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1.
Proactive Monitoring of Adalimumab Trough Concentration Associated With Increased Clinical Remission in Children With Crohn's Disease Compared With Reactive Monitoring.
Assa, A, Matar, M, Turner, D, Broide, E, Weiss, B, Ledder, O, Guz-Mark, A, Rinawi, F, Cohen, S, Topf-Olivestone, C, et al
Gastroenterology. 2019;(4):985-996.e2
Abstract
BACKGROUND & AIMS Proactive monitoring of drug trough concentrations and antibodies against drugs might help determine whether patients are likely to respond to treatment and increase efficacy. We investigated whether proactive drug monitoring is associated with higher rates of clinical remission in pediatric patients with Crohn's disease (CD). METHODS We performed a nonblinded, randomized controlled trial of 78 children with CD (6-18 years old; 29% female; mean age, 14.3 ± 2.6 years) who had not received prior treatment with a biologic agent but had responded to adalimumab induction therapy, under scheduled monitoring of clinical and biologic measures (based on clinical factors and levels of C-reactive protein and fecal calprotectin), at pediatric gastroenterology units in Israel from July 2015 through December 2018. The patients were randomly assigned to groups that received proactive monitoring (trough concentrations measured at weeks 4 and 8 and then every 8 weeks until week 72, n = 38) or reactive monitoring (physicians were informed of trough concentrations after loss of response, n = 40). In both groups, doses and intervals of adalimumab were adjusted to achieve trough concentrations of 5 μg/mL. The primary endpoint was sustained corticosteroid-free clinical remission at all visits (week 8 through week 72). RESULTS The primary endpoint was achieved by 31 children (82%) in the proactive group and 19 children (48%) in the reactive group (P = .002). Sixteen patients in the proactive monitoring group (42%) achieved a composite outcome of sustained corticosteroid-free remission, C-reactive protein ≤0.5 mg/dL, and level of fecal calprotectin ≤150 μg/g compared with 5 patients in the reactive monitoring group (12%) (P = .003). By week 72 of treatment, 33 patients in the proactive monitoring group had received adalimumab intensification (87%) compared with 24 patients in the reactive monitoring group (60%) (P = .001). CONCLUSIONS In a randomized controlled trial of pediatric patients with CD, we found that proactive monitoring of adalimumab trough concentrations and adjustment of doses and intervals resulted in significantly higher rates corticosteroid-free clinical remission than reactive monitoring (measuring trough concentration after loss of response). Clinicaltrials.gov no.: NCT02256462.
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2.
Real-Life Use of Neurohormonal Antagonists and Loop Diuretics in Chronic Heart Failure: Analysis of Serial Biomarker Measurements and Clinical Outcome.
Brankovic, M, Akkerhuis, KM, van Boven, N, Manintveld, O, Germans, T, Brugts, J, Caliskan, K, Umans, V, Constantinescu, A, Kardys, I
Clinical pharmacology and therapeutics. 2018;(2):346-355
Abstract
We determined the temporal effects of neurohormonal antagonists and loop diuretics on serially assessed (3-monthly) cardiorenal biomarkers, functional status, and clinical outcomes in 250 patients with chronic heart failure (CHF) with reduced ejection fraction. In blood, we measured NT-proBNP, troponin T, C-reactive protein, creatinine, cystatin C; in urine, N-acetyl-beta-d-glucosaminidase and kidney-injury-molecule-1. Angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) were inversely associated with cardiac impairment, inflammation, and renal tubular damage, but not with glomerular dysfunction. Diuretics were associated with worse biomarker profiles and with a hazard ratio for adverse clinical outcome of 1.12 (95% confidence interval: 1.03-1.22) per 40 mg higher doses. ACE-inhibitors/ARBs were more frequently downtitrated and diuretics more frequently uptitrated in patients who experienced endpoints than in those who did not. In conclusion, a decrease or withholding of ACE-inhibitors/ARBs solely based on glomerular function is not justified because of the beneficial effects on the heart, inflammation, and renal tubules. Higher and increased diuretic doses mark progression towards endstage CHF.
