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BMJ (Clinical Research Ed.) Jun 2021To determine the efficacy and safety of dalteparin postoperative bridging treatment versus placebo for patients with atrial fibrillation or mechanical heart valves when... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To determine the efficacy and safety of dalteparin postoperative bridging treatment versus placebo for patients with atrial fibrillation or mechanical heart valves when warfarin is temporarily interrupted for a planned procedure.
DESIGN
Prospective, double blind, randomised controlled trial.
SETTING
10 thrombosis research sites in Canada and India between February 2007 and March 2016.
PARTICIPANTS
1471 patients aged 18 years or older with atrial fibrillation or mechanical heart valves who required temporary interruption of warfarin for a procedure.
INTERVENTION
Random assignment to dalteparin (n=821; one patient withdrew consent immediately after randomisation) or placebo (n=650) after the procedure.
MAIN OUTCOME MEASURES
Major thromboembolism (stroke, transient ischaemic attack, proximal deep vein thrombosis, pulmonary embolism, myocardial infarction, peripheral embolism, or vascular death) and major bleeding according to the International Society on Thrombosis and Haemostasis criteria within 90 days of the procedure.
RESULTS
The rate of major thromboembolism within 90 days was 1.2% (eight events in 650 patients) for placebo and 1.0% (eight events in 820 patients) for dalteparin (P=0.64, risk difference -0.3%, 95% confidence interval -1.3 to 0.8). The rate of major bleeding was 2.0% (13 events in 650 patients) for placebo and 1.3% (11 events in 820 patients) for dalteparin (P=0.32, risk difference -0.7, 95% confidence interval -2.0 to 0.7). The results were consistent for the atrial fibrillation and mechanical heart valves groups.
CONCLUSIONS
In patients with atrial fibrillation or mechanical heart valves who had warfarin interrupted for a procedure, no significant benefit was found for postoperative dalteparin bridging to prevent major thromboembolism.
TRIAL REGISTRATION
Clinicaltrials.gov NCT00432796.
Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Dalteparin; Double-Blind Method; Female; Heart Valve Prosthesis; Humans; Male; Middle Aged; Postoperative Period; Prospective Studies; Surgical Procedures, Operative; Thromboembolism; Warfarin
PubMed: 34108229
DOI: 10.1136/bmj.n1205 -
Research and Practice in Thrombosis and... Mar 2021Apixaban, a direct factor Xa inhibitor, has been shown to be at least as safe and probably more effective than dalteparin for the treatment of cancer-associated...
INTRODUCTION
Apixaban, a direct factor Xa inhibitor, has been shown to be at least as safe and probably more effective than dalteparin for the treatment of cancer-associated thrombosis (CAT) as reported in the ADAM-VTE and Caravaggio studies, which included a low percentage of underweight patients. Lower-weight-based dosing is supported by cancer-specific studies such as half-dose edoxaban in the Hokusai-VTE cancer trial in individuals weighing <60 kg.
OBJECTIVE
To examine apixaban plasma trough levels in low-weight individuals with CAT, stably anticoagulated with full or half-dose apixaban.
METHODS
This was a cross-sectional study of 61 routinely treated patients with active cancer and venous thromboembolism comparing three groups: patients weighing >60 kg treated with apixaban 5 mg twice daily, patients weighing ≤60 kg also receiving apixaban 5 mg twice daily, and patients weighing ≤60 kg given half-dose apixaban (2.5 mg twice daily). Apixaban plasma steady-state trough levels were determined on a single occasion.
RESULTS
Mean apixaban plasma trough levels were similar for patients weighing >60 kg on full-dose apixaban to those weighing ≤60 kg taking 2.5 mg twice daily (mean, 109 ng/dL; 95% confidence interval [CI], 74-145; standard deviation [SD]: 77.6; and mean,101 ng/dL, 95% CI, 67-135; SD: 80, respectively). Mean values for low-weight patients (≤60 kg) on the full 5 mg twice-daily dosing tended to be higher (mean, 136 ng/dL; 95%CI, 70-201; SD:114), without statistical significance ( = .22).
