Anticoagulation during pregnancy in women with prosthetic valves: evidence, guidelines and unanswered questions

Heart

Managementof this patient group remains difficult and controversial. There is no ideal anticoagulation regimen as there are inherent risks and benefits of each approach for both mother and foetus. There are limited data on optimal treatment strategy for an individual patient.

 

FDA approves licensing of edoxaban (Savaysa) tablets

US Food and Drug Administration

The FDA has approved edoxaban, a factor Xa inhibitor, to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.

 

d-Dimer Testing to Select Patients With a First Unprovoked Venous Thromboembolism Who Can Stop Anticoagulant Therapy: A Cohort Study

Annals of Internal Medicine

This cohort study found a 6.7% per patient-year (PPY) risk for recurrent VTE in patients with a first unprovoked proximal DVT or PE who had a negative d-dimer test result during anticoagulant therapy and 1 month after withdrawal; the recurrence risk was higher in men (9.7% PPY).

 

Misperceptions of aspirin efficacy and safety may perpetuate anticoagulant underutilization in atrial fibrillation

European Heart Journal

The authors of this discussion conclude it may be necessary to exclude aspirin for stroke prevention in AF (without comorbid conditions requiring its use) from all AF guidelines, as done by NICE, to remove the 'soft option' of prescribing a drug that is neither effective nor safe.

 

 

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

Biologics license application submitted to FDA for BAX111 for the treatment of Von Willebrand Disease

Biospace Inc.

BAX111 is the first highly-purified recombinant von Willebrand Factor in clinical development, as a treatment option for patients with von Willebrand disease. BAX111 has orphan-drug designation in the EU.

 

Supplemental New Drug Application submitted to FDA for use of eltrombopag for treatment of chronic ITP in children

Biospace Inc.

The license extension application will be for use in children aged over 6 years who have had an insufficient response to corticosteroids, immunoglobulins or splenectomy. Currently, eltrombopag is not licensed in any country for treatment of chronic ITP in the paediatric setting.

 

Duration of Anticoagulation for Venous Thromboembolic Events

Circulation

This review, based on a case vignette, discusses the evidence for anticoagulant selection and the recommended duration of therapy in patients presenting with venous thromboembolic events

 

 

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

Outpatient versus inpatient treatment for acute pulmonary embolism

Cochrane Database of Systematic Reviews

Current very low quality evidence from one published RCT did not provide sufficient evidence to assess efficacy and safety of outpatient versus inpatient treatment for acute PE in overall mortality, bleeding and recurrence of PE adequately.

 

A Randomized Trial of Intraarterial Treatment for Acute Ischemic Stroke

New England Journal of Medicine

RCT (n=500) found intraarterial treatment (IAT) given within 6 hours after stroke led to shift in distribution of score on modified Rankin scale at 90 days vs. usual care in favour of IAT (OR 1.67; 95% CI, 1.21 to 2.30) and likewise in proportion who were functionally independent.

 

Biologics License Application submitted to FDA for recombinant Factor VIII (BAY 81-8973) for the treatment of haemophilia A in adults and children

Biospace Inc.

The submission was based on results from the LEOPOLD (Long-Term Efficacy Open-Label Program in Severe Hemophilia A Disease) clinical trials, which evaluated rFVIII administered in two-to-three-times-per-week prophylaxis dosing regimens.

 

Dabigatran etexilate for the treatment and secondary prevention of deep vein thrombosis and/or pulmonary embolism – guidance (TA327)

National Institute for Health and Care Excellence

Dabigatran etexilate is recommended, within its marketing authorisation, as an option for treating and for preventing recurrent deep vein thrombosis and pulmonary embolism in adults.

 

Clinical outcomes and management associated with major bleeding in patients with atrial fibrillation treated with apixaban or warfarin: insights from the ARISTOTLE trial

European Heart Journal

In the ARISTOTLE study, major bleeds were associated with an increased risk of death, ischaemic stroke, or MI, especially following intracerebral haemorrhage. This risk was similarly elevated regardless of whether the patient was treated with apixaban or warfarin.

 

 


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 and Outcomes Associated with Bridging During Anticoagulation Interruptions in Patients with Atrial Fibrillation: Findings from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF)

Circulation
This study noted that bridging anticoagulation is used in a-quarter of anticoagulation interruptions and is linked to higher risk for bleeding (5.0 vs. 1.3%, OR 3.84, p<0.0001) and adverse events (13 vs. 6.3%; OR 1.94, p=0.0001) vs. non-bridging.