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3.
Prospective, Multicenter Study of 5-Fluorouracil Therapeutic Drug Monitoring in Metastatic Colorectal Cancer Treated in Routine Clinical Practice.
Wilhelm, M, Mueller, L, Miller, MC, Link, K, Holdenrieder, S, Bertsch, T, Kunzmann, V, Stoetzer, OJ, Suttmann, I, Braess, J, et al
Clinical colorectal cancer. 2016;(4):381-388
Abstract
BACKGROUND Studies have demonstrated that body surface area-based dosing of chemotherapy drugs leads to significant individual exposure variability, with a substantial risk of under- or overdosing. The present study was initiated to validate the use of therapeutic drug management (TDM) to personalize 5-fluorouracil (5-FU) dosing in patients with metastatic colorectal cancer treated in routine clinical practice. PATIENTS AND METHODS A total of 75 patients with metastatic colorectal cancer from 8 German medical centers received ≤ 6 administrations of infusional 5-FU according to the AIO (folinate, 5-FU; n = 16), FOLFOX6 (leucovorin calcium [folinic acid], 5-FU, and oxaliplatin; n = 26), or FUFOX (oxaliplatin plus 5-FU/folinic acid; n = 33) regimen. Initial infusional 5-FU dosing for all patients was determined by the BSA. Individual 5-FU exposure (area under the curve [AUC]) was measured using an immunoassay of a blood sample taken during each infusion. To achieve a target AUC of 20 to 30 mg × h/L, subsequent infusional 5-FU doses were adjusted according to the previous cycle's 5-FU AUC. The primary objective was to confirm that TDM of infusional 5-FU resulted in an increased proportion of patients in the target AUC range at the fourth versus the first administration. The secondary objective was to determine whether 5-FU TDM reduced the treatment-related toxicities compared with the historical data. RESULTS The average 5-FU AUC at the first administration was 18 ± 6 mg × h/L, with 64%, 33%, and 3% of the patients below, within, or above the target AUC range, respectively. By the fourth administration, the average 5-FU AUC was 25 ± 7 mg × h/L (P < .001), with 54% of patients within the target 5-FU AUC range (P = .0294). The incidence of 5-FU-related grade 3 and 4 diarrhea (4.6%), nausea (3.4%), fatigue (0.0%), and mucositis (0.2%) was reduced compared with the historical data, despite 55% of the patients receiving increased doses. CONCLUSION Personalization of 5-FU dosing using TDM in routine clinical practice resulted in significantly improved 5-FU exposure and suggested a lower incidence of 5-FU-related toxicities.
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4.
The HIPOGAIA study: Monitoring of oral anticoagulation with vitamin K antagonists in the municipality of Gaia.
Guedes, M, Rego, C
Revista portuguesa de cardiologia : orgao oficial da Sociedade Portuguesa de Cardiologia = Portuguese journal of cardiology : an official journal of the Portuguese Society of Cardiology. 2016;(9):459-65
Abstract
INTRODUCTION Anticoagulant therapy is an effective measure in preventing thromboembolic adverse events. Of the diseases in which this treatment is indicated, atrial fibrillation (AF) has the highest incidence worldwide, with a prevalence of 1.5-2%. OBJECTIVES To assess the quality of monitoring of patients with non-valvular AF under oral anticoagulation with vitamin K antagonists in Vila Nova de Gaia healthcare units. METHODS This was a retrospective observational analytical study of the population registered at the 37 healthcare units of the Vila Nova de Gaia and Espinho health center area under oral anticoagulation with vitamin K antagonists during 2014. The data were collected using TAONet(®) software. The variables studied were health units, age, gender, INR value, time in therapeutic range (TTR) and medication. TTR was calculated for each patient using the Rosendaal linear interpolation method. It was stipulated that each patient should have undergone at least six INR measurements. Data were analyzed using Microsoft Excel(®) 2010 and SPSS(®) version 21, using descriptive and inferential statistical techniques. RESULTS A total of 479 patients with non-valvular AF were studied, corresponding to 5883 INR tests. Mean TTR was 67.4±6.5%, and 35.3% of patients exhibited poor control (TTR <60%). DISCUSSION Our study showed moderate control of coagulation parameters, but better than in many international clinical trials and in another Portuguese observational study. Nevertheless, there is still room for improvement in anticoagulation monitoring in primary health care.
