Number Of Dose Changes Research Articles

Enoxaparin for thrombosis in neonates: preliminary

Objectives – To investigate the dose of enoxaparin required in neonates to achieve target therapeutic ranges of anti factor Xa 48 hours after starting therapy, and compare this dose to recommended guideline dosages for neonates. Methods – We retrospectively reviewed 19 records of newborns who received enoxaparin at different doses for the treatment of thrombosis and evaluated how many among them reached the target anti-factor Xa level after 48 hours. Results – Only 1/5 neonates (20%) treated with 150 UI/kg twice a day, but 100% (6/6) of those treated with 175 UI/kg twice a day reached therapeutic levels of anti-factor Xa at 48 hours. Of the 8 neonates treated with lower starting doses none reached the therapeutic range after 48 hours and these required the highest number of dose changes. Conclusions – Our results reinforce the need to increase in neonates the dosage of enoxaparin suggested in published guidelines, in order to shorten the time-delay in achieving a therapeutic level of anti-factor Xa, and also reducing the number of blood tests necessary for dosing anti-factor Xa.

Evaluation of 2 Nomogram-Based Strategies for Dosing Argatroban in Patients With Known or Suspected Heparin-Induced Thrombocytopenia

No study has compared 2 different dosing strategies for argatroban titration nor has any published nomogram demonstrated improvement in outcomes. This study was conducted to evaluate the effectiveness of 2 argatroban nomograms on reaching therapeutic anticoagulation. Patients treated with argatroban were separated into 2 sliding scale groups, percentage adjustments (PAs) and predefined dose increments (PDIs). The primary outcome was the time to reach a therapeutic activated partial thromboplastin time (aPTT). The average initial dose and dose to achieve a therapeutic aPTT were similar between the groups. There was also no difference in the number of dose changes. The time to reach a therapeutic aPTT was 2 hours shorter in the PDI compared to the PA group, 8 ± 4 hours versus 10 ± 4 hours, P = .015. This study demonstrates a significant time advantage associated with a PDI nomogram compared to a PA nomogram but no difference with respect to the number of rate changes.

Effect of 200μG/day of vitamin k1 on the variability of anticoagulation control in patients on warfarin: A randomized controlled trial

Controversy exists whether low-dose vitamin K supplementation can improve anticoagulation control in patients with unstable anticoagulation under warfarin. In a single- centre randomized, double-blind, placebo-controlled study, we evaluated the effectiveness of 200 μg/day of vitamin K1 in patients with unstable control under warfarin. Effectiveness of Vitamin K1 supplementation was primarily assessed by the percentage (%) of Time-in-Therapeutic-Range (TTR) and secondarily by the standard deviation (SD) of the patient's INR values; the proportion of out-of-range INRs; and the number of dose changes on warfarin. Their change scores were obtained by subtracting the mean value in the 6 months pre-randomization from the mean value in the 6 months post-randomization. Multivariable linear-regressions identified factors associated with anticoagulation instability. Fifty out of 54 patients were analyzed (intervention: n=26; placebo: n=24). Most indications (87%) for anticoagulation were venous thromboembolism (VTE). The intervention was associated with a greater reduction in the change scores for the SD of INRs between the pre and post-randomization periods compared with placebo. The mean change score was -0.259±0.307 with the intervention and -0.046±0.345 with placebo (p=0.026). There was no effect on the change scores of the (%) TTR (p=0.98), the number of INRs out-of-range (p=0.58) and the number of dose changes (p=0.604). Factors independently associated with increased variability in the SD of INRs were increased alcoholic drinks/week (p=0.017), dosing errors (p=0.0009) and missed INR appointments (p=0.035). Vitamin K1 supplementation reduces the SD of INRs as an indicator of the variability in anticoagulation control in patients treated with warfarin for VTE.

Monthly CERA Treatment Maintains Stable Hemoglobin Levels in Routine Clinical Practice of Peritoneal Dialysis Patients

