Publications by authors named "Michiel Coppens"

79 Publications

Incidence and mortality rates of intracranial hemorrhage in hemophilia: a systematic review and meta-analysis.

Blood 2021 Aug 19. Epub 2021 Aug 19.

Amsterdam UMC, Amsterdam, Netherlands.

Intracranial hemorrhage (ICH) is a severe complication that is relatively common among hemophilia patients. This systematic review aimed to obtain more precise estimates of ICH incidence and mortality in hemophilia, which may be important for patients, caregivers, researchers and health policy-makers. PubMed and EMBASE were systematically searched using terms related to "hemophilia" and "intracranial hemorrhage" or "mortality". Studies that allowed calculation of ICH incidence or mortality rates in a hemophilia population of at least 50 patients were included. We summarized evidence on ICH incidence and calculated pooled ICH incidence and mortality in three age groups: (1) persons of all ages with hemophilia, (2) children and young adults below 25 years of age with hemophilia and (3) neonates with hemophilia. Incidence and mortality were pooled with a Poisson-Normal model or a Binomial-Normal model. We included 45 studies that represented 54 470 patients, 809 151 person-years and 5326 live births of hemophilia patients. In persons of all ages, the pooled ICH incidence and mortality rates were 2.3 (95% CI 1.2-4.8) and 0.8 (95% CI 0.5-1.2) per 1000 person-years, respectively. In children and young adults, the pooled ICH incidence and mortality rates were 7.4 (95% CI 4.9-11.1) and 0.5 (95% CI 0.3-0.9) per 1000 person-years, respectively. In neonates, the pooled cumulative ICH incidence was 2.1% (95% CI 1.5-2.8) per 100 live births. ICH was classified as spontaneous in 35-58% of cases. Our findings suggest that ICH is an important problem in hemophilia that occurs among all ages, requiring adequate preventive strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2021011849DOI Listing
August 2021

Recurrent bleeding and thrombotic events after resumption of oral anticoagulants following gastrointestinal bleeding: Communication from the ISTH SSC Subcommittee on Control of Anticoagulation.

J Thromb Haemost 2021 Jul 28. Epub 2021 Jul 28.

Department of Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Center, Amsterdam, the Netherlands.

Background: Gastrointestinal bleeding frequently complicates anticoagulant therapy causing treatment discontinuation. Data to guide the decision regarding whether and when to resume anticoagulation based on the risks of thromboembolism and recurrent bleeding are scarce.

Objectives: We aimed to retrospectively evaluate the incidence of these events after anticoagulant-related gastrointestinal bleeding and assess their relationship with timing of anticoagulation resumption.

Methods: Patients hospitalized because of gastrointestinal bleeding during oral anticoagulation for any indication were eligible. All patients were followed up to 2 years after the index bleeding for recurrent major or clinically relevant non-major bleeding, venous or arterial thromboembolism, and mortality.

Results: We included 948 patients hospitalized for gastrointestinal bleeding occurring during treatment with vitamin K antagonists (n = 531) or direct oral anticoagulants (n = 417). In time-dependent analysis, anticoagulant treatment was associated with a higher risk of recurrent clinically relevant bleeding (hazard ratio [HR] 1.55; 95% confidence interval [CI] 1.08-2.22), but lower risk of thromboembolism (HR 0.34; 95% CI 0.21-0.55), and death (HR 0.50; 95% CI 0.36-0.68). Previous bleeding, index major bleeding, and lower glomerular filtration rate were associated with a higher risk of recurrent bleeding. The incidence of recurrent bleeding increased after anticoagulation restart independently of timing of resumption.

Conclusions: Anticoagulant treatment after gastrointestinal bleeding is associated with a lower risk of thromboembolism and death, but higher risk of recurrent bleeding. The latter seemed to be influenced by patient characteristics and less impacted by time of anticoagulation resumption.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jth.15476DOI Listing
July 2021

Quality of life in patients with pulmonary embolism treated with edoxaban versus warfarin.

Res Pract Thromb Haemost 2021 Jul 14;5(5):e12566. Epub 2021 Jul 14.

Daiichi Sankyo Pharma Development Basking Ridge NJ USA.

Background: Long-term sequelae of acute pulmonary embolism (PE) include decreased quality of life (QoL). Evidence suggests that adequacy of initial anticoagulant treatment in the acute phase of venous thrombosis has a key impact on late postthrombotic complications. We hypothesize that patients with acute PE treated with edoxaban for acute PE experience have improved QoL compared to those treated with warfarin.

Methods: Patients with PE who participated in the Hokusai-VTE trial were contacted between June 2017 and September 2020 for a single long-term follow-up visit. Main outcomes were the generic and disease-specific QoL measured by the 36-Item Short Form Health Survey (SF-36) and Pulmonary Embolism Quality of Life questionnaire.

Results: We included 251 patients from 26 centers in eight countries, of which 129 (51%) had been assigned to edoxaban and 122 (49%) to warfarin. Patient- and thrombus-specific characteristics were similar in both groups. Mean time since randomization in the Hokusai-VTE trial was 7.0 years (standard deviation, 1.0). No relevant or statistical differences were observed in the QoL for patients treated with edoxaban compared to patients treated with warfarin. The mean difference between patients treated with edoxaban and patients with PE treated with warfarin was 0.8 (95% confidence interval [CI]. -1.6 to 3.2) for the SF-36 summary mental score and 1.6 (95% CI, -0.9 to 4.1) for summary physical score.

Conclusion: Our findings indicate that patients with an index PE treated with edoxaban or warfarin have a similar long-term QoL. Since our study was a follow-up study from a well-controlled clinical trial setting, future studies should be designed in a daily clinical practice setting. We suggest a longitudinal design for investigation of changes in QoL over time.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/rth2.12566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279124PMC
July 2021

Validation of PROMIS Profile-29 in adults with hemophilia in the Netherlands.

J Thromb Haemost 2021 Jul 10. Epub 2021 Jul 10.

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.

Background: The Patient-Reported Outcomes Measurement Information System (PROMIS) Profile-29 questionnaire is widely used worldwide, but it has not yet been validated in the Netherlands, nor in persons with hemophilia.

Objective: To validate the Dutch-Flemish version of the PROMIS-29 Profile v2.01 in adults with hemophilia.

Methods: Dutch males with hemophilia (all severities) completed questionnaires that contained sociodemographic and clinical characteristics, the PROMIS-29, RAND-36, and the Hemophilia Activities List (HAL). Structural validity of each subscale was assessed with confirmatory factor analysis (CFA). Internal consistency was calculated for each subscale with sufficient model fit in CFA. Construct validity was assessed by testing hypotheses about (1) correlations of each PROMIS-29 subscale with corresponding scales of RAND-36 and domains of HAL, and (2) mean differences in T-scores between subgroups with different hemophilia severities, self-reported joint impairment, and HIV infection status. We considered ≥75% of data in accordance with the hypotheses evidence for construct validity.