 

Factor XI Antisense Oligonucleotide for Prevention of Venous Thrombosis

New England Journal of Medicine

RCT in 300 patients found FXI-ASO was non-inferior (200mg OD) or superior (300mg OD) to enoxaparin 40mg OD daily in prevention of VTE in patients undergoing total knee arthroplasty (VTE in 27%, 4% and 30%; and bleeding in 3%, 3%, and 8%; respectively).

 

Conference report: Phase I study reports idarucizumab reverses anticoagulant effects of dabigatran in middle-aged, elderly and renally impaired volunteers

Biospace Inc.

Administration of idarucizumab in these groups (n=46) resulted in immediate, complete and sustained reversal of the anticoagulation effects of dabigatran. Anticoagulation was restored when volunteers were re-dosed with dabigatran 24 hours after idarucizumab was administered.

 

 

 

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

Meta-analysis on Risk of Bleeding with Apixaban in Patients with Renal Impairment

American Journal of Cardiology

In 6 trials (n= 40,145), risk of bleeding with apixaban in patients with mild renal impairment (RI) was significantly less (RR, 0.80; 95% CI, 0.66 to 0.96) vs. conventional anticoagulants, but was similar in patients with moderate-severe RI (1.01; 0.49 to 2.10).

 

Warfarin Versus Novel Oral Anticoagulants: How to Choose?

Circulation

This article for patient describes the differences between NOACs and warfarin, use of NOACs for mechanical heart valves and how to select an agent.

 

Effect of Alteplase Within 6 Hours of Acute Ischemic Stroke on All-Cause Mortality (Third International Stroke Trial)

Stroke

This exploratory analysis of RCT (n=3035) examining whether long-term survival varied by baseline characteristics after alteplase treatment supports improving acute stroke patients' access to earlier (<3 vs. 3–6 hours) alteplase treatment and treating those with poor prognosis.

 

Thrombolysis and clinical outcome in patients with stroke after implementation of the Tyrol Stroke Pathway: a retrospective observational study

The Lancet Neurology

This pathway provided information campaigns for the public and standardised the entire treatment pathway from stroke onset to outpatient rehabilitation, leading to an increase in use of thrombolysis and an improvement in clinical outcome, although mortality did not change.

 

 

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

 

CHMP issues positive opinion on licensing of vorapaxar (Zontivity) in EU

European Medicines Agency

Vorapaxar 2mg film tablet is intended for the reduction of atherothrombotic events in adult patients with a history of MI and should be co-administered with aspirin, and where appropriate, with clopidogrel.

 

Six-month versus 24-month dual antiplatelet therapy after implantation of drug eluting stents in patients non-resistant to aspirin: ITALIC, a randomized multicenter trial

Journal of the American College of Cardiology

This RCT, terminated early due to recruitment problems (n=2031 of planned 2475) found rates of bleeding and of thrombotic events were not significantly different for 6- vs. 24-month dual antiplatelet therapy after PCI with new-generation DES in aspirin responders.

 

Percutaneous Left Atrial Appendage Closure vs Warfarin for Atrial Fibrillation: A Randomized Clinical Trial

Journal of the American Medical Association

This study found mechanical left atrial appendage closure to be non-inferior and superior to warfarin in patients with nonvalvular AF and CHADS2 score ≥1 in preventing the combined outcome of stroke, systemic embolism and CV death (rate of 2.3 v 3.8 events per 100 patient-years).

 

Interim data on dabigatran versus warfarin for AF in routine care

Biospace Inc.

An interim analysis of two health insurance databases show that patients with non-valvular AF treated with dabigatran had a lower rate of major haemorrhage (354 v 395 events; HR 0.75) and stroke (62 v 69; HR 0.77, not statistically significant) vs. those receiving warfarin.

 

Ponatinib (Iclusig▼): risk of vascular occlusive events

Medicines and Healthcare products Regulatory Agency

An EU review on the risk of serious vascular occlusive events with ponatinib has been completed. The available evidence shows that the risk is likely to be dose-dependent; however the data are insufficient to recommend reducing the ponatinib dose.

 

Relation of Nonsteroidal Anti-inflammatory Drugs to Serious Bleeding and Thromboembolism Risk in Patients With Atrial Fibrillation Receiving Antithrombotic Therapy: A Nationwide Cohort Study

Annals of Internal Medicine

In patients with AF receiving anticoagulants, exposure to NSAIDs increased the risk of serious bleeding (additional 1.9 events per 1000 patients). The majority of events (38.7%) were gastrointestinal; 18.9% were intracranial. Thromboembolism risk was also increased.

 

Edoxaban Effects on Bleeding Following Punch Biopsy and Reversal by a 4-Factor Prothrombin Complex Concentrate

Circulation

In this randomised, placebo-controlled Phase 1 study (n=110), a 4-factor prothrombin complex concentrate reversed the effects of edoxaban on bleeding duration following punch biopsy in a dose-dependent manner, with complete reversal observed following 50 IU/kg.