CONCLUSIONS
This study supports the rationale for studying weight-based adjustments in apixaban dosing in prospective studies evaluating safety and efficacy of dose reduction in low-weight patients with cancer.
PubMed: 33870027
DOI: 10.1002/rth2.12492 -
Basic and Clinical Neuroscience 2020Hepcidin is the main modulator of systemic iron metabolism, and its role in the brain has been clarified recently. Studies have shown that hepcidin plays an important...
INTRODUCTION
Hepcidin is the main modulator of systemic iron metabolism, and its role in the brain has been clarified recently. Studies have shown that hepcidin plays an important role in neuronal iron load and inflammation. This issue is of significance because neuronal iron load and inflammation are pathophysiological processes that are highly linked to neurodegeneration. Moreover, the activity of hepcidin has recently been manipulated to recover the neuronal impairment caused by brain inflammation in animal models.
METHODS
Streptozotocin (STZ) was used to induce type 1 diabetes. Male Wistar rats (n = 40) with a weight range of 200-250 g were divided into control, diabetic, diabetic + insulin, and diabetic + dalteparin groups. Dalteparin (100 mg/kg IP) and insulin (100 mg/kg SC) were administered for 8 weeks. At the end of the experiment, Y-maze and passive avoidance tasks were carried out. The animals were perfused randomly and their hippocampal tissue was isolated for the analysis of markers such as lipid peroxidation like Malondialdehyde (MDA), hepcidin expression, iron, and ferritin. Blood samples were taken for the measurement of serum inflammatory cytokine Interleukin (IL)-6.
RESULTS
The findings indicated that treatment with dalteparin reduced IL-6, MDA, ferritin, and hepcidin expression in diabetic rats compared to treatment with insulin (P<0.05). Moreover, treatment with dalteparin did not decrease the iron level or prevented its decline.
CONCLUSION
Treatment with dalteparin improved the cognitive dysfunctions and symptoms of Alzheimer disease in STZ-induced diabetic rats by appropriately modulating and reducing oxidative stress and neuroinflammation. This may enhance the existing knowledge of therapeutics to reduce cognitive impairment in diabetes and is suggested to be a potential therapeutic agent in diabetes.
PubMed: 33850616
DOI: 10.32598/bcn.11.6.1775.1 -
Neonatology 2021Neonatal thrombosis is a frequently encountered complication in a neonatal intensive care unit. Dalteparin can be used to treat thrombosis in newborn infants.
BACKGROUND
Neonatal thrombosis is a frequently encountered complication in a neonatal intensive care unit. Dalteparin can be used to treat thrombosis in newborn infants.
OBJECTIVES
In this study, we evaluate the current recommended starting dose of 129 ± 43 U/kg/24 h, hypothesizing that this dose is too low to reach therapeutic anti-Xa levels.
METHODS
From 2008 until 2017, all infants treated with dalteparin in the University Medical Centre Utrecht were included in this study. In this retrospective cohort study, the correlation between dose and anti-Xa level was observed.
RESULTS
Sixty-six infants were included. The most common thrombus types were catheter-related (29 patients, 44%) and venous sinus thrombosis (28 patients, 43%). The mean dalteparin dose needed for the first adequate anti-Xa level (0.5-1.0 IU/mL) was 297.6 U/kg/12 h. Two infants developed a first bleeding episode under dalteparin therapy; they both had anti-Xa levels in the therapeutic range.
CONCLUSION
The increase of the starting dose of dalteparin will lead to earlier therapeutic levels of anti-Xa in the studied population and appears to be safe. However, this needs to be evaluated in further study.
Topics: Anticoagulants; Dalteparin; Humans; Infant; Infant, Newborn; Retrospective Studies; Thrombosis; Treatment Outcome
PubMed: 33735895
DOI: 10.1159/000513784 -
Trials Mar 2021To determine the effect of therapeutic anticoagulation, with low molecular weight heparin (LMWH) or unfractionated heparin (UFH, high dose nomogram), compared to...
