Calciphylaxis

New England Journal of Medicine

Calciphylaxis is a life-threatening syndrome of vascular calcification characterised by occlusion of microvessels in the subcutaneous adipose tissue and dermis. This review presents current understanding of the condition and provides a framework for interdisciplinary management.

Antifibrinolytic drugs for treating primary postpartum haemorrhage

Cochrane Database of Systematic Reviews

Review of data from 3 RCTs (n=20,412) concludes tranexamic acid, when administered intravenously, reduces mortality due to bleeding in women with primary postpartum haemorrhage, irrespective of mode of birth, and without increasing the risk of thromboembolic events.

Treatment for superficial thrombophlebitis of the leg

Cochrane Database of Systematic Reviews

Review of 33 RCTs (n=7296) concludes prophylactic dose fondaparinux given for 45 days appears to be a valid therapeutic option for superficial thrombophlebitis of the legs for most people. Evidence on topical treatment/surgery is too limited and cannot inform clinical practice.

Fostamatinib for the Treatment of Adult Persistent and Chronic Immune Thrombocytopenia: Results of Two Phase 3, Randomized, Placebo-Controlled Trials

American Journal of Hematology

Results from these RCTs (n=150) show that stable responses (defined as platelets ≥50,000/μL at ≥4 of 6 biweekly visits) occurred in 18% of patients on fostamatinib vs. 2% on placebo (P=0.0003). Median time to response was 15 days (on 100mg bd).

Genotype‐guided warfarin dosing versus conventional dosing strategies: a systematic review and meta‐analysis of randomized controlled trials

British Journal of Clinical Pharmacology

Genotype‐guided dosing (GGD; n=5230) reduced time‐to‐first therapeutic INR (mean 2.6 days; P<0.0001; I2 0%) and time‐to‐first stable INR (5.9 days; P<0.01; I2 94%) vs conventional dosing. GGD also increased time in therapeutic range and reduced risks of INR ≥ 4 and bleeding.

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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Tenecteplase versus Alteplase before Thrombectomy for Ischemic Stroke

New England Journal of Medicine

RCT (n=202) found tenecteplase before thrombectomy was linked to higher incidence of reperfusion (22 v. 10%, p=0.002 noninferiority; p=0.03 superiority), and better functional vs. alteplase among patients with ischaemic stroke treated within 4.5 hours after symptom onset.

Triple antithrombotic therapy after ACS and PCI in patients on chronic oral anticoagulation: update

Heart

Update describes clinical risks and benefits, provides a state-of-the-art exposition of clinical studies in the field, including recent studies of DOACs, and explores clinically oriented scenarios, and theory/practice of using combinations of anticoagulant and antiplatelet drugs.

Incident Risk Factors and Major Bleeding in Patients with Atrial Fibrillation Treated with Oral Anticoagulants: A Comparison of Baseline, Follow-up and Delta HAS-BLED Scores with an Approach Focused on Modifiable Bleeding Risk Factors

Thrombosis and Haemostasis

In atrial fibrillation patients (n=19,566) receiving warfarin, follow-up HAS-BLED i.e. 'delta HAS-BLED score' was more predictive of major bleeding compared with baseline HAS-BLED or the simple determination of 'modifiable bleeding risk factors'.

Stroke prevention in atrial fibrillation: re-defining ‘real-world data’ within the broader data universe

European Heart Journal

This review describes the strengths and weaknesses of observational and non-observational studies, and studies involving real-world data (RWD) and non-RWD, focusing on anticoagulation for atrial fibrillation.

Home versus in-patient treatment for deep vein thrombosis

Cochrane Database of Systematic Reviews

Review of 7 RCTs (n=1839) found low-quality evidence that patients treated at home with low molecular weight heparin are less likely to have VTE recurrence vs. those treated in hospital. However, data show no clear differences in major/minor bleeding, nor in mortality.

Oral antiplatelet agents – are they safe in breastfeeding?

Specialist Pharmacy Service

This updated medicines Q&A provides advice on the safety of oral antiplatelet agents (aspirin, dipyridamole, clopidogrel, prasugrel, and ticagrelor) in breastfeeding mothers.

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

Preventability of serious thromboembolic and bleeding events related to the use of oral anticoagulants: a prospective study

British Journal of Clinical Pharmacology

Analysis of data from 46 DOAC and 43 VKA patients admitted with a thrombotic or bleeding event shows that 53% of DOAC‐ and 61% of VKA‐related serious ADRs were deemed potentially preventable, with prescribing issues and inadequate monitoring the most pertinent causative factors.

