ObjectivesThis study aimed to evaluate the adherence to protocols for the use of reversal agents in direct oral anticoagulant (DOAC) users in Dutch hospitals.MethodsA retrospective cohort study was... Show moreObjectivesThis study aimed to evaluate the adherence to protocols for the use of reversal agents in direct oral anticoagulant (DOAC) users in Dutch hospitals.MethodsA retrospective cohort study was conducted in seven hospitals in the Netherlands. Treatment protocols for bleeding and (urgent) procedures in patients on DOAC were collected from each hospital. All patient data on the use of reversal agents were retrospectively collected from September 2021 to April 2022 and compared to the protocols. The degree of per-protocol adherence (compliance score) was categorized into four levels as follows: poor (<45%), moderate (45-79%), high (80-89%), and full (> 90%) adherence rates.ResultsA total of 290 patients were included in our study. In patients with bleeding under DOAC, the protocol adherence for prothrombin complex concentrate (PCC) was "moderate" (61%). In the remaining cases (39%), non-adherence was mainly caused by underdosing (68%), overdosing (12%), and a lack of indication (14%). Furthermore, idarucizumab was administered for bleeding with "full" adherence (96%). For andexanet al.fa, adherence to the hospital bleeding protocol was "moderate" (67%), with a lack of indication being the only reason for non-adherence. In case of reversal for an urgent procedure, the protocol adherence for PCC was "low" (45%), with underdosing, a lack of indication, and missing lab data being the main reasons for non-adherence. Missing lab data on dabigatran plasma concentration before reversal was the main reason for "low" adherence (26%) in idarucizumab. The adherence for andexanet al.fa was also "low" (0%).ConclusionIn case of reversal for bleeding under DOAC, overall adherence to the protocol was "moderate"; however, in patients needing an urgent procedure, it was "low." The major reasons for non-adherence were underdosing, off-label use, and a lack of specific lab testing. The results of this study can assist in improving the implementation of hospital protocols. Show less
Objective To describe treatment patterns, low-density lipoprotein cholesterol (LDL-C) levels and healthcare resource utilization (HCRU) in the Netherlands in 2018 of patients with... Show moreObjective To describe treatment patterns, low-density lipoprotein cholesterol (LDL-C) levels and healthcare resource utilization (HCRU) in the Netherlands in 2018 of patients with hypercholesterolaemia or mixed dyslipidaemia at high or very high cardiovascular (CV) risk. Methods From the PHARMO Database Network adult patients with a diagnosis or receiving lipid lowering therapy (LLT) between 2009 and 2018 were selected. Patients at high or very high CV risk according to 2016 ESC/EAS guidelines with recorded LDL-C levels who were treated with LLT or were characterized as statin intolerant in 2018 were included. LLT treatment patterns, LDL-C levels and HCRU (General Practitioner [GP] consultations and hospitalizations) were assessed. Results The study population included 54,346 patients, of which 70% were at very high CV risk and 30% at high CV risk. The majority (93%) received statin monotherapy, mostly of moderate (73%) or high (15%) intensity. Only 3% received a combination of statin and ezetimibe. Statin intolerance, based on a treatment algorithm, was estimated at 3%. Average LDL-C decreased with LLT intensity. Overall, 74% reached LDL-C < 2.5 mmol/l and 34% <1.8 mmol/l with their current treatment, and 46% reached their LDL-C goal according to 2016 ESC/EAS guidelines. The highest rates of hospitalizations and GP consultations, including home visits, were recorded in patients with peripheral artery disease or polyvascular disease. Conclusion The treatment of hypercholesterolaemia and mixed dyslipidaemia in patients at high or very high CV risk in the Netherlands was suboptimal in 2018. To further lower CV risk alternative treatment strategies using add-on therapies are needed. Show less
Objective: To evaluate, post hoc, the efficacy and safety of abaloparatide by degree of renal impairment. Methods: ACTIVE was a phase 3, 18-month, randomized, double-blind, active-comparator,... Show moreObjective: To evaluate, post hoc, the efficacy and safety of abaloparatide by degree of renal impairment. Methods: ACTIVE was a phase 3, 18-month, randomized, double-blind, active-comparator, placebo-controlled study of postmenopausal women with osteoporosis who received subcutaneous abaloparatide 80 mu g, placebo, or open-label teriparatide 20 mu g daily. Patients with serum creatinine >2.0 mg/dL or 1.5-2.0 mg/dL with an estimated glomerular filtration rate (eGFR) <37 mL/min, calculated by Cockcroft-Gault formula, were excluded. Results: At baseline, 660 patients had eGFR >= 90 mL/min, 1276 had 60 to <90 mL/min, and 527 had <60 mL/min. Older age and lower T-scores