Coagulopathy of hospitalised COVID-19: A Pragmatic Randomised Controlled Trial of Therapeutic Anticoagulation versus Standard Care as a Rapid Response to the COVID-19 Pandemic (RAPID COVID COAG - RAPID Trial): A structured summary of a study protocol for a randomised controlled trial.
OBJECTIVES
To determine the effect of therapeutic anticoagulation, with low molecular weight heparin (LMWH) or unfractionated heparin (UFH, high dose nomogram), compared to standard care in hospitalized patients admitted for COVID-19 with an elevated D-dimer on the composite outcome of intensive care unit (ICU) admission, non-invasive positive pressure ventilation, invasive mechanical ventilation or death up to 28 days.
TRIAL DESIGN
Open-label, parallel, 1:1, phase 3, 2-arm randomized controlled trial PARTICIPANTS: The study population includes hospitalized adults admitted for COVID-19 prior to the development of critical illness. Excluded individuals are those where the bleeding risk or risk of transfusion would generally be considered unacceptable, those already therapeutically anticoagulated and those who have already have any component of the primary composite outcome. Participants are recruited from hospital sites in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, and the United States of America. The inclusion criteria are: 1) Laboratory confirmed COVID-19 (diagnosis of SARS-CoV-2 via reverse transcriptase polymerase chain reaction as per the World Health Organization protocol or by nucleic acid based isothermal amplification) prior to hospital admission OR within first 5 days (i.e. 120 hours) after hospital admission; 2) Admitted to hospital for COVID-19; 3) One D-dimer value above the upper limit of normal (ULN) (within 5 days (i.e. 120 hours) of hospital admission) AND EITHER: a. D-Dimer ≥2 times ULN OR b. D-Dimer above ULN and Oxygen saturation ≤ 93% on room air; 4) > 18 years of age; 5) Informed consent from the patient (or legally authorized substitute decision maker). The exclusion criteria are: 1) pregnancy; 2) hemoglobin <80 g/L in the last 72 hours; 3) platelet count <50 x 10/L in the last 72 hours; 4) known fibrinogen <1.5 g/L (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation); 5) known INR >1.8 (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation); 6) patient already prescribed intermediate dosing of LMWH that cannot be changed (determination of what constitutes an intermediate dose is to be at the discretion of the treating clinician taking the local institutional thromboprophylaxis protocol for high risk patients into consideration); 7) patient already prescribed therapeutic anticoagulation at the time of screening [low or high dose nomogram UFH, LMWH, warfarin, direct oral anticoagulant (any dose of dabigatran, apixaban, rivaroxaban, edoxaban)]; 8) patient prescribed dual antiplatelet therapy, when one of the agents cannot be stopped safely; 9) known bleeding within the last 30 days requiring emergency room presentation or hospitalization; 10) known history of a bleeding disorder of an inherited or active acquired bleeding disorder; 11) known history of heparin-induced thrombocytopenia; 12) known allergy to UFH or LMWH; 13) admitted to the intensive care unit at the time of screening; 14) treated with non-invasive positive pressure ventilation or invasive mechanical ventilation at the time of screening; 15) Imminent death according to the judgement of the most responsible physician; 16) enrollment in another clinical trial of antithrombotic therapy involving hospitalized patients.
INTERVENTION AND COMPARATOR
Intervention: Therapeutic dose of LMWH (dalteparin, enoxaparin, tinzaparin) or high dose nomogram of UFH. The choice of LMWH versus UFH will be at the clinician's discretion and dependent on local institutional supply. Comparator: Standard care [thromboprophylactic doses of LMWH (dalteparin, enoxaparin, tinzaparin, fondaparinux)] or UFH. Administration of LMWH, UFH or fondaparinux at thromboprophylactic doses for acutely ill hospitalized medical patients, in the absence of contraindication, is generally considered standard care.