US FDA grants “Breakthrough Therapy Designation” for emicizumab (Hemlibra) for hemophilia A without factor VIII inhibitors

Biospace Inc.

The designation was based on results from the Phase III HAVEN 3 clinical trial, in which patients received the drug subcutaneously. Those receiving the drug showed a reduction in treated bleeds compared to the group that did not receive prophylactic treatment.

US FDA approves fostamatinib disodium hexahydrate for thrombocytopenia in adults with chronic immune thrombocytopenia

PharmaTimes

The approval for use is in patients who have failed to respond to previous treatment. Fostamatinib is a Spleen tyrosine kinase (Syk) inhibitor, currently in phase III development in the EU.

US FDA approves Vonvendi (von Willebrand factors) for perioperative management of bleeding in adults with von Willebrand disease

PharmaTimes

The therapy was initially approved in the US for on-demand treatment and control of bleeding episodes, and is the first and only recombinant treatment for adults living with von Willebrand disease, the most common inherited bleeding disorder.

Direct oral anticoagulants versus warfarin for preventing stroke and systemic embolic events among atrial fibrillation patients with chronic kidney disease

Cochrane Database of Systematic Reviews

This review (5 studies; n=12,545) concludes that DOAC are as likely as warfarin to prevent all strokes and systemic embolic events without increasing risk of major bleeding events among AF patients with kidney impairment. The results chiefly apply to CKD stage G3 patients.

Safety and efficacy of dual vs. triple antithrombotic therapy in patients with atrial fibrillation following percutaneous coronary intervention: a systematic review and meta-analysis of randomized clinical trials

European Heart Journal

Review (4 RCTs; n=5137), found that dual antithrombotic therapy reduced TIMI major or minor bleeding by 47% vs triple therapy [4.3 vs. 9.0%; HR, 0.53) with comparable outcomes of major adverse cardiac events (10.4% vs. 10.0%; 0.85).

Anticoagulation for the initial treatment of venous thromboembolism in people with cancer

Cochrane Database of Systematic Reviews

This review (15 RCTs; n=1615) concludes LMWH likely decreases 3-month mortality compared to UFH (risk difference: 57 fewer per 1000; 95% CI 101 fewer to 17 more; moderate evidence). The choice should balance benefits and harms and consider the person's values and preferences.

Prognostic Significance of Nuisance Bleeding in Anticoagulated Patients with Atrial Fibrillation

Circulation

This analysis of registry data (n=6771) found documented minor bleeding was common (20%) but not associated with a statistically significantly increased risk of major bleeding or stroke/systemic embolism, suggesting occurrence should not lead to changes in treatment strategy.

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

Apixaban compared to heparin/vitamin K antagonist in patients with atrial fibrillation scheduled for cardioversion: the EMANATE trial

European Heart Journal

In this randomised comparison involving 1500 patients it was shown that rates of strokes, systemic emboli, deaths, and bleeds were low for both apixaban and heparin/vitamin K antagonist (eg warfarin) treated AF patients undergoing cardioversion.

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

NIHR Signal: Adding a third antiplatelet drug after a stroke increases harms but not benefits

National Institute for Health Research Signal

Expert commentary notes even with rapid implementation of secondary prevention, risk of recurrent ischaemic stroke is high with greatest risk in first 30 days, hence temptation to add antiplatelet agents, though this results in no additional benefit and increases bleeding.

Dual Antiplatelet Therapy in Transient Ischemic Attack and Minor Stroke With Different Infarction Patterns: Subgroup Analysis of CHANCE Randomized Clinical Trial

JAMA Neurology

Imaging substudy of CHANCE (n=1089) found infarction (IF) patterns can efficiently stratify risk of recurrent stroke within 3 months of non-cardioembolic TIA/minor ischaemic stroke. Patients with multiple acute IFs received most pronounced clinical benefit from dual 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

European CHMP does not recommend approval of the factor Xa inhibitor betrixaban (Dexxience), intended for the prevention of venous thromboembolism

European Medicines Agency

The CHMP considered that the main study did not satisfactorily show that its benefits outweighed its risk when used for preventing blood clots in patients admitted to hospital for recent medical illness. It was approved in the US in June 2017.

