DOCSLIB.ORG

9/28/2020 1 Use of Direct-Acting Oral Anticoagulants in Heparin- Induced Thrombocytopenia

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
9/28/2020 1 Use of Direct-Acting Oral Anticoagulants in Heparin- Induced Thrombocytopenia 9/28/2020 Use of Direct-acting Oral Anticoagulants in Heparin- Induced Thrombocytopenia Jennifer Austin Szwak, PharmD, BCPS Clinical Pharmacy Specialist, Internal Medicine University of Chicago Medicine Financial Disclosure & Conflict of Interest • No relevant conflicts of interest Learning Objectives • Describe the pathophysiology of heparin-induced thrombocytopenia (HIT) • Compare guideline recommendations for the treatment of HIT from the American College of Chest Physicians and American Society of Hematology • Review current literature describing the use of direct-acting oral anticoagulants (DOACs) in HIT 1 9/28/2020 Heparin-Induced Thrombocytopenia (HIT) • Immune-mediated reaction • Hypercoaguable state • Occurs in approximately <0.1 – 7% of patients exposed to heparins • 35 – 50% of patients will develop new or recurrent thrombosis if not treated • Typically manifests as a significant drop in platelets after heparin exposure New Engl J Med 2006; 355(8):809-17 Blood 2012; 120(20): 4160-67 Pathophysiology IgG antibody heparin Heparin-PF4 complex platelet Immune PF4 complexes Circulation 2005;111:2671-83. Testing Algorithm Suspected HIT Assess 4Ts Score Blood Adv 2018; 2(22): 3360-92 2 9/28/2020 4Ts Score Category 2 points 1 point 0 points Thrombocytopenia Platelet count fall >50% Platelet count fall 30-50% Platelet count fall <30% or and platelet nadir ≥ 20 or platelet nadir 10-19 platelet nadir <10 Timing of platelet count Clear onset days 5-10 or Consistent with days 5-10, Platelet count ≤4 days fall platelet fall ≤1 day with but not clear; onset after without recent heparin prior heparin exposure day 10; or fall ≤1 day with exposure within 30 days prior heparin exposure in previous 30-100 days Thrombosis or other New thrombus Progressive or recurrent None sequelae (confirmed); skin thrombosis; non- necrosis; acute systemic necrotizing skin lesions; reaction post IV heparin suspected thrombosis OTher causes of None Possible Definite thrombocytopenia Blood 2012; 120(20): 4160-67. Testing Algorithm 4Ts Score Intermediate Low (1-3) High (6-8) (4-5) No HIT Obtain laboratory immunoassay testing Blood Adv 2018; 2(22): 3360-92 PF4 Enzyme-linked immunoassay (ELISA) • Detects binding of patient antibodies to PF4 complex • Binding causes color change • Most assays measure IgG, IgM, and IgA antibodies • Measuring only IgG antibodies increases specificity of test CHEST 2005; 127: 35S-45S 3 9/28/2020 Evaluation of PF4 Result PF4 OD Result Likelihood of HIT Interpretation < 0.4 0 Negative 0.4 – 1 ~3% Lab dependent 1 – 1.4 ~15 – 20% Positive 1.4 – 2 ~50% Positive > 2 ~90% Positive CHEST 2005; 127: 35S-45S Testing Algorithm Immunoassay Positive Negative Stop non-heparin Obtain functional product & resume assay heparin, if indicated Blood Adv 2018; 2(22): 3360-92 Serotonin Release Assay (SRA) • Functional assay • Platelets are “washed” resulting in high sensitivity to activation by HIT serum • At pharmacologic heparin concentrations, high platelet activation occurs releasing radiolabeled serotonin CHEST 2005; 127: 35S-45S 4 9/28/2020 Testing Algorithm SRA Positive Negative Stop non-heparin HIT Likely product & resume heparin, if indicated Blood Adv 2018; 2(22): 3360-92 Stages of HIT Suspected Subacute Subacute Remote Acute HIT HIT HIT A HIT B HIT Platelet ↓ ↓ Normal Normal Normal count Functional ? + + - - assay Immuno- ? + + + - assay Blood Adv 2018; 2(22): 3360-92 Treatment of HIT 5 9/28/2020 Standard HIT Treatment • Therapeutic anticoagulation with a non-heparin agent • If taking a vitamin K