Results: In total, 770 persons with hemophilia participated in this cross-sectional study. CFA revealed sufficient structural validity for five subscales: Physical Function, Depression, Sleep Disturbance, Ability to Participate in Social Roles and Activities, and Pain Interference. Internal consistency was high and Cronbach's alpha ranged from 0.79 for Sleep Disturbance to 0.96 for Pain Interference. Differences between clinical subgroups were in the expected direction. Construct validity was confirmed for Physical Function, Anxiety, Depression, Fatigue, Sleep Disturbance, and Pain Intensity.

Conclusion: This study revealed sufficient evidence for structural validity, internal consistency, and construct validity for most PROMIS Profile-29 subscales among people with hemophilia in the Netherlands.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jth.15454DOI Listing
July 2021

Perioperative pharmacokinetic-guided factor VIII concentrate dosing in haemophilia (OPTI-CLOT trial): an open-label, multicentre, randomised, controlled trial.

Lancet Haematol 2021 Jul;8(7):e492-e502

Department of Pediatric Hematology, Erasmus MC Sophia Children's Hospital, Rotterdam, Netherlands. Electronic address:

Background: Dosing of replacement therapy with factor VIII concentrate in patients with haemophilia A in the perioperative setting is challenging. Underdosing and overdosing of factor VIII concentrate should be avoided to minimise risk of perioperative bleeding and treatment costs. We hypothesised that dosing of factor VIII concentrate on the basis of a patient's pharmacokinetic profile instead of bodyweight, which is standard treatment, would reduce factor VIII consumption and improve the accuracy of attained factor VIII levels.

Methods: In this open-label, multicentre, randomised, controlled trial (OPTI-CLOT), patients were recruited from nine centres in Rotterdam, Groningen, Utrecht, Nijmegen, The Hague, Leiden, Amsterdam, Eindhoven, and Maastricht in The Netherlands. Eligible patients were aged 12 years or older with severe or moderate haemophilia A (severe haemophilia was defined as factor VIII concentrations of <0·01 IU/mL, and moderate haemophilia as 0·01-0·05 IU/mL), without factor VIII inhibitors, and planned for elective low or medium risk surgery as defined by surgical risk score. Patients were randomly assigned (1:1) using a web-based randomisation system and treatment minimisation, stratified by method of administration of factor VIII concentrate (continuous infusion vs bolus administration) and risk level of surgery (low and medium risk surgery), to the pharmacokinetic-guided or standard treatment group. The primary endpoint was total amount of infused factor VIII concentrate (IU per kg bodyweight) during perioperative period (from day of surgery up to 14 days after surgery). Analysis was by intention to treat and the safety analysis population comprised all participants who underwent surgery with factor VIII concentrate. This study is registered with the Netherlands Trial Registry, NL3955, and is now closed to accrual.

Findings: Between May 1, 2014, and March 1, 2020, 98 patients were assessed for eligibility and 66 were enrolled in the trial and randomly assigned to the pharmacokinetic-guided treatment group (34 [52%]) or the standard treatment group (32 [48%]). Median age was 49·1 years (IQR 35·0 to 62·1) and all participants were male. No difference was seen in consumption of factor VIII concentrate during the perioperative period between groups (mean consumption of 365 IU/kg [SD 202] in pharmacokinetic-guided treatment group vs 379 IU/kg [202] in standard treatment group; adjusted difference -6 IU/kg [95% CI -88 to 100]). Postoperative bleeding occurred in six (18%) of 34 patients in the pharmacokinetic-guided treatment group and three (9%) of 32 in the standard treatment group. One grade 4 postoperative bleeding event occurred, which was in one (3%) patient in the standard treatment group. No treatment-related deaths occurred.

Interpretation: Although perioperative pharmacokinetic-guided dosing is safe, it leads to similar perioperative factor VIII consumption when compared with standard treatment. However, pharmacokinetic-guided dosing showed an improvement in obtaining factor VIII concentrations within the desired perioperative factor VIII range. These findings provide support to further investigation of pharmacokinetic-guided dosing in perioperative haemophilia care.

Funding: Dutch Research Council (NWO)-ZonMw and Takeda.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2352-3026(21)00135-6DOI Listing
July 2021

Similar sports participation as the general population in Dutch persons with haemophilia; results from a nationwide study.

Haemophilia 2021 Sep 19;27(5):876-885. Epub 2021 Jun 19.

Van Creveldkliniek, University Medical Center Utrecht, Utrecht, The Netherlands.

Introduction: Although sports participation is advocated in people with haemophilia (PWH), detailed data concerning sports participation in Dutch PWH is lacking.

Aim: to assess sports participation in Dutch PWH (6-65 years) compared to the Dutch general population (GP).

Methods: Data from a nationwide, cross-sectional study in PWH were analysed. Sports participation (type, duration, frequency) was assessed by the Modifiable Activities Questionnaire (MAQ), limitations in activities using the (Paediatric) Haemophilia Activities List ((Ped)HAL). Sports in the two highest categories according to the National Hemophilia Foundation classification were considered high-risk sports. Groups were compared using Chi-square testing.

Results: A total of 524 Adult PWH (median age: 45 (IQR: 30-55); 37% severe) and 126 paediatric PWH (median age: 11 (IQR: 8-14); 52% severe) were included. Sports participation was higher in adults (70%) than the GP (58%) and similar to the GP in children (PWH: 68%, GP: 72%). High-risk sports participation decreased with age in PWH: from 65% (6-12 years) to 17% (50-65 years), which was also observed in the GP. Sports participation in children was independent of severity (non-severe: 67% vs. severe: 65%; P = 0.97), but not in adults (non-severe: 75%, severe: 62%; P < 0.01). Non-severe PWH played more high-risk sports than severe PWH: children at 65% vs. 48% (P = 0.05), adults at 25% vs. 15% (P = 0.07).

Discussion: These results suggest that sports participation in PWH was comparable to the GP. Sports participation was dependent of haemophilia severity in adults. Children were more involved in high-risk sports than adults. More studies on sports-related injury-risk are needed for adequate counselling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/hae.14366DOI Listing
September 2021

Health and treatment outcomes of patients with hemophilia in the Netherlands, 1972-2019.

J Thromb Haemost 2021 Jun 12. Epub 2021 Jun 12.

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.

Introduction: We conducted six cross-sectional nationwide questionnaire studies among all patients with hemophilia in the Netherlands from 1972 until 2019 to assess how health outcomes have changed, with a special focus on patients >50 years of age.

Methods: Data were collected on patient characteristics, treatment, (joint) bleeding, joint impairment, hospitalizations, human immunodeficiency virus and hepatitis C infections, and general health status (RAND-36).