Data on routine use of continuous erythropoietin receptor activator (CERA) in peritoneal dialysis patients are scarce. This study aimed to assess the efficacy of CERA administered once monthly in maintaining stable Hb levels in patients on peritoneal dialysis under routine medical practice. This was a 12-month, observational, prospective and multicenter study. A total of 83 patients with anemia secondary to chronic kidney disease (CKD) on peritoneal dialysis for more than 3 months, on once-monthly subcutaneous CERA treatment, were followed up over a period of 1 year. Efficacy evaluation included Hb levels, mean time in which the Hb level was maintained within target range, CERA doses and number of dose changes. Median Hb level (interquartile range [IQR]) remained stable during the evaluation period [11.8 ± 1.4 g/dL at baseline, 11.8 ± 1.4 g/dL at month 6 and 11.8 ± 1.5 g/dL at month 12 (p > 0.05)]. The median (IQR) time of Hb level maintained within target range (11–13 mg/dL) was 6 (4–10) months. Ferritin, transferrin saturation index, and Fe were also stable and well maintained during the 12 months (p > 0.05). CERA mean dose (SD) was [115.4 (56.2) μg baseline; 117.2 (58.5) μg 6 months; 126.0 (65.9) μg 12 months (p = 0.127)]. The mean number of CERA dose changes per patient during the study was 1.6 (SD 1.3). Serious adverse events were not related to CERA treatment. The results suggest that once-monthly CERA successfully corrects anemia and maintains stable Hb levels within the recommended target range on peritoneal dialysis under routine medical practice.

Faisabilité de la stratégie d’administration de la darbepoetin alfa tous les 15 jours : expérience 2005–2007 d’un centre de dialyse

Darbepoetin alfa is a recombinant erythropoiesis-stimulating agent, with a longer half-life leaving the possibility to extending dosing administration in haemodialysis patients. A protocol of injection every 2 weeks was initiated in the dialysis unit. From 2005 to 2007, 176 dialysis patients were studied with a target haemoglobin level between 11 and 12.5 g/dL: the median haemoglobin level was ranged from 11.32 and 11.72 g/dL during the study with a median darbepoetin alfa dose injected between 60 and 64 μg per injection (0.46 to 0.47 μg/kg per week). The mean number of dose changes was three per year per patient. The diabetic population did not differ from the general population in terms of haemoglobin levels and doses of darbepoetin alfa. Ten percent of the patients had to resume one injection per week for medical reasons: the profile of these patients was carefully studied. Hospitalisations resulted in a decrease in haemoglobin level and an increase in the darbepoetin alfa doses. Patients who died showed during the last 3 months, a particular profile. Hyporesponsiveness has been explored. Time saving with this protocol was important for all the nursing staff. Although numerous factors of variability have been studied, there still a room for improvement of anemia management in haemodialysis patient.

Evaluation of Anemia Management by Algorithms in Patients with Chronic Kidney Disease Who Are Not Receiving Dialysis

Anemia commonly develops in patients with chronic kidney disease and is strongly associated with adverse clinical outcomes. There are currently no published studies evaluating the efficacy of a nurse-driven anemia-management protocol for patients with chronic kidney disease who are not receiving dialysis. To evaluate the efficacy of an anemia-management protocol in terms of achieving hemoglobin and transferrin saturation levels within the target range, as well as associated utilization of medications, relative to individualized dosing of medications by nephrologists. An algorithm for nurse-driven management of anemia was introduced in April 2009 at a kidney function clinic in a large urban centre. The charts of patients with chronic kidney disease who were not undergoing dialysis were reviewed before (July to December 2007) and after (July to December 2009) implementation of the protocol. Patients' data for hemoglobin, transferrin saturation, and doses of iron and erythropoiesis-stimulating agents were collected for each of the 6-month study periods. In total, 390 patients were treated for anemia before and 434 patients after introduction of the protocol. The anemia-management protocol was non-inferior to individualized dosing for maintenance of hemoglobin levels within the target range of 110-120 g/L: percentage of measured levels within target range 33.3% (485/1456) before versus 34.2% (504/1472) after (absolute difference 0.9 percentage points, 95% confidence interval [CI] -2.5 to 4.4). The criteria for non-inferiority were not met for maintenance of transferrin saturation within the target range of 22%-50%: percentage of levels within target range 58.8% (374/636) before versus 56.9% (403/708) after (absolute difference 1.9 percentage points, 95% CI -3.4 to 7.2). There were no statistically significant differences in mean doses of epoetin alfa, darbepoetin, or iron before and after introduction of the protocol. Similarly, there were no statistically significant differences in number of dose changes for epoetin alfa, darbepoetin, or iron. The nurse-driven anemia-management protocol was non-inferior to dosing by nephrologists in terms of managing hemoglobin levels. It would be reasonable to use an anemia-management protocol for patients with chronic kidney disease who are not receiving dialysis.