antagonist (VKA) at the time of HIT onset, administer intravenous vitamin K with non-heparin agent • Do NOT initiate VKA before platelet recovery (usually ≥ 150x 109/L) • Non-heparin anticoagulant should overlap for a minimum of 5 days and until INR is in goal range • Treatment duration: • No thrombosis: at least until platelet recovery & not longer than 3 months • HIT with thrombosis (HITT): 3-6 months CHEST 2012; 141(2):e495S–e530S Blood Adv 2018; 2(22): 3360-92 2012 ACCP Guidelines • Non-heparin anticoagulants (argatroban, lepirudin, or danaparoid) are recommended over heparin, low molecular weight heparins, or initiation/continuation of VKA (Grade 1C) • Argatroban is preferred over other agents in HITT (Grade 2C) CHEST 2012; 141(2):e495S–e530S 2018 ASH Guidelines • When selecting a non-heparin anticoagulant, argatroban, bivalirudin, danaparoid, fondaparinux or DOACs are suggested (+) • Argatroban or bivalirudin recommended if critically ill, increased bleeding risk, potential need for urgent procedures, or life-/limb-threatening thromboembolism • Fondaparinux or DOACs reasonable choice if clinically stable and average bleeding risk • In subacute HIT A (normal platelets, positive immunoassays), DOACs are suggested over VKA (+++) +: conditional recommendation, low certainty in evidence about effects +++: conditional recommendation, moderate certainty in evidence about effects Blood Adv 2018; 2(22): 3360-92 6 9/28/2020 Recommendations re: DOACs 2012 ACCP Guidelines 2018 ASH Guidelines • No published evidence to • DOACs may be used in clinically support the use of DOACS for stable patients with average treatment of HITT bleed risk • No recommendations • Similar contraindications to use in VTE should be applied • Rivaroxaban has the most published data CHEST 2012; 141(2):e495S–e530S Blood Adv 2018; 2(22): 3360-92 Why the difference? DOACs in HIT 7 9/28/2020 DOACs & Platelets • No platelet activation in presence of HIT antibodies • No release of PF4 from resting or activated platelets • No interactaction with PF4 Br J Haematology 2008; 143: 92-99 Blood 2012; 119(5): 1248-55 Clin Appl Thromb Hemost 2013; 19(5):482-7 Sharifi et al, 2015 Study design Retrospective identification of patients, prospective follow-up HIT definition - History of recent heparin exposure + 50% reduction of platelet count or platelets <100 without other explainable causes - PF4 sent for all cases - SRA only sent if PF4 negative Treatment - All heparin discontinued - Argatroban 0.3-0.5mcg/kg/min (goal aPTT 50-90) - DOAC initiated 2h after argatroban discontinuation Outcomes - Mortality - Venous or arterial thrombosis - Limb loss - Bleeding n = 22 Thromb Res 2015;135(4):607–9. Sharifi et al, 2015 Platelet count, Baseline: 168.8 x109 (87.1) mean (SD) Nadir: 82.1 x109 (38.6) Discharge: 188.4 x109 (52.5) HIT testing 20/22 (91%) PF4+ Associated 5 patients with DVTs & 2 superficial thrombi thrombosis Initial treatment - All patients received argatroban - Mean duration 32 ± 4 hours Oral treatment - Dabigatran 150mg BID (n = 6)* - Rivaroxaban 20mg daily (n = 11)* - Apixaban 5mg BID (n = 5) Treatment - Minimum 3 months duration - 82% extended to at least 6 months Outcomes - No deaths attributed to thrombotic events - No bleeding Thromb Res 2015;135(4):607–9. 