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To describe the association between levels of homocitrulline (HCit) and the degree of albumin carbamylation in a cohort of hemodialyzed patients. Plasma total and protein-bound HCit concentrations in samples from hemodialyzed patients included in NICOREN trial were determined by LC-MS/MS at baseline and after 24 weeks of treatment with either sevelamer or nicotinamide. HCit concentrations at all timepoints and in both groups were positively and significantly correlated with the degree of albumin carbamylation. Plasma concentrations of total HCit, protein-bound HCit and carbamylated albumin did not decrease after 24 weeks of treatment with either sevelamer or nicotinamide. The present results demonstrate that plasma total and protein-bound HCit concentrations were closely associated with albumin carbamylation in hemodialyzed patients. Therefore, total and protein-bound HCit concentrations might be valuable biomarkers of the overall intensity of protein carbamylation in this context. Given the less complex and time-consuming analytical methods required, these markers should be favored in future clinical studies of carbamylation reaction.
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Carbamilación de Proteína , Espectrometría de Masas en Tándem , Humanos , Albúminas , Biomarcadores , Cromatografía Liquida , Niacinamida , SevelamerRESUMEN
PURPOSE: To evaluate adherence (as measured by the medication possession ratio) to the first ever course of oral antineoplasic treatment in cancer patients before and after the implementation of a multidisciplinary consultation program (involving an oncologist, a pharmacist, and a nurse) and to investigate the program's impact on adverse events and drug-related problems. PATIENTS AND METHODS: In a retrospective single-center study, we compared the medication possession ratio 2 months after treatment initiation in a control group (before multidisciplinary consultation program implementation) versus an interventional group (after multidisciplinary consultation program implementation). RESULTS: Two months after oral antineoplasic treatment initiation, the mean ± standard deviation medication possession ratio did not differ significantly when comparing the interventional (multidisciplinary consultation program) group (n = 33; 0.99 ± 0.06) with the control group (n = 64; 0.94 ± 0.16) (p = 0.062). Patients in the multidisciplinary consultation program group had fewer adverse events in general (41, vs 109 in the control group; p = 0.048) and digestive adverse events in particular (6 vs 29, respectively; p = 0.007). A total of 53 and 40 drug-related problems were identified in the control and multidisciplinary consultation program groups, respectively (p = 0.074). CONCLUSIONS: Implementation of an multidisciplinary consultation program was not associated with a significant difference in drug adherence (as assessed by the medication possession ratio), which was good before and after implementation. The multidisciplinary consultation program was associated with a lower incidence of adverse events.
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Antineoplásicos , Neoplasias , Antineoplásicos/efectos adversos , Humanos , Cumplimiento de la Medicación , Neoplasias/tratamiento farmacológico , Farmacéuticos , Derivación y Consulta , Estudios RetrospectivosRESUMEN
BACKGROUND: Vascular calcification (VC) is common in type 2 diabetes, and is associated with cardiovascular complications. Recent preclinical data suggest that metformin inhibits VC both in vitro and in animal models. However, metformin's effects in patients with diabetic VC have not previously been characterized. The present study investigated the association between metformin use and lower-limb arterial calcification in patients with type 2 diabetes and high cardiovascular risk. METHODS: The DIACART cross-sectional cohort study included 198 patients with type 2 diabetes but without severe chronic kidney disease. Below-the-knee calcification scores were assessed by computed tomography and supplemented by colour duplex ultrasonography. Data on anti-diabetic drugs were carefully collected from the patients' medical records and during patient interviews. Biochemical and clinical data were studied as potential confounding factors. RESULTS: Metformin-treated patients had a significantly lower calcification score than metformin-free patients (mean ± standard deviation: 2033 ± 4514 and 4684 ± 9291, respectively; p = 0.01). A univariate analysis showed that metformin was associated with a significantly lower prevalence of severe below-the-knee arterial calcification (p = 0.02). VC was not significantly associated with the use of other antidiabetic drugs, including sulfonylureas, insulin, gliptin, and glucagon like peptide-1 analogues. A multivariate logistic regression analysis indicated that the association between metformin use and calcification score (odds ratio [95% confidence interval] = 0.33 [0.11-0.98]; p = 0.045) was independent of age, gender, tobacco use, renal function, previous cardiovascular disease, diabetes duration, neuropathy, retinopathy, HbA1c levels, and inflammation. CONCLUSIONS: In patients with type 2 diabetes, metformin use was independently associated with a lower below-the-knee arterial calcification score. This association may contribute to metformin's well-known vascular protective effect. Further prospective investigations of metformin's potential ability to inhibit VC in patients with and without type 2 diabetes are now needed to confirm these results.