were associated with greater renal impairment. Among renal-function subgroups, there were no meaningful changes in bone mineral density, fracture risk reduction, or overall incidence of treatment-emergent adverse events in the active-treatment arms. Anemia, nausea, hypercalcemia, and upper-respiratory-tract infection tended to be more frequent with increasing renal impairment. Hypercalcemia measured by albumin-adjusted serum calcium occurred significantly less frequently with abaloparatide than teriparatide in patients with eGFR <60 mL/min (3.6% versus 10.9%; p = .008) and in the overall ACTIVE safety population (3.4% versus 6.4%; p = .006). Computed tomography scans in 376 patients revealed no evidence of increased renal calcification. Conclusion: Increased exposure to abaloparatide and teriparatide in patients with renal impairment led to no meaningful differences in efficacy or safety. These results support the use of abaloparatide without dosage adjustment in patients with renal impairment, provided those with severe renal impairments are monitored for adverse events. Show less
Since 2003, the European Medicines Agency (EMA) document, 'Points to consider on clinical investigation of medicinal products other than NSAIDs (nonsteroidal anti-inflammatory drugs) for the... Show moreSince 2003, the European Medicines Agency (EMA) document, 'Points to consider on clinical investigation of medicinal products other than NSAIDs (nonsteroidal anti-inflammatory drugs) for the treatment of rheumatoid arthritis' has provided guidance for the clinical development of both biologic and non-biologic disease-modifying antirheumatic drugs (DMARDs). In the last few years, several new products have been developed or are in development for the treatment of RA, which offer significant efficacy with regard to disease control, including prevention of structural damage and disability. Concurrently, novel insights have been gained with respect to the assessment of disease activity, joint damage and disability. New treatment strategies have been established which relate to early therapy, tight control and rapid switching of medication. Accordingly, several new EULAR/ACR recommendations have been or are being developed. Several important additions and changes are needed in the 2003 guidance to incorporate the current scientific knowledge into clinical trial design for the development of future products. Under the auspices of the Group for the Respect of Ethics and Excellence in Science (GREES), a group of experts in the field of RA and clinical trial design met to provide a consensus recommendation for an update to the 2003 EMA guidance document. Show less
Dalcetrapib increases high-density lipoprotein cholesterol (HDL-C) levels through effects on cholesteryl ester transfer protein (CETP). As part of the dalcetrapib dal-HEART clinical trial programme... Show moreDalcetrapib increases high-density lipoprotein cholesterol (HDL-C) levels through effects on cholesteryl ester transfer protein (CETP). As part of the dalcetrapib dal-HEART clinical trial programme, the efficacy and safety of dalcetrapib is assessed in coronary heart disease (CHD) patients in the dal-VESSEL study (ClinicalTrials.gov identifier: NCT00655538), the design and methods of which are presented here. Men and women with CHD or CHD risk equivalent, with HDL-C levels < 50 mg/dL were recruited for a 36-week, double-blinded, placebo-controlled trial. After a pre-randomisation phase of up to 8 weeks, patients received dalcetrapib 600 mg/day or placebo in addition to their existing treatments. Brachial flow-mediated dilatation (FMD) measured by B-mode ultrasound represents endothelial function and is a validated marker for early atherosclerosis and cardiovascular disease risk. The primary efficacy outcome is change from baseline in brachial FMD after 12 weeks. The primary safety endpoint is 24-hour ambulatory blood pressure monitoring (ABPM) assessed at week 4. Secondary endpoints include brachial FMD at 36 weeks, ABPM at 12 and 36 weeks, lipid profile, CETP mass and activity, and markers of inflammation, oxidation, and cardiovascular risk. Clinical endpoints are assessed as a composite endpoint for the dal-HEART Program. In 19 European clinical centres, 476 subjects met inclusion criteria and have entered the study. In conclusion, the dal-VESSEL study is the largest multicentre trial with brachial FMD ever performed. The study assesses efficacy and safety of dalcetrapib on endothelial function, blood pressure, lipids, and clinical outcomes in CHD patients with below average HDL-C and will therefore provide vital information regarding its potential role in the preventative treatment of CHD risk. Show less