8 9/28/2020 Sharifi et al, 2015 Pros Cons • Extended prospective follow up • HIT diagnosis inconsistent with • Several patients with HITT guideline recommendations • Platelets recovered with early • Specifics about patients are switch to DOAC agents lacking • No recurrent events or bleeding • Apixaban and rivaroxaban dosing are lower than typical VTE dosing Kunk et al, 2017 Study Design Retrospective chart review HIT definition Positive SRA Treatment Argatroban or bivalirudin infusion until platelets ≥ 50 x 103/µL Transitioned to rivaroxaban or apixaban Exclusion Patients without clinic follow up or ability to capture bleeding & thrombotic events Outcomes Recurrent thrombotic events Major bleeding events Days to platelet recovery n = 12 J Thromb Thrombolysis 2017;43(1):79–85. Kunk et al, 2017 Platelet count, Nadir: 49 x103/µL (16-147) median (range) HIT testing PF4+: 9/12 (75%) SRA+: 12/12 (100%) Associated 9 patients with thrombi at time of diagnosis thrombosis Initial treatment All patients received argatroban (n = 6) or bivalirudin (n = 6) Duration: 6 days (range 2 – 25 days) Oral treatment Rivaroxaban (n = 2) Apixaban (n = 10) Treatment No HITT: 1 – 2 months duration HITT: minimum 3 months (range 3 – 16 months) Outcomes No recurrent thrombi 2 major bleeding events (GI bleed, hemoptysis) J Thromb Thrombolysis 2017;43(1):79–85. 9 9/28/2020 KunkSummaryet al, 2017 Pros Cons • Follow up in all patients • DOAC dosing strategy not • Several patients with HITT described • No recurrent events • Platelets at time of transition to DOAC unclear • Broad range of parenteral agent use • 2 major bleeding events Davis et al, 2017 Study Design Retrospective chart review HIT definition 4Ts score ≥ 4 Positive PF4 (OD > 0.4) or positive SRA Treatment Argatroban or bivalirudin infusion until platelets ≥ 50 x 103/µL Transitioned to rivaroxaban or apixaban Exclusion Negative SRA History of HIT Admission <48 hours Outcomes Newly diagnosed venous or arterial thromboembolism, gangrene, or amputation for critical leg ischemia during hospitalization following DOAC initiation Major bleeding 30 day mortality Time to platelet recovery (>150 x 109/L or baseline) n = 12 Eur J Haematol. 2017;99:332–335. Davis et al, 2017 Platelet count, Nadir: 58 x103/µL (12-91) median (range) Time to platelet recovery: 7.5 days (3 – 14) HIT testing Mean PF4 OD: 1.66units (range 0.24 – 3.34) SRA+: 4/12 (33%) Associated 5 patients with thrombi at time of diagnosis thrombosis Parenteral 7 patients received argatroban (range: 24 – 530 hours) treatment 5 patients did not receive parenteral therapy Oral treatment Apixaban 10mg BID (n = 1) Apixaban 5mg BID (n = 7) Apixaban 2.5mg BID (n = 1) Rivaroxaban 15mg BID (n = 3) Treatment Mean inpatient DOAC treatment: 9.3days (range:
Load more

Recommended publications
  • Treatment of 51 Pregnancies with Danaparoid Because of Heparin
    ©2005 Schattauer GmbH,Stuttgart Blood Coagulation, Fibrinolysis and CellularHaemostasis Treatment of 51 pregnancies withdanaparoidbecause of heparin intolerance EdelgardLindhoff-Last1 ,Hans-Joachim Kreutzenbeck2 ,Harry N. Magnani3 1 Division ofVascular Medicine,Department of Internal Medicine,University Hospital Frankfurt, Germany 2 MedicalDepartment, Celltech, Essen, Germany 3 Clinical Consultant Marketing, OrganonBV, Oss,The Netherlands Summary Pregnant patients withacute venous thrombosis or ahistoryof required (3/14) or an adverse eventled to atreatment discon- thrombosis mayneed alternative anticoagulation, when heparin tinuation (11/14).Four maternal bleeding events were recorded intolerance occurs. Onlylimited dataonthe useofthe hepari- during pregnancy, deliveryorpostpartum, twoofthemwere noiddanaparoid areavailable in literature.We reviewedthe use fatal duetoplacental problems.Three fetal deathswererec- of danaparoid in 51 pregnancies of 49 patients identified in litera- orded,all associated with maternal complications antedating da- turebetween 1981 and 2004.All patients had developed hepa- naparoiduse.Danaparoid cross-reactivity was suspectedin4 rin intolerance (32 duetoheparin-induced thrombocytopenia, HITpatientsand 5non-HITpatientswith skin reactions and was 19 mainlydue to heparin-induced skin rashes)and had acurrent confirmedserologicallyinone of the twoHIT patients tested.In and/or pasthistoryofthromboembolic complications.The initial none of fivefetal cordblood- andthree maternal breast milk- danaparoid doseregimens ranged
