Anticoagulation news items. Week commencing 11th December 2017
Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism
New England Journal of Medicine
RCT (n=1046) found edoxaban was non-inferior to dalteparin given for 6-12 months in terms of composite of recurrent VTE or major bleeding during 12 months after randomisation (12.8% for edoxaban vs 13.5% for dalteparin (HR 0.97; P=0.006 for noninferiority).
Thrombosis Reasearch
Analysis of five RCTs comparing DOACs to warfarin in atrial fibrillation (n=72,608) found stroke risk was lower with DOACs than warfarin in both mild (RR 0.79; 95% CI 0.68–0.91) and moderate (0.80, 0.69–0.92) renal impairment, with no major differences in normal renal function.
Cochrane Database of Systematic Reviews
There were no clear differences between low-molecular weight heparin (LMWH) and vitamin K antagonists (VKA) in preventing symptomatic VTE /death after a DVT episode. There were also no clear differences in bleeding episodes when only high-quality studies were considered.
The above records have been identified by UKMi and feature in the NICE Medicines Awareness Service. Further details on this service can be found at:
http://www.evidence.nhs.uk/about-evidence-services/content-and-sources/medicines-information/new-medicines-awareness-services
Anticoagulation news items. Week commencing 4th December 2017
Pharmacomechanical Catheter-Directed Thrombolysis for Deep-Vein Thrombosis
New England Journal of Medicine
RCT (n-692) found that between 6 and 24 months, addition of catheter-directed thrombolysis to anticoagulation did not result in lower risk of post-thrombotic syndrome (47% vs. 48%, respectively) but did result in higher risk of major bleeding. (1.7% vs. 0.3%, p= 0.049).
The Lancet Haematology
This RCT (n=865) reports post-thrombotic syndrome occurred in 29% of patients receiving individualised duration of therapy and 28% of patients receiving standard duration of therapy (absolute difference was 1.1% (95% CI −5.2 to 7.3), thus meeting the non-inferiority margin.
Annals of Internal Medicine
In this discussion, experts review the 2016 US Aspirin Use for the Primary Prevention of Cardiovascular Disease.
Thrombo-embolic prevention after transcatheter aortic valve implantation (TAVI)
European Heart Journal
Optimal antithrombotic strategy and duration to mitigate thrombotic and bleeding risks associated with TAVI remains unclear. This review provides an overview of recent insights in this field, and highlights antithrombotic trials focusing on optimising outcomes in this setting.
Perioperative management of anticoagulant and antiplatelet therapy
Heart
This narrative review discusses assessment of whether interruption of anticoagulation is required, need for and management of perioperative bridging, management of patients who are receiving direct oral anticoagulants (DOACs) and management of those receiving antiplatelets.
The above records have been identified by UKMi and feature in the NICE Medicines Awareness Service. Further details on this service can be found at:
http://www.evidence.nhs.uk/about-evidence-services/content-and-sources/medicines-information/new-medicines-awareness-services
Anticoagulation news items. Week commencing 27th November 2017
British Medical Journal
Review of 23 RCTs (n=94,656) found that apixaban 5mg and dabigatran 150mg twice daily reduced the risk of stroke or systemic embolism vs warfarin. The difference vs warfarin for rivaroxaban or edoxaban was not statistically significant.
Thrombosis and Haemostasis
Pooled analysis (n=5,107) suggests that dabigatran has better efficacy than warfarin in renal impairment, probably because of an increase in the concentration of dabigatran. Incidence of major bleeding increased with increasing renal impairment for both dabigatran and warfarin.
Biospace Inc.
The market authorisation application in the US is based on the ADAPT 1 and ADAPT 2 phase 3 trials. Avatrombopag is a second generation orally administered thrombopoetin receptor agonist currently under investigation.
British Medical Journal
RCT (n=251) does not support use of low dose aspirin (150mg daily) as adjuvant treatment for venous leg ulcers (median number of days to healing of largest ulcer: 77 for aspirin vs 69 for placebo; HR 0.85, 95% CI, 0.64 to 1.13, P=0.25).
The above records have been identified by UKMi and feature in the NICE Medicines Awareness Service. Further details on this service can be found at:
http://www.evidence.nhs.uk/about-evidence-services/content-and-sources/medicines-information/new-medicines-awareness-services
Anticoagulation news items. Week commencing 20th November 2017
Revised SPC: Xarelto (rivaroxaban) film-coated tablets (10mg, 15mg and 20mg)
electronic Medicines compendium
SPC now states when 'extended prevention of recurrent DVT and PE' is indicated (after ≥6 months therapy for DVT/PE), recommended dose is 10mg daily; 20mg should be considered in those at high risk of recurrent DVT/PE. Duration/dose should be based on benefit vs. bleeding risk.
