Risks and benefits of direct oral anticoagulants versus warfarin in a real world setting: cohort study in primary care

British Medical Journal

Trial (n=132 231 warfarin [WF],7744 dabigatran,37 863 rivaroxaban [RV],18 223 apixaban [AP] users) found AP to be safest drug with reduced risks of major, intracranial and GI bleeding vs. WF. RV and low dose AP were, however, linked to increased risks of all-cause mortality.

Variation in anticoagulation for atrial fibrillation between English clinical commissioning groups: an observational study

British Journal of General Practice

This study found the proportion of eligible AF patients prescribed anticoagulants improved from 65.1% in 2012/2013 to 77.9% in 2015/2016, with considerable increases in the eligible population as a result of decreased exception reporting and the use of the CHA2DS2VASc score.

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

Outcomes Associated with Apixaban Use in End-Stage Kidney Disease Patients with Atrial Fibrillation in the United States

Circulation

Retrospective cohort study (n=2351 on apixaban; 23,172 on warfarin) found apixaban use may be linked to lower risk of major bleeding vs. warfarin (HR 0.72, 95% CI 0.59-0.87; P<0.001) with standard 5mg BD dose also linked to reductions in thromboembolic and mortality risk.

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

Antithrombotic Therapy for Peripheral Artery Disease in 2018

Journal of the American Medical Association

This article, form the US perspective, reviews current evidence and makes recommendations on antithrombotic therapy in patients with or without ischaemic limb symptoms, as well as in patients with or without manifest coronary or cerebrovascular disease.

Can small volume intramuscular injections be given to patients taking oral anticoagulants?

Specialist Pharmacy Service

Q+A notes most of published studies relate to IM influenza vaccination in patients on older anticoagulants. Data are limited and some findings are contradictory. There is very little published information about the risks of adverse effects with DOACs and IM injections.

Venous thromboembolism after induced abortion: a population-based, propensity-score-matched cohort study in Canada

The Lancet Haematology

Study (n= 176,001 matched to 880,005 non-pregnant) found 42-day risk of venous thromboembolism after induced abortion is double that of matched non-pregnant woman (30.1 v. 13.5/100,000; HR 2.23, 95% CI, 1.61–3.08), but is significantly lower than after livebirth (0.16; 0.12–0.22).

Roche introduces CoaguChek Vantus system with built in Bluetooth® technology in US

Biospace Inc.

Roche says this is first self-testing device for coagulation monitoring with built in Bluetooth technology. Patients can use tablet/smartphone with compatible app to send results via wireless connectivity, enabling healthcare providers to receive patients' INR results.

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 of Studies Comparing Dual- Versus Mono-Antiplatelet Therapy Following Transcatheter Aortic Valve Implantation

American Journal of Cardiology

Analysis of 8 studies (n=2439) found dual antiplatelets (vs. mono) linked to increased risk at 30 days of all-cause mortality, major/life-threatening bleeding, and major vascular complications without decrease in ischaemic complications;at 6 months, excess bleeding risk persisted.

A clinical prediction model for cancer-associated venous thromboembolism: a development and validation study in two independent prospective cohorts

The Lancet Haematology

Data from CATS cohort (n=1423) were used to select prognostic variables for inclusion in clinical prediction model. Two in final model that were externally validated (tumour-site category/ D-dimer) predicted risk of venous thromboembolism in ambulatory patients with solid cancers.

Aspirin may be a follow-on option to prevent blood clots, starting five days after hip or knee surgery

National Institute for Health Research Signal

Expert commentary is provided for an RCT which found aspirin as effective as rivaroxaban at preventing VTE post hip or knee surgery. While there are implications for savings, the key message is that postoperative prophylaxis is the most important factor for attenuating VTE risk.

Gastrointestinal bleeding risk of selective serotonin reuptake inhibitors by level of kidney function: a population‐based cohort study

British Journal of Clinical Pharmacology

Cohort study (n=413,116) found an increasing adjusted rate difference of GI bleeding for SSRIs vs no SSRIs as kidney function deteriorated (2.0 events per 1000 person-years for no CKD vs 7.9 events per 1000 person-years for CKD stage 4/5, p-trend = 0.001).

Antithrombotic Therapy for Peripheral Artery Disease in 2018

Heart

This article reviews cardiovascular risk stratification of patients with peripheral artery disease and current standards of practice for use of antiplatelet and anticoagulant therapies.

Revised SPC: Eliquis (apixaban) 2.5 mg film-coated tablets

electronic Medicines compendium

The SPC has been amended to state that 'apixaban can be initiated or continued in NVAF patients who may require cardioversion', and to include detail on dose in relation to cardioversion. Data from the EMANATE study (conducted in patients undergoing cardioversion) has been added.