    [Show full text]
  • Heparin-Induced Thrombocytopenia (Hit)
    HEPARIN‐INDUCED THROMBOCYTOPENIA (HIT) OBJECTIVE: To assist clinicians with the diagnosis and initial management of heparin‐induced thrombocytopenia (HIT) and suspected HIT. BACKGROUND: HIT is a transient, immune‐mediated adverse drug reaction in patients recently exposed to heparin that generally produces thrombocytopenia and often results in venous and/or arterial thrombosis. HIT occurs in up to 5% of patients receiving unfractionated heparin (UFH) and in <1% who receive low molecular weight heparin (LMWH). HIT is characterised by immunoglobulin G (IgG) antibodies that recognize an antigen complex of platelet factor 4 (PF4) bound to heparin. These antibodies trigger a highly prothrombotic state by causing intravascular platelet aggregation, intense platelet, monocyte and endothelial cell activation and excessive thrombin generation. CLINICAL FEATURES: HIT typically presents with a fall in platelet count with or without venous and/or arterial thrombosis. Thrombocytopenia: A platelet count fall >30% beginning 5‐10 days after heparin exposure, in the absence of other causes of thrombocytopenia, should be considered to be HIT, unless proven otherwise. A more rapid onset of platelet count fall (often within 24 hours of heparin exposure) can occur when there is a history of heparin exposure within the preceding 3 months. Bleeding is very infrequent. Thrombosis: HIT is associated with a high risk (30‐50%) of new venous or arterial thromboembolism. Thrombosis may be the presenting clinical manifestation of HIT or can occur during or shortly after the thrombocytopenia. Other clinical manifestations of HIT: Less frequent manifestations include heparin‐induced skin lesions, adrenal hemorrhagic infarction, transient global amnesia, and acute systemic reactions (e.g. chills, dyspnea, cardiac or respiratory arrest following IV heparin bolus).
    [Show full text]
  • Low Molecular Weight Heparins and Heparinoids
    NEW DRUGS, OLD DRUGS NEW DRUGS, OLD DRUGS Low molecular weight heparins and heparinoids John W Eikelboom and Graeme J Hankey UNFRACTIONATED HEPARIN has been used in clinical ABSTRACT practice for more than 50 years and is established as an effective parenteral anticoagulant for the prevention and ■ Several low molecular weight (LMW) heparin treatment of various thrombotic disorders. However, low preparations, including dalteparin, enoxaparin and molecularThe Medical weight Journal (LMW) of heparinsAustralia haveISSN: recently 0025-729X emerged 7 October as nadroparin, as well as the heparinoid danaparoid sodium, more2002 convenient, 177 6 379-383 safe and effective alternatives to unfrac- are approved for use in Australia. 1 tionated©The heparin Medical (BoxJournal 1). of AustraliaIn Australia, 2002 wwwLMW.mja.com.au heparins are ■ LMW heparins are replacing unfractionated heparin for replacingNew Drugs,unfractionated Old Drugs heparin for preventing and treating the prevention and treatment of venous thromboembolism venous thromboembolism and for the initial treatment of and the treatment of non-ST-segment-elevation acute unstable acute coronary syndromes. The LMW heparinoid coronary syndromes. danaparoid sodium is widely used to treat immune heparin- ■ induced thrombocytopenia. The advantages of LMW heparins over unfractionated heparin include a longer half-life (allowing once-daily or twice-daily subcutaneous dosing), high bioavailability and Limitations of unfractionated heparin predictable anticoagulant response (avoiding the need
    [Show full text]
  • Low Molecular Weight Heparinoid, ORG 10172 (Danaparoid), and Outcome After Acute Ischemic Stroke a Randomized Controlled Trial