Section 4.5 now advises that as with other anticoagulants the possibility may exist that patients are at increased risk of bleeding in case of concomitant use with SSRIs or SNRIs due to their reported effect on platelets.
Low-dose aspirin and risk of intracranial bleeds: An observational study in UK general practice
Neurology
Population-based cohort study of 398,158 users and non-users of prophylactic low-dose aspirin (followed over a median of 5.4 years) reports low-dose aspirin is not associated with an increased risk of any type of intracranial bleeds (1,611 cases of intracranial bleeds identified).
European Heart Journal
Danish cohort study (n=4541) reported that AF patients resuming oral anticoagulation following traumatic injury have lower hazard of all-cause mortality and ischaemic stroke, increased hazard of major bleeding but without additional hazards of recurrent traumatic injury.
European Journal of Hospital Pharmacy
In this Iraqi case series (n=115; mean age: 58 years; male sex: 73.9%) of whom 18.3% were clopidogrel non-responders, the major independent predictive factors for non-responsiveness were diabetes mellitus, hypertension, obesity and male sex.
The above records have been identified by UKMi and feature in the NICE Medicines Awareness Service. Further details on this service can be found at:
http://www.evidence.nhs.uk/about-evidence-services/content-and-sources/medicines-information/new-medicines-awareness-services
Anticoagulation news items. Week commencing 13th November 2017
The Lancet Haematology
Study (n=1757) found of 1052 (60%) patients with low clinical probability of PE, 49 (4.7%) had venous thromboembolism. In patients with low implicit clinical probability, 337 (32%) had negative PERC, of whom 4 (1.2%) had PE, suggesting PERC can exclude PE with few false-negatives.
Biospace Inc.
Of the 137 patients enrolled with a GI bleed, complete reversal of anticoagulant effect was observed in over 95% patients. Idarucizumab also rapidly and completely reversed the anticoagulant effect of dabigatran in approximately 98% patients requiring an urgent procedure.
Shortage of tranexamic acid tablets 500mg (all brands)
Specialist Pharmacy Service
There are limited supplies of generic tranexamic acid (TA) 500mg tablets due to difficulty sourcing raw material. Branded TA (Cyklokapron), OTC product (Cyklo-f) and some generics continue to be remain available, but there may be intermittent supplies issues until at least 2018.
Annals of Internal Medicine
Retrospective analysis of 50,578 started on dabigatran or warfarin showed no significant difference in rates of ischaemic stroke, or extracranial haemorrhage between the 2 groups, but those on dabigatran were less likely to have intracranial bleeding and more likely to suffer MI.
European Medicines Agency
The additional indication is for patients aged one year of age and older who are refractory to other treatments (e.g. corticosteroids, immunoglobulins).
Biospace Inc.
In the Phase III HAVEN 1 and 2 studies, prophylaxis with emicizumab was associated with a reduction in treated bleeds in adults and children with haemophilia A and factor VIII inhibitors. It will have a boxed warning regarding risk of severe blood clots.
The above records have been identified by UKMi and feature in the NICE Medicines Awareness Service. Further details on this service can be found at:
http://www.evidence.nhs.uk/about-evidence-services/content-and-sources/medicines-information/new-medicines-awareness-services
Anticoagulation news items. Week commencing 6th November 2017
An update on the bleeding risks associated with DOACs
Drug and Therapeutics Bulletin
There is uncertainty on optimal lab monitoring of anticoagulation, perioperative management and treatment of bleeding with DOACs, and currently only one licensed reversal agent in UK. Review discusses DOAC-related bleeding and role of drugs to reverse their anticoagulant action.
Mechanical or Biologic Prostheses for Aortic-Valve and Mitral-Valve Replacement
New England Journal of Medicine
Study (n=25,445) found mechanical (MC) mitral valves were linked to lower mortality than biologic valves in patients up to 70 years of age, whereas benefit of MC aortic valve disappeared by 55 years of age. In both cases, MC prosthesis was linked to lower risk of reoperation.
The Lancet
Tranexamic acid (TA) increased survival from bleeding (OR 1.20, 95% CI 1.08–1.33; p=0.001). Immediate TA improved survival by > 70% (1.72; 1.42–2.10; p<0.0001) vs later treatment. Thereafter, benefit decreased by 10% for every 15 min delay until 3 h after onset of bleeding.
Association of Warfarin Use With Lower Overall Cancer Incidence Among Patients Older Than 50 Years
JAMA Internal Medicine
A lower incidence of cancer associated with warfarin was noted in a Norweigian population-level study (n=1,256 725), which was reinforced by a subgroup analysis of patients with AF. Further studies are required to fully elucidate mechanisms underpinning these observations.
