Direct-acting oral anticoagulants (DOACs): increased risk of recurrent thrombotic events in patients with antiphospholipid syndrome

Medicines and Healthcare products Regulatory Agency

MHRA advises that DOACs are not recommended in patients with antiphospholipid syndrome, particularly high-risk patients (those who test positive for all 3 antiphospholipid tests — lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2 glycoprotein I antibodies).

 

Safety and Efficacy of Antithrombotic Strategies in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention: A Network Meta-analysis of Randomized Controlled Trials

JAMA Cardiology

Review of 4 RCTs (n = 10 026) found DOAC plus P2Y12 inhibitor was linked to less bleeding vs. vitamin K antagonists + dual antiplatelets; strategies omitting aspirin caused less bleeding without significant difference in major adverse CV event vs. strategies including aspirin.

 

Warfarin dose requirement in patients having severe thrombosis or thrombophilia

British Journal of Clinical Pharmacology

Study (n=50) found that currently the most used pharmacogenetics dosing algorithms (IWPC and Gage) underestimate the warfarin dose required for effective anticoagulation in thrombogenic young (age <50 years) patients, particularly those who are at the highest thrombotic risk.

 

Revised SPC: Brilique (ticagrelor) tablets

electronic Medicines compendium

Thrombotic thrombocytopenic purpura has been added as a potential adverse effect of treatment (frequency unknown).

 

Ticagrelor Versus Clopidogrel in Patients With STEMI Treated With Fibrinolysis: TREAT Trial

Journal of the American College of Cardiology

Open-label RCT (n=3,799) found that ticagrelor did not significantly reduce the frequency of CV events vs clopidogrel when used after fibrinolytic therapy (combined outcome of CV mortality, MI or stroke = 6.7% vs 7.3% for ticagrelor vs clopidogrel, HR 0.93, 95% CI 0.73-1.18).

 

Oral anticoagulants in atrial fibrillation with valvular heart disease and bioprosthetic heart valves

European Heart Journal

Network meta-analysis (n=13,574) found that NOACs are superior, vs warfarin, in reducing stroke or systemic embolisation, MI and intracranial haemorrhage in AF and valvular heart disease. Analysis of 280 patients with AF and bioprosthetic heart valve showed similar outcomes.

 

 

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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Revised SPCs: Eliquis (apixaban) film-coated tablets- all strengths

electronic Medicines compendium

SPCs highlight DOACs are not recommended for patients with history of thrombosis diagnosed with antiphospholipid syndrome, in particular, triple positive patients, where use of DOACs could be associated with increased rates of recurrent thrombotic events vs. vitamin K antagonists.

 

 

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

Rivaroxaban With or Without Aspirin in Patients with Heart Failure and Chronic Coronary or Peripheral Artery Disease: The COMPASS Trial

Circulation

Analysis of data from the COMPASS RCT (n=27,395) found that in heart failure patients specifically (5,902 patients), rivaroxaban plus aspirin was similarly superior to aspirin alone as per the overall trial population.

 

Evaluation of the Incidence of New-Onset Atrial Fibrillation After Aortic Valve Replacement

JAMA Internal Medicine

This population-based study reports new-onset AF was present in 50% of hospitalisations for transcatheter aortic valve implantation and aortic valve replacement. It advises shared patient-doctor decision making regarding potential need for anticoagulation after these procedures.

 

 

 

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

Efficacy and safety of direct oral factor Xa inhibitors compared with warfarin in patients with morbid obesity: a single-centre, retrospective analysis of chart data

The Lancet Haematology

Retrospective analysis of data evaluating safety and efficacy of direct oral anticoagulants and warfarin in 795 morbidly obese patients (BMI>40kg/m2) suggests concludes similar efficacy and safety of apixaban and rivaroxaban, compared to warfarin in patients with AF and VTE.

 

Randomized trial of ticagrelor vs. aspirin in patients after coronary artery bypass grafting: the TiCAB trial

European Heart Journal

Study (n=1,859) showed no significant difference in major cardiovascular events occurring in 9.7% ticagrelor patients vs. 8.2% aspirin patients [HR 1.19; 95% CI 0.87–1.62; p= 0.28]), or in major bleeding. RCT was terminated early & underpowered however due to recruitment issues.

 

 

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

 

Treatment and Long-Term Clinical Outcomes of Incidental Pulmonary Embolism in Patients With Cancer: An International Prospective Cohort Study

Journal of Clinical Oncology

Observational study of 695 patients with cancer and incidental diagnosis of PE suggests despite anticoagulant therapy, recurrent VTE occurred in 6% of patients, strengthening current guideline advice to treat incidental PE as symptomatic PE for at least 3 to 6 months.