    Original Contributions Low Molecular Weight Heparinoid, ORG 10172 (Danaparoid), and Outcome After Acute Ischemic Stroke A Randomized Controlled Trial The Publications Committee for the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators Context.—Anticoagulation with unfractionated heparin is used commonly for ANTICOAGULATION with unfrac- treatment of acute ischemic stroke, but its use remains controversial because it has tionated heparin commonly is used to not been shown to be effective or safe. Low molecular weight heparins and hepa- treat persons with acute ischemic 1 rinoids have been shown to be effective in preventing deep vein thrombosis in per- stroke. However, the use of heparin re- mains controversial because it is not es- sons with stroke, and they might be effective in reducing unfavorable outcomes fol- 2-6 lowing ischemic stroke. tablished as safe or effective. A recent open trial demonstrated a modest effect Objective.—To test whether an intravenously administered low molecular from subcutaneously administered hep- weight heparinoid, ORG 10172 (danaparoid sodium), increases the likelihood of a arin in preventing recurrent stroke favorable outcome at 3 months after acute ischemic stroke. within 14 days but no improvement in Design.—Randomized, double-blind, placebo-controlled, multicenter trial. outcomes.7 Thus, whether an intrave- Setting and Participants.—Between December 22, 1990, and December 6, nously administered anticoagulant that 1997, 1281 persons with acute stroke were enrolled at 36 centers across the United would act more rapidly would be effec- States. tiveremainsunanswered.Thesearchfor Intervention.—A 7-day course of ORG 10172 or placebo was given initially as alternative medications that possess the a bolus within 24 hours of stroke, followed by continuous infusion in addition to the antithrombotic characteristics of hepa- best medical care.
    [Show full text]
  • Guidelines for Administration of Anticoagulation for Patients Receiving Haemodialysis Lead Clinician
    Guidelines for administration of Anticoagulation for patients receiving haemodialysis Lead Clinician: Dr. Diwaker Implementation date: January 2014 Last updated: April 2017 Last review date: May 2017 Planned review date: May 2019 Department: Renal Services SaTH Directorate: Medicine Hospital Site: SaTH Keywords: Tinzaparin, Heparin, anti-coagulant, HIT Comments: 1.0 INTRODUCTION The anticoagulant regime should be tailored to the needs of the individual patient, this includes the appropriate anticoagulant drug for the patients clinical condition. When blood comes into contact with the extra corporeal circuit, platelet adherence and activation of the intrinsic clotting cascade occurs, leading to thrombosis. Clots in the dialyser reduce the effective surface area of the dialyser and in extreme situations clots in the circuit may prevent treatment from continuing and result in loss of blood in the circuit. The aim is to anticoagulate the circuit without putting the patient at risk of bleeding. Fractionated heparin (Tinzaparin) is the recommended choice for stable patients on haemodialysis. Heparin is widely used for anticoagulation as the dose can be adjusted. It’s half-life is dramatically less than Tinzaparin. (30mins-2 hours rather than 4-5 hours) Indications for use of heparin would be the unwell CHD, AKI, uraemic patient. Heparin is the anti-coagulant of choice for those patients on Warfarin. We audit the loss of Haemodialysis circuits (ie when the dialysis lines are clotted and blood is lost to the patient). This audit trail shows that the majority of “Lost Circuits” occur when the patient is being dialysed “Heparin Free” or when the ACT guidelines have been misinterpreted.