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Angiopatías Diabéticas/prevención & control , Hipoglucemiantes/uso terapéutico , Pierna/irrigación sanguínea , Metformina/uso terapéutico , Enfermedad Arterial Periférica/prevención & control , Calcificación Vascular/prevención & control , Anciano , Distribución de Chi-Cuadrado , Angiografía por Tomografía Computarizada , Estudios Transversales , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/diagnóstico , Angiopatías Diabéticas/diagnóstico por imagen , Angiopatías Diabéticas/etiología , Femenino , Humanos , Hipoglucemiantes/efectos adversos , Modelos Logísticos , Masculino , Metformina/efectos adversos , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Enfermedad Arterial Periférica/diagnóstico por imagen , Enfermedad Arterial Periférica/etiología , Factores Protectores , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Ultrasonografía Doppler en Color , Calcificación Vascular/diagnóstico por imagen , Calcificación Vascular/etiologíaRESUMEN
BACKGROUND: Nicotinamide (NAM) has been proposed as an alternative treatment to phosphate binders for hyperphosphataemia in chronic kidney disease. METHODS: The NICOREN multicentre, open-label and randomized study was designed to examine non-inferiority and safety of NAM when compared with sevelamer (SEV) in chronic haemodialysis patients. One hundred patients were randomized to either NAM or SEV treatment for 24 weeks. Serum biochemistry and NAM's main metabolite, N -methyl-2-pyridone-5-carboxamide (2PY), were measured to assess compliance, efficacy and safety. RESULTS: After 24 weeks, we observed a comparable decrease in serum phosphorus in the NAM and SEV treatment arms, from 2.1 ± 0.4 to 1.8 ± 0.5 and 2.3 ± 0.5 to 1.7 ± 0.5 mM (P = not significant), respectively. The criterion for non-inferiority was, however, not met due to a more limited number of patients being included than planned. Treatment discontinuation due to adverse events was 1.6 times higher in the NAM than in the SEV group with only 55% of study completers in the NAM arm versus 90% in the SEV arm. Thrombocytopenia was observed in four NAM-treated patients. Serum 2PY levels were comparable at baseline, but increased markedly in the NAM group, but not in the SEV group, at 24 weeks (P < 0.0001). CONCLUSIONS: Thus, both drugs are equally effective in lowering serum phosphorus, but patients' tolerance of NAM was largely inferior to that of SEV. Extremely high 2PY levels may contribute to NAM's side effects.
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Hiperfosfatemia/tratamiento farmacológico , Niacinamida/administración & dosificación , Fósforo/sangre , Diálisis Renal , Insuficiencia Renal Crónica/complicaciones , Sevelamer/administración & dosificación , Adulto , Anciano , Femenino , Humanos , Hiperfosfatemia/etiología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Insuficiencia Renal Crónica/terapiaRESUMEN
BACKGROUND: Randomized controlled trials (RCTs) of direct oral anticoagulants (DOACs) included a low proportion of atrial fibrillation (AF) patients with chronic kidney disease (CKD), and suggested that DOACs are safe and effective in patients with mild-to-moderate CKD. In a metanalysis of RCTs and observational studies, DOACs were associated with better efficacy (vs warfarin) in early CKD and had similar efficacy and safety profiles in patients with stages IV-V CKD. But few studies have provided data on the safety and effectiveness of each DOAC vs warfarin in patients with stage III CKD. The effectiveness and safety of DOACs in those patients are still subject to debate. AIM: To assess and compare the effectiveness and safety of apixaban and rivaroxaban vs warfarin in this patient population. METHODS: A cohort of patients with an inpatient or outpatient code for AF and stage III CKD who were newly prescribed apixaban and rivaroxaban was created using the administrative databases from the Quebec province of Canada between 2013 and 2017. The primary effectiveness outcome was a composite of ischemic stroke, systemic embolism, and death, whereas the primary safety outcome was a composite of major bleeding within a year of DOAC vs warfarin initiation. Treatment groups were compared in an under-treatment analysis using inverse probability of treatment weighting and Cox proportional hazards. RESULTS: A total of 8899 included patients filled out a new oral anticoagulation therapy claim; 3335 for warfarin and 5564 for DOACs. Compared with warfarin, 15 mg and 20 mg rivaroxaban presented a similar effectiveness and safety composite risk. Apixaban 5.0 mg was associated with a lower effectiveness composite risk [Hazard ratio (HR) 0.76; 95% confidence interval (CI): 0.65-0.88] and a similar safety risk (HR 0.94; 95%CI: 0.66-1.35). Apixaban 2.5 mg was associated with a similar effectiveness composite (HR 1.00; 95%CI: 0.79-1.26) and a lower safety risk (HR 0.65; 95%CI: 0.43-0.99. Although, apixaban 5.0 mg was associated with a better effectiveness (HR 0.76; 95%CI: 0.65-0.88), but a similar safety risk profile (HR 0.94; 95%CI: 0.66-1.35). The observed improvement in the effectiveness composite for apixaban 5.0 mg was driven by a reduction in mortality (HR 0.61; 95%CI: 0.43-0.88). CONCLUSION: In comparison with warfarin, rivaroxaban and apixaban appear to be effective and safe in AF patients with stage III CKD.