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5.
Alternative calculations of individual patient time in therapeutic range while taking warfarin: results from the ROCKET AF trial.
Singer, DE, Hellkamp, AS, Yuan, Z, Lokhnygina, Y, Patel, MR, Piccini, JP, Hankey, GJ, Breithardt, G, Halperin, JL, Becker, RC, et al
Journal of the American Heart Association. 2015;(3):e001349
Abstract
BACKGROUND In the ROCKET AF (Rivaroxaban-Once-daily, oral, direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) trial, marked regional differences in control of warfarin anticoagulation, measured as the average individual patient time in the therapeutic range (iTTR) of the international normalized ratio (INR), were associated with longer inter-INR test intervals. The standard Rosendaal approach can produce biased low estimates of TTR after an appropriate dose change if the follow-up INR test interval is prolonged. We explored the effect of alternative calculations of TTR that more immediately account for dose changes on regional differences in mean iTTR in the ROCKET AF trial. METHODS AND RESULTS We used an INR imputation method that accounts for dose change. We compared group mean iTTR values between our dose change-based method with the standard Rosendaal method and determined that the differences between approaches depended on the balance of dose changes that produced in-range INRs ("corrections") versus INRs that were out of range in the opposite direction ("overshoots"). In ROCKET AF, the overall mean iTTR of 55.2% (Rosendaal) increased up to 3.1% by using the dose change-based approach, depending on assumptions. However, large inter-regional differences in anticoagulation control persisted. CONCLUSIONS TTR, the standard measure of control of warfarin anticoagulation, depends on imputing daily INR values for the vast majority of follow-up days. Our TTR calculation method may better reflect the impact of warfarin dose changes than the Rosendaal approach. In the ROCKET AF trial, this dose change-based approach led to a modest increase in overall mean iTTR but did not materially affect the large inter-regional differences previously reported. CLINICAL TRIAL REGISTRATION URL: ClinicalTrials.gov. Unique identifier: NCT00403767.
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Effect of protoconized therapy for renal anemia on adverse events of patients with maintenance hemodialysis.
Kuragano, T, Yahiro, M, Kida, A, Furuta, M, Nagasawa, Y, Hasuike, Y, Nanami, M, Nakanishi, T
The International journal of artificial organs. 2014;(12):865-74
Abstract
PURPOSE We evaluate the effect of the protoconized anemia therapy on adverse events using the Hb and ferritin levels of individual patients undergoing maintenance hemodialysis (MHD). METHODS Design: A randomized, parallel group, multi-center study. PATIENTS Two hundred sixty-six MHD patients. Intervention group: The doses of erythropoietin, iron, and vitamin C were adjusted every month based on the ferritin and hemoglobin (Hb) levels according to the protocol. Non-intervention group: The attending physician determined the doses of erythropoietin and iron. RESULTS The maintenance rate of target Hb and ferritin levels were significantly higher in the Intervention group than in the Non-intervention group. The frequency of hospitalization was significantly lower for patients with a higher maintenance rate of target Hb levels than for those with a lower maintenance rate. CONCLUSIONS Using an anemia treatment protocol according to the individual Hb and ferritin levels of hemodialysis patients might stabilize the Hb and ferritin levels, which in turn could contribute to the lower frequency of adverse events in MHD patients.
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7.
Impact of global geographic region on time in therapeutic range on warfarin anticoagulant therapy: data from the ROCKET AF clinical trial.