 

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

The Lancet

RCT (n=537) reports 4% of participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage vs 9% allocated to avoid antiplatelet therapy (HR 0.51, p=0.060), whilst 7% and 9% of patients respectively experienced major haemorrhagic events (HR 0.71, p=0.27).

 

Defining High Bleeding Risk in Patients Undergoing Percutaneous Coronary Intervention: A Consensus Document From the Academic Research Consortium for High Bleeding Risk

Circulation

The consensus document represents the first pragmatic approach to a consistent definition of high bleeding risk in clinical trials evaluating the safety and effectiveness of devices and drug regimens for patients undergoing percutaneous coronary intervention.

 

Extending thrombolysis to 4·5–9 h and wake-up stroke using perfusion imaging: a systematic review and meta-analysis of individual patient data

The Lancet

Review of 3 RCTs (n=414) found that more patients given alteplase achieved excellent functional outcomes at 3 months vs placebo (36% vs 29%, OR 1.86, p=0.011). Intracerebral haemorrhage was more common with alteplase (5% vs 1%, OR 9.7, p=0.031).

 

Revised SPC@ Pradaxa (dabigatran etexilate mesilate) hard capsules (all strengths)

electronic Medicines compendium

Section 4.4 has been updated to include a warning regarding thromboembolic risk in patients with antiphospholipid syndrome.

 

Tofacitinib (Xeljanz▼): restriction of 10 mg twice-daily dose in patients at high risk of pulmonary embolism while safety review is ongoing

Medicines and Healthcare products Regulatory Agency

Following an increased risk of pulmonary embolism and overall mortality with tofacitinib 10 mg twice-daily in the study A3921133 rheumatoid arthritis study, a safety review has started and this dose (authorised for ulcerative colitis) is contraindicated in patients at high risk of VTE.

 

Early discharge and home treatment of patients with low-risk pulmonary embolism with the oral factor Xa inhibitor rivaroxaban: an international multicentre single-arm clinical trial

European Heart Journal

Study suggests that early discharge with continuation of rivaroxaban at home is safe and effective in certain low-risk patients with acute PE. Rate of symptomatic recurrent VTE or PE-related death within 3 months (primary outcome) occurred in 3 of 525 patients (0.6%; P <0.0001).

 

The rise and fall of aspirin in the primary prevention of cardiovascular disease

The Lancet

This narrative review discusses the role of aspirin in primary prevention of cardiovascular disease, contextualising data from historical and contemporary trials.

 

 

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

Dabigatran for Prevention of Stroke after Embolic Stroke of Undetermined Source

New England Journal of Medicine

RCT (n=5390) found that dabigatran was not superior to aspirin in preventing recurrent stroke, which occurred in 6.6% (4.1%/year) and 7.7% (4.8%/year), of patients, respectively. Incidence of major bleeding was not significantly greater in dabigatran group (1.7 vs. 1.4%).

 

Frequency of Intracranial Hemorrhage With Low-Dose Aspirin in Individuals Without Symptomatic Cardiovascular Disease: A Systematic Review and Meta-analysis

JAMA Neurology

Review of 13 RCTs (n=134,446) reports low-dose aspirin use among individuals without symptomatic cardiovascular disease (primary prevention) was associated with an increased risk of any intracranial bleeding especially in Asians, or people with a low body mass index.

 

Antifibrinolytic therapy for preventing oral bleeding in patients with haemophilia or Von Willebrand disease undergoing minor oral surgery or dental extractions

Cochrane Database of Systematic Reviews

Review found 2 RCTs of 59 haemophiliacs only and reports beneficial effect of systemically administered tranexamic acid & epsilon aminocaproic acid in preventing postoperative bleeding. Definite efficacy in oral or dental procedures however is uncertain, due to limited evidence.

 

Less dementia and stroke in low-risk patients with atrial fibrillation taking oral anticoagulation

European Heart Journal

Study (n=91,254 with baseline CHA2DS2-VASc score ≤ 1) reports treatment with oral anticoagulation was associated with lower risk of dementia (subhazard ratio 0.6, 95% CI 0.48–0.81) in people aged >65 years; but the risk: benefit profile in <60 years is not so favourable.

