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).

 

Meta-analysis of safety and efficacy for direct oral anticoagulation treatment of non-valvular atrial fibrillation in relation to renal function

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.

 

Vitamin K antagonists versus low‐molecular‐weight heparin for the long term treatment of symptomatic venous thromboembolism

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

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).

 

Individualised versus standard duration of elastic compression therapy for prevention of post-thrombotic syndrome (IDEAL DVT): a multicentre, randomised, single-blind, allocation-concealed, non-inferiority trial

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.

 

Should This Patient Receive Aspirin?: Grand Rounds Discussion From Beth Israel Deaconess Medical Center

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

Oral anticoagulants for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis, and cost effectiveness analysis

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.

 

Dabigatran versus Warfarin for Acute Venous Thromboembolism in Elderly or Impaired Renal Function Patients: Pooled Analysis of RE-COVER and RE-COVER II

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.

 

FDA grant priority review for avatrombopag for thrombocytopenia in patients with chronic liver disease

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.

 

Low dose aspirin as adjuvant treatment for venous leg ulceration: pragmatic, randomised, double blind, placebo controlled trial (Aspirin4VLU)

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

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).

 

Resumption of oral anticoagulation following traumatic injury and risk of stroke and bleeding in patients with atrial fibrillation: a nationwide cohort study

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.

 

Clopidogrel non-responsiveness in patients undergoing percutaneous coronary intervention using the VerifyNow test: frequency and predictors

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

Pulmonary embolism rule-out criteria (PERC) rule in European patients with low implicit clinical probability (PERCEPIC): a multicentre, prospective, observational study

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.

 

Boehringer Ingelheim's presents subgroup analyses of RE-VERSE AD on impact of idarucizumab in patients on dabigatran with gastrointestinal bleeding or needing emergency surgery

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.

 

Outcomes of Dabigatran and Warfarin for Atrial Fibrillation in Contemporary Practice: A Retrospective Cohort Study

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 CHMP issues positive opinion for paediatric license extension of Nplate (romiplostim) for chronic immune (idiopathic) thrombocytopenic purpura

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).

 

US FDA approves emicizumab-kxwh (Hemlibra) for prophylaxis in adult and paediatric patients with haemophilia A with inhibitors

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

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.

 

Effect of treatment delay on the effectiveness and safety of antifibrinolytics in acute severe haemorrhage: a meta-analysis of individual patient-level data from 40 138 bleeding patients

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

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.

 

Hospital admissions for bleeding events associated with treatment with apixaban, dabigatran and rivaroxaban

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.

 

US FDA approves 10mg dose of rivaroxaban for reduction of continued risk of venous thromboembolism (VTE)

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.

 

The Efficacy and Safety of the Use of Non-Vitamin-K Antagonist Oral Anticoagulants in Patients with Non-Valvular Atrial Fibrillation and Concomitant Aspirin Therapy: A Meta-Analysis of Randomized Trials

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).

 

Conference report: Three months of dual antiplatelet therapy (DAPT) non-inferior to 12 months DAPT in patients with acute coronary syndrome (ACS) treated with the COMBO Dual Therapy Stent

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).

 

Lower dose of rivaroxaban (Xarelto) for extended prevention of recurrent venous thromboembolism (VTE) approved in Europe

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

 

Pregnancy, thrombophilia, and the risk of a first venous thrombosis: systematic review and bayesian meta-analysis

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.

 

Streamlining primary and secondary care management pathways for stroke prevention in atrial fibrillation

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

Safety and efficacy of long-term treatment of chronic/persistent ITP with eltrombopag: final results of the EXTEND study

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.

 

Comparative safety of direct oral anticoagulants and warfarin in venous thromboembolism: multicentre, population based, observational study

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.

 

Co-administration of cyclosporine and ticagrelor may lead to a higher exposure to cyclosporine: a case report of a 49-year-old man

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

Venous thromboembolism in over 16s: reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism (Update): Draft guidance consultation

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.

 

Anticoagulation combined with antiplatelet therapy in patients with left ventricular thrombus after first acute myocardial infarction

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).

 

Association Between Use of Non–Vitamin K Oral Anticoagulants With and Without Concurrent Medications and Risk of Major Bleeding in Nonvalvular Atrial Fibrillation

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).

 

Clinical impact of major bleeding in patients with venous thromboembolism treated with factor Xa inhibitors or vitamin K antagonists

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.

 

Low-Dose vs Standard-Dose Alteplase for Patients With Acute Ischemic Stroke: Secondary Analysis of the ENCHANTED Randomized Clinical Trial

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

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