Nederlands Platform voor Farmaceutisch Onderzoek
Busulfanblootstelling geassocieerd met event-vrije overleving na allogene stamceltransplantatie bij kinderen: een retrospectieve multicentrumstudie
Busulfan exposure associated with event-free survival in children after allogeneic haematopoietic stem cell transplantation: a retrospective multicenter cohort study
To determine the relationship between busulfan cumulative area under the curve (AUC) and event-free survival (EFS) in children undergoing allogeneic haematopoietic stem cell transplantation (alloHCT).
Retrospective, multicenter cohort study.
Children who underwent alloHCT in 15 different centres worldwide were included in this study (2000-2013). Participants had to be on intravenous busulfan and pharmacokinetic samples had to be available. Exposure of interest was the cumulative AUC of busulfan, and primary outcome was EFS (time to graft failure, relapse or all-cause mortality). Cox regression models were used to derive relative risks (RR), and the optimal busulfan AUC level was estimated using propensity adjusted Weibull models.
A total of 674 subjects (41% malignant, 59% non-malignant) with a median age of 4.5 years (interquartile range 1.4-10.7 years) were included in the analysis. We observed a significant U-shaped relationship between busulfan cumulative AUC and EFS (P = 0.011). The optimal target was estimated at 90 mg·h/L (78-101 mg·h/L), and was independent of any of the investigated patient characteristics. An AUC below the target increased the risk of graft failure and relapse (relative risk 1.75, P = 0.004), while transplant-related mortality was more pronounced when the AUC was too high (relative risk 2.99, P < 0.001).
This is the largest study on the relationship between busulfan and clinical outcomes in children undergoing alloHCT. Our results strongly advocate the use of therapeutic drug monitoring of busulfan, using 90 mg·h/L (78-101 mg·h/L) as a target.
|Datum:||20 februari 2017|
Guideline adherence with regard to direct acting oral anticoagulants use
To determine guideline adherence regarding prescribing direct acting oral anticoagulants (DOACs) in daily clinical practice, distinguishing clinical and outpatient cardiology and orthopaedy patients.
Observational retrospective cross-sectional study.
Four guidelines for prescribing DOACs were summarized. Medical records were used to identify patients who received rivaroxaban, dabigatran or apixaban. Baseline characteristics and adherence to the guidelines regarding interactions, CHA2DS2-VASc, HAS-BLED, dosage, renal function etc. were compared between clinical and outpatient cardiology and orthopaedy groups.
100 patients were included in all three groups. In four cases an interaction with possible clinical implications was found. Among almost half of the patients the CHA2DS2-VASc score was not registered. The HAS-BLED score was only determined for a handful of patients. Overtreatment was found in 3% of clinical cardiology patients and 7% of cardiology outpatients. Complications during VKA use prompted a switch to DOACs in only few cases. In 32% of orthopaedy patients and 41% of cardiology outpatients the renal function measurement was older than 60 days; in three cases the renal function was unknown. One patient with a prior cerebral haemorrhage received a DOAC without consent from a neurologist. 76% of patients in the outpatient group and 91% in the clinical cardiology group were prescribed the appropriate dose. A lower dose than appropriate was more common than a higher dose.
In general adherence to guidelines is good, but there is room for improvement. Verifying the absence of interactions, checking renal function and offering help with appropriate dosing can be performed by the hospital pharmacy. A way to improve determination and recording of CHA2DS2-VASc and HAS-BLED scores needs to be determined.
|Datum:||20 februari 2017|
Use of high-dose intermittent glucocorticoids and the risk of fracture in patients with COPD
To investigate the effects of high-dose intermittent glucocorticoid (GC) use on fracture risk in patients with chronic obstructive pulmonary disease (COPD).
Population-based retrospective case-control study.
We conducted this study using data from the Danish National Databases. Cases were subjects ≥ 45 years with COPD, who sustained an osteoporotic fracture during the study period (1996-2011). To each case, a control without a fracture was matched by gender and year of birth. Also oral glucocorticoid use was evaluated before the index date. Associations between glucocorticoid use and fracture risk were determined using conditional logistic regression. Adjustments were made for comorbidities, drug use and disease severity.