 

Effects of Golden Hour Thrombolysis: A Prehospital Acute Neurological Treatment and Optimization of Medical Care in Stroke (PHANTOM-S) Substudy

JAMA Neurology

The availability of a stroke emergency mobile unit increased rates of thrombolysis overall (32.6% v 22% with conventional care; P<0.001) and the rates delivered within the first 'golden hour' after symptom onset (31.0% v 4.9%; P<0.01). Short-term mortality rates were similar.


Controversies in cardiovascular medicine – pre-treatment with P2Y12 inhibitors in NSTEMI

Circulation

Two linked articles discuss whether pre-treatment with P2Y12 inhibitors in Non–ST-segment–elevation acute coronary syndrome is clinically justified.

 

Extended duration dual antiplatelet therapy and mortality: a systematic review and meta-analysis

The Lancet

This analysis of 14 trials that randomised participants to different durations of dual antiplatelet therapy (DAPT) did not find any difference in all-cause, cardiovascular (CV) or non-CV mortality between extended duration and short-duration DAPT (≤6 months) or aspirin alone.

 

Twelve or 30 Months of Dual Antiplatelet Therapy after Drug-Eluting Stents

New England Journal of Medicine

Patients with a drug-eluting stent who continued dual antiplatelet therapy >1 year had a lower risk of stent thrombosis and major adverse cardiovascular and cerebrovascular events, but increased all-cause mortality (secondary endpoint; HR 1.36; 95% CI, 1.00 to 1.85; P=0.05).

 

 

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

Development of investigational antibody MEDI2452 for reversal of antiplatelet effects of ticagrelor

Biospace Inc.
A pre-clinical development program is evaluating the ability of MEDI2452 to rapidly and specifically reverse the antiplatelet effects of ticagrelor in emergency situations that cause major bleeding, such as surgery.

 

Anticoagulant therapy during primary percutaneous coronary intervention for acute myocardial infarction: a meta-analysis of randomized trials in the era of stents and P2Y12 inhibitors

British Medical Journal

In patients with STEMI undergoing primary PCI, unfractionated heparin plus GpIIb/IIIa inhibitor (GPI) and LMWH plus GPI were most efficacious in terms of avoiding major adverse cardiovascular events in the short-term; bivalirudin was associated with the lowest bleeding risk.

 

Platelet Transfusion: A Clinical Practice Guideline From the AABB

Annals of Internal Medicine

These US guidelines provide pragmatic recommendations on the appropriate use of platelet transfusion (prophylactic and therapeutic) in adults, based on the best available published evidence.

 

Vitamin K for Patients with High International Normalized Ratios (INRs): Safety

Canadian Agency for Drugs and Technologies in Health

A limited literature search identified one non-randomised study which found that withholding warfarin or giving vitamin K treatment to patients on oral anticoagulants who have an INR >9 did not effectively reduce the INR within 24 hours.

 

RAC recommends further assessment of risk of developing inhibitors with Kogenate Bayer/Helixate NexGen (factor VIII)

European Medicines Agency

The PRAC is recommending further examination of the available evidence for Kogenate Bayer/Helixate NexGen, as new evidence has shown it may be associated with a higher risk of inhibitor (antibody) development than other FVIII products in treatment-naïve haemophilia patients.

 

 

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 PER977 to Reverse the Anticoagulant Effect of Edoxaban

New England Journal of Medicine

In double-blind, placebo-controlled dose escalation trial in 80 healthy people given 60mg edoxaban, baseline haemostasis was restored from anticoagulated state in 10-30 minutes after administration of 100-300 mg of PER977 and was sustained for 24 hours. Phase 2 studies underway.

 

Costs and Benefits of Antithrombotic Therapy in Atrial Fibrillation in England: An Economic Analysis based on GRASP-AF

NHS Improving Quality

53.6% suitable patients (pts) in England are on anticoagulants. If warfarin prescribed for all of above with CHA2DS2-VASc ≥2, further 11,600 AF-related CVAs would be averted/year, with additional 1500 excess bleeds, and decrease in number of deaths in AF pts over 1-year by 3500.

 

Secondary Prevention of Cardiovascular Disease With Vorapaxar: A New Era of 3-Drug Antiplatelet Therapy?

JAMA Internal Medicine

The authors of this viewpoint article discuss the risks and benefits of vorapaxar and conclude that although it has a potential role in the secondary prevention of cardiovascular disease, they remain sceptical of its widespread use as part of a 3-drug antiplatelet regimen.