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Since beta-2 microglobulin (B2M) is a surrogate marker for middle molecular weight uremic toxins and the major protein component in dialysis-related amyloidosis, it has been frequently studied in dialysis patients. It is not known, however, whether B2M has an impact in patients with chronic kidney disease (CKD) not yet on dialysis. Here we studied the relationship of plasma B2M levels to clinical and cardiovascular outcomes in 142 patients (mean age of 67 years) at different stages of CKD. B2M levels increased with CKD stage and thus were highest in hemodialysis patients. Baseline B2M levels were associated with vascular calcification but not with arterial stiffness or bone density. During a mean follow-up of 969 days, 44 patients died and 49 suffered a cardiovascular event. Higher B2M levels were independently associated with overall and cardiovascular mortality and cardiovascular events in the whole cohort and with cardiovascular events in the predialysis cohort. Moreover, B2M appeared to be a better predictor than well-established factors associated with outcomes in this population, such as estimated glomerular filtration rate ((eGFR), only for predialysis patients), inflammation biomarkers, and other factors included in a propensity score. Thus, we confirm the strong relationship between B2M levels and eGFR and confirm the power of B2M to predict overall and cardiovascular mortality and cardiovascular events in patients at different stages of CKD.
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Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/etiología , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/complicaciones , Uremia/sangre , Uremia/etiología , Microglobulina beta-2/sangre , Anciano , Anciano de 80 o más Años , Biomarcadores/análisis , Densidad Ósea , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/fisiopatología , Distribución de Chi-Cuadrado , Supervivencia sin Enfermedad , Femenino , Tasa de Filtración Glomerular , Humanos , Estimación de Kaplan-Meier , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Puntaje de Propensión , Modelos de Riesgos Proporcionales , Diálisis Renal , Insuficiencia Renal Crónica/mortalidad , Insuficiencia Renal Crónica/fisiopatología , Insuficiencia Renal Crónica/terapia , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Regulación hacia Arriba , Uremia/mortalidad , Uremia/fisiopatología , Uremia/terapia , Calcificación Vascular/sangre , Calcificación Vascular/etiología , Rigidez VascularRESUMEN
BACKGROUND: Low-dose direct oral anticoagulant (DOAC) use is quite prevalent in clinical practice, but evidence of its effectiveness and safety compared with high-dose DOAC in patients with atrial fibrillation (AF) remains limited. We aimed to assess the effectiveness and safety of low-dose and high-dose DOACs in patients with AF with similar baseline characteristics. METHODS: We used a cohort of hospitalized patients with a primary or secondary diagnosis of AF after discharge to the community, whose data were stored in the Quebec administrative databases, from 2011 to 2017. Older adults with AF newly prescribed with rivaroxaban (15 or 20 mg) or apixaban (2.5 mg or 5 mg) were classified as under treatment (UT) and intent to treat (ITT). We used an inverse probability treatment weighting study of new users of rivaroxaban and apixaban to address confounding by indication. The primary effectiveness outcome was ischemic stroke/systemic embolism (SE), while the primary safety outcome was major bleeding (MB). We used Cox proportional models to estimate the marginal hazard ratios (HRs). FINDINGS: A total of 1,722 and 4,639 patients used low-dose and standard-dose rivaroxaban, respectively, while 3,833 and 6,773 patients used low-dose and standard-dose apixaban, respectively. No significant difference was observed in the incidence of comparative stroke/SE and MB between low-dose and standard-dose rivaroxaban, except for the risk of acute myocardial infarction (AMI), which was increased with the low dose in the UT analysis. For apixaban, no difference was found in the bleeding rates, but the risk of stroke/SE (HR: 1.95; 95% confidence interval (CI): 1.38-2.76) and death (HR: 1.99; 95% CI: 1.46-2.70) were greater in the low-dose group than in the standard-dose group in the UT analysis. Similar results were observed for the ITT analysis. CONCLUSION: No significant differences were observed in the effectiveness or safety outcome between low-dose and standard-dose rivaroxaban, except for AMI. However, low-dose apixaban was associated with a greater risk of stroke/SE and death without a reduction in the bleeding rates.