Dabigatran in patients with myocardial injury after non-cardiac surgery (MANAGE): an international, randomised, placebo-controlled trial

The Lancet

In this study (n=1,754), the incidence of the primary composite endpoint was lower in those randomised to dabigatran 110mg BD (11% vs 15% with placebo; HR 0.72; 95% CI 0.55-0.93; p=0.0115), with no significant increase in major bleeding (3% v 4%; HR 0.92; 0.55-1.53; p=0.76).

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

Periprocedural Outcomes of Direct Oral Anticoagulants vs. Warfarin in Non-Valvular Atrial Fibrillation: A Meta-analysis of Phase III Trials

Circulation

Meta-analysis of sub-analysis of RE-LY, ROCKET AF, ARISTOTLE, and ENGAGE AF trials found in short-term, safety/efficacy of DOACs and warfarin (WF) periprocedurally are not different. DOACs were linked to 38% lower risk of major bleeding vs. WF with uninterrupted anticoagulation.

Factor Xa inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in patients with atrial fibrillation

Cochrane Database of Systematic Reviews

Review of 13 RCTs (n=67,688), most of which involved apixaban, edoxaban, rivaroxaban, found treatment with factor Xa inhibitors significantly reduced number of strokes and systemic embolic events vs. warfarin with AF; the absolute effect vs. warfarin was, however, rather small.

US FDA accepts supplemental biologics license application for prophylactic and paediatric use of Coagadex® (Coagulation Factor X, Human) for treatment of hereditary factor X deficiency

Biospace Inc.

Application relates to use in children under 12 years of age and is based on data from phase 3 prospective TEN02 study in children with moderate to severe deficiency. Coagadex is currently only licensed in UK for use in children over age of 12 years.

Data from Haven III and Haven IV trials suggest efficacy of emicizumab in haemophilia patients without factor VIII inhibitors

PharmaTimes

A 96% and 97% reduction in treated bleed were found in these studies respectively vs no prophylaxis. Emicizumab is currently licensed for routine prophylaxis of bleeding episodes in patients with haemophilia A with factor VIII inhibitors.

US FDA approves avatrombopag (Doptelet) for treatment of thrombocytopenia in patients with chronic liver scheduled to undergo a medical or dental procedure

Biospace Inc.

This thrombopoietin receptor agonist has been evaluated in ADAPT-1 /ADAPT-2 trials (n=435) which reported higher proportion of patients had increased platelet (PL) counts and did not require PL transfusion/rescue therapy on day of -and up to 7 days after procedure vs. placebo.

Use of Venous Thromboembolism Prophylaxis in Hospitalized Patients

JAMA Internal Medicine

Analysis (n=44,775 in 52 Michigan hospitals) noted anticoagulant (AC) use among low-risk patients (18 584 [57.1%]) was most important contributor to excess use of VTE prophylaxis. Excess use of mechanical VTE prophylaxis was common among both low-and high risk patients.

Effectiveness and Safety of Apixaban, Dabigatran, and Rivaroxaban Versus Warfarin in Frail Patients With Nonvalvular Atrial Fibrillation

Journal of the American Heart Association

At 2 yrs, database study (n=19077) found no difference in stroke or systemic embolism (SE) with apixaban or dabigatran (HR=0.78 % 0.94) or major bleeding (0.72 & 0.87) vs warfarin. Rivaroxaban reduced stroke or SE (0.68) without altering major bleeding risk (1.07) vs warfarin.

Revised SPC: Brilique (ticagrelor) – all formulations

electronic Medicines compendium

SPC now states that delayed and decreased exposure to oral P2Y12 inhibitors, including ticagrelor (TG) and active metabolite, has been observed in patients with ACS on morphine (35% reduction in TG exposure). May apply to other opioids; clinical relevance unknown.

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

New product: Exembol (argatroban) 1 mg/mL Solution for Infusion - Ready to Use

electronic Medicines compendium

This is a new additional presentation of argatroban (other formulation is multidose 100 mg/ml concentrate that needs to be diluted), which is licensed for anticoagulation in adult patients with heparin-induced thrombocytopenia type II who require parenteral antithrombotic therapy.

Pharmacogenomic Approach to Selecting Antiplatelet Therapy in Patients With Acute Coronary Syndromes: The PHARMCLO Trial

Journal of the American College of Cardiology

Study (n=888) which was prematurely stopped, suggests personalised approach to selecting antiplatelet may reduce ischaemic and bleeding events [primary endpoint occurred in 71 (15.9%) in pharmacogenomic and 114 (25.9%) in standard-of-care arm; HR 0.58;95% CI; 0.43-0.78;p <0.001].