 

Medicines Evidence Commentary : Non-steroidal anti-inflammatory drugs and risk of venous thromboembolism

National Institute for Health and Care Excellence

A systematic review and meta-analysis of observational studies found that there was a statistically significantly increased risk of venous thromboembolism (VTE) among users of NSAIDs compared to non-users of NSAIDs. However, the meta-analysis has a number of important limitations.

 

Oral anticoagulation therapy after radiofrequency ablation of atrial fibrillation and the risk of thromboembolism and serious bleeding: long-term follow-up in nationwide cohort of Denmark

European Heart Journal

This study reports a relatively low risk of VTE beyond 3 months after radiofrequency ablation for AF. The authors suggest the risk of bleeding with oral anticoagulation may outweigh benefits in this setting, but randomised studies are required to confirm their findings.

 

Risk of Bleeding With Dabigatran in Atrial Fibrillation

JAMA Internal Medicine

This analysis of Medicare patients who started warfarin (n=8102) or dabigatran (n=1302) within 60 days of AF diagnosis reports that dabigatran was associated with a higher risk of overall, major and GI bleeding (HR 1.30, 1.58 and 1.85 v warfarin) but lower risk of ICH (HR 0.32).

 

European Medicines Agency accepts Marketing Authorisation Application for ELOCTA™ (rFVIIIFc) for haemophilia A

Biospace Inc.

The EMA has validated an application seeking approval of Elocta™, a recombinant factor VIII Fc fusion protein product candidate for the treatment of haemophilia A. The application includes results from the A-LONG and Kids A-LONG Phase III studies.

 

 

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

 

 

Cardiovascular, Bleeding, and Mortality Risks in Elderly Medicare Patients Treated with Dabigatran or Warfarin for Non-Valvular Atrial Fibrillation

Circulation

Retrospective cohort study in general practice found dabigatran linked to reduced risk of ischaemic stroke, intracranial bleed, and death, and increased risk of major GI bleed vs. warfarin in elderly patients with non-valvular AF. These links more pronounced with 150mg BD dose.

 

Effect of intermittent pneumatic compression on disability, living circumstances, quality of life, and hospital costs after stroke: secondary analyses from CLOTS 3, a randomised trial

The Lancet Neurology

RCT (n=2876) found despite previously reported decrease proximal DVT risk at 30 days (primary endpoint), there were no significant differences in disability, living circumstances, or health-related QoL in patients using or not using intermittent pneumatic compression.

 

Deep vein thrombosis, pulmonary embolism - dabigatran etexilate (treatment, prevention): final appraisal determination

National Institute for Health and Care Excellence

DRAFT guidance recommends dabigatran etexilate, within its marketing authorisation, as an option for treating and for preventing recurrent deep vein thrombosis and pulmonary embolism in adults.

 

Common Questions and Answers on the Practical Use of Oral Anticoagulants in Non-Valvular Atrial Fibrillation

UKMi
This document highlights key factors influencing anticoagulant choice, identification of patients taking anticoagulants, when might warfarin be the preferred option, and active swapping from warfarin to novel agents.

 

FDA advisory panel recommends approval of edoxaban 60mg in selected AF patients

Reuters
Advisory panel to FDA has recommended approval of 60 mg dose of edoxaban, a once-daily anticoagulant that inhibits Factor Xa, for use in patients with AF, but only in those with mild renal impairment, as outcomes vs. warfarin were worse in those with normal renal function.

 

FDA Approves Obizur (Antihaemophilic Factor (Recombinant), Porcine Sequence) for Acquired Haemophilia A

US Food and Drug Administration
The US FDA has approved Obizur (Antihaemophilic Factor (Recombinant), Porcine Sequence) for the treatment of bleeding episodes in adults with acquired haemophilia A.

 

 

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

 

 

Acute coronary syndrome - rivaroxaban [ID532]: consultation document

National Institute for Health and Care Excellence

DRAFT guidance recommends rivaroxaban as option, in combination with aspirin plus clopidogrel/aspirin alone, for preventing atherothrombotic events in people who have had an ACS with elevated cardiac biomarkers. Risk of bleeding should be assessed before treatment is started.

 

Chronic vitamin K antagonist therapy and bleeding risk in ST elevation myocardial infarction patients

Heart

In patients with STEMI treated with primary PCI, chronic use of vitamin K antagonist (VKA) was associated with an increased risk of in-hospital major bleed (17.0% v 10.1% in those not on VKA). In those on VKA, glycoprotein inhibitors were associated with increased bleeding risk.

 

New product: Nuwiq (human coagulation factor VIII, simoctocog alfa)

electronic Medicines Compendium

Nuwiq is licensed for the treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII deficiency). Dose and duration depend on the severity of the factor VIII deficiency, location and extent of the bleeding and the patient's clinical condition.

 

 

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