Results: In 2019, 1009 patients participated, of whom 48% had mild, 15% moderate, and 37% severe hemophilia. From 1972 to 2019, the use of prophylaxis among patients with severe hemophilia increased from 30% to 89%. Their median annual bleeding rate decreased from 25 to 2 bleeds. Patients with severe hemophilia aged <16 years reported joint impairment less often over time, but in those aged >40 years joint status did not improve. In 2019, 5% of all 1009 patients were positive for the human immunodeficiency virus. The proportion of patients with an active hepatitis C infection drastically decreased from 45% in 2001 to 2% in 2019 due to new anti-hepatitis C treatment options. Twenty-five percent had significant liver fibrosis even after successful therapy. Compared to the general male population, patients aged >50 years reported much lower scores on the RAND-36, especially on physical functioning.

Discussion/conclusion: Our study shows that increased use of prophylactic treatment and effective hepatitis C treatment have improved joint health and nearly eradicated hepatitis C infection in patients with hemophilia in the Netherlands. However, patients still suffer from hemophilia-related complications, especially patients aged >50 years.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jth.15424DOI Listing
June 2021

Treatment-related risk factors for inhibitor development in non-severe hemophilia A after 50 cumulative exposure days: A case-control study.

J Thromb Haemost 2021 Sep 19;19(9):2171-2181. Epub 2021 Jul 19.

Pediatric Hematology, Emma Children's Hospital, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Background: Non-severe hemophilia A patients have a life-long inhibitor risk. Yet, no studies have analyzed risk factors for inhibitor development after 50 factor VIII (FVIII) exposure days (EDs).

Objectives: This case-control study investigated treatment-related risk factors for inhibitor development in non-severe hemophilia A and assessed whether these risk factors were different for early versus late inhibitor development.

Patients/methods: Non-severe hemophilia A patients (FVIII:C 2%-40%) were selected from the INSIGHT study. Inhibitor-positive patients were defined as early (<50 EDs) or late (>50EDs) cases and matched to 1-4 inhibitor-negative controls by year of birth, cumulative number of EDs, and center/country. We investigated treatment intensity during the last 10 EDs prior to inhibitor development. Intensive treatment was defined as: surgery, peak treatment (10 consecutive EDs), and high mean FVIII dose (>45 IU/kg/ED). Odds ratios (OR) were calculated by logistic regression.

Results: Of 2709 patients, we analyzed 63 early and 26 late cases and 195 and 71 respectively matched controls. Peak treatment was associated with early and late inhibitor risk (crude OR 1.8, 95% confidence interval [CI] 1.0-3.4; 4.0, 95%CI 1.1-14.3). This association was slightly less pronounced after adjustment for mean FVIII dose. High mean FVIII dose was also associated with early and late inhibitor risk (crude OR 2.8, 95%CI 1.5-5.1; 4.5, 95%CI 1.2-16.6). Surgery increased inhibitor risk for early cases. This was less pronounced for late cases.

Conclusions: Our findings suggest that intensive FVIII treatment remains a risk factor for inhibitor development in non-severe hemophilia A after more than 50 EDs. Therefore, persistent caution is required throughout the life-time treatment course.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jth.15419DOI Listing
September 2021

CAVA (Ultrasound-Accelerated Catheter-Directed Thrombolysis on Preventing Post-Thrombotic Syndrome) Trial: Long-Term Follow-Up Results.

J Am Heart Assoc 2021 Jun 25;10(11):e018973. Epub 2021 May 25.

CARIM Cardiovascular Research Institute MaastrichtSchool for Cardiovascular DiseasesMaastricht University Medical Centre Maastricht the Netherlands.

Background The CAVA (Ultrasound-Accelerated Catheter-Directed Thrombolysis Versus Anticoagulation for the Prevention of Post-Thrombotic Syndrome) trial did not show a reduction of post-thrombotic syndrome (PTS) after additional ultrasound-accelerated catheter-directed thrombolysis in patients with acute iliofemoral deep vein thrombosis at 1-year follow-up. This prespecified analysis of the CAVA trial aimed to determine the impact of additional thrombolysis on outcomes of PTS at long-term follow-up. Methods and Results Patients aged 18 to 85 years with a first-time acute iliofemoral deep vein thrombosis were included and randomly assigned (1:1) to either standard treatment plus ultrasound-accelerated catheter-directed thrombolysis or standard treatment alone. The primary outcome was the proportion of PTS (Villalta score ≥5 on 2 occasions ≥3 months apart or venous ulceration) at the final follow-up visit. Additionally, PTS according to the International Society on Thrombosis and Haemostasis (ISTH) consensus definition was assessed to allow external comparability. Major bleedings were the main safety outcome. At a median follow-up of 39.0 months (interquartile range, 23.3-63.8), 120 patients (79.8%) participated in the final follow-up visit: 62 from the intervention group and 58 from the standard treatment group. PTS developed in 19 (30.6%) versus 26 (44.8%) patients, respectively (odds ratio [OR], 0.54; 95% CI, 0.26 to 1.15 [=0.11]), with an absolute difference between groups of -14.2% (95% CI, -32.0% to 4.8%). Using the ISTH consensus definition, a significant reduction in PTS was observed (29 [46.8%] versus 40 [69.0%]) (OR, 0.40; 95% CI, 0.19-0.84 [=0.01]) with an absolute difference between groups of -22.2% (95% CI, -39.8% to -2.8%). No new major bleedings occurred following the 12-month follow-up. Conclusions The impact of additional ultrasound-accelerated catheter-directed thrombolysis on the prevention of PTS was found to increase with time. Although this study was limited by its sample size, the overall findings indicate a reduction of mild PTS without impact on quality of life. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00970619.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/JAHA.120.018973DOI Listing
June 2021

Vascular mechanisms and manifestations of COVID-19.

Lancet Respir Med 2021 06 18;9(6):551-553. Epub 2021 May 18.

University College London Hospitals NHS Foundation Trust, Department of Medicine, and Cardiometabolic Programme-National Institute for Health Research UCLH/UCL Biomedical Research Centre, London, UK.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2213-2600(21)00221-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128673PMC
June 2021

Intracranial hemorrhage with direct oral anticoagulants in patients with brain metastases.

Blood Adv 2020 12;4(24):6291-6297

Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

Direct oral anticoagulants (DOACs) are increasingly prescribed in treatment of cancer-associated thrombosis, but limited data exist regarding safety of DOACs in patients with brain metastases. We aimed to determine the incidence of intracranial hemorrhage (ICH) in patients with brain metastases receiving DOACs or low-molecular-weight heparin (LMWH) for venous thromboembolism or atrial fibrillation. An international 2-center retrospective cohort study was designed. Follow-up started on the first day of concomitant anticoagulation and brain tumor diagnosis. At least 2 brain imaging studies were mandated. The primary outcome was the cumulative incidence of any spontaneous ICH at 12-month follow-up with death as a competing risk. Major ICH was defined as spontaneous, ≥10 mL in volume, symptomatic, or requiring surgical intervention. Imaging studies were centrally reviewed by a neuroradiologist blinded for anticoagulant type. PANWARDS (platelets, albumin, no congestive heart failure, warfarin, age, race, diastolic blood pressure, stroke) score for prediction of ICH was calculated. We included 96 patients with brain metastases (41 DOAC, 55 LMWH). The 12-month cumulative incidence of major ICH was 5.1% in DOAC-treated patients and 11.1% in those treated with LMWH (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.09-2.21). When anticoagulation was analyzed as a time-varying covariate, the risk of any ICH did not differ between DOAC- and LMWH-treated patients (HR, 0.98; 95% CI, 0.28-3.40). PANWARDS score was not associated with ICH risk. This international 2-center study suggests comparable safety of LMWH and DOACs in patients with brain metastases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2020003238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756985PMC
December 2020

Mortality, life expectancy, and causes of death of persons with hemophilia in the Netherlands 2001-2018.