MAIN OUTCOMES
The primary composite outcome of ICU admission, non-invasive positive pressure ventilation, invasive mechanical ventilation or death at 28 days. Secondary outcomes include (evaluated up to day 28): 1. All-cause death 2. Composite of ICU admission or all-cause death 3. Composite of mechanical ventilation or all-cause death 4. Major bleeding as defined by the ISTH Scientific and Standardization Committee (ISTH-SSC) recommendation; 5. Red blood cell transfusion (>1 unit); 6. Transfusion of platelets, frozen plasma, prothrombin complex concentrate, cryoprecipitate and/or fibrinogen concentrate; 7. Renal replacement therapy; 8. Hospital-free days alive; 9. ICU-free days alive; 10. Ventilator-free days alive; 11. Organ support-free days alive; 12. Venous thromboembolism (defined as symptomatic or incidental, suspected or confirmed via diagnostic imaging and/or electrocardiogram where appropriate); 13. Arterial thromboembolism (defined as suspected or confirmed via diagnostic imaging and/or electrocardiogram where appropriate); 14. Heparin induced thrombocytopenia; 15. Trajectories of COVID-19 disease-related coagulation and inflammatory biomarkers.
RANDOMISATION
Randomisation will be stratified by site and age (>65 versus ≤65 years) using a 1:1 computer-generated random allocation sequence with variable block sizes. Randomization will occur within the first 5 days (i.e. 120 hours) of participant hospital admission. However, it is recommended that randomization occurs as early as possible after hospital admission. Central randomization using an interactive web response system will ensure allocation concealment.
BLINDING (MASKING)
No blinding involved. This is an open-label trial.
NUMBERS TO BE RANDOMISED (SAMPLE SIZE)
462 patients (231 per group) are needed to detect a 15% risk difference, from 50% in the control group to 35% in the experimental group, with power of 90% at a two-sided alpha of 0.05.
TRIAL STATUS
Protocol Version Number 1.4. Recruitment began on May 11, 2020. Recruitment is expected to be completed March 2022. Recruitment is ongoing.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04362085 Date of Trial Registration: April 24, 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
Topics: Anticoagulants; Blood Coagulation Disorders; COVID-19; Clinical Trials, Phase III as Topic; Fibrin Fibrinogen Degradation Products; Heparin; Heparin, Low-Molecular-Weight; Hospitalization; Humans; Intensive Care Units; Noninvasive Ventilation; Pragmatic Clinical Trials as Topic; Randomized Controlled Trials as Topic; Respiration, Artificial; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 33691765
DOI: 10.1186/s13063-021-05076-0 -
Bone Marrow Transplantation Jul 2021Hepatic veno-occlusive disease or sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of allogeneic hematopoietic stem cell...
Hepatic veno-occlusive disease or sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In the present prospective study, we aimed to investigate the incidence, management, and outcome of VOD/SOS in patients with thalassemia major (TM) who received allo-HSCT. VOD/SOS was diagnosed and classified based on the modified Seattle criteria. The prophylactic regimen for VOD/SOS was a combination treatment of dalteparin and lipo-PGE1. VOD/SOS was managed through an approach consisting of adequate supportive measures, short-term withdrawal of calcineurin inhibitors (CNIs), and the use of methylprednisolone and basiliximab for graft-versus-host disease prophylaxis. VOD/SOS was found in 54 of 521 patients (10.4%) at a median time of 12 days after allo-HSCT. The cumulative incidence of all-grade and moderate VOD/SOS was 10.4% and 4.2%, respectively. Among the 54 VOD/SOS patients, no patient developed severe grade and died from VOD/SOS. Besides, the cumulative incidence of transplant-related mortality on day 100 for patients with or without VOD/SOS was 0% vs. 4.0% (P = 0.187), respectively, and the 3-year overall survival rates were 94.3% vs. 93.2% (P = 0.707), respectively. Collectively, we concluded that appropriate symptomatic therapy and short-term withdrawal of CNIs safely mitigated the mortality of VOD/SOS in TM patients who underwent allo-HSCT.
Topics: Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Incidence; Polydeoxyribonucleotides; Prospective Studies; beta-Thalassemia
PubMed: 33608657
DOI: 10.1038/s41409-021-01233-w -
Journal of Veterinary Diagnostic... Mar 2021To date, coagulation tests are unable to reflect in vivo coagulation status in the same system, including platelet function, fibrin clot formation, and whole blood flow....