Objective: This analysis of the Lipid Treatment Assessment Project 2 population compared lipid goal attainment by diabetes and metabolic syndrome status. Research design and methods: Dyslipidaemic... Show moreObjective: This analysis of the Lipid Treatment Assessment Project 2 population compared lipid goal attainment by diabetes and metabolic syndrome status. Research design and methods: Dyslipidaemic patients aged >= 20 years on stable lipid lowering therapy had their lipid levels determined once during enrolment at investigation sites in nine countries between September 2006 and April 2007. Achievement of low-density lipoprotein (LDL) cholesterol success, triglycerides < 150 mg/dl (1.7 mmol/l), and high-density lipoprotein (HDL) cholesterol success (> 40 mg/dl [1.0 mmol/l] in men or > 50 mg/dl [1.3 mmol/l] in women) was compared using logistic regression. Results: A total of 9955 patients were evaluated. Patients with diabetes, compared with those without diabetes, had lower achievement of LDL cholesterol goals (according to National Cholesterol Education Program Adult Treatment Panel [NCEP ATP] III guidelines; 67% vs. 75%), triglycerides < 150 mg/dl (55% vs. 64%), and HDL cholesterol success (61% vs. 74%; p < 0.0001 for all comparisons). The significantly lower lipid goal attainment in patients with diabetes was consistent across participating world regions. Patients with metabolic syndrome, compared with those without metabolic syndrome, had lower achievement of NCEP ATP III LDL cholesterol goals (69% vs. 76%), triglycerides < 150 mg/dl (36% vs. 83%), and HDL cholesterol success (49% vs. 89%; p < 0.0001 for all comparisons). As the number of metabolic syndrome components increased, lipid success rates progressively decreased (p < 0.0001 for LDL cholesterol success, triglycerides < 150 mg/dl, and HDL cholesterol success). Conclusions: This analysis indicates that despite their increased cardiovascular risk, patients with diabetes or metabolic syndrome remain undertreated. Show less
This paper contains detailed results of a sub-population of the prospective randomized RADAR (Rosuvastatin and Atorvastatin in different Dosages And Reverse cholesterol transport) study. Objective:... Show moreThis paper contains detailed results of a sub-population of the prospective randomized RADAR (Rosuvastatin and Atorvastatin in different Dosages And Reverse cholesterol transport) study. Objective: Statin treatment results in substantially decreased incidence of cardiovascular events but the exact pathophysiological mechanism of their beneficial effect is yet unclear. We aimed to examine the effects of up-titrated doses of two widely used statins (atorvastatin (ATOR) and rosuvastatin (ROSU)) on parameters involved in lipoprotein metabolism, in patients with low high density lipoprotein cholesterol values (HDL-C). Research design and methods: In this RADAR substudy, 80 patients, aged 40-80 years, with known cardiovascular disease and low HDL-C (<1.0 mmol/l), were randomized to receive, after an initial 6 week dietary run-in phase, either ATOR 20 mg (n = 41) or ROSU 10 mg (n = 39). The doses were up-titrated (in 6 week intervals) to 80 mg of ATOR or 40 mg of ROSU at 12 weeks. Serum lipoproteins and lipoprotein metabolism parameters were measured at baseline and at 6 and 18 weeks of follow up. Results: Both statins significantly reduced total cholesterol (TChol) and non-HDL-C values with ROSU being more effective for the doses studied (p<0.05). No statistically significant effect on HDL-C was observed for either statin. Apolipoproteins (apo) B, CI, CIII, AV and E were significantly reduced in both groups (p<0.05), while the ratio of HDL particles containing both apoAI and apoAII (LpAI-AII) over HDL containing apoAI alone (LpAI) was changed for both statins with the decrease of LpAI being more prominent in the ATOR group (p = 0.028). Cholesterol ester transfer protein (CETP) mass and activity, phospholipid transfer protein (PLTP) activity and lipoprotein-associated phospholipase A2 (Lp-PLA2) mass and activity were all significantly reduced in both treatment groups over the follow-up period (p<0.001). ATOR displayed a more prominent decrease of PLTP activity compared to ROSU (p=0.043), while ROSU displayed a more prominent decrease of Lp-PLA2 activity compared to ATOR (p=0.04). Both statins effectively reduced, in a dose-dependent way, high sensitivity C-reactive protein values over time, while no effect on the levels of circulating inter cellular adhesion molecule 1 (cICAM-1) was observed. Conclusions: The effects of statin treatment extend further and beyond a mere TChol and LDL cholesterol reduction, as demonstrated by the aforementioned alterations of lipoproteins, enzymes and lipid transfer proteins involved in lipoprotein metabolism and pro-atherogenic and inflammatory molecules. ROSU and ATOR displayed a similar pattern of effect on lipid metabolism with discrete differences in the magnitude of this effect in certain variables. Despite the limitations of small population size and lack of clinical end points, reported data provide an insight for the possible pathophysiological mechanisms implicated in the effect of increasing dosages of different statin treatments. Show less