Fracture risk in COPD patients currently using high-dose intermittent glucocorticoids was not increased (corrected odds ratio [ORcorr] 0.70; 95% confidence interval [CI95] 0.49-0.99). GC users with average daily dose ≥ 15 mg and cumulative dose ≥ 1 g did have a significant increased fracture risk (ORcorr 1.34, CI95 1.09-1.64). Stratification of current GC use to average daily dose did not show a clear dose-effect relationship (< 7.5 mg: ORcorr 1.08, CI95 0.99-1.17; 7.5-14.9 mg: ORcorr 1.20, CI95 1.07-1.34; ≥ 15 mg: ORcorr 1.15, CI95 0.96-1.37). For cumulative dose a trend was seen (cumulative dose ≥ 5 g: ORcorr 1.15, CI95 1.02-1.31).
COPD patients using high-dose intermittent glucocorticoids do not have an increased risk of osteoporotic fractures, regardless of disease severity. On the contrary, long-term heavy users have a clear fracture risk which is in line with guideline recommendations on fracture prevention.
|Datum:||7 februari 2017|
Medisch-farmaceutische beslisregels en nierfunctiemeting in de openbare apotheek: wat levert het op?
Clinical decision rules and measuring renal function in community pharmacy: what do we get out of it?
To investigate the frequency and management of drug therapy alerts about drug use in patients with (potential) renal impairment, to investigate the contribution of point-of-care testing (PoCT) of renal function in community pharmacy to the availability of information on renal function, and to investigate pharmacists’ experiences with drug therapy alerts and PoCT.
DESIGN AND METHODS
A clinical decision support system with clinical decision rules for eleven drugs (seven antibiotics, sotalol, digoxin, allopurinol and spironolactone) and PoCT of renal function were implemented in community pharmacies. The clinical decision rules generated an alert when dose adjustment was advised based on a registered impaired renal function, and when information on the renal function was lacking for patients over 70 years of age with a prescription for one of the selected drugs. Data registered in the clinical decision support system regarding generated alerts, renal functions and alert management were analysed retrospectively. In addition, the participating pharmacists filled out a questionnaire about their experiences.
336 pharmacists managed 27.307 alerts for 21.494 patients, leading to 362 dose adjustments and 65 drug replacements. For 16.208 of these patients, renal function has been registered in the clinical decision support system, including over 400 PoCT measurements. Based on PoCT, 25 cases of impaired renal function have been registered, leading to two therapy adjustments. The participating pharmacists were positive about the project.
Advanced clinical decision rules on renal function led to over 400 therapy adjustments. PoCT is a potentially useful source of information on renal function in a limited number of cases, when this information is urgently needed and not available from other sources.
|Datum:||9 januari 2017|
Life-threatening side effect after adding sitagliptin to enalapril
Angioedema is localised subcutaneous or submucosal oedema due to extravasation of fluid with a predominance for occurring in the face or airway. Because of the sudden onset with possibility of rapid progression it can be life-threatening.
We describe the case of a patient with life-threatening angioedema after adding the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin to enalapril. Angioedema persisted for multiple days despite treatment with H1 and H2 antihistamines and glucocorticoids. Absence of response to this therapy in combination with the history and course of the disease make a bradykinin-mediated etiology of the angioedema likely.
Inhibiting angiotensin-converting enzyme and DPP-4 inhibits two important routes to eliminate bradykinin, which can explain the development of angioedema in our patient. There are some case reports of angioedema caused by the combination of a DPP-4 inhibitor and ACE inhibition, although structured clinical evidence is weak.
We recommend to avoid the combination of DDP-4 inhibitors and ACE inhibitors in patients with previously known angioedema. Alertness to the risk of developing angioedema can prevent under-reporting of this potentially life-threatening side effect.
|Datum:||9 januari 2017|