To date, coagulation tests are unable to reflect in vivo coagulation status in the same system, including platelet function, fibrin clot formation, and whole blood flow. The Total Thrombus Analysis System (T-TAS), which is a microfluidic assay that simulates conditions in vivo, measures whole blood flow at defined shear rates under conditions designed to assess platelet function (PL-chip) or coagulation and fibrin clot formation (AR-chip). The T-TAS records occlusion start time, occlusion time, and area under the curve. We evaluated this test in healthy control dogs. We also investigated the effect in vivo of acetylsalicylic acid (ASA), and the effect in vitro of an anticoagulation drug (dalteparin; low-molecular-weight heparin; LMWH). The CV of the AUC of both chips was good (CVs of 6.45% [PL] and 1.57% [AR]). The inhibition of platelet function by ASA was evident in the right-shift in the PL test pressure curve. The right-shift in the AR test pressure curves showed that the administration of LMWH inhibited both platelets and the coagulation cascade. The T-TAS may be useful in the evaluation of canine blood coagulation.
Topics: Animals; Anticoagulants; Aspirin; Blood Coagulation; Blood Coagulation Tests; Dalteparin; Dogs; Female; Male; Microfluidic Analytical Techniques; Thrombosis
PubMed: 33559534
DOI: 10.1177/1040638721991862 -
Taiwanese Journal of Obstetrics &... Jan 2021To assess the roles of the low molecular weight heparin (LMWH) on recurrent pregnancy loss (RPL). The relevant studies of all randomized controlled trials (RCTs) were... (Meta-Analysis)
Meta-Analysis
To assess the roles of the low molecular weight heparin (LMWH) on recurrent pregnancy loss (RPL). The relevant studies of all randomized controlled trials (RCTs) were retrieved, and the systematic evaluation was conducted. PubMed, Embase, and Cochrane library databases were searched by using keywords, including low-molecular-weight heparin or LMWH, and recurrent miscarriage or recurrent pregnancy loss in pregnant women from their earliest data to February 2020. Two investigators independently evaluated eligibility. Risk ratios (RRs) and their corresponding 95% confidence interval (CI) were determined. To pool the results, this meta-analysis was performed using random-effect model due to the high heterogeneity among these eight studies. A total of eight RCTs involving 1854 participants were included in the meta-analysis involving 963 patients with RPL who were prescribed LMWH (enoxaparin, tinzaparin, or dalteparin) alone and 891 patients who were treated with no LMWH interventions (placebo, folic acid or non-treatment) were compared. Pooled data from the remaining eight RCTs showed the differences between intervention groups and control groups. Compared with control groups, LMWH had significantly improved live births (RR,1.19; 95%CI, 1.03 to 1.38; P = 0.02), and reduced miscarriage rates (RR, 0.62; 95%CI, 0.43 to 0.91; P = 0.01). The study suggested that LMWH could improve the live births and reduce the miscarriage rates of RPL. Therefore, LMWH might be a good treatment choice for women with unexplained PRL.
Topics: Abortion, Habitual; Adult; Cardiovascular Agents; Female; Heparin, Low-Molecular-Weight; Humans; Live Birth; Pregnancy; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 33494980
DOI: 10.1016/j.tjog.2020.11.001 -
BMJ Open Nov 2020In the 'Comparison of an Oral Factor Xa Inhibitor With Low Molecular Weight Heparin in Patients With Cancer With Venous Thromboembolism' (SELECT-D) trial, rivaroxaban... (Clinical Trial)
Clinical Trial
OBJECTIVES
In the 'Comparison of an Oral Factor Xa Inhibitor With Low Molecular Weight Heparin in Patients With Cancer With Venous Thromboembolism' (SELECT-D) trial, rivaroxaban showed relatively low venous thromboembolism (VTE) recurrence but higher bleeding compared with dalteparin in patients with cancer. We aim to calculate the cost-effectiveness and budget impact of rivaroxaban compared with dalteparin in patients with cancer at risk of recurrent VTE.
SETTING
We built a Markov model to calculate the cost-effectiveness from a societal perspective over a 5-year time horizon for the Dutch healthcare setting.