J Thromb Haemost 2021 03 18;19(3):645-653. Epub 2020 Dec 18.

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.

Background: Treatment of patients with hemophilia has advanced over the past decades, but it is unknown whether this has resulted in a normal life expectancy in the Netherlands.

Objective: This observational cohort study aimed to assess all-cause and cause-specific mortality in patients with hemophilia in the Netherlands between 2001 and 2018 and to compare mortality and life expectancy with previous survival assessments from 1973 onward.

Patients/methods: All 1066 patients with hemophilia who participated in a nationwide survey in 2001 were followed until July 2018.

Results: Information on 1031 individuals (97%) was available, of whom 142 (14%) deceased during follow-up. Compared with the general Dutch male population, mortality of patients with hemophilia was still increased (standardized mortality ratio: 1.4, 95% confidence interval: 1.2-1.7). Intracranial bleeding and malignancies were the most common causes of death. Estimated median life expectancy of patients with hemophilia was 77 years, 6 years lower than the median life expectancy of the general Dutch male population (83 years). Over the past 45 years, death rates of patients with hemophilia have consistently decreased, approaching the survival experience of the general population. Over the past decades, mortality due to human immunodeficiency virus and hepatitis C virus infections has decreased, death due to intracranial hemorrhages has increased, and death due to ischemic heart disease has remained consistently low over time.

Conclusions: Survival in patients with hemophilia in the Netherlands has improved over time but is still lower than that of the general population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jth.15182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986360PMC
March 2021

Outcome of intracranial bleeding managed with prothrombin complex concentrate in patients on direct factor Xa inhibitors or vitamin K antagonists.

Thromb Res 2020 12 21;196:404-409. Epub 2020 Sep 21.

Amsterdam UMC, University of Amsterdam, Department of Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands. Electronic address:

Intracranial hemorrhage (ICH) is the most feared complication of anticoagulation with a high mortality and morbidity. Before registration of a specific reversal agent for factor Xa inhibitors (FXa-I), international guidelines recommended prothrombin complex concentrate (PCC), which also is the specific reversal agent for vitamin K antagonists (VKA). In two contemporary cohorts, we compared clinical outcomes between patients with FXa-I and VKA related ICH treated with PCC between 2014 and 2018. Primary outcome was effective hemostasis after 24 h, according to the International Society of Thrombosis and Hemostasis definition. Safety outcomes were defined as venous and arterial thromboembolic complications and death within 30 days. Thirty-six patients with FXa-I-ICH and 39 patients with VKA-ICH were available for analysis. Baseline characteristics were comparable between both groups, except for time from start of symptoms to presentation at the hospital. In the FXa-I-ICH cohort, 24 (73%) patients achieved effective hemostasis compared to 23 (62%) patients in the VKA-ICH cohort (crude odds ratio [OR] 1.62 [95%CI 0.59-4.48], adjusted OR 1.45 [95%CI 0.44-4.83]). Eight (24%) patients with FXa-I-ICH deceased compared to 17 (45%) patients with VKA-ICH (crude OR 0.38 [95%CI 0.14-1.24], adjusted OR 0.41 [95%CI 0.12-1.24]). In this observational cohort study, the outcome of ICH managed with PCC was similar in patients with FXa-I-ICH and in patients with VKA-ICH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.thromres.2020.09.028DOI Listing
December 2020

Treatment of acquired hemophilia A, a balancing act: results from a 27-year Dutch cohort study.

Am J Hematol 2021 01 10;96(1):51-59. Epub 2020 Oct 10.

Van Creveldkliniek, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands.

Acquired hemophilia A (AHA) is a severe auto-immune bleeding disorder. Treatment of AHA is burdensome and optimal management is still unresolved. Therefore a retrospective nationwide multi-center cohort study (1992-2018) was performed to evaluate clinical presentation and treatment efficacy and safety of AHA in the Netherlands. Multivariate logistic and Cox regression analysis was used to study independent associations between patient characteristics and clinical outcomes. A total of 143 patients (median age 73 years; 52.4% male) were included with a median follow-up of 16.8 months (IQR 3.6-41.5 months). First-line immunosuppressive treatment was mostly steroid monotherapy (67.6%), steroids/cyclophosphamide (11.9%) and steroids/rituximab (11.9%), with success rates of 35.2%, 80.0% and 66.7% respectively, P < .05. Eventually 75% of patients achieved complete remission (CR). A high anti-FVIII antibody titer, severe bleeding and steroid monotherapy were associated with lower CR rates. Infections, the most important adverse event, occurred significantly more often with steroid combination therapy compared to steroids alone (38.7% vs 10.6%; P = .001). Overall mortality was 38.2%, mostly due to infections (19.2%) compared to 7.7% fatal bleeds. Advanced age, underlying malignancy and ICU admission were predictors for mortality. This study showed that AHA is characterized by significant disease-related and treatment-related morbidity and mortality. A high anti-FVIII titer, severe bleeding and steroid monotherapy were associated with a lower CR rate. The efficacy of steroid combination therapies however, was overshadowed by higher infection rates and infections represented the most important cause of death. The challenging and delicate balance between treatment effectivity and safety requires ongoing monitoring of AHA and further identification of prognostic markers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajh.26009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756759PMC
January 2021

ETNA-VTE Europe: Benefits and risks of venous thromboembolism treatment using edoxaban in the first 3 months.

Thromb Res 2020 12 12;196:297-304. Epub 2020 Sep 12.

Guy's and St Thomas' NHS Foundation Trust, King's College London, United Kingdom. Electronic address:

Introduction: Edoxaban had a positive risk-benefit ratio for the treatment of venous thromboembolism (VTE) compared to conventional therapy with warfarin. The objective of this analysis of the ongoing ETNA-VTE Europe study was to assess the real-world benefits and risks of edoxaban during the first 3 months of treatment, the highest risk period for further VTE events.

Methods: ETNA-VTE Europe is a prospective, non-interventional, post-authorization study, conducted in eight European countries. Participants had initial or recurrent acute VTE (deep vein thrombosis [DVT] and/or pulmonary embolism [PE]) that occurred ≤2 weeks prior to enrolment and received edoxaban therapy.