 

Fragmin (dalteparin sodium) approved by FDA as first anticoagulant for children

PharmaTimes

The FDA has approved use in paediatric patients' ≥ 1 month of age to reduce recurrence of symptomatic venous thromboembolism. Approval was based on a single trial of 38 children with symptomatic deep vein thrombosis and pulmonary embolism treated with Fragmin for up to 3 months.

 

 

 

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

 

 

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

Spontaneous haemorrhage on apixaban masquerading as obstructive cholangitis after heart surgery

European Heart Journal

This case was a 73-year-old with a presentation of obstructive cholangitis, likely secondary to migration of blood into the common bile duct as a complication of apixaban (2.5 mg 2×/day) 16 days post coronary artery bypass grafting.

 

Meta-Analysis of Direct-Acting Oral Anticoagulants Compared With Warfarin in Patients >75 Years of Age

American Journal of Cardiology

Review (5 studies, n=28,135) reports DOACs have superior efficacy compared to warfarin in reducing stroke or systemic embolisation (HR 0.76, 95% CI 0.67 to 0.86, p <0.01). Apixaban appeared to have the best benefit vs risk profile in this population.

 

Thrombolysis Guided by Perfusion Imaging up to 9 Hours after Onset of Stroke

New England Journal of Medicine

RCT (n=225) found use of alteplase between 4.5 and 9.0 hours after stroke onset resulted in higher proportion of patients with no/minor neurologic deficits vs placebo (35.4 vs.29.5%;risk ratio, 1.44; 95% CI, 1.01 to 2.06; p=0.04) but more cases of symptomatic cerebral haemorrhage.

 

 

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

Stroke and transient ischaemic attack in over 16s: diagnosis and initial management – guidance (NG128)

National Institute for Health and Care Excellence

This guideline covers interventions in the acute stage of a stroke or transient ischaemic attack (TIA). It offers the best clinical advice on the diagnosis and acute management of stroke and TIA in the 48 hours after onset of symptoms.

 

Outpatient versus inpatient treatment for acute pulmonary embolism

Cochrane Database of Systematic Reviews

Low‐quality evidence (2 RCTs; n= 451) suggests that there is no clear difference between the interventions in overall mortality, bleeding and recurrence of pulmonary embolism.

 

Optimal Timing of P2Y12 Inhibitor Loading in Patients Undergoing PCI: A Meta-Analysis

Thrombosis and Haemostasis

Review of 23 studies (n=60,907) reported that early P2Y12 inhibitor loading (> 2 hours pre-PCI) was associated with better outcomes vs versus late (< 2 hours pre-PCI or post-PCI; RRR; 22% for MACE, 30% for MI, 25% for death; all p<0.001), without an impact on major bleeding.

 

Risk for Major Hemorrhages in Patients Receiving Clopidogrel and Aspirin Compared With Aspirin Alone After Transient Ischemic Attack or Minor Ischemic Stroke: A Secondary Analysis of the POINT Randomized Clinical Trial

JAMA Neurology

Secondary analysis of POINT RCT (n= 4881) reported a low risk of major hemorrhages in patients receiving either clopidogrel plus aspirin or aspirin alone (0.9% vs 0.2%; HR, 3.57; P = 0.003; NNH, 159). However, risk was still increased with dual therapy vs aspirin monotherapy.

 

Comparative Risk of Venous Thromboembolism in Rheumatoid Arthritis Patients Receiving Tofacitinib Versus Those Receiving Tumor Necrosis Factor Inhibitors: An Observational Cohort Study

Arthritis & Rheumatology

Review of 2 databases (n=50,865) found that occurrence of venous thromboembolism when initiating treatment with tofacitinib or a TNF inhibitor was infrequent (<1 per 100 person‐years), with no statistically significant difference in risk between the two treatments.

 

Combination Antiplatelet and Oral Anticoagulant Therapy in Patients With Coronary and Peripheral Artery Disease

Circulation

This review discusses developments in the roles of platelets and coagulation factors in atherothrombosis and addresses the rationale and clinical evidence for combining antiplatelet and oral anticoagulant therapy in patients with coronary and peripheral artery disease.

 

Drug-eluting or bare-metal stents for percutaneous coronary intervention: a systematic review and individual patient data meta-analysis of randomised clinical trials

The Lancet

Analysis (20 RCTs;n=26,616) found risk of primary outcome was reduced with new-generation drug-eluting vs. bare-metal stents (HR 0.84, 95% CI 0.78–0.90,p<0·001) due to reduced risk of MI (HR 0·79,0·71–0·88;p<0.001) and possible slight but non-significant cardiac mortality benefit.