PARTICIPANTS
A hypothetical cohort of 1000 cancer patients with VTE entered the model with baseline characteristics based on the SELECT-D trial.
INTERVENTION
Six months of treatment with rivaroxaban (15 mg two times per day for first 3 weeks followed by 20 mg once daily) was compared with 6 months of treatment with dalteparin (200 IU/kg daily during month 1 followed by 150 IU/kg daily).
PRIMARY AND SECONDARY OUTCOME MEASURES
The primary outcome of the cost-effectiveness analysis was the incremental cost-effectiveness ratio (ICER). The robustness of the model was evaluated in probabilistic and univariate sensitivity analyses. A budget impact analysis was performed to calculate the total annual financial consequences for a societal perspective in the Netherlands.
RESULTS
In the base case and all scenarios, rivaroxaban were cost-saving while also slightly improving the patient's health, resulting in economically dominant ICERs. In the probabilistic sensitivity analysis, 77.8% and 98.7% of the simulations showed rivaroxaban to be cost-saving and more effective for a 5-year and 6-month time horizon, respectively. Rivaroxaban can save up to €11 326 763 (CI €5 164 254 to €17 363 231) in approximately 8000 cancer patients with VTE per year compared with dalteparin based on a 1-year time horizon.
CONCLUSIONS
Treatment with rivaroxaban is economically dominant over dalteparin in patients with cancer at risk for recurrent VTE in the Netherlands. The use of rivaroxaban instead of dalteparin can save over €10 million per year, primarily driven by the difference in drug costs.
Topics: Aged; Anticoagulants; Cost-Benefit Analysis; Dalteparin; Female; Humans; Male; Neoplasms; Netherlands; Rivaroxaban; Venous Thromboembolism
PubMed: 33444193
DOI: 10.1136/bmjopen-2020-039057 -
Seminars in Thrombosis and Hemostasis Nov 2020Anticoagulants are frequently used as thromboprophylaxis and in patients with atrial fibrillation (AF) or venous thromboembolism (VTE). While obesity rates are reaching...
Anticoagulants are frequently used as thromboprophylaxis and in patients with atrial fibrillation (AF) or venous thromboembolism (VTE). While obesity rates are reaching epidemic proportions worldwide, the optimal dosage for obese patients has not been established for most anticoagulants, including low-molecular-weight heparin (LMWH), non-vitamin K antagonist oral anticoagulants (NOAC), and pentasaccharides (fondaparinux). The aim of the present systematic review was to summarize the current knowledge and provide recommendations on dosage of LMWH, NOAC, and fondaparinux in obese patients (body mass index [BMI] ≥ 30 kg/m or body weight ≥ 100 kg). Based on a systematic search in PubMed and Embase, a total of 72 studies were identified. For thromboprophylaxis with LMWH in bariatric surgery ( = 20 studies), enoxaparin 40 mg twice daily, dalteparin 5,000 IE twice daily, or tinzaparin 75 IU/kg once daily should be considered for patients with BMI ≥ 40 kg/m. For thromboprophylaxis with LMWH in nonbariatric surgery and in medical inpatients ( = 8 studies), enoxaparin 0.5 mg/kg once or twice daily or tinzaparin 75 IU/kg once daily may be considered in obese patients. For treatment with LMWH ( = 18 studies), a reduced weight-based dose of enoxaparin 0.8 mg/kg twice daily should be considered in patients with BMI ≥ 40 kg/m, and no dose capping of dalteparin and tinzaparin should be applied for body weight < 140 kg. As regards NOAC, rivaroxaban, apixaban, or dabigatran may be used as thromboprophylaxis in patients with BMI < 40 kg/m ( = 4 studies), whereas rivaroxaban and apixaban may be administered to obese patients with VTE or AF, including BMI > 40 kg/m, at standard fixed-dose ( = 20 studies). The limited available evidence on fondaparinux ( = 3 studies) indicated that the treatment dose should be increased to 10 mg once daily in patients weighing > 100 kg.
Topics: Anticoagulants; Heparin, Low-Molecular-Weight; Humans; Obesity
PubMed: 33368113
DOI: 10.1055/s-0040-1718405