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Fibrilación Atrial , Infarto del Miocardio , Accidente Cerebrovascular , Humanos , Anciano , Rivaroxabán/efectos adversos , Fibrilación Atrial/tratamiento farmacológico , Piridonas/efectos adversos , Anticoagulantes , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/prevención & controlRESUMEN
The aim was to identify sex-specific factors linked with oral anticoagulant initiation in a cohort of patients with atrial fibrillation using administrative data from Quebec (Canada) between 2014 and 2017. Cohort entry defined as new users, that is, no claims in last 12 months, a cohort of 32 050 patients was stratified in two groups, that is, women and men. Multivariable regression models were used to identify factors of initiations for low- and standard-dose direct oral anticoagulants (DOACs) versus warfarin, and low- versus standard-dose DOACs. In both sexes, warfarin initiation decreased and DOAC initiation increased, with year of initiation as major factors of DOACs use. In 2017, the increase was of 2- to 4-fold and 3- to 8-fold for low- and standard-dose DOACs (vs. warfarin), respectively. The proportion of patients starting on a low-dose DOAC was higher in women than men. Older age for both sexes and CHADS2 score ≥2 (only women) were major factors of low-dose dabigatran and rivaroxaban versus warfarin use. The only significant factor of standard-dose DOAC versus warfarin use was age of 65-79 for women or men treated with apixaban by 1.8- and 1.4-fold, respectively. Factors that made women and men less likely to receive a standard-dose DOAC versus warfarin were higher CHADS2 (for dabigatran and rivaroxaban), HAS-BLED and frailty scores, prior coronary disease, major bleeding, and chronic kidney disease (CKD) status. The choice of a low- versus standard-dose DOAC was mainly driven by age and CKD, and higher CHADS2 score (for dabigatran and apixaban) for both sexes.
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Fibrilación Atrial , Insuficiencia Renal Crónica , Masculino , Humanos , Femenino , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/inducido químicamente , Warfarina/uso terapéutico , Dabigatrán/uso terapéutico , Rivaroxabán/uso terapéutico , Administración Oral , Anticoagulantes/uso terapéutico , Hemorragia/inducido químicamente , Hemorragia/epidemiología , Insuficiencia Renal Crónica/inducido químicamenteRESUMEN
Introduction: Performing pharmacist interventions (PIs) during the medication review helps to improve the quality of care. The acceptance by the physician of these PIs is a good indicator of the quality of this clinical pharmacy activity. The objective of this study was to determine, in the Amiens-Picardie teaching hospital (France), factors of acceptance in a variable environment of activity (central pharmacy, in the care units, computer assisted). Methods: All PIs transcribed by pharmacists on the Act-IP© site between November 2018 and April 2019 were analyzed using a complementary search in patient records. The environment, type, and clinical impact on patient health of each PI was collected. Linear mixed-effects models with a random pharmacist intercept were used to investigate the relationship between PI modalities and their chance of being accepted. Results: A total of 3,100 PIs were traced, of which 2,930 had been followed over time. Of these, 2,930 PIs, 1,504 (51.3%) were performed by a postgraduate pharmacist and 1,426 (48.7%) by a pharmacy resident, 1,623 (55.4%) were performed by verbal exchange, 455 (15.5%) by telephone, 846 (28.9%) by computer software, and 6 (0.2%) by paper. The clinical impact on patient health was major for 976 PIs (33.3%) and vital for 26 PIs (0.9%). According to the Anatomical Therapeutic Chemical Classification (ATC), they were mainly related to anti-infectives (30.3%), the nervous system (18.7%), and blood and blood-forming organs (17.3%). In total, 2,415 PIs (82.4%) were accepted. According to the multivariate model, a PI was more often accepted when it was transmitted orally rather than by software (+27.7%, 95% CI: +23.2 to +32.1%) and when it was transmitted to a medical resident rather than a postgraduate physician (+4.4%, 95% CI: 1.2-7.6%). In these cases, there was a major rather than a moderate clinical impact on patient health (+4.3%, 95% CI: +1.1-+7.6%). Conclusion: This study highlights the importance of the quality of the exchange with the prescriber and the prioritization of high-risk interventions as key points of medication review to improve rate of pharmacist interventions accepted by physician.
