#280 Effectiveness and safety of direct oral anticoagulants vs VKA in patients on chronic dialysis: a target trial emulation using nationwide registry data

International audienceBackground and Aims The mortality and morbidity rates among patients on dialysis remain high and cardiovascular disease is the leading cause of death in this population. In chronic kidney disease (CKD), a major thromboembolic risk is paradoxically associated with a major haemorrhagic risk. Hence, the prescription of oral anticoagulants in CKD patients is challenging. Clinical trials of direct oral anticoagulants (DOAC) are scarce and inconclusive in patients who are receiving dialysis, for whom DOAC are not labelled in Europe. In an exhaustive French nationwide registry of patients undergoing chronic dialysis, we compared the effectiveness and safety of off-label DOAC use versus approved vitamin K antagonist (VKA). Method Data on patients on dialysis were extracted from the French Renal Epidemiology and Information Network (REIN) registry and merged with data from the French national healthcare system database (Système National des Données de Santé, SNDS). Patients on dialysis who had initiated treatment with an oral anticoagulant between January 1st, 2012, and December 31st, 2020, were eligible for inclusion. The primary safety outcome was the occurrence of major bleeding events and the primary effectiveness outcome was the occurrence of thrombotic events. Using target trial emulation design, we compared the safety and effectiveness outcomes for DOAC and VKA using propensity-score-weighted cause-specific Cox regression. Results 8 954 patients received an oral anticoagulant (483 DOAC and 8 471 VKA) for the first time after the initiation of dialysis. Over a median [interquartile range] follow-up period of 1.7 [0.8-3.2] years, 2 567 patients presented a first thromboembolic event and 1 254 patients had a bleeding event. After propensity score adjustment, the risk of a thromboembolic event was significantly lower in patients treated with a DOAC than in patients treated with a VKA (weighted hazard ratio (HR) [95% confidence interval (CI)]: 0.66 [0.46; 0.94] (Figure). A non-significant trend toward lower risk of major bleeding events was found in patients treated with a DOAC compared to patients treated with a VKA (weighted HR [95% CI]: 0.68 [0.41; 1.12]) (Figure). Sensitivity analyses showed the same trends. Conclusion The fact that patients on dialysis are excluded from large, cardiovascular-disease-focused randomized controlled trials (such as those with DOACs) significantly limits the evidence needed to make clinical decisions. Most of the retrospective cohort studies comparing these two drug classes were performed in the USA, where, in contrast to Europe, apixaban has been approved for the treatment of non-valvular fibrillation in patients on haemodialysis. Our real-world study of patients on dialysis is one of the first of its type to have assessed the effectiveness and safety of off-label DOAC prescription (relative to VKA prescription) in Europe. In a large group of dialysis patients initiating oral anticoagulation, the off-label use of DOACs was associated with a statistically significant lower risk of thromboembolic events, and a non-significant trend toward lower risk of bleeding relative to VKA use. These results are reassuring with regard to the off-label use of DOACs and might facilitate the establishment of an expert consensus and guidelines on antithrombotic therapy in patients with ESKD

Reply to ``Restricting maintenance allopurinol dose according to kidney function in patients with gout is inappropriate!'' by Stamp et al.

International audienc

Intestinal Chelators, Sorbants, and Gut-Derived Uremic Toxins

International audienceChronic kidney disease (CKD) is a highly prevalent condition and is associated with a high comorbidity burden, polymedication, and a high mortality rate. A number of conventional and nonconventional risk factors for comorbidities and mortality in CKD have been identified. Among the nonconventional risk factors, uremic toxins are valuable therapeutic targets. The fact that some uremic toxins are gut-derived suggests that intestinal chelators might have a therapeutic effect. The phosphate binders used to prevent hyperphosphatemia in hemodialysis patients act by complexing inorganic phosphate in the gastrointestinal tract but might conceivably have a nonspecific action on gut-derived uremic toxins. Since phosphorous is a major nutrient for the survival and reproduction of bacteria, changes in its intestinal concentration may impact the gut microbiota's activity and composition. Furthermore, AST-120 is an orally administered activated charcoal adsorbent that is widely used in Asian countries to specifically decrease uremic toxin levels. In this narrative review, we examine the latest data on the use of oral nonspecific and specific intestinal chelators to reduce levels of gut-derived uremic toxins

Ionized Magnesium Levels In Patients With Moderate-To-Advanced Chronic Kidney Disease: Relationship With Total Magnesium And Associated Factors