Singer, DE, Hellkamp, AS, Piccini, JP, Mahaffey, KW, Lokhnygina, Y, Pan, G, Halperin, JL, Becker, RC, Breithardt, G, Hankey, GJ, et al
Journal of the American Heart Association. 2013;(1):e000067
Abstract
BACKGROUND Vitamin K antagonist (VKA) therapy remains the most common method of stroke prevention in patients with atrial fibrillation. Time in therapeutic range (TTR) is a widely cited measure of the quality of VKA therapy. We sought to identify factors associated with TTR in a large, international clinical trial. METHODS AND RESULTS TTR (international normalized ratio [INR] 2.0 to 3.0) was determined using standard linear interpolation in patients randomized to warfarin in the ROCKET AF trial. Factors associated with TTR at the individual patient level (i-TTR) were determined via multivariable linear regression. Among 6983 patients taking warfarin, recruited from 45 countries grouped into 7 regions, the mean i-TTR was 55.2% (SD 21.3%) and the median i-TTR was 57.9% (interquartile range 43.0% to 70.6%). The mean time with INR <2 was 29.1% and the mean time with an INR >3 was 15.7%. While multiple clinical features were associated with i-TTR, dominant determinants were previous warfarin use (mean i-TTR of 61.1% for warfarin-experienced versus 47.4% in VKA-naïve patients) and geographic region where patients were managed (mean i-TTR varied from 64.1% to 35.9%). These effects persisted in multivariable analysis. Regions with the lowest i-TTRs had INR distributions shifted toward lower INR values and had longer inter-INR test intervals. CONCLUSIONS Independent of patient clinical features, the regional location of medical care is a dominant determinant of variation in i-TTR in global studies of warfarin. Regional differences in mean i-TTR are heavily influenced by subtherapeutic INR values and are associated with reduced frequency of INR testing. CLINICAL TRIAL REGISTRATION URL: ClinicalTrials.gov. Unique identifier: NCT00403767.
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Low 25-OH vitamin D serum levels correlate with severe fibrosis in HIV-HCV co-infected patients with chronic hepatitis.
Terrier, B, Carrat, F, Geri, G, Pol, S, Piroth, L, Halfon, P, Poynard, T, Souberbielle, JC, Cacoub, P
Journal of hepatology. 2011;(4):756-61
Abstract
BACKGROUND & AIMS Recent findings in hepatitis C virus (HCV)-monoinfected patients have shown a correlation between low serum levels of 25-OH vitamin D3 [25(OH)D3] and severe liver fibrosis and low sustained virologic response to therapy. Data are lacking in HIV-HCV coinfected patients. METHODS One hundred and eighty nine HIV-HCV coinfected patients, who received ≥80% of interferon (IFN) plus ribavirin therapy, were analyzed for baseline serum 25(OH)D3 levels. Correlations between serum 25(OH)D3 levels, chronic hepatitis C features, HCV virologic response to antiviral therapy, and HIV infection characteristics were analyzed. RESULTS Mean serum 25(OH)D3 level was 18.5 ± 9.8 ng/ml, including 162 (85%) patients with level ≤30 ng/ml. Serum 25(OH)D3 levels were significantly correlated with the histological Metavir fibrosis score (r = -0.16; p = 0.027). Patients with severe fibrosis (Metavir F3/F4) had lower serum 25(OH)D3 levels compared to F2 and F1 patients (16.2 ± 10.0 vs. 18.9 ± 8.5 and 20.9 ± 11.1 ng/ml, respectively; p = 0.06). In multivariate analysis, low serum 25(OH)D levels were independently associated with severe liver fibrosis (p = 0.04) and cold season (p = 0.0002). Serum levels of 25(OH)D3 were also significantly correlated with liver fibrosis as assessed by FibroTest® (r = -0.22; p = 0.008) and serum α2-macroglobulin levels (r = -0.23; p = 0.006). In contrast, no correlation was found between 25(OH)D3 levels and HCV sustained virologic response to IFN-based therapy [OR 0.98 (0.95-1.01); p = 0.22]. No association was found between 25(OH)D3 levels and markers of HIV-related immunodeficiency. CONCLUSIONS In HIV-HCV coinfected patients, low serum 25(OH)D3 levels correlate with severe liver fibrosis. In contrast, serum 25(OH)D3 levels are not linked to HCV virologic response to therapy or severity of immunodeficiency.