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AIMS: To assess (a) plasma osteopontin (pOPN) in a cohort of chronic kidney disease (CKD) patients; (b) the relationship between pOPN and aortic calcification and stiffness, and (c) the association between pOPN and the overall and cardiovascular mortality risk. METHODS: pOPN, the abdominal aortic calcification score and pulse wave velocity (PWV) were determined in 94 CKD patients (68 ± 13 years; 60% males; 31% at CKD stages 2-3, 31% at stages 4-5, 38% at stage 5D), prospectively followed for mortality. RESULTS: pOPN was higher in CKD patients than in controls. Interleukin (IL)-6 (r(2) = 0.086; p = 0.004), CRP (r(2) = 0.046; p = 0.038), iPTH (r(2) = 0.065; p = 0.014), albumin (r(2) = 0.210; p < 0.0001) and statin use (r(2) = 0.038; p = 0.059) were associated with pOPN. There was no association between pOPN and the aortic calcification score or PWV. During follow-up (969 ± 405 days), 32 patients died. In crude analysis, pOPN >167 ng/ml predicted overall and cardiovascular mortality (p = 0.02 and 0.01, respectively), but this effect was lost after adjustment for albumin or IL-6. CONCLUSIONS: pOPN is elevated from the early stages of CKD onward. We found no associations between pOPN and the aortic calcification score or the PWV. The positive association between pOPN and clinical outcomes was dependent of the patients' inflammatory status.
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Fallo Renal Crónico/sangre , Fallo Renal Crónico/diagnóstico , Osteopontina/sangre , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Fallo Renal Crónico/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Tasa de Supervivencia/tendenciasRESUMEN
BACKGROUND AND OBJECTIVE: In end-stage kidney disease, high urea levels promote the carbamylation of lysine side chains on a variety of proteins, including albumin. Albumin carbamylation has been identified as a risk factor for mortality and sevelamer led to a decrease in urea levels in dialysis patients. In the present secondary analysis of the NICOREN trial, we investigated the putative impacts of sevelamer and nicotinamide on albumin carbamylation, and the potential correlation between carbamylation and vascular calcifications. METHODS: All possible carbamylation of circulating albumin were screened for with high-resolution liquid chromatography-tandem mass spectrometry. Levels of three carbamylated peptides were then measured as a guide to the extent of albumin carbamylation. Carbamylation was measured at baseline in 55 patients included in the NICOREN trial and 29 patients at 24 weeks of treatment. Calcifications on plain radiographs were quantified as the Kauppila score and the Adragao score. RESULTS: Baseline albumin carbamylation was present at three different sites in subjects with end-stage kidney disease. At baseline, we observed only a correlation between urea and the KQTA carbamylation site in these patients. Albumin carbamylation levels did not decrease after 24 weeks of treatment with either sevelamer or nicotinamide. Furthermore, the proportion of carbamylated serum albumin was not correlated with vascular calcification scores in this population. CONCLUSIONS: Our results confirmed the presence of carbamylated albumin in patients with end-stage kidney disease and demonstrated the presence of carbamylation beyond the LRVP residues. The results also demonstrated the lack of impact of sevelamer or nicotinamide on albumin carbamylation levels. Therapeutic strategies to lower carbamylation load should probably be focused on direct anti-carbamylation processes and/or potentially anti-inflammatory therapies.