Dosing and monitoring of enoxaparin (Low molecular weight heparin) therapy in children

Low molecular weight heparins (LMWHs) are commonly used in paediatric tertiary institutions for primary prophylaxis and treatment of thromboembolic events. Despite this widespread use, the therapeutic and prophylactic guidelines for LMWH therapy in children are extrapolated from adult guidelines. In fact, there is very little information regarding the pharmacokinetics, clinical effectiveness, adverse event profile and optimal dose schedule for LMWH therapy in children. This study was designed to determine whether paediatric-specific dosage requirements for LMWH are justified, by investigating the doses required to achieve target therapeutic ranges. Patients who were treated with enoxaparin between October 2003 and July 2007 were identified for inclusion in this study. One hundred forty patients had an anti-activated factor X assay result with a total of 55 (39%) patients achieving therapeutic levels 4-6 h post dose. Children younger than 1 year required the highest dose of enoxaparin/kg and highest number of dose changes to achieve the target therapeutic range. Major bleeding occurred in one patient, equating to 0.7%, with complete clot resolution recorded in 16 (11%) patients. This study demonstrated a 2-3-fold variation in individual dose requirements for LMWH in children <or=5 years of age, and further mandates the need for age-specific dosage requirements in children receiving enoxaparin.

Intercurrent events and comorbid conditions influence hemoglobin level variability in dialysis patients

To help identify factors contributing to intra-patient Hb variability, pooled records were analyzed from 5,592 patients undergoing hemodialysis (HD) in European, multicenter, open-label, single-arm Phase 3b trials. Patients previously treated with recombinant human erythropoietin (rHuEPO) were switched to darbepoietin-alpha administered once a week (QW) or once every 2 weeks (Q2W), maintaining the same dosing schedule and route of ESA administration (intravenous or subcutaneous) up to and through the evaluation period. Patients were treated with darbepoietin-alpha to maintain Hb levels between 10 and 13 g/dl. Intrapatient variability was calculated using the SD model, taking all of an individual patient's Hb values during the evaluation period (Weeks 21 - 24 after conversion) and calculating the SD of these Hb values. Adverse events (AE) of infection or inflammation were recorded. Smaller variability was seen for patients 65 years of age or older compared with younger patients (p = 0.0044) and greater variability for patients less than 40 years of age compared with older patients (p < 0.01). Little difference in variability was seen in relation to sex overall or to the presence or absence of diabetes. Intra-patient Hb variability was greater in the presence of intercurrent conditions, including infection or inflammation (p = 0.0032), blood transfusion (p < 0.0001), hospitalization (p < 0.0001), or hospitalization for cardiovascular (CV) causes (p = 0.0012), than in their absence. Iron status differences had little detectable effect on intra-patient Hb variability. A larger number of changes made to the ESA dose during the evaluation period was also associated with greater Hb variability compared with fewer dose changes, but this association could not be proved as being causative. Although p values were calculated for some comparisons, statistical significance might not indicate clinical significance because of the large sample size. Multivariable analysis to assess the association between AE status and intra-patient Hb variability, adjusting for age, sex, diabetes status, number of dose changes and iron status showed that AE status was significantly associated with Hb variability. Additional studies would be needed to further investigate causes and effects of Hb variability and intercurrent events.

Warfarin dose management affects INR control.

Little is known about how patterns of warfarin dose management contribute to percentage time in the therapeutic International Normalized Ratio (INR) range (TTR). To quantify the contribution of warfarin dose management to TTR and to define an optimal dose management strategy. We enrolled 3961 patients receiving warfarin from 94 community-based clinics. We derived and validated a model for the probability of a warfarin dose change under various conditions. For each patient, we computed an observed minus expected (O - E) score, comparing the number of dose changes predicted by our model to the number of changes observed. We examined the ability of O - E scores to predict TTR, and simulated various dose management strategies in the context of our model. Patients were observed for a mean of 15.2 months. Patients who deviated the least from the predicted number of dose changes achieved the best INR control (mean TTR 70.1% unadjusted); patients with greater deviations had lower TTR (65.8% and 62.0% for fewer and more dose changes respectively, Bonferroni-adjusted P < 0.05/3 for both comparisons). On average, clinicians in our study changed the dose when the INR was 1.8 or lower/3.2 or higher (mean TTR: 68%); optimal management would have been to change the dose when the INR was 1.7 or lower/3.3 or higher (predicted TTR: 74%). Our observational study suggests that INR control could be improved considerably by changing the warfarin dose only when the INR is 1.7 or lower/3.3 or higher. This should be confirmed in a randomized trial.