Cerebral microbleeds and intracranial haemorrhage risk in patients anticoagulated for atrial fibrillation after acute ischaemic stroke or transient ischaemic attack (CROMIS-2): a multicentre observational cohort study

The Lancet Neurology

Study (n=1447) found that in patients with AF anticoagulated after recent ischaemic stroke /TIA, cerebral microbleed presence is linked to symptomatic intracranial haemorrhage risk (HR 3.67,95% CI 1.27–10.60 vs.absence microbleeds) and could help inform anticoagulation decisions.

Prevention of cardiovascular events in Asian patients with ischaemic stroke at high risk of cerebral haemorrhage (PICASSO): a multicentre, randomised controlled trial

The Lancet Neurology

RCT (n=1534 from 3 Asian countries) reported cilostazol was non-inferior to aspirin for the prevention of cardiovascular events (HR 0.80, 95% CI 0.57–1.11; non-inferiority p=0.0077); but did not reduce the risk of haemorrhagic stroke(HR 0.51, 97.5% CI 0.20–1.27).

Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA

New England Journal of Medicine

RCT (n=4,881) found that clopidogrel plus aspirin was associated with a lower risk of major ischaemic events vs aspirin alone at 90 days (5% vs 6.5%, HR 0.75, p=0.02) but an increased risk of major haemorrhage (0.9% vs 0.4%, 2.32, p=0.02).

MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset

New England Journal of Medicine

RCT was stopped early owing to cessation of funding (n=503 from 800 anticipated). Favourable outcome (score of 0 or 1 on the modified Rankin scale of neurologic disability) was reported in 53.3% given altepase vs 41.8% for placebo (adjusted OR 1.61, p=0.02).

Rivaroxaban for Stroke Prevention after Embolic Stroke of Undetermined Source

New England Journal of Medicine

RCT (n=7,213) was terminated early due to lack of benefit in stroke risk and worse bleeding outcomes for rivaroxaban vs aspirin (annualised major bleeding with rivaroxaban was 1.8% vs 0.7% for aspirin, HR 2.72, p<0.001).

Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2): an international randomised, placebo-controlled, phase 3 superiority trial

The Lancet

RCT (n=2.325) found no difference in functional status at day 90 (primary outcome) for tranexamic acid vs placebo (adjusted OR 0.88, 95% CI 0.76 to 1.03), although there were fewer deaths by day 7 with tranexamic acid (9% vs 11% 0.73, 0.53 to 0.99).

Management of Bleeding in Patients Taking Oral Anticoagulants

Journal of the American Medical Association

This US decision pathway from the American College of Cardiology details management of patients who experience either life-threatening bleeding or major bleeding at a critical site. Ceasing the anticoagulant, supportive measures and reversal agents are the major strategies.

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

Comparison of an Oral Factor Xa Inhibitor With Low Molecular Weight Heparin in Patients With Cancer With Venous Thromboembolism: Results of a Randomized Trial (SELECT-D)

Journal of Clinical Oncology

RCT (n=203) found that rivaroxaban was associated with relatively low venous thromboembolism VTE recurrence vs dalteparin (6 month recurrence rate 11% vs 4%; HR 0.43; 95% CI, 0.19 to 0.99). Corresponding 6 months rates of clinically relevant non-major bleeding were 4% vs 13%.

Appropriateness of oral anticoagulant therapy prescription and its associated factors in hospitalized older people with atrial fibrillation

British Journal of Clinical Pharmacology

Of 328 Italian patients, 143 were inappropriately prescribed with oral anticoagulants (OACs), 88 of which were under prescribed or prescribed with an inappropriate drug. Among 55 of 221 patients prescribed OACs, dosing errors were the most frequent cause of inappropriate use.

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

European Journal of Hospital Pharmacy

This retrospective observational study identified 37 hospitalisation episodes for DOAC-induced bleeding in 32 patients (15 rivaroxaban, 9 apixaban and 8 dabigatran; incidence rate 3.44 [95% CI 2.35 to 4.86] per 100 person-years), most commonly gastrointestinal (27 cases, 73.0%).

Stability of repackaged dabigatran etexilate capsules in dose administration aids

European Journal of Hospital Pharmacy

Repackaged capsules stored in the refrigerator for 28 days had a drug content of 98.2% and dissolution was not significantly affected (p=0.132). If repackaging of Pradaxa capsules is required, storage under refrigerated conditions ensures quality for 28 days.

Periprocedural management of patients receiving novel oral anticoagulants

European Journal of Hospital Pharmacy

This review of guidelines and evidence for the use of non-vitamin K oral antagonists highlights discrepancies between US and European guidelines. However, consensus about postoperative resumption is clear: 24 and 48–72hours, after low- and high-risk bleeding surgery, respectively.

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

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:

http://www.evidence.nhs.uk/about-evidence-services/content-and-sources/medicines-information/new-medicines-awareness-services

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