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Fallo Renal Crónico , Carbamilación de Proteína , Humanos , Fallo Renal Crónico/tratamiento farmacológico , Niacinamida/uso terapéutico , Albúmina Sérica/metabolismo , SevelamerRESUMEN
Aims: Observational studies of various dose levels of direct oral anticoagulants (DOACs) for patients with atrial fibrillation (AF) found that a high proportion of patients received a dose lower than the target dose tested in randomized controlled trials. There is a need to compare low-dose DOACs with warfarin or other DOACs on effectiveness and safety. Methods: Using administrative data from Quebec province, Canada, we built a cohort of new warfarin or DOAC users discharged from hospital between 2011 and 2017. We determined CHA2DS2-VASc and HAS-BLED scores, and comorbidities for 3-year prior cohort entry. The primary effectiveness endpoint was a composite of ischemic stroke/systemic embolism (SE), and secondary outcomes included a safety composite of major bleeding (MB) events and effectiveness composite (stroke/SE, death) at 1-year follow-up. We contrasted each low-dose DOAC with warfarin or other DOACs as references using inverse probability of treatment weighting to estimate marginal Cox hazard ratios (HRs). Results: The cohort comprised 22,969 patients (mean age: 80-86). We did not find a significant risk reduction for the stroke/SE primary effectiveness endpoint for DOACs vs. warfarin; however, we observed a significantly lower risk for low-dose dabigatran vs. warfarin (HR [95%CI]: 0.59 [0.42-0.81]) for effectiveness composite, mainly due to a lower death rate. The differences in effectiveness and safety composites between low-dose rivaroxaban vs. warfarin were not significant. However, low-dose apixaban had a better safety composite (HR: 0.68 [0.53-0.88]) vs. warfarin. Comparisons of dabigatran vs. apixaban showed a lower risk of stroke/SE (HR: 0.53 [0.30-0.93]) and a 2-fold higher risk of MB. The MB risk was higher for rivaroxaban than for apixaban (HR: 1.58 [1.09-2.29]). Conclusions: The results of this population-based study suggest that low-dose dabigatran has a better effective composite than warfarin. Compared with apixaban, low-dose dabigatran had a better effectiveness composite but a worse safety profile. Low-dose apixaban had a better safety composite than warfarin and other low-dose DOACs. Given that the comparative effectiveness and safety seem to vary from one DOAC to another, pharmacokinetic data for specific populations are now warranted.
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STUDY OBJECTIVE: Observational studies assessing direct oral anticoagulant (DOACs) dosage in atrial fibrillation (AF) reported that a lower proportion of patients received high-dose DOACs compared to those in randomized controlled trials (RCTs). Effectiveness and safety of high-dose DOACs relative to apixaban in a real-world AF population need to be addressed. The aim is to assess comparative effectiveness and safety of high-dose rivaroxaban relative to apixaban. DESIGN: We conducted a cohort study. Setting We built a cohort of patients hospitalized and discharged in community with a primary or secondary AF diagnosis from 2011-2017 using Quebec administrative databases (Med-Echo and RAMQ). Patients Cohort entry was defined as the first OAC claim in new users of high-dose rivaroxaban and apixaban, with no OAC claims in the prior year. Intervention To compare effectiveness and safety of high-dose rivaroxaban to apixaban. Measurement We ascertained patient demographics, comorbidities, CHA2DS2-VASc and HASBLED scores and Charlson score within 3 years prior to cohort entry. Primary effectiveness and safety were a composite of ischemic stroke/systemic thrombosis, death, myocardial infarction, and of intracranial bleeding (ICH), extracranial major bleeding, in the first year following drug initiation. We conducted propensity score matching and estimated hazard ratios (HRs) for outcomes using Cox proportional hazard models. All the analyses were conducted to account for competing risks. Main results The cohort consisted of 4,632 and 6,771 patients received high-dose rivaroxaban and apixaban, respectively. High-dose rivaroxaban users were younger with a mean age of 73.2 years, presented less associated comorbidities and had lower CHA2DS2-VASc scores compared to apixaban. High-dose rivaroxaban at the intention to treat was associated with a higher risk of stroke/SE/death (HR 1.21, 95% CI 1.04-1.40) and worse composite effectiveness (HR 1.21: 1.05-1.40); under treatment exposure, those values were at HR (1.66: 1.21-2.29) and HR (1.58:1.19-2.10), respectively. And, rivaroxaban presented a less favorable safety profile relative to apixaban. Conclusion In this study, composite effectiveness and safety varied between rivaroxaban and apixaban. High-dose apixaban was observed to have a better effectiveness and safety.