Clinical Outcomes of Renal Transplantation Using Liquid Chromatographic Monitoring of Tacrolimus

It is suggested that specific methods of Tacrolimus monitoring rather than immunoassays which over-estimate Tacrolimus levels, should be used in transplant recipients. There is limited data, however, comparing clinical outcomes of renal transplantation using each of these techniques. In this study, 40 renal transplant recipients with Tacrolimus monitoring by Microparticle Enzyme Immunoassay (MEIA; target trough level 10-15 ng/ml) were compared with 40 patients monitored by High Performance Liquid Chromatography with Tandem Mass Spectrometry (HPLC-MS; target trough level 8-13 ng/ml). All received anti CD25 antibody induction and Mycophenolate Mofetil in a steroid sparing protocol. No demographic differences were seen between MEIA and HPLC-MS groups. All patients were followed for 6 months. Patient survival was 100% in both groups; graft survival was 100% in the MEIA group and 97.5% in the HPLC-MS group. The groups did not differ in the number of dose changes required in the first 6 months or in the number of patients displaying Tacrolimus levels within target range at three and six months. Delayed graft function occurred in 14 patients in the MEIA group and 12 patients in the HPLC-MS group (P = NS). Biopsy-proven acute rejection occurred in 4 patients in the MEIA group and 1 patient in the HPLC-MS group (P = 0.17). Biopsy proven acute Tacrolimus nephrotoxicity occurred in 6 patients in the MEIA group, and 7 in the HPLC-MS group (P = NS). No difference was seen in serum creatinine or estimated creatinine clearance at 3 or 6 months. No difference between groups was seen in systolic or diastolic blood pressure, or total cholesterol at 3 or 6 months. 2 patients in the MEIA group developed CMV disease and 1 developed posttransplantation diabetes mellitus. CMV and posttransplantation diabetes were not seen in the HPLC-MS group. 2 patients in each group developed reversible tremor. This study suggests that renal transplantation with HPLC-MS monitoring of Tacrolimus is safe and effective.

Tacrolimus Monitoring in Renal Transplantation: A Comparison Between High-Performance Liquid Chromatography and Immunoassay

It is recommended that specific methods of tacrolimus monitoring rather than immunoassays, which overestimate tacrolimus levels, should be used in transplant recipients. Direct comparison of these techniques, however, has not been conducted in renal transplantation. In this study, 40 renal transplant recipients with tacrolimus monitoring by microparticle enzyme immunoassay (MEIA; target trough level 10 to 15 ng/mL) were compared with 40 patients monitored by high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS; target trough level 8 to 13 ng/mL). All patients received anti CD25 antibody induction and mycophenolate mofetil in a steroid-sparing protocol. No differences were seen between MEIA and HPLC-MS groups in patient demographics. All patients were followed for 6 months. Patient survival was 100% in both groups; graft survival was 100% in the MEIA group and 97.5% in the HPLC-MS group. The groups did not differ in the number of dose changes required in the first 6 months or in the number of patients displaying tacrolimus levels within target range at 3 and 6 months. Delayed graft function occurred in 14 patients in the MEIA group and 12 patients in the HPLC-MS group ( P = NS). Biopsy-proven acute rejection occurred in four patients in the MEIA group and one patient in the HPLC-MS group ( P < .2). No differences were seen for the following parameters at 3 or 6 months: biopsy-proven tacrolimus nephrotoxicity, serum creatinine or estimated creatinine clearance, systolic or diastolic blood pressure, cholesterol, cytomegalovirus disease, posttransplant diabetes, or tremor. This study suggests that renal transplantation with HPLC-MS monitoring of tacrolimus is safe and effective.

Use of low molecular mass heparin (enoxaparin) in newborn infants: a prospective cohort study of 62 patients

Objective: To detail low molecular mass heparin (enoxaparin) use in the first few months of life. Design: Prospective, consecutive cohort of unselected newborn infants. Methods: Newborn infants were divided into...

Pharmacokinetics of tacrolimus-based combination therapies.