Bayer files for approval of low-dose rivaroxaban-aspirin combination therapy in EU
PharmaTimes
Bayer is seeking approval for a low-dose formulation of rivaroxaban 2.5mg administered twice daily alongside aspirin 100mg once daily for reduction of cardiovascular events in patients with coronary or peripheral artery disease. Submission is based on data from Compass study.
The above records have been identified by UKMi and feature in the NICE Medicines Awareness Service. Further details on this service can be found at:
http://www.evidence.nhs.uk/about-evidence-services/content-and-sources/medicines-information/new-medicines-awareness-services
Anticoagulation news items. Week commencing 30th October 2017
Use of oral anticoagulants in combination with antiplatelet(s) in atrial fibrillation
Heart
Analysis of Danish registry data (n=2946) found that from 2011 to 2016, the use of a NOAC in combination with antiplatelet(s) increased from 10% to 52% in patients with AF following MI/PCI, and exceeded the use of vitamin K antagonist in combination with antiplatelet(s) by 2016.
European Journal of Hospital Pharmacy
Retrospective observational study identified 37 hospitalisation episodes for DOAC-induced bleeding in 32 patients (15 rivaroxaban, 9 apixaban, 8 dabigatran), representing incidence rate of 3.44/ 100 person-years. Most common bleeding site was GI. Intracranial bleeding was rare.
Biospace Inc.
FDA has approved 10 mg dose for reducing continued risk for VTE after completing at least 6-months of initial anticoagulation. Approval is based on data from EINSTEIN CHOICE, which showed superior efficacy in reducing VTE risk and with major bleeding rates similar to aspirin.
International Expert Consensus on Switching Platelet P2Y12 Receptor-Inhibiting Therapies
Circulation
This expert consensus provides an overview of the pharmacology of P2Y12 inhibitors, different modalities and definitions of switching, and available literature and recommendations for switching between P2Y12 inhibitors.
Bayer files for approval of long-acting haemophilia therapy damoctocog alfa pegol (BAY94-9027) in US
PharmaTimes
BAY94-9027 is engineered to potentially prolong factor VIII activity in the blood while preserving coagulation activity using site-specific PEGylation technology, thus reducing the number of infusions necessary to prevent bleeds in patients with haemophilia A.
Revised SPC: Pradaxa (dabigatran) hard capsules (all strengths)
electronic Medicines compendium
Sections 4.2 (Posology and method of administration), 4.4 (Special warnings and precautions for use) and 5.1 (Pharmacodynamic properties) have been updated to include information regarding catheter ablation for atrial fibrillation.
Revised SPCs: Xarelto (rivaroxaban) film-coated tablets (all strengths)
electronic Medicines compendium
As with other anticoagulants, the possibility may exist that patients are at increased risk of bleeding in case of concomitant use with SSRIs or SNRIs. When concomitantly used in the clinical program, numerically higher rates of clinically relevant bleeding were observed.
Circulation
This analysis of 4 RCTs found that in patients receiving aspirin (n=21,722), NOACs were more effective than vitamin K antagonists (e.g. HR 0.78; 95% CI 0.67-0.91 for stroke/systemic embolism), as safe for major bleeding and safer for intracranial haemorrhage (HR 0.38; 0.26-0.56).
Biospace Inc.
The overall incidence of the primary endpoint (composite of all-cause mortality, myocardial infarction, stent thrombosis, stroke, target vessel revascularisation, moderate/major bleeding within 360 days) was 8.2% for 3 months v 8.4% for 12 months DAPT; P non-inferiority <0.001).
PharmaTimes
The European Commission has approved a 10mg once daily dose for extended prevention of recurrent VTE, for patients who have already received at least six months of initial anticoagulation. The approval is based on data from the EINSTEIN CHOICE study.
The above records have been identified by UKMi and feature in the NICE Medicines Awareness Service. Further details on this service can be found at:
http://www.evidence.nhs.uk/about-evidence-services/content-and-sources/medicines-information/new-medicines-awareness-services
Anticoagulation news items. Week commencing 23rd October 2017
British Medical Journal
This review of 36 cohort or case-control studies (41,297 reported pregnancies) found all inherited thrombophilias increased the risk for pregnancy associated VTE, with the highest risks seen for antithrombin, protein C and protein S deficiency, and homozygous factor V Leiden.
Less dementia with oral anticoagulation in atrial fibrillation
European Heart Journal
Swedish retrospective registry study (n=444,106) found anticoagulant treatment at baseline was associated with 29% lower risk of dementia than in patients not on anticoagulant [HR 0.71, 95% CI, 0.68–0.74]. Direct comparison between DOACs and warfarin showed no difference.