Results: The analysis set included 2672 patients (PE ± DVT, n = 1117; DVT only, n = 1555); mean age 62.9 ± 16.0 years, bodyweight 81.9 ± 17.4 kg, estimated glomerular filtration rate 95.4 ± 42.8 mL/min; 46.4% were female. Overall, 66.4% of patients (PE ± DVT, 68.5%; DVT-only, 64.8%) received heparin lead-in treatment for at least 5 days. Most patients (87.7%) received edoxaban at a dose of 60 mg once daily. Event rates at 3 months were: recurrent VTE 0.34% (n = 9), major bleeding 0.97% (n = 26), all-cause mortality 0.79% (n = 21). Rates were numerically higher in the PE ± DVT group compared with the DVT-only group (recurrent VTE, 0.45% (n = 5) versus 0.26% (n = 4); major bleeding, 1.34% (n = 15) versus 0.71% (n = 11); and all-cause mortality 1.16% (n = 13) versus 0.51% (n = 8)).

Conclusions: The results support the safety and effectiveness of edoxaban in a general VTE population during the most critical time period, the first 3 months. The outcomes of this study extend the principal efficacy and safety data on edoxaban into the routine clinical practice setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.thromres.2020.09.001DOI Listing
December 2020

Illness cognitions associated with health-related quality of life in young adult men with haemophilia.

Haemophilia 2020 Sep 25;26(5):793-799. Epub 2020 Aug 25.

Psychosocial Department, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Introduction And Aim: Knowledge on patterns of beliefs about the illness (illness cognitions) can provide insight into individual differences in adjustment to haemophilia. The current study aimed to identify (a) which sociodemographic and disease characteristics were associated with illness cognitions and (b) which illness cognitions were associated with health-related quality of life (HRQOL) in young adult men with haemophilia, besides sociodemographic and disease characteristics.

Methods: Young adult men (18-30 years) with haemophilia in the Netherlands participated in an online multicentre cross-sectional study. Participants completed the Pediatric Quality of Life Inventory Young Adult version (PedsQL_YA). Potential sociodemographic determinants were assessed with the Course of Life Questionnaire (CoLQ) and illness cognitions with the Illness Cognition Questionnaire (ICQ). Multiple linear regression analyses were performed to assess potential determinants of illness cognitions and HRQOL.

Results: Seventy young adult men with haemophilia (mean age 24.7 years, SD 3.5) participated. Born outside the Netherlands (β -0.24) and >1 bleed past 6 months (β -0.32) were associated with less acceptance of the disease. More acceptance was associated with better HRQOL in all domains: β 0.23-0.39. More helplessness was associated with worse total (β -0.30) and physical (β -0.42) HRQOL. Disease benefits, sociodemographic and disease characteristics were not associated with HRQOL.

Conclusion: Illness cognitions are associated with HRQOL in young adult men with haemophilia. Early recognition and identification of illness cognitions are important to facilitate support and psychosocial treatment to optimize young adults' well-being. Extra attention is needed for young adult men with frequent bleeds because they are at risk of lowered levels of acceptance of the disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/hae.14120DOI Listing
September 2020

Optimal trough levels in haemophilia B: Raising expectations.

Haemophilia 2020 Nov 25;26(6):e334-e336. Epub 2020 Aug 25.

University of Colorado, Boulder, CO, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/hae.14098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818248PMC
November 2020

ETNA VTE Europe: A contemporary snapshot of patients treated with edoxaban in clinical practice across eight European countries.

Eur J Intern Med 2020 12 18;82:48-55. Epub 2020 Aug 18.

Internal and Cardiovascular Medicine-Stroke Unit, University of Perugia, Perugia, Italy. Electronic address:

Introduction: Edoxaban has proven its efficacy and safety in the ENGAGE AF-TIMI 48 and HOKUSAI-VTE clinical trials. Clinical practice patients, however, may differ from those enolled in clinical trials. We aimed to compare patients from the HOKUSAI-VTE clinical trial with those treated in clinical practice.

Materials And Methods: ETNA-VTE-Europe is a prospective, non-interventional post-authorisation safety study conducted in eight European countries.

Results: A total of 2,879 patients presenting with acute symptomatic venous thromboembolism (VTE) were enrolled at 339 sites. Of the 2,680 patients with complete data, 23.6% reported prior VTE and 2.8% had a history of bleeding. Patients in ETNA-VTE were older (65vs.57 years), more likely to be female (46.5vs.39.8%) and had a higher prevalence of chronic venous insufficiency (11.1vs.1.6%) than those in the European cohort of the HOKUSAI-VTE trial (n=1,512). Bodyweight and creatinine clearance were substantially lower in clinical practice. Edoxaban dosing was adherent to label in 90% of patients, with higher (60 mg) and lower than recommended doses (30 mg) used in 6.6% and 3.3% of the patients, respectively. Heparin lead-in was used in 84.7% of the patients overall, and was more frequently used in patients with PE than patients with DVT only (91.3% vs. 80.1%; p<0.0001).

Conclusions: These data reinforce the largely appropriate use of edoxaban in routine clinical practice, where the study population differs from those in prior randomised controlled trials. CLINICALTRIALS.

Gov Identifier: NCT02943993.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejim.2020.08.014DOI Listing
December 2020

Predictors of preprocedural direct oral anticoagulant levels in patients having an elective surgery or procedure.

Blood Adv 2020 08;4(15):3520-3527

Department of Medicine, McMaster University, Hamilton, ON, Canada.

The Perioperative Anticoagulation Use for Surgery Evaluation (PAUSE) study prospectively evaluated a prespecified periprocedural-interruption strategy of direct oral anticoagulants (DOACs) among patients with atrial fibrillation. Logistic regression analyses were performed to identify clinical parameters associated with residual DOAC levels ≥30 ng/mL or ≥50 ng/mL. Patients undergoing low-bleed-risk procedures were more likely to have residual levels of ≥30 ng/mL and ≥50 ng/mL. For low-risk procedures, age ≥75 years, female sex, a creatinine clearance (CrCl) <50 mL/min, and an interruption of <36 hours were associated with a greater likelihood of levels ≥30 ng/mL, whereas age ≥75 years, female sex, a CrCl of <50 mL/min, and standard DOAC dosing were associated with levels ≥50 ng/mL. For high-risk procedures, weight of <70 kg, CrCl <50 mL/min, and standard DOAC dosing were associated with residual levels ≥30 ng/mL, whereas female sex was associated with levels ≥50 ng/mL. For low-risk procedures, apixaban was associated with a higher likelihood of levels ≥30 ng/mL as compared with dabigatran (P = .0019) and of levels ≥50 ng/mL when compared with rivaroxaban (P = .0003). For high-risk procedures, apixaban was marginally associated with a higher likelihood of residual levels ≥30 ng/mL when compared with dabigatran (P = .05), whereas rivaroxaban was associated with a higher likelihood of levels ≥30 ng/mL as compared with apixaban. Further study is required to determine whether adjustments to perioperative plans based on these clinical parameters could result in a lower risk of residual DOAC levels. The PAUSE trial was registered at www.clinicaltrials.gov as #NCT2228798.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2020002335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7422107PMC
August 2020

Bleeding phenotype and diagnostic characterization of patients with congenital platelet defects.