Venous thromboembolism in over 16s: reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism- guidance (NG89)

National Institute for Health and Care Excellence

This guideline aims to help healthcare professionals identify people most at risk and describes interventions that can be used to reduce the risk of venous thromboembolism (VTE).

Non-Vitamin K Antagonist Oral Anticoagulants and Risk of Serious Liver Injury

Journal of the American College of Cardiology

Analysis of Canadian administrative data (n=51,887) found current use of NOACs was not linked with increased risk of serious liver injury in patients without/with prior liver disease vs. use of vitamin K antagonists (HR:0.99;95% CI:0.68-1.45 and 0.68;0.33-1.37 respectively).

Association between Nonsteroidal Anti‐inflammatory Drugs and Atrial Fibrillation among a Middle‐aged Population: A Nationwide Population‐based Cohort

British Journal of Clinical Pharmacology

Taiwanese study (n= 57,058) reported that NSAID users had elevated risk of AF vs non‐users (adjusted OR=1.18, 95% CI: 1.14‐1.23). Users of non‐selective, and combined selective and non‐selective NSAIDs had elevated risk of AF (1.18; 1.13‐1.23 and 1.30; 1.21‐1.39, respectively).

Apixaban in patients at risk of stroke undergoing atrial fibrillation ablation

European Heart Journal

This RCT (n=633) reports primary outcome events (bleeding, stroke, or death) were observed in 6.9% of patients on apixaban, vs 7.3% of patients on vitamin K antagonists during ablation (difference −0.4%, non-inferiority P = 0.0002 based on definition used).

British Society of Haematology Guideline: management of thrombotic and haemostatic issues in paediatric malignancy

British Society for Haematology

The purpose of this guideline is to provide information and guidance on the management of venous thromboembolism (VTE) and bleeding complications of cancer and its treatment especially for children with leukaemia and other forms of cancer.

British Society of Haematology Guidelines on the spectrum of fresh frozen plasma and cryoprecipitate products: their handling and use in various patient groups in the absence of major bleeding

British Society for Haematology

This revised guideline discusses administration of fresh frozen plasma (FFP) primarily for 3 indications: prevention of bleeding, to stop bleeding (therapeutic) or for plasma exchange, suggesting many indications in patients without major bleeding are not substantiated.

The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation

European Heart Journal

This guide addresses management of non-vitamin K antagonist oral anticoagulants in various clinical situations eg how to deal with dosing errors, oral anticoagulant plasma level measurement (rare indications, precautions and potential pitfalls), management of bleeding etc.

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: Urokinase products

electronic Medicines compendium

Diluent for further dilution, previously unspecified, is now named as sodium chloride 0.9 % solution for injection. SPC now advises that after reconstitution and further dilution in glucose 5% / 10%, urokinase solution should be used immediately, due to risk of loss in activity.

Effectiveness of new antiplatelets in the prevention of recurrent myocardial infarction

Heart

Real-world study (n=1047 cases;2234 controls) found recurrent MI risk is lower with ticagrelor or prasugrel vs clopidogrel;magnitude of which was larger than observed effect in trials: OR 0.65;95% CI 0.52 -0.81 and 0.71;0.53-0.96 vs 0.84 0.77-0.9 and 0.81;0.73- 0.90, respectively.

Imaging is the only way to diagnose blood clots in pregnancy

National Institute for Health Research Signal

An expert commentary is provided on this study which concluded biomarkers, including the D-dimer test were not useful in diagnosing PE and DVT, and imaging tests are therefore required in this population.

6-month versus 12-month or longer dual antiplatelet therapy after percutaneous coronary intervention in patients with acute coronary syndrome (SMART-DATE): a randomised, open-label, non-inferiority trial

The Lancet

RCT (n=2,712) found that 6 months dual therapy was non-inferior to 12 months or longer in terms of composite risk of all cause death myocardial infarction, or stroke (absolute risk difference +0.5%, upper limit of 95% CI = 1.8% [pre-defined non-inferiority margin was 2.0%]).

Pharmacodynamic Effects of Switching From Ticagrelor to Clopidogrel in Patients With Coronary Artery Disease: Results of the SWAP (Switching Antiplatelet Therapy)-4 Study

Circulation

Pharmacodynamic study (n=80) reported that de-escalation from ticagrelor to clopidogrel therapy is associated with an increase in platelet reactivity suggestive of a drug–drug interaction. A 600mg loading dose of clopidogrel is proposed except in patients who are bleeding.

