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


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:

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:

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

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:

Use of oral anticoagulants in combination with antiplatelet(s) in atrial fibrillation


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


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


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


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


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:


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:

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


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:

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


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:

Miconazole (Daktarin): over-the-counter oral gel contraindicated in patients taking warfarin

Medicines and Healthcare products Regulatory Agency

Patients taking warfarin should not use over-the-counter miconazole oral gel. If concomitant use is planned via prescription, the anticoagulant effect of warfarin should be monitored carefully. Patients who experience signs of bleeding should seek immediate medical attention.


Meta-Analysis of Safety and Efficacy of Uninterrupted Non–Vitamin K Antagonist Oral Anticoagulants Versus Vitamin K Antagonists for Catheter Ablation of Atrial Fibrillation

American Journal of Cardiology

Review of 13 studies (3 RCTs and 10 observational studies, total n=4,878) found no significant difference in the risk of major bleeding, systemic thromboembolism and symptomatic stroke/TIA, though the evidence was not of high quality.


Evolving landscape of stroke prevention in atrial fibrillation within the UK between 2012 and 2016: a cross-sectional analysis study using CPRD

BMJ Open

Cohort study showed an increasing proportions of patients with non-valvular AF receiving anticoagulant therapy (16.7% rise), together with similar reductions in antiplatelet (16.8% decrease). The proportion of patients not receiving antithrombotics remained the same (15%).


Effect of Genotype-Guided Warfarin Dosing on Clinical Events and Anticoagulation Control Among Patients Undergoing Hip or Knee Arthroplasty: The GIFT Randomized Clinical Trial

Journal of the American Medical Association

RCT (n=1,650) found that fewer patients in the geno-type guided group had a composite outcome event (major bleeding, INR>4, VTE or death) vs clinically guided warfarin (10.8% vs 14.7%, RR 0.73, 95% 0.56 to 0.95).


Phase III L-PLUS2 study investigating lusutrombopag for the treatment of thrombocytopenia in patient with chronic liver disease undergoing elective invasive procedures meets primary endpoint

Biospace Inc.

This study (n=215) reports that more patients on lusutrombopag vs placebo (64.8% vs 29.0%) met the primary efficacy endpoint (defined as proportion of patients who required no platelet transfusion prior to the invasive procedure) and no rescue therapy for bleeding post procedure.


Interhospital Transfer Prior to Thrombectomy is Associated with Delayed Treatment and Worse Outcome in the STRATIS Registry


Median onset-to-revascularisation time was 202 minutes for direct presentation vs 311 minutes for interhospital transfer in 984 patients undergoing mechanical thrombectomy for severe stroke (p<0.001). Mortality did not differ and IV alteplase did not impact outcomes.


New Drug Application submission to FDA for avatrombopag, an oral second generation thrombopoietin receptor agonist

Biospace Inc.

The NDA was based on data from two Phase III trials, ADAPT-1 and ADAPT-2, that evaluated the efficacy and safety of avatrombopag for the treatment of severe thrombocytopenia (<50,000/μL) in patients with chronic liver disease who are scheduled to undergo a procedure.


Diagnosis and management of postpartum haemorrhage

British Medical Journal

Review notes this is second leading direct cause of maternal deaths in UK. It recommends tranexamic acid for all women with atonic and traumatic postpartum haemorrhage as well as for ongoing haemorrhage during a caesarean section.


National community pharmacy oral anticoagulant safety audit

Specialist Pharmacy Service

This audit will provide insight on patient awareness of key information about their anticoagulant, use of alert cards and compliance with monitoring requirements. Results will be used to inform a national update of patient held oral anticoagulant information and alert cards.



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:

Screening for Occult Cancer in Patients With Unprovoked Venous Thromboembolism: A Systematic Review and Meta-analysis of Individual Patient Data

Annals of Internal Medicine

10 studies (n=2,316) found a 12 month prevalence of cancer after VTE of 5.2%. The point prevalence of cancer was higher in those with extensive screening vs limited screening initially (OR 2.0, 95% CI 1.2 to 3.4), but not at 12 months (OR 1.4, 95% CI 0.89 to 2.1).


Effects of Anticoagulants in Patients With Cirrhosis and Portal Vein Thrombosis: A Systematic Review and Meta-analysis


Review of 8 studies (n=353) found that more patients given anticoagulants underwent portal vein thrombosis recanalization vs no treatment (71% vs 42%, p<0.0001). There was no difference in major or minor bleeding in the 6 studies that reported this.


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:

Bleeding-related hospital admissions and 30-day readmissions in patients with non-valvular atrial fibrillation treated with dabigatran versus warfarin

Journal of Thrombosis and Haemastasis

Dabigatran vs warfarin, was associated with comparable incidence of first hospital admission (incidence rate ratio, 0.92; 95% CI, 0.66-1.28) but higher risk of 30-day readmission with respect to bleeding (adjusted HR, 2.87; 95%CI, 1.10-7.43) in 51,946 Hong Kong patients with AF.


The management of antiplatelet therapy in acute coronary syndrome patients with thrombocytopenia: a clinical conundrum

European Heart Journal

In the absence of clinical guidance, this review discusses the evidence and proposes management strategies for antiplatelet therapy in patients with acute coronary syndrome and thrombocytopenia.


Rivaroxaban vs Warfarin Sodium in the Ultra-Early Period After Atrial Fibrillation–Related Mild Ischemic Stroke A Randomized Clinical Trial

JAMA Neurology

This RCT (n=195) reports in patients with mild acute ischaemic stroke and AF, new ischaemic lesions or intracranial haemorrhage (noted on MRI imaging) after 4 weeks occurred in 49.5% of patients receiving rivaroxaban v 54.5% receiving warfarin (nonsignificant difference, p=0.49).


Long-term mortality and prehospital tirofiban treatment in patients with ST elevation myocardial infarction

Subgroup analysis of the On-TIME 2 trial (n=984) found that baseline N-terminal pro-B-type natriuretic peptide level predicted long-term mortality. In those with high levels, early prehospital treatment with tirofiban significantly reduced 30-day and 1-year mortality vs placebo.


Factor VIII medicines: no clear and consistent evidence of difference in risk of inhibitor development between classes

European Medicines Agency

The European Medicines Agency has concluded there is no clear evidence of a difference in risk of inhibitor development between recombinant factor VIII medicines and those derived from plasma. The risk of inhibitor development should be evaluated individually for each medicine.



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:




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