Am J Hematol 2020 Jun 19. Epub 2020 Jun 19.

Van Creveldkliniek, University Medical Center Utrecht, University Utrecht, Utrecht, the Netherlands.

Phenotypic characterization of congenital platelet defects (CPDs) could help physicians recognize CPD subtypes and can inform on prognostic implications. We report the analyses of the bleeding phenotype and diagnostic characteristics of a large cohort of adult patients with a confirmed CPD. A total of 96 patients were analyzed and they were classified as Glanzmann thrombasthenia, Bernard-Soulier syndrome, dense granule deficiency, defects in the ADP or thromboxane A2 (TxA2) pathway, isolated thrombocytopenia or complex abnormalities. The median ISTH-BAT bleeding score was nine (IQR 5-13). Heavy menstrual bleeding (HMB) (80%), post-partum hemorrhage (74%), post-operative bleeds (64%) and post-dental extraction bleeds (57%) occurred most frequently. Rare bleeding symptoms were bleeds from the urinary tract (4%) and central nervous system (CNS) bleeds (2%). Domains with a large proportion of severe bleeds were CNS bleeding, HMB and post-dental extraction bleeding. Glanzmann thrombasthenia and female sex were associated with a more severe bleeding phenotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajh.25910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540397PMC
June 2020

Emergencies on direct oral anticoagulants: Management, outcomes, and laboratory effects of prothrombin complex concentrate.

Res Pract Thromb Haemost 2020 May 23;4(4):569-581. Epub 2020 Apr 23.

Department of Vascular Medicine Amsterdam Cardiovascular Sciences Amsterdam UMC University of Amsterdam Amsterdam The Netherlands.

Background: In the initial absence of specific reversal agents for factor Xa inhibitors (FXa-Is), prothrombin complex concentrate (PCC) as a hemostatic agent has been recommended by guidelines. Since 2017, idarucizumab has been registered for dabigatran reversal. Still, data on the clinical outcome of direct oral anticoagulant (DOAC)-related emergencies (major bleeding or urgent interventions) is scarce. In addition, it is unknown to what extent PCC restores thrombin generation in FXa-I-related emergencies. Our aim was to describe management and clinical outcomes of DOAC-related emergencies and to assess the laboratory effect of PCC in patients with FXa-I emergencies.

Methods: In this prospective cohort study in 5 Dutch hospitals, patients presenting with DOAC-related emergencies were eligible. The primary outcome was effective hemostasis according to the ISTH definition. Safety outcomes were 30-day mortality and thromboembolic rate. In patients treated with PCC, additional blood samples were taken to assess the effect on thrombin generation.

Results: We included 101 patients with major bleeding (FXa-I, 76; dabigatran, 25) and 21 patients requiring an urgent intervention (FXa-I, 16; dabigatran, 5). Of patients with major bleeding, 67% were treated with PCC or idarucizumab. Effective hemostasis, 30-day mortality, and thromboembolism rate were 67%, 22%, and 1%, respectively. In a subset of bleeding patients on FXa-I managed with PCC, thrombin generation increased, with 96% immediately after PCC administration. In patients requiring an urgent intervention, effective hemostasis, 30-day mortality, and thromboembolic rate were 95%, 14%, and 5%.

Conclusions: Effective hemostasis was achieved in the majority of patients presenting with DOAC-related emergencies;, thromboembolic complications were rare, and mortality was quite high.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/rth2.12336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292661PMC
May 2020

Incidence of venous thromboembolism in hospitalized patients with COVID-19.

J Thromb Haemost 2020 Aug 27;18(8):1995-2002. Epub 2020 Jul 27.

Department of Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Background: Coronavirus disease 2019 (COVID-19) can lead to systemic coagulation activation and thrombotic complications.

Objectives: To investigate the incidence of objectively confirmed venous thromboembolism (VTE) in hospitalized patients with COVID-19.

Methods: Single-center cohort study of 198 hospitalized patients with COVID-19.

Results: Seventy-five patients (38%) were admitted to the intensive care unit (ICU). At time of data collection, 16 (8%) were still hospitalized and 19% had died. During a median follow-up of 7 days (IQR, 3-13), 39 patients (20%) were diagnosed with VTE of whom 25 (13%) had symptomatic VTE, despite routine thrombosis prophylaxis. The cumulative incidences of VTE at 7, 14 and 21 days were 16% (95% CI, 10-22), 33% (95% CI, 23-43) and 42% (95% CI 30-54) respectively. For symptomatic VTE, these were 10% (95% CI, 5.8-16), 21% (95% CI, 14-30) and 25% (95% CI 16-36). VTE appeared to be associated with death (adjusted HR, 2.4; 95% CI, 1.02-5.5). The cumulative incidence of VTE was higher in the ICU (26% (95% CI, 17-37), 47% (95% CI, 34-58), and 59% (95% CI, 42-72) at 7, 14 and 21 days) than on the wards (any VTE and symptomatic VTE 5.8% (95% CI, 1.4-15), 9.2% (95% CI, 2.6-21), and 9.2% (2.6-21) at 7, 14, and 21 days).

Conclusions: The observed risk for VTE in COVID-19 is high, particularly in ICU patients, which should lead to a high level of clinical suspicion and low threshold for diagnostic imaging for DVT or PE. Future research should focus on optimal diagnostic and prophylactic strategies to prevent VTE and potentially improve survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jth.14888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497052PMC
August 2020

Pregnancy outcome in afibrinogenemia: Are we giving enough fibrinogen concentrate? A case series.

Res Pract Thromb Haemost 2020 Feb 22;4(2):343-346. Epub 2020 Jan 22.

Department of Hematology Radboud Universisty Medical Center Nijmegen The Netherlands.

Congenital afibrinogenemia is a rare autosomal recessive disorder associated with an increased risk of hemorrhage, thrombosis, and obstetric complications. This case series of 4 pregnancies in 2 related patients seeks to address the key clinical question of the necessary doses of fibrinogen concentrate during pregnancy and puerperium. One pregnancy without the prophylactic use of fibrinogen concentrate resulted in spontaneous abortion. The second pregnancy was complicated by a subchorionic hematoma despite the prophylactic administration of fibrinogen concentrate to maintain the plasma trough levels at ≥0.6 g/L. Labor was complicated by postpartum hemorrhage with a blood loss volume of 1480 cc. Two weeks later, the patient presented with postpartum thrombosis. The other 2 pregnancies were uncomplicated with fibrinogen trough levels ≥1.0 g/L during pregnancy and ≥1.5 g/L during labor. These cases illustrate that during pregnancy, patients may benefit from fibrinogen trough levels ≥1.0 g/L. In addition, the increased risk of postpartum thrombosis with prolonged fibrinogen supplementation warrants personalized postpartum advice that is guided by postpartum blood loss.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/rth2.12300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7040545PMC
February 2020

Congenital platelet disorders and health status-related quality of life.