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

Association of Varicose Veins With Incident Venous Thromboembolism and Peripheral Artery Disease

Journal of the American Medical Association

Retrospective Taiwanese study (n=212 984 varicose veins [VVs];212 984 controls) found significantly increased risk of incident DVT among adults with VVs (6.55 vs 1.23 per 1000 person-years; HR 5.30; 95% CI, 5.05-5.56). Findings for PE and peripheral artery disease are less clear.

Meta-Analysis of Genotype-Guided Versus Standard Dosing of Vitamin K Antagonists

American Journal of Cardiology

Review of 20 RCTs (total n=5,980) found a greater improvement in time in therapeutic range for genotype guided vs standard treatment (difference 3.41%, p=0.01). There were also reductions in major and all bleeding events, but no difference for INR >4 or serious adverse events.

Oral Anticoagulation in Very Elderly Patients with Atrial Fibrillation - A Nationwide Cohort Study

Circulation

Taiwanese cohort study in those ≥90 years (11, 064 with AF vs 14,658 controls) found that warfarin was associated with a lower risk of stroke vs no treatment (3.83 vs 5.75% per year, HR 0.69, 95% CI 0.49 to 0.96). Warfarin was associated with a positive net clinical benefit.

Market Authorisation Application submitted in EU and USE for turoctocog alfa pegol for haemophilia

PharmaTimes

Turoctocog alfa pegol is an extended half-life factor VIII treatment currently under investigation. Data from the pathfinder clinical trial programme form the evidence base for the submission.

Emicizumab approved for use in EU for prevention of bleeding in haemophilia A

PharmaTimes

This bispecific monoclonal antibody simultaneously binds factor IXa & factor X, exerting the same function as factor VIII but not expected to be susceptible to neutralising antibodies. It has been approved for use on the basis of the HAVEN trial programme.

Anticoagulants, including non-vitamin K antagonist oral anticoagulants (NOACs): Key therapeutic topic [KTT16]

National Institute for Health and Care Excellence

This document summarises the evidence-base on anticoagulants, including non-vitamin K antagonist oral anticoagulants (NOACs). It is a key therapeutic topic which has been identified to support medicines optimisation. It is not formal NICE guidance.

Management of therapeutic anticoagulation in patients with intracerebral haemorrhage and mechanical heart valves

European Heart Journal

Analysis of 137 mechanical heart valve patients reports restarting therapeutic anticoagulation (TA) within 2 weeks was associated with increased haemorrhagic complications v no-TA (26% v 6%, P < 0.01); however, a non-significant decrease in thromboembolic complications was noted.

Antithrombotic therapy and body mass: an expert position paper of the ESC Working Group on Thrombosis

European Heart Journal

Consensus paper addresses issue of whether modified antithrombotic management strategies are required for patients at extremes of body weight. More focus is given to obesity due to higher prevalence in cardiovascular disease and complexities with pharmacology and pathophysiology.

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

Aspirin or Rivaroxaban for VTE Prophylaxis after Hip or Knee Arthroplasty

New England Journal of Medicine

RCT (n=3424 on rivaroxaban [RV] 10mg for 5 days initially) found no significant differences in symptomatic venous thromboembolism in group who continued RV or switched to aspirin (81mg daily) for additional 9 days after total knee or for 30 days after total hip arthroplasty.

Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging

New England Journal of Medicine

RCT terminated early for efficacy (n=182 in US) found endovascular thrombectomy plus standard medical therapy (SMT) resulted in better functional outcomes (FOs) vs. SMT alone with favorable shift in distribution of FOs on modified Rankin scale at 90 days (OR, 2.77; p<0.001).

A Comparison of Reduced-Dose Prasugrel and Standard-Dose Clopidogrel in Elderly Patients with Acute Coronary Syndromes Undergoing Early Percutaneous Revascularization

Circulation

This study in 1443 elderly ACS patients showed no difference in primary endpoint (composite of death, MI, stroke and re-hospitalisation for CV causes/bleeding within 1 year) between reduced-dose prasugrel and standard-dose clopidogrel (17% v 16.6% respectively; HR 1.007, P=0.955).

Antiplatelet and anticoagulant agents for secondary prevention of stroke and other thromboembolic events in people with antiphospholipid syndrome

Cochrane Database of Systematic Reviews

Review based on poor quality evidence from 5RCTs concludes that there is not enough evidence for or against NOACs or for high-intensity VKA.