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Fibrilación Atrial , Pirazoles , Piridonas , Rivaroxabán , Anciano , Fibrilación Atrial/tratamiento farmacológico , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Humanos , Puntaje de Propensión , Pirazoles/administración & dosificación , Pirazoles/efectos adversos , Piridonas/administración & dosificación , Piridonas/efectos adversos , Rivaroxabán/administración & dosificación , Rivaroxabán/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: Hyperphosphatemia control is a major issue in hemodialysis patients. Both sevelamer and nicotinamide are prescribed for this purpose. In addition, they exert pleiotropic effects such as an improvement of inflammatory status and potentially enhanced clearance of uremic toxins. In the present secondary analysis of the NICOREN trial, we investigated the impact of sevelamer and nicotinamide on uremic toxins, toxin precursors, and endotoxemia in chronic hemodialysis patients. METHODS: Circulating uremic toxins (including phenylacetylglutamine, trimethylamine-N-oxide, p-cresyl sulfate, indoxyl sulfate, kynurenine, hippuric acid, indole-3-acetic acid, 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid, kynurenic acid, and p-cresyl glucuronide) and precursors were measured by ultra-performance liquid chromatography-tandem mass spectrometry, and urea, uric acid, phosphate, C-reactive protein, and intact parathyroid hormone by routine biochemistry methods. Serum endotoxin (evaluated by lipopolysaccharide levels) and C-terminal fibroblast growth factor-23 levels were measured using enzyme-linked immunosorbent assay kits. RESULTS: One hundred hemodialysis patients were randomized to receive either nicotinamide or sevelamer treatment. Among them, 63% were male, mean (± standard deviation) age was 65 ± 14 years, 47% had diabetes mellitus, and 51% had a history of cardiovascular disease. In the sevelamer group, but not the nicotinamide group, serum levels of urea, uric acid, and fibroblast growth factor-23 were significantly reduced after 6 months of treatment. The other circulating uremic toxins and toxin precursors remained unchanged in response to either phosphate-lowering agent. Sevelamer treatment led to a marked decrease in serum lipopolysaccharide (p < 0.001) whereas nicotinamide treatment induced an only modest decrease of borderline significance (p = 0.057). There was no change in C-reactive protein levels. CONCLUSION: In contrast to sevelamer, nicotinamide did not reduce circulating levels of low-molecular-weight uremic toxins other than phosphate, and neither agent reduced circulating uremic toxins of high-molecular-weight or protein-bound toxins. Sevelamer, but not nicotinamide, reduced serum endotoxin levels. Despite no change in serum C-reactive protein, the endotoxin-lowering effect of sevelamer may help to attenuate the inflammatory status of patients with chronic kidney disease.
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Endotoxemia/tratamiento farmacológico , Endotoxinas/sangre , Niacinamida/administración & dosificación , Insuficiencia Renal Crónica/tratamiento farmacológico , Sevelamer/administración & dosificación , Anciano , Femenino , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/sangre , Humanos , Hiperfosfatemia/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Fosfatos/sangre , Diálisis Renal , Ácido Úrico/sangreAsunto(s)
Albuterol/efectos adversos , Broncodilatadores/efectos adversos , Quemaduras Químicas/etiología , Trastornos Relacionados con Sustancias/complicaciones , Adolescente , Albuterol/administración & dosificación , Broncodilatadores/administración & dosificación , Quemaduras Químicas/patología , Femenino , Humanos , Nebulizadores y Vaporizadores , Piel/patología , Trastornos Relacionados con Sustancias/patologíaRESUMEN
N-methyl-2-pyridone-5-carboxamide (2PY, a major metabolite of nicotinamide, NAM) was recently identified as a uremic toxin. Recent interventional trials using NAM to treat high levels of phosphorus in end-stage renal disease have highlighted new potential uremic toxicities of 2PY. In the context of uremia, the accumulation of 2PY could be harmful-perhaps by inhibiting poly (ADP-ribose) polymerase-1 activity. Here, we review recently published data on 2PY's metabolism and toxicological profile.
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Niacinamida/análogos & derivados , Niacinamida/metabolismo , Toxinas Biológicas/metabolismo , Uremia/metabolismo , Animales , Humanos , Insuficiencia Renal Crónica/metabolismoRESUMEN
Hyperphosphatemia in chronic kidney disease (CKD) has been associated with elevated cardiovascular morbidity and mortality. Serum phosphate control remains a cornerstone of the clinical management of patients with CKD, in order to both attenuate the progression of secondary hyperparathyroidism or bone disease and (possibly) reduce the risk of vascular calcification. Despite technical improvements in dialysis and the use of dietary restrictions, drug therapy is often required to control phosphate levels in patients with end-stage renal disease (ESRD). Currently available medications for hyperphosphatemia in ESRD are very expensive and not always well tolerated. The discovery and development of new drugs in this indication is therefore a priority for both medical and health-economic reasons. Nicotinamide (an amide derivative of the water-soluble vitamin B3) is a potentially interesting alternative to phosphate binders. In vitro and in vivo data show that nicotinamide reduces hyperphosphatemia by inhibiting sodium-dependent phosphate co-transport in the renal proximal tubule and in the intestine. Accordingly, targeting the sodium-dependent phosphate co-transporter 2b by using nicotinamide as an alternative or adjunct to classical phosphate binders may be a therapeutic option for modulating serum phosphate in CKD. Several recent clinical studies have explored the potential value of nicotinamide in phosphate control (as well as its effects on lipid levels) in dialysis patients. However, we consider that more data on pharmacodynamics, pharmacokinetics and safety are needed before this compound can be recommended as a treatment for hyperphosphatemia in ESRD patients.