Res Pract Thromb Haemost 2020 Jan 11;4(1):100-105. Epub 2019 Dec 11.

Van Creveldkliniek University Medical Center Utrecht University Utrecht Utrecht The Netherlands.

Background: Patients with congenital blood platelet disorders (CPDs) demonstrate a predominantly mucocutaneous bleeding tendency. Repeated bleeds throughout life can have a significant impact on health status-related quality of life (HR-QoL), but few studies have investigated HR-QoL in patients with CPDs.

Objectives: To determine HR-QoL in patients with suspected or confirmed CPDs as compared with the general Dutch population and to assess the association between bleeding phenotype and HR-QoL.

Methods: Data were derived from the Thrombocytopathy in the Netherlands (TiN) study, a cross-sectional study of individuals suspected for a congenital platelet defect. TiN patients with an increased ISTH Bleeding Assessment Tool (ISTH-BAT) score (>3 in men and > 5 in women) were included for analysis. HR-QoL was assessed with the Short Form (SF)-36 survey. Bleeding symptoms were evaluated with the ISTH-BAT, resulting in a bleeding score.

Results: One hundred fifty-six patients were analyzed, of whom 126 (81%) were women. Sixty-two patients (40%) had a confirmed CPD. Compared to the general Dutch population, patients with a suspected or confirmed CPD reported decreased physical functioning, limitations in daily activities due to physical health problems, limitations in social activities, decreased energy levels and fatigue, pain, and lower general health status. HR-QoL was not correlated with the ISTH-BAT score and was similar in patients with a confirmed CPD and those in whom a CPD could not be diagnosed.

Conclusion: A bleeding tendency in patients with a suspected or confirmed CPD significantly impacts HR-QoL, independent of a confirmed explanatory diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/rth2.12281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971322PMC
January 2020

Flow cytometric mepacrine fluorescence can be used for the exclusion of platelet dense granule deficiency.

J Thromb Haemost 2020 03 27;18(3):706-713. Epub 2019 Dec 27.

Van Creveld Laboratory, University Medical Center Utrecht, Utrecht, The Netherlands.

Background: δ-storage pool disease (δ-SPD) is a bleeding disorder characterized by a reduced number of platelet-dense granules. The diagnosis of δ-SPD depends on the measurement of platelet ADP content, but this test is time consuming and requires a relatively large blood volume. Flow cytometric analysis of platelet mepacrine uptake is a potential alternative, but this approach lacks validation, which precludes its use in a diagnostic setting.

Objectives: To evaluate the performance of platelet mepacrine uptake as a diagnostic test for δ-SPD.

Patients/methods: Mepacrine fluorescence was determined with flow cytometry before and after platelet activation in 156 patients with a suspected platelet function disorder and compared with platelet ADP content as a reference test. Performance was analyzed with a receiver operating characteristic (ROC) curve.

Results: Eleven of 156 patients had δ-SPD based on platelet ADP content. Mepacrine fluorescence was inferior to platelet ADP content in identifying patients with δ-SPD, but both mepacrine uptake (area under the ROC curve [AUC] 0.87) and mepacrine release after platelet activation (AUC 0.80) had good discriminative ability. In our tertiary reference center, mepacrine uptake showed high negative predicitive value (97%) with low positive predictive value (35%). Combined with a negative likelihood ratio of 0.1, these data indicate that mepacrine uptake can be used to exclude δ-SPD in patients with a bleeding tendency.

Conclusion: Mepacrine fluorescence can be used as a screening tool to exclude δ-SPD in a large number of patients with a suspected platelet function disorder.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jth.14698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065135PMC
March 2020

Ultrasound-accelerated catheter-directed thrombolysis versus anticoagulation for the prevention of post-thrombotic syndrome (CAVA): a single-blind, multicentre, randomised trial.

Lancet Haematol 2020 Jan 27;7(1):e40-e49. Epub 2019 Nov 27.

Department of Vascular Surgery, Maastricht University Medical Centre, Maastricht, Netherlands; Department of Vascular Surgery, Aachen University Medical Centre, Aachen, Germany.

Background: Early thrombus removal might prevent post-thrombotic syndrome by preserving venous function and restoring flow. Previous trials comparing additional catheter-directed thrombolysis to standard treatment showed conflicting outcomes. We aimed to assess the benefit of additional ultrasound-accelerated catheter-directed thrombolysis for the prevention of post-thrombotic syndrome compared with standard therapy in patients with iliofemoral deep-vein thrombosis.

Methods: We did a multicentre, randomised, single-blind, allocation-concealed, parallel group, superiority trial in 15 hospitals in the Netherlands. Patients aged 18-85 years with a first-time acute iliofemoral deep-vein thrombosis and symptoms for no more than 14 days were randomly assigned (1:1) to either standard treatment with additional ultrasound-accelerated catheter-directed thrombolysis or standard treatment alone. Randomisation was done with a web-based automatic programme and a random varying block size (2-12), stratified by age and centre. Standard treatment included anticoagulant therapy, compression therapy (knee-high elastic compression stockings; 30-40 mmHg), and early ambulation. Additional ultrasound-accelerated catheter-directed thrombolysis was done with urokinase with a starting bolus of 250 000 international units (IU) in 10 mL NaCl followed by a continuous dose of 100 000 IU/h for a maximum of 96 h through the Ekos Endowave-system. Adjunctive percutaneous transluminal angioplasty, thrombosuction, or stenting was performed at the discretion of the physician who performed the intervention. The primary outcome was the proportion of patients with post-thrombotic syndrome at 12 months diagnosed according to the original Villalta criteria-a Villalta-score of at least 5 on two consecutive occasions at least 3 months apart or the occurrence of venous ulceration-and was assessed in a modified intention-to-treat population of all randomly assigned patients who passed screening and started treatment. The safety analysis was assessed in the same modified intention-to-treat population. This study is complete and is registered at ClinicalTrials.gov, NCT00970619.

Findings: Between May 28, 2010, and Sept 18, 2017, 184 patients were randomly assigned to either additional ultrasound-accelerated catheter-directed thrombolysis (n=91) or standard treatment alone (n=93). Exclusion because of screening failure or early withdrawal of informed consent resulted in 77 patients in the intervention group and 75 in the standard treatment group starting allocated treatment. Median follow-up was 12·0 months (IQR 6·0-12·0). 12-month post-thrombotic syndrome occurred in 22 (29%) patients allocated to additional treatment versus 26 (35%) patients receiving standard treatment alone (odds ratio 0·75 [95% CI 0·38 to 1·50]; p=0·42). Major bleeding occurred in four (5%) patients in the intervention group, with associated neuropraxia or the peroneal nerve in one patient, and no events in the standard treatment group. No serious adverse events occurred. None of the four deaths (one [1%] in the intervention group vs three [4%] in the standard treatment group) were treatment related.

