxaban (HR 0.87, 95% CI 0.65-1.18) versus warfarin. Dabigatran (150 mg twice daily) and apixaban reduced risk of stroke or systemic embolism significantly more than warfarin for moderate CKD patients (HR 0.55, 95% CI 0.34-0.89 and HR 0.61, 95% CI 0.39-0.94, respectively). Edoxaban and apixaban were associated with reduced major bleeding events (HR 0.50-0.76) compared with warfarin. Rivaroxaban and dabigatran 110 mg and 150 mg showed no significant difference in major bleeding versus warfarin. In hemodialysis (HD) patients, there was no difference in stroke outcomes between apixaban, dabigatran [relative risk (RR) 1.71, 95% CI 0.97-2.99] or rivaroxaban (RR 1.8, 95% CI 0.89-3.64) versus warfarin. In HD patients, rivaroxaban and dabigatran were associated with an increased major bleeding risk (RR 1.45-1.76), whereas there was no major bleeding difference with apixaban compared to warfarin. Limitations The heterogeneity of major bleeding and stroke definitions of the 10 included studies. Conclusions Clinicians should continue to weigh the risk of stroke versus bleeding before prescribing DOACs in the CKD and dialysis population.

Vasculitis and IgA monoclonal gammopathy of cutaneous significance

IgA vasculitis (Henoch-Schonlein purpura) is a small vessel systemic vasculitis involving IgA immunoglobulin polyclonal activation1. Monoclonal gammopathy of cutaneous significance is a subgroup of monoclonal gammopathy with skin disease, without myeloma or lymphoproliferative disorder2. We report 3 patients with vasculitis and IgA monoclonal gammopathy of cutaneous significance. Three men, 38, 37 and 50 years old, had a vascular purpura for more than 10 years with partial remission and frequent necrotic flares (Figure 1). This article is protected by copyright. All rights reserved.