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Hiperfosfatemia/tratamiento farmacológico , Niacinamida/uso terapéutico , Diálisis Renal , Humanos , Hiperfosfatemia/sangre , Hiperfosfatemia/etiología , Fallo Renal Crónico/sangre , Fallo Renal Crónico/terapia , Niacinamida/administración & dosificación , Niacinamida/farmacocinética , Fosfatos/sangre , Diálisis Renal/efectos adversos , Proteínas Cotransportadoras de Sodio-Fosfato/antagonistas & inhibidores , Distribución TisularRESUMEN
Immunoglobulin free light chains (FLCs) form part of the middle molecule group of uremic toxins. Accumulation of FLCs has been observed in patients with chronic kidney disease (CKD). The aim of the present study was to measure FLC levels in patients at different CKD stages and to assess putative associations between FLC levels on one hand and biochemical/clinical parameters and mortality on the other. One hundred and forty patients at CKD stages 2-5D were included in the present study. Routine clinical biochemistry assays and assays for FLC kappa (κ) and lambda (λ) and other uremic toxins were performed. Vascular calcification was evaluated using radiological techniques. The enrolled patients were prospectively monitored for mortality. Free light chain κ and λ levels were found to be elevated in CKD patients (especially in those on hemodialysis). Furthermore, FLC κ and λ levels were positively correlated with inflammation, aortic calcification and the levels of various uremic toxins levels. A multivariate linear regression analysis indicated that FLC κ and λ levels were independently associated with CKD stages and ß2 microglobulin levels. Elevated FLC κ and λ levels appeared to be associated with mortality. However, this association disappeared after adjustment for a propensity score including age, CKD stage and aortic calcification. In conclusion, our results indicate that FLC κ and λ levels are elevated in CKD patients and are associated with inflammation, vascular calcification and levels of other uremic toxins. The observed link between elevated FLC levels and mortality appears to depend on other well-known factors.
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Cadenas kappa de Inmunoglobulina/sangre , Cadenas lambda de Inmunoglobulina/sangre , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/mortalidad , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Femenino , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Análisis Multivariante , Diálisis Renal , Toxinas Biológicas/toxicidad , Microglobulina beta-2/sangreRESUMEN
BACKGROUND: Recent research has clarified the relationship between adipokines, metabolic syndrome (MS) and cardiovascular disease (CVD). The results of animal and clinical studies have revealed a positive relationship between leptin and vascular smooth muscle cell counts and calcification, arterial rigidity, carotid thickness and the incidence of CVD. However, despite leptin fulfilling the definition of a uremic toxin, its exact role in chronic kidney disease (CKD) has yet to be determined. METHODS: One hundred and forty-two CKD patients (stages 2-5D) participated in this study, and were followed for a minimum of 20 months at Amiens University Medical Center. RESULTS: Leptin was negatively correlated with the glomerular filtration rate (GFR), total adiponectin (TAdip) and high-molecular weight adiponectin and positively correlated with age, waist circumference, body mass index (BMI), aortic calcification score (ACS), C-reactive protein (CRP), triglycerides, insulin and parathormone (PTH). Leptin and insulin were significantly correlated with the MS score. The BMI, insulin, MS score and PTH were independent predictors of leptin levels (P = 0.002, 0.016, 0.028 and 0.017, respectively). Leptin, insulin and TAdip were independent predictors of the presence of MS (P = 0.05, 0.04 and 0.04). However, leptin levels were not significantly predictive of the clinical outcomes. CONCLUSIONS: Our study was the first to demonstrate a significant, independent link between leptin and MS (but not clinical outcomes) and PTH in patients at different CKD stages. Future studies will have to assess the involvement of leptin in MS and clinical outcomes in CKD, and the potential modulation of leptin by PTH.