    [Show full text]
  • Treatment of Acute Ischemic Stroke
    The New England Journal of Medicine Drug Therapy The molecular events initiated by acute focal ische- mia can be summarized as a time-dependent cascade, characterized by decreased energy production; over- A LASTAIR J.J. WOOD, M.D., Editor stimulation of neuronal glutamate receptors (excito- toxicity); excessive intraneuronal accumulation of sodium, chloride, and calcium ions; mitochondrial in- TREATMENT OF ACUTE ISCHEMIC jury; and eventual cell death (Fig. 1).7, 1 4 -1 6 The funda- STROKE mental goals of intervention are to restore normal cer- ebral blood flow as soon as possible and to protect THOMAS BROTT, M.D., AND JULIEN BOGOUSSLAVSKY, M.D. neurons by interrupting or slowing the ischemic cas- cade.7, 1 4 , 1 5 Studies using magnetic resonance imaging (MRI) and positron-emission tomography suggest that critical ischemia rapidly produces a core of in- SCHEMIC stroke exacts a heavy toll in death and farcted brain tissue surrounded by hypoxic but po- disability worldwide. In the United States, where tentially salvageable tissue.8,17,18 Iit is the third leading cause of death and the lead- ing cause of serious long-term disability, approxi- EARLY EVALUATION AND SUPPORTIVE mately 750,000 strokes occur annually, with an an- TREATMENT nual mortality rate exceeding 150,000.1-4 Only about one third of patients who are having a In June 1996, the Food and Drug Administration stroke are aware of its symptoms, and most bystand- (FDA) approved tissue plasminogen activator (t-PA) ers are not knowledgeable about the signs of stroke. as a safe and effective treatment for stroke if it is giv- When symptoms or signs are recognized, emergency en within three hours after the onset of symptoms of medical services should be notified.19,20 Assessment stroke.5 Subsequently, results of large clinical trials should begin with evaluation of the patient’s airway, testing the efficacy of antiplatelet, antithrombotic, breathing, and circulation — the “ABCs” of resusci- and neuroprotective treatments appeared.
    [Show full text]
  • Danaparoid Sodium Lowers Proteinuria in Diabetic Nephropathy
    Danaparoid Sodium Lowers Proteinuria in Diabetic Nephropathy JOHAN W. VAN DER PIJL,* FOKKO J. VAN DER WOUDE,* PETRONELLA H. L. M. GEELHOEDDUIJVESTIJN,t MARIJKE FROLICH, FELIX J. M. VAN DER MEER, HERMAN H. P.J. LEMKES,” and LEENDERT A. VAN ES,* *Department of Nephrology, Leiden University Hospital, P0 Box 9600, 2300 RC Leiden, The Netherlands; tDepartment of Internal Medicine, Den Haag, The Netherlands; *Department of Clinical Chemistry, Leiden University Hospital, Leiden, The Netherlands; Department of Hematology, Leiden University Hospital, Leiden, The Netherlands; ‘Department of Endocrinology, Leiden University Hospital, Leiden, The Netherlands. Abstract. Diabetic nephropathy is a progressive renal disease sodium, the albumin excretion ratio standardized for urinary with thickening of the gbomerular basement membrane and creatinine reduced with 17% in comparison with an increase of mesangial expansion and proliferation as histological hall- 23% after placebo (95% confidence interval of the difference, marks. The presence of the glycosaminoglycan side chains of -75.9-3.9%; P = 0.03). The percentage change of the urinary heparan sulfate proteoglycan, an important constituent of the protein excretion corrected for urinary creatinine differed at 8 glomerular basement membrane, is decreased in diabetic ne- wk significantly between both treatment arms (P 0.001). phropathy proportionally to the degree of proteinuria. Danap- Additional parameters for safety as hematobogical, hemostasis, aroid sodium is a mixture of sulfated glycosaminoglycans biochemical parameters, and fundusphotography did not show consisting mainly of heparan sulfate. The study presented here any clinically significant difference for both groups. Only two involved performing a randomized placebo-controlled cross- patients had minor skin hematomas at the injection site while over study with danaparoid sodium in diabetic patients with using danaparoid sodium.
    [Show full text]
  • Is Danaparoid Anticoagulation Suitable for Patients with HIT and ARF Requiring CVVRT? an Analysis of Case Reports
    Magnani and Wester, 1:9 http://dx.doi.org/10.4172/scientificreports.423 Open Access Open Access Scientific Reports Scientific Reports Case Report OpenOpen Access Access Is Danaparoid Anticoagulation Suitable for Patients with HIT and ARF Requiring CVVRT? An Analysis of Case Reports Magnani HN1* and Wester JPJ2 1Clinical consultant, Oss, The Netherlands 2Department of Intensive Care Medicine, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands Abstract Purpose: To assess the efficacy and safety outcomes of case reports of danaparoid anticoagulation in critically ill ICU patients suffering from HIT who require CRRT. Method: A retrospective analysis of 103 cases. Results: Based on clinical signs, pre-treatment 4T scores and serological testing, HIT was reasonably ‘confirmed’ in 67.0% of the cases and ‘suspected’ in the remainder. The patients, with HIT and ARF received the danaparoid treatment regimen for CRRT for 1–39 (median 7) days. Dose adaptation was necessary in 40.2% of the patients to overcome thrombosis or bleeding (risk). Satisfactory CRRT anticoagulation was provided for 93.6% of 94 cases with information, 53.9% of the patients survived. The hospital mortality of 46.1% was mainly attributed to concomitant morbidity, but 5 deaths were related to thrombosis (n=2) or bleeding (n=3). Maintenance plasma anti-Xa activity correlated poorly with bleeding or thrombotic complications but positively with the minor bleeding frequency, hence advice to restrict the upper limit to 0.8 U/mL or preferably to use evidence of bleeding and systemic thrombosis/ circuit clotting to judge the need for dose adaptation. The benefit (no thrombosis)/harm (bleeding induction) ratio and combined inefficacy and major haemorrhagic frequency were 10.5 and 16.6% respectively, showing a generally favourable response to danaparoid.