European Heart Journal
This article outlines the collaborative working between primary and secondary care in one CCG in the development of a simple and practical decision-making pathway for stroke prevention in atrial fibrillation.
The above records have been identified by UKMi and feature in the NICE Medicines Awareness Service. Further details on this service can be found at:
http://www.evidence.nhs.uk/about-evidence-services/content-and-sources/medicines-information/new-medicines-awareness-services
Anticoagulation news items. Week commencing 9th October and 16th October 2017
Blood
Over median duration of 2.37 years, 259 patients (85.8%) achieved response (platelets ≥50×109/L at least once in absence of rescue) and 133 of 257 (52%) achieved continuous response ≥25 weeks. Rate of thromboembolic events (6%) did not increase with treatment duration past 1 year.
British Medical Journal
Retrospective study (n=12,489 on DOACs and 47,036 on warfarin in Canada and US with new diagnosis of venous thromboembolism) found treatment with DOACs, compared with warfarin, was not linked to increased risk of major bleeding or all-cause mortality in first 90 days of treatment.
British Journal of Clinical Pharmacology
Timeline for increase in trough level of cyclosporine after introduction of ticagrelor (TC) for unstable angina was considered consistent with appearance of an interaction, thought to be due to inhibition of CYP3A4 and P-glycoprotein by TC, which was managed by cessation of TC.
The above records have been identified by UKMi and feature in the NICE Medicines Awareness Service. Further details on this service can be found at:
http://www.evidence.nhs.uk/about-evidence-services/content-and-sources/medicines-information/new-medicines-awareness-services
Anticoagulation news items. Week commencing 2nd October 2017
National Institute for Health and Care Excellence
A DRAFT update of NICE guideline CG92 (published January 2010), which includes new and updated recommendations on the risk assessment and prophylaxis of people at risk of venous thromboembolism, is now available for consultation.
Bayer halts Phase III study of rivaroxaban in embolic stroke
PharmaTimes
Bayer has halted a Phase III study investigating rivaroxaban in patients with embolic stroke of undetermined source after it showed no improvements in efficacy when compared to aspirin. Bleeding rates were low overall but higher in the rivaroxaban arm (no data presented).
In Use Product Safety Assessment report for Inhixa (enoxaparin biosimilar)
Specialist Pharmacy Service
This assessment, produced using the validated UKMi product assessment tool, discusses practical safety considerations associated with the introduction of this biosimilar product, including the need to ensure prescribing of product by brand name.
European Heart Journal
Review (n=1850 with MI) found that among those with a left ventricular thrombus given a vitamin K antagonist, those with a time in therapeutic range (TTR) ≥50% had a lower risk of thromboembolism vs those with TTR <50% (2.9% vs 19%, p=0.036) with no difference in major bleeding.
Indications for anticoagulant and antiplatelet combined therapy
British Medical Journal
Review notes combination treatment increases risk of bleeding, and this risk should be estimated and discussed with patients to guide treatment decisions (e.g. using risk scores such as HAS-BLED). Consideration should be given to addition of H2 antagonist or proton pump inhibitor.
Association Between Use of Antithrombotic Medication and Hematuria-Related Complications
Journal of the American Medical Association
Canadian retrospective cohort study (n=808,897) found that over a median follow-up of 7.3 years the rate of haematuria complications was higher in those exposed to antithrombotics vs those not exposed (123.95 vs 80.17 per 1000 person years, Rate Ratio 1.44, 95% CI 1.42-1.46).
Journal of the American Medical Association
Taiwanese study (91,330 patients on NOACs) found that those on concurrent amiodarone, fluconazole, rifampicin and phenytoin had a significant increased risk of major bleeding vs NOAC use alone (difference +13.94, +138.46 +36.90 and +52.31 incidents per 1000 person years).
Thrombosis and Haemostasis
Combined data from the EINSTEIN, AMPLIFY and HOKUSAI-VTE studies found that factor Xa inhibitor associated major bleeding events in these studies had a less severe presentation and similar course compared to vitamin K antagonists.
Shortage of abciximab (Reopro) 2mg/ml solution for injection or infusion
Specialist Pharmacy Service
There is a potential 6 month supply issue affecting abciximab from October through till March 2018. This memo advises on alternative treatment options in the interim should stock run out.
JAMA Internal Medicine
This secondary analysis of a RCT that involved 3310 patients with acute ischaemic stroke found no clear differential benefits of low-dose alteplase compared with standard-dose alteplase in disability outcomes, irrespective of age, race/ethnicity, and neurological severity.
The above records have been identified by UKMi and feature in the NICE Medicines Awareness Service. Further details on this service can be found at:
http://www.evidence.nhs.uk/about-evidence-services/content-and-sources/medicines-information/new-medicines-awareness-services