Interpretation: This study showed that additional ultrasound-accelerated catheter-directed thrombolysis does not change the risk of post-thrombotic syndrome 1 year after acute iliofemoral deep-vein thrombosis compared with standard therapy alone. Although this trial is inconclusive, the outcome suggests the possibility of a moderate beneficial effect with additional ultrasound-accelerated catheter-directed thrombolysis. Further research is therefore warranted to better understand this outcome in the context of previous trials, preferably by combining the available evidence in an individual patient data meta-analysis.

Funding: The Netherlands Organisation for Health Research and Development (ZonMw), Maastricht University Medical Centre, BTG-Interventional Medicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2352-3026(19)30209-1DOI Listing
January 2020

Patient Perspectives on Novel Treatments in Haemophilia: A Qualitative Study.

Patient 2020 04;13(2):201-210

Department of Clinical Epidemiology, Leiden University Medical Center, Postzone C7-P, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.

Background And Objective: New treatments for haemophilia are under development or entering the market, including extended half-life products, designer drugs and gene therapy, thereby increasing treatment options for haemophilia. It is currently unknown how people with haemophilia decide whether to switch to a new treatment. Therefore, the objective of this study was to explore what factors may play a role when Dutch patients and parents of boys with moderate or severe haemophilia make decisions about whether to switch to a different treatment, and how disease and treatment characteristics may affect these decisions. This may aid clinical teams in tailored information provision and shared decision making.

Methods: We conducted interviews among adults with moderately severe or severe haemophilia and parents of young boys with severe haemophilia. We aimed to include participants from a variety of backgrounds in terms of involvement in the haemophilia community, age, treatment centre and treatments. Participants were recruited through the Netherlands Haemophilia Society and a haemophilia treatment centre. Semi-structured interviews were recorded and transcribed verbatim. Thematic content analysis was used to analyse the data.

Results: Twelve people with haemophilia and two mothers of boys with haemophilia were included. In general, participants reported to be satisfied with their current treatment. However, they considered ease of use of the medication (fewer injections, easier handling, alternative administration) an added value of new treatments. Participants were aware of the high cost of coagulation factor products and some expressed their concern about the Netherlands Haemophilia Society's long-term willingness to pay for current and novel treatments, especially for increased usage due to high-risk activities. Participants also expressed their concerns about the short- and long-term safety of new treatments and believed the effects of gene therapy were not yet fully understood. Participants expected their treatment team to inform them when a particular new treatment would be suitable for them.

Conclusions: With the number of treatment options set to increase, it is important for healthcare providers to be aware of how patient experiences shape patients' decisions about new therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40271-019-00395-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075838PMC
April 2020

Perioperative Management of Patients With Atrial Fibrillation Receiving a Direct Oral Anticoagulant.

JAMA Intern Med 2019 Nov;179(11):1469-1478

Department of Anesthesiology, Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada.

Importance: Patients with atrial fibrillation (AF) who use a direct oral anticoagulant (DOAC) and request elective surgery or procedure present a common clinical situation yet perioperative management is uncertain.

Objective: To investigate the safety of a standardized perioperative DOAC management strategy.

Design, Setting, And Participants: The Perioperative Anticoagulation Use for Surgery Evaluation (PAUSE) cohort study conducted at 23 clinical centers in Canada, the United States, and Europe enrolled and screened patients from August 1, 2014, through July 31, 2018. Participants (n = 3007) had AF; were 18 years of age or older; were long-term users of apixaban, dabigatran etexilate, or rivaroxaban; were scheduled for an elective surgery or procedure; and could adhere to the DOAC therapy interruption protocol.

Interventions: A simple standardized perioperative DOAC therapy interruption and resumption strategy based on DOAC pharmacokinetic properties, procedure-associated bleeding risk, and creatinine clearance levels. The DOAC regimens were omitted for 1 day before a low-bleeding-risk procedure and 2 days before a high-bleeding-risk procedure. The DOAC regimens were resumed 1 day after a low-bleeding-risk procedure and 2 to 3 days after a high-bleeding-risk procedure. Follow-up of patients occurred for 30 days after the operation.

Main Outcomes And Measures: Major bleeding and arterial thromboembolism (ischemic stroke, systemic embolism, and transient ischemic attack) and the proportion of patients with an undetectable or minimal residual anticoagulant level (<50 ng/mL) at the time of the procedure.

Results: The 3007 patients with AF (mean [SD] age of 72.5 [9.39] years; 1988 men [66.1%]) comprised 1257 (41.8%) in the apixaban cohort, 668 (22.2%) in the dabigatran cohort, and 1082 (36.0%) in the rivaroxaban cohort; 1007 patients (33.5%) had a high-bleeding-risk procedure. The 30-day postoperative rate of major bleeding was 1.35% (95% CI, 0%-2.00%) in the apixaban cohort, 0.90% (95% CI, 0%-1.73%) in the dabigatran cohort, and 1.85% (95% CI, 0%-2.65%) in the rivaroxaban cohort. The rate of arterial thromboembolism was 0.16% (95% CI, 0%-0.48%) in the apixaban cohort, 0.60% (95% CI, 0%-1.33%) in the dabigatran cohort, and 0.37% (95% CI, 0%-0.82%) in the rivaroxaban cohort. In patients with a high-bleeding-risk procedure, the rates of major bleeding were 2.96% (95% CI, 0%-4.68%) in the apixaban cohort and 2.95% (95% CI, 0%-4.76%) in the rivaroxaban cohort.

Conclusions And Relevance: In this study, patients with AF who had DOAC therapy interruption for elective surgery or procedure, a perioperative management strategy without heparin bridging or coagulation function testing was associated with low rates of major bleeding and arterial thromboembolism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamainternmed.2019.2431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686768PMC
November 2019

Switching patients in the age of long-acting recombinant products?

Expert Rev Hematol 2019 ;12(sup1):1-13

g National Reference Centre for Haemophilia, Louis Pradel Hospital , University Claude Bernard Lyon I , Lyon , France.

: Prophylaxis with factor replacement therapy is the gold standard for the treatment of hemophilia, but this often requires frequent infusions. A number of long-acting factor products have been developed to reduce the burden on patients. : This is an overview of information presented at two symposia held at the World Federation of Hemophilia and International Society on Thrombosis and Haemostasis - Scientific and Standardization Committee annual meetings. The pharmacokinetic, safety and efficacy data for long-acting recombinant products are reviewed, with a focus on recombinant factor IX albumin fusion protein (rIX-FP) and rVIII-SingleChain. This overview also provides a guide for managing a patient's switch to long-acting products. : Long-acting products may allow patients to maintain or decrease bleeding rates whilst increasing their dosing interval, which may in turn reduce the burden on patients and caregivers. When switching patients to long-acting products health-care professionals should provide balanced and thorough education to the patient, whilst supporting their emotional well-being. Regimens should address patients' needs and goals but should also be guided by clinical phenotype and pharmacokinetic assessment. Follow-up should assess safety concerns, bleeding rates, joint health and the impact of the regimen on patients' lifestyle.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17474086.2018.1564032DOI Listing
June 2020
-->