International audienceAbstract Background and Aims Magnesium (Mg) is involved in a multitude of essential physiological processes. In chronic kidney disease (CKD), the mechanisms compensating for the decrease in glomerular filtration rate (eGFR) become insufficient and Mg excretion tends to decrease, potentially resulting in hypermagnesemia. On the other hand, hypomagnesemia seems also to be common in CKD, due to changes in Mg intake through diet, reduced absorption and drug-induced hypomagnesemia. To date, a few studies have shown an association between increased cardiovascular risk in CKD and either low or high total Mg levels. However, the physiologically active fraction of extracellular Mg is ionized Mg (iMg), which is not routinely measured. In critical ill patients, the correlation between iMg and total Mg has been shown to be poor. Similar data on patients with CKD would be important to future studies aiming at clarifying the link between Mg and outcomes, and ultimately to determine the interest of iMg assay in routine practice. The objectives of this study are i) to study the correlation between total Mg and iMg and ii) to evaluate the relation between serum ionized magnesemia, estimated GFR (eGFR) and demographic and biologic parameters. Method CKD-REIN is a French, prospective, nationally representative cohort study of 3033 CKD patients under nephrology care not receiving maintenance dialysis (stage 3-5: eGFR<60 mL/min/1.73 m² based on 2009 CKD-EPI equation). Baseline iMg and total Mg serum concentrations were respectively centrally measured using the NOVA BIOMEDICAL Stat Profile PRIME ES analyser and with Atellica® CH SIEMENS analyser. Normal range of serum total Mg considered was 0.66 to 1.06 mmol/L (from Atellica®). Mean ± standard deviation (SD) ionized Mg level evaluated in a cohort of 457 healthy volunteers (age = 45 ± 17 years; eGFR = 72.3 ± 13 mL/min/1.73m²) was 0.49 ± 0.05 mmol/L (median [tertile 1 – tertile 3] = 0.49 [0.45-0.52] mmol/L). Correlation between iMg and total Mg was estimated overall. Multivariate linear regressions were performed to identify factors associated with iMg and total Mg levels. Results Among 1741 patients with iMg and total Mg at baseline, the median age was 68 years [59-76], 65% were men, and the mean eGFR was 35 ± 14 mL/min/1.73m². The mean baseline iMg level was 0.48 ± 0.1 mmol/L, 615 patients had an ionized Mg <0.45 mmol/L (Tertile 1), 599 had an iMg between 0.46 and 0.52 mmol/L (Tertile 2), and 527 had an iMg >0.52 mmol/L (Tertile 3). Compared to healthy volunteers, mean iMg levels were significantly lower in CKD patients. However, the difference was small (difference CKD-heatlhy = 0.01 mmol/L). Most of patients were within the total Mg normal range (n = 1522), 12% (n = 208) and 1% (n = 11) presented hypo- and hypermagnesemia, respectively. Correlation between iMg and total Mg was very high (r = 0.88; p<0.001). (Figure). Ionized Mg was weakly inversely correlated with eGFR (r = -0.22; p<0.001). Consequently, the mean iMg level differed according to CKD stages, being more elevated in the advanced stages (0.45 mmol/L in stages 2-3A; 0.47 mmol/L in stage 3B; 0.50 mmol/L in stages 4-5 (p<0.001)). In a fully adjusted linear regression model, iMg concentration was significantly associated with age, decline of eGFR, history of cardiovascular disease and the use of diuretics, and inversely associated with calcium and triglycerides levels, systolic blood pressure, diabetes, and the use of proton pump inhibitors and potassium chelators. The same factors were associated with total Mg. Conclusion Total Mg and iMg were strongly correlated. Decline of kidney function was associated to an increase of iMg in patients with moderate-to-advanced CKD. Additional studies need to compare the difference between total Mg and iMg as a biomarker to predict hard outcomes

Risk of acute kidney injury, end-stage kidney disease and mortality associated with proton pump inhbitor use in patients with chronic kidney disease

56th Congress of the European-Renal-Association (ERA)-European-Dialysis-and-Transplant-Association (EDTA) - Burden, Access and Disparities in Kidney Disease, Budapest, HUNGARY, JUN 13-16, 2019International audienc

Acute kidney injury associated with febuxostat and allopurinol: a post-marketing study

International audienceBackground For patients with recurrent flares of gout, tophi, urate crystal arthropathy, and renal stones, urate-lowering therapies (ULTs, including allopurinol and febuxostat) are the first-line treatment. Due to the widespread use of these ULTs (especially in patients with impaired renal function), assessment of the associated renal risk is essential. Accordingly, we performed a disproportionality analysis of reported cases of acute renal failure (ARF) associated with allopurinol and febuxostat. Methods We carried out a case/non-case study of the World Health Organization's VigiBase (R) pharmacovigilance database between January 1, 2008, and December 31, 2018. The frequency of reports of ARF as a standardized Medical Dictionary for Regulatory Activities query for allopurinol and febuxostat was compared with that of all other reports for the two drugs and quoted as the reporting odds ratio (ROR) [95% confidence interval (CI)]. The results' stability was assessed in a series of sensitivity analyses (notably after the exclusion of putative competing drugs). Results Among 3509 ``suspected drug'' notifications for febuxostat and 18,730 for allopurinol, we identified respectively 317 and 1008 cases of ARF. Acute renal failure was reported significantly more frequently for febuxostat and allopurinol than for other drugs (ROR [95%CI] 5.67 [5.05-6.36] and 3.25 [3.05-3.47], respectively). For both drugs, the ROR was higher in women than in men, respectively 11.60 [9.74-13.82] vs. 3.14 [2.69-3.67] for febuxostat and 4.45 [4.04-4.91] vs. 2.29 [2.11-2.50] for allopurinol. The sensitivity analyses confirmed the disproportionality for these two ULTs. Conclusions Acute renal failure was reported respectively 5.7 and 3.3 times more frequently for febuxostat and for allopurinol than for other drugs. Due to the potential consequences of ARF, physicians should take account of this disproportionality signal when prescribing the ULTs febuxostat and allopurinol