Deep vein thrombosis

British Medical Journal
This clinical update discusses the initial approach to managing patients with suspected DVT, including presentation, diagnosis, complications and treatment (direct oral anticoagulants, low molecular weight heparin and warfarin, role of compression stockings).

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

Parenteral anticoagulation in ambulatory patients with cancer

Cochrane Database of Systematic Reviews

Review of 19 RCTs (n=9650) suggests heparin appears to have no effect on mortality at 12 and 24 months. Whilst it reduces symptomatic VTE, it likely increases major and minor bleeding. The decision for a patient with cancer to start heparin therapy should balance risks/benefits.

NIHR Signal: Direct acting oral anticoagulants likely to be better than warfarin for people taking them for atrial fibrillation

National Institute for Health Research Signal

An expert comment is provided of a network meta-analysis which compared 4 DOACs at various doses, warfarin and an antiplatelet agent for prevention of strokes in people with AF concluding apixaban 5mg bd was the most effective and safest intervention for several outcomes.

Less dementia with oral anticoagulation in atrial fibrillation

European Heart Journal

Analysis of data from Swedish Registry (n=444,106) reports anticoagulant treatment at baseline was associated with 29% lower risk of dementia than patients without anticoagulant treatment (incidence rate of dementia 1.14 vs. 1.78 per 100 patient years at risk, P < 0.001).

Atrial fibrillation – Updated Quality Standard [QS93]

National Institute for Health and Care Excellence

This updated quality standard has been changed to include edoxaban as an option for anticoagulation in the "rationale and definition" section; this reflects the NICE technology appraisal on edoxaban for preventing stroke and systemic embolism in people with non-valvular AF.

Current evidence of oral anticoagulant reversal: A systematic review

Thrombosis Reasearch

Review of 33 studies (4783 on vitamin K antagonist [VKA] and 529 on DOACs) supports use of prothrombin complex for VKA reversal. There are no studies on clinical efficacy of non-specific agents for DOAC reversal and inconsistent evidence for laboratory reversal.

Association of different antiplatelet therapies with mortality after primary percutaneous coronary intervention

European Journal of Heart Failure

Compared to clopidogrel (n>89,000), prasugrel was associated with lower mortality at 30 days (OR 0.87, 95% CI 0.78 to 0.97, P=0.014) and 1 year (0.89; 0.82 to 0.97, P=0.011) post PCI but ticagrelor was not.

NIHR Signal: Rivaroxaban plus aspirin may reduce heart attack and strokes in people with peripheral arterial disease (PAD), but with an added risk of bleeding

National Institute for Health Research Signal

Commentary notes the combination of low dose rivaroxaban plus aspirin could reduce risk of CV death, heart attack and stroke at the expense of a small increase in major bleeding in patients with stable PAD; a cost-effectiveness analysis would be helpful to determine net benefit.

Moving anticoagulation initiation and monitoring services into the community: evaluation of the Brighton and Hove community pharmacy service

BMC Health Services Research

The majority (98.6%) of patients attending a Community Pharmacy Anticoagulation Management Service rated it as good, very good or excellent, with 65.4% of INR readings within the target range (national target 60%) and 72.5% of time spent in therapeutic range (national target 70%).

Ischaemic stroke, haemorrhage, and mortality in older patients with chronic kidney disease newly started on anticoagulation for atrial fibrillation: a population based study from UK primary care

British Medical Journal

In patients aged ≥65 with chronic kidney disease, receipt of an anticoagulant within 60 days of AF diagnosis was associated with an increased risk of ischaemic stroke (HR 2.60; 95% CI 2.00 to 3.38) and haemorrhage (2.42; 1.44 to 4.05) but a lower risk of all-cause mortality.

Impact of anticoagulation therapy on valve haemodynamic deterioration following transcatheter aortic valve replacement

Heart

Study (n=2466) found lack of anticoagulation post-transcatheter aortic valve replacement was linked to significant increments in transvalvular gradients and greater risk of valve haemodynamic deterioration, which was not linked to major adverse clinical events in most cases.

 New Product: Enoxaparin BECAT pre-filled syringes with safety device

electronic Medicines compendium

This biosimilar enoxaparin is licensed for the treatment and prophylaxis of thromboembolism, for prevention of thrombus formation in extracorporeal circulation during haemodialysis, and treatment of acute coronary syndromes.

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