    [Show full text]
  • Non-Interventional (Ni) Study Protocol
    Apixaban B0661069 NON-INTERVENTIONAL STUDY PROTOCOL Update 1, 08 January 2016 NON-INTERVENTIONAL (NI) STUDY PROTOCOL Post Author isation Safet y St udi es (PA SS) infor mation Title CARBOS – Comparative risk of major bleeding with new oral anticoagulants (NOACs) and Phenprocoumon in patients with atrial fibrillation: a retrospective claims database study in Germany Protocol number B0661069 Protocol version identifier Update 1.0 Date of last version of protocol 08 January 2016 EU Post Authorisation Study (PAS) ENCEPP/SDPP/11313 register number Active substance Apixaban (B01AF02) Phenprocoumon (B01AA04) Rivaroxaban (B01AX06; B01AF01) Dabigatran (B01AX06) Product reference EU/1/11/691/006 EU/1/11/691/007 EU/1/11/691/008 EU/1/11/691/009 EU/1/11/691/010 EU/1/11/691/011 Pfizer Confidential Page 1 of 112 Apixaban B0661069 NON-INTERVENTIONAL STUDY PROTOCOL Update 1, 08 January 2016 EU/1/11/691/012 EU/1/11/691/014 Procedure number Not Available Marketing Authorisation Holder (MAH) Pfizer Pharma GmbH Joint PASS No Research question and objectives The aim of this study is to investigate whether there are differences in the occurrence of major bleeding events in patients with NVAF and prescribed oral anticoagulation therapies in a real-world setting. It will be investigated whether the occurrence of major bleeding events in NVAF patients under anticoagulant therapy differs between patients treated with VKA (e.g. Phenprocoumon) and patients treated with Apixaban, Dabigatran or Rivaroxaban respectively. Country of study Germany Author Fabian Volz Pfizer
    [Show full text]
  • RBCH VTE Prevention Guidelines
    VTE Prevention Guidelines (Venous Thromboembolism) (Venous Thromboembolism) When using this document please ensure that the version you are using is the most up to date either by checking on the Trust intranet or if the review date has passed, please contact the author. ‘Out of date policy documents must not be relied upon’ Approval Version Issue Date Review Date Document Author Committee Drugs & 1.2 July 2010 July 2012 Dr Joseph Chacko Therapeutics Consultant Haematologist Jacqui Bowden Clinical Pharmacy Manager D&TC 2 July 2012 July 2014 Kareena Marotta & Jason Mainwaring Version Control Version Date Author Section Principle Amendment Changes 2 July 2012 Kareena Changed Enoxaparin to Dalteparin Marotta & Amended HIT monitoring guidance Jason Changed Lepirudin to Danaparoid Mainwaring Added audit section VTE Prevention Guidelines – Version 2 Page 1 of 22 July 2012 Contents 3 Introduction 3 Definitions and abbreviations 4 Assessing risks of VTE and bleeding 5 Care pathway 6 Using VTE prophylaxis Pharmacological Mechanical 9 Medical patients 10 Stroke 11 Cancer and patients with a central venous catheter 12 Palliative care 13 Non-orthopaedic surgery 14 Orthopaedic surgery 15 Critical care 16 Pregnancy and post-partum – see separate guidelines: Reducing the risk and management of venous thromboembolism (VTE) in pregnancy 17 Planning for discharge 18 Monitoring, diagnosing and managing heparin-induced thrombocytopaenia (HIT) 21 References 22 Appendices I. Risk assessment for venous thromboembolism (VTE) for adult patients admitted to hospital (page 2 of the Acute Prescription and Administration Record) II. Guide to using the VTE Risk Assessment Form III. Preventing blood clots in hospital (patient information leaflet) IV.