This paper reviews the pharmacokinetics of tacrolimus, with special reference to its combination with adjunctive immunosuppressants. Oral bioavailability of tacrolimus, which is variable between patients, averages approximately 25%. This is largely due to extrahepatic metabolism of tacrolimus in the gastrointestinal epithelium. Nevertheless, intra-patient variability is low, as evidenced by the small number of dose changes required to maintain patients within the recommended tacrolimus target levels. Tacrolimus is distributed extensively in the body with most partitioned outside the blood compartment. Concentrations of tacrolimus in blood are used as a surrogate marker of clinically relevant concentration of the drug at the site(s) of action. Convenient whole-blood sampling within a +/-2-h window around 12 h post-dose (C(min)) is highly predictive of systemic exposure to tacrolimus and is thus used to optimise therapy. Sampling at other time-points offers no advantage over C(min) monitoring. The interactions of tacrolimus with other immunosuppressive agents are well characterized. After cessation of concomitant corticosteroid treatment, exposure to tacrolimus increases by approximately 25%. In contrast, there is no pharmacokinetic interaction between mycophenolate mofetil (MMF) and tacrolimus. Therefore, systemic exposure to the active metabolite of MMF, mycophenolic acid, is higher with MMF-tacrolimus combination than with MMF-cyclosporin combination. Therefore, 1 g/day MMF may be an adequate maintenance dose in tacrolimus-based regimens. Co-administration of tacrolimus and sirolimus, while having no effect on exposure to sirolimus, results in reduced exposure to tacrolimus at sirolimus doses of 2 mg/day and above. In conclusion, tacrolimus levels should be monitored when sirolimus is co-administered at doses >2 mg/day and after cessation of corticosteroid treatment.

Postoperative Hypertension

OBJECTIVE To compare the efficacy and safety of iv nicardipine with sodium nitroprusside in the treatment of postoperative hypertension after both cardiac and noncardiac surgery. DESIGN Multicenter, prospective, randomized, open-label study. SETTING Six tertiary referral medical centers (recovery rooms and surgical ICUs). PATIENTS A total of 139 patients with postoperative hypertension: i.v. nicardipine (n = 71), sodium nitroprusside (n = 68). INTERVENTION Administration of i.v. nicardipine or sodium nitroprusside. MEASUREMENTS Vital signs (BP, heart rate), hemodynamic variables, medication dosage, total number of dose changes, and time to achieve BP control were recorded. MAIN RESULTS Both medications were equally effective in reducing BP in both the cardiac and noncardiac surgical groups. Under the conditions of the study, i.v. nicardipine controlled hypertension more rapidly than sodium nitroprusside (i.v. nicardipine 14.0 +/- 1.0 mins and sodium nitroprusside 30.4 +/- 3.5 mins, p = .0029). The total number of dose changes required to achieve therapeutic BP response was significantly less in the i.v. nicardipine-treated patients (i.v. nicardipine 1.5 +/- 0.2 vs. sodium nitroprusside 5.1 +/- 1.4, p < .05). Adverse effects were observed with both drugs (i.v. nicardipine 7% [5/71] and sodium nitroprusside 18% [12/68] [NS]). CONCLUSIONS Intravenous nicardipine is as effective as sodium nitroprusside in the therapy of postoperative hypertension. Specific advantages have been identified. The use of i.v. nicardipine should be considered in the therapy of postoperative hypertension.

Postoperative hypertension

To compare the efficacy and safety of iv nicardipine with sodium nitroprusside in the treatment of postoperative hypertension after both cardiac and noncardiac surgery. Multicenter, prospective, randomized, open-label study. Six tertiary referral medical centers (recovery rooms and surgical ICUs). A total of 139 patients with postoperative hypertension: i.v. nicardipine (n = 71), sodium nitroprusside (n = 68). Administration of i.v. nicardipine or sodium nitroprusside. Vital signs (BP, heart rate), hemodynamic variables, medication dosage, total number of dose changes, and time to achieve BP control were recorded. Both medications were equally effective in reducing BP in both the cardiac and noncardiac surgical groups. Under the conditions of the study, i.v. nicardipine controlled hypertension more rapidly than sodium nitroprusside (i.v. nicardipine 14.0 +/- 1.0 mins and sodium nitroprusside 30.4 +/- 3.5 mins, p = .0029). The total number of dose changes required to achieve therapeutic BP response was significantly less in the i.v. nicardipine-treated patients (i.v. nicardipine 1.5 +/- 0.2 vs. sodium nitroprusside 5.1 +/- 1.4, p < .05). Adverse effects were observed with both drugs (i.v. nicardipine 7% [5/71] and sodium nitroprusside 18% [12/68] [NS]). Intravenous nicardipine is as effective as sodium nitroprusside in the therapy of postoperative hypertension. Specific advantages have been identified. The use of i.v. nicardipine should be considered in the therapy of postoperative hypertension.