Incidence and determinants of adverse drug reactions in patients with CKD from the CKD-rein cohort study

56th Congress of the European-Renal-Association (ERA)-European-Dialysis-and-Transplant-Association (EDTA) - Burden, Access and Disparities in Kidney Disease, Budapest, HUNGARY, JUN 13-16, 2019International audienc

EVALUATION OF THE ADEQUACY OF DRUG PRESCRIPTIONS IN PATIENTS WITH MODERATE OR ADVANCED CHRONIC KIDNEY DISEASE : RESULTS FROM THE FRENCH CKD-REIN COHORT

55th Congress of the European-Renal-Association (ERA) and European-Dialysis-and-Transplantation-Association (EDTA), Copenhagen, DENMARK, MAY 24-27, 2018International audienc

#1135 Evaluation of the adequacy of urate lowering therapy prescriptions in patients with chronic kidney disease: results from the CKD-REIN cohort

International audienceBackground and Aims Urate Lowering Therapy (ULT) is frequently prescribed to patients with chronic kidney disease (CKD). However, these prescriptions are often inadequate when considering kidney function. Studies evaluating the appropriateness of ULT in the CKD population are predominantly cross-sectional. Yet, the evolution and reassessment of prescriptions remain unexplored in this context. This study aims to assess the prevalence of inappropriate ULT prescriptions (whether contraindications or inappropriately high doses) with regard to kidney function in patients with CKD. Method We used 5-year longitudinal data from the CKD-REIN cohort, a nationwide sample of 3033 nephrology outpatients with moderate-to-advanced CKD. Prescriptions for colchicine, used in the treatment of acute gout attacks, and ULT, such as allopurinol and febuxostat, were prospectively recorded. An inappropriate prescription was defined as the reported prescription of either a contraindicated drug, an indicated drug at an inappropriately high dose level, or a non-recommended prescription relative to the patient's eGFR, as estimated with de-indexed CKD-EPI equation and according to the European (or French if not available) summary of product characteristics. For patients initiating ULT during follow-up, uric acid levels were compared six months before and after the initiation of ULT. Results At baseline, 987 (33%) out of the 3033 included patients (mean ± standard deviation age 67 ± 13 years, 65% men) were prescribed ULT, with 781 (26%) receiving allopurinol and 206 (7%) receiving febuxostat. Compared to patients without a prescription for ULT, those with a ULT prescription were more frequently male, older, had lower kidney function, higher cardiovascular comorbidities, and were more commonly prescribed diuretics and inhibitors of the renin-angiotensin system. Moreover, their uric acid levels were lower (patients with ULT prescription 377.0 ± 110.4 µmol/L versus without ULT prescription 456.5 ± 116.4 µmol/L, p < 0.001). Notably, 316 (40%) allopurinol prescriptions were prescribed at inappropriately high dosages, while 77 (37%) febuxostat prescriptions were not recommended (resulting in a total of 393 (40%) inappropriate ULT prescriptions at baseline). Of the 54 colchicine prescriptions, one-third (n = 18) were contraindicated according to kidney function and nine were prescribed “on-demand” for crisis anticipation. During a median follow-up of 5.0 [1st-3rd quartile, 4.0–5.1] years, 253 patients were newly prescribed allopurinol and 176 were newly prescribed febuxostat, 54 (21%) out of 253 new allopurinol prescriptions were at inappropriately high dosages, and 68 (39%) out of the 176 new febuxostat prescriptions were not recommended based on the patient's kidney function (Figure). The majority of initially inappropriate ULT prescriptions (n = 393) remained so during follow-up (274 (70%)). Among the 179 patients initiating ULT during follow-up and with available data on uric acid levels, there was a significant decrease in uric acid levels after ULT initiation compared to before initiation (before: 494.5 ± 146.2 µmol/L versus after 408.5 ± 130.9 µmol/L, p < 0.001). A total of 197 patients had initiated colchicine during follow-up, with 61 (31%) receiving contraindicated prescriptions, and 18 (9%) having “on-demand” prescriptions. Conclusion Our findings emphasize the lack of reassessment of ULT prescriptions during the follow-up of patients with CKD. Colchicine prescriptions in case of severe kidney impairment persist despite contraindications. Further evaluation is required to understand the association between ULT prescriptions and the progression of kidney disease

ADVERSE OUTCOMES ASSOCIATED WITH ORAL ANTITHROMBOTIC USE IN PATIENTS WITH MODERATE-TO-ADVANCED CHRONIC KIDNEY DISEASE

58th Congress of the European-Renal-Association (ERA)-European-Dialysis-and-Transplant-Association (EDTA), ELECTR NETWORK, JUN 05-08, 2021International audienc