    [Show full text]
  • Protocol for Non-Interventional Studies Based on Existing Data TITLE PAGE Document Number: C30445781-01
    ABCD Protocol for non-interventional studies based on existing data TITLE PAGE Document Number: c30445781-01 BI Study Number: 1237-0090 BI Investigational Stiolto® Respimat® Product(s): The Role of Inhaler Device in the Treatment Persistence with Dual Title: Bronchodilators in Patients with COPD Protocol version 1.0 identifier: Date of last version of N/A protocol: PASS: No EU PAS register Study not registered number: Olodaterol and Tiotropium Bromide (ATC R03AL06) Active substance: Umeclidinium and Vilanterol (ATC R03AL03) Medicinal product: Stiolto® Respimat®; Anoro® Ellipta® Product reference: N/A Procedure number: N/A Joint PASS: No The primary objective of the study is to use US data to determine relative persistence between Olodaterol/Tiotropium Bromide delivered with the Respimat soft mist inhaler and Umeclidinium/Vilanterol delivered with the Ellipta dry powder inhaler using a 1:2 propensity score matched analysis. The secondary objectives of the study are as follows: Research question and - Characterize new users of Olodaterol/Tiotropium Bromide objectives: and Umeclidinium/Vilanterol in terms of demographics, medication use, comorbidities, and other variables, before and after propensity score matching. - Determine the incidence rate and proportion of patients discontinuing or switching among new users of Olodaterol/Tiotropium Bromide and Umeclidinium/ Vilanterol. - Determine the relative rate and proportion of patients discontinuing between Olodaterol/ Tiotropium Bromide and 001-MCG-102_RD-02 (1.0) / Saved on: 22 Oct 2015 Boehringer Ingelheim Page 2 of 69 Protocol for non-interventional studies based on existing data BI Study Number 1237-0090 c30445781-01 Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies Umeclidinium/Vilanterol.
    [Show full text]
  • COMPARISON of the WHO ATC CLASSIFICATION & Ephmra/Intellus Worldwide ANATOMICAL CLASSIFICATION
    COMPARISON OF THE WHO ATC CLASSIFICATION & EphMRA/Intellus Worldwide ANATOMICAL CLASSIFICATION November 2020 Comparison of the WHO ATC Classification and EphMRA / Intellus Worldwide Anatomical Classification The following booklet is designed to improve the understanding of the two classification systems. The development of the two systems had previously taken place separately. EphMRA and WHO are now working together to ensure that there is a convergence of the 2 systems rather than a divergence. In order to better understand the two classification systems, we should pay attention to the way in which substances/products are classified. WHO mainly classifies substances according to the therapeutic or pharmaceutical aspects and in one class only (particular formulations or strengths can be given separate codes, e.g. clonidine in C02A as antihypertensive agent, N02C as anti-migraine product and S01E as ophthalmic product). EphMRA classifies products, mainly according to their indications and use. Therefore, it is possible to find the same compound in several classes, depending on the product, e.g., NAPROXEN tablets can be classified in M1A (antirheumatic), N2B (analgesic) and G2C if indicated for gynaecological conditions only. The purposes of classification are also different: The main purpose of the WHO classification is for international drug utilisation research and for adverse drug reaction monitoring. This classification is recommended by the WHO for use in international drug utilisation research. The EphMRA/Intellus Worldwide classification has a primary objective to satisfy the marketing needs of the pharmaceutical companies. Therefore, a direct comparison is sometimes difficult due to the different nature and purpose of the two systems. The aim of harmonisation is to reach a “full” agreement of all mono substances in a given class as listed in the WHO ATC Index, mainly at third level: whenever this is not possible, or harmonisation of third level is too difficult or makes no sense (e.g.
    [Show full text]