 

Individual Treatment Effect Estimation of 2 Doses of Dabigatran on Stroke and Major Bleeding in Atrial Fibrillation: Results from the RE-LY Trial

Circulation

Paper describes the derivation and validation of a prediction model for ischaemic stroke/ systemic embolism (SE) and major bleeding in patients with AF from the 3 treatment arms of the RE-LY trial (n=11,955 in derivation cohort, n=6,158 in validation cohort).

 

Atrial fibrillation type and renal dysfunction as important predictors of left atrial thrombus

Heart

In a real-world population of patients with AF, most on oral anticoagulation, left atrial appendage (LAA) thrombus was found in ~6%. Two variables not included in CHA2DS2-VASc score (AF type and renal dysfunction) proved strong, independent predictors of LAA thrombus.

 

Perception of the Risk of Stroke and the Risks and Benefits of Oral Anticoagulation for Stroke Prevention in Patients With Atrial Fibrillation: A Cross-Sectional Study

Mayo Clinic Proceedings

Study of 227 patients with mean CHA2DS2-VASc score 4.3, and HAS-BLED score 2.3, found negligible correlation between patient perceived and estimated risk of stroke (r=0.07; p=0.32), and bleeding (r=0.16; p=0.02). Most patients overestimated their risks of stroke 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

 

 

Association of Rivaroxaban With Thromboembolic Events in Patients With Heart Failure, Coronary Disease, and Sinus Rhythm: A Post Hoc Analysis of the COMMANDER HF Trial

JAMA Cardiology

Analysis (n=5022) found over median follow-up of 19.6months, fewer patients on rivaroxaban (vs placebo) had thromboembolic event (TE) including sudden/unwitnessed deaths (SWD; 13.1 vs 15.5%; HR 0.83; 95% CI, 0.72-0.96; p=0 .01). When SWD were excluded, results on TEs were similar.

 

Thromboembolism After Shoulder Arthoplasty and Arthroscopy

Journal of the American Academy of Orthopaedic Surgeons

Review notes that symptomatic VTE after shoulder surgery is an apparently rare but serious event; risk is higher after shoulder arthroplasty than arthroscopy. Asymptomatic VTE is more common. Prevention strategies should balance the risks of VTE with the risks of treatment.

 

Prolonged thromboprophylaxis with low molecular weight heparin for abdominal or pelvic surgery

Cochrane Database of Systematic Reviews

Review of 7 RCTs (n=1,728) found that prolonged thromboprophylaxis significantly reduces the risk of VTE vs thromboprophylaxis during hospital admittance only (5.3% vs 13.2%, OR 0.38, 95% CI 0.26-0.54), without increasing bleeding complications or mortality.

 

Optimal Duration of Aspirin Plus Clopidogrel After Ischemic Stroke or Transient Ischemic Attack: A Systematic Review and Meta-Analysis

Stroke

Review of 10 RCTs (n=15,434) comparing aspirin vs clopidogrel (A+C) to aspirin alone found that short term (≤1 month) & intermediate term A+C (≤3 month) reduced the risk of recurrent stroke and major cardiovascular events, but long term A+C was not associated with benefit.

 

Thromboembolic and haemorrhagic events in patients with atrial fibrillation: a prospective cohort study in UK primary and secondary care

British Journal of General Practice

Study (n=4.943) found antiplatelets were linked to a higher risk of stroke or TIA vs vitamin K antagonists (VKAs) (HR 1.51, 95% CI 1.09-2.09) as well as to an increased risk of GI haemorrhage (1.79, 1.01-3.18). The risk was similar for those on direct oral anticoagulants or VKAs.

 

 

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: FibCLOT (human fibrinogen) injection/infusion

electronic Medicines compendium

SPC has now been updated to detail the licence extension for paediatric use.

 

Anticoagulation therapy in heart failure and sinus rhythm: a systematic review and meta-analysis

Heart

Analysis of 5 trials found anticoagulation (AC) reduced rate of non-fatal stroke (RR 0.63, 95% CI, 0.49-0.81, p=0.001) but increased major haemorrhage (1.88; 1.49-2.38, p=0.001). AC did not reduce all-cause mortality, heart failure (re)hospitalisation or non-fatal MI, vs. control.

 

Recurrent Stroke With Rivaroxaban Compared With Aspirin According to Predictors of Atrial Fibrillation: Secondary Analysis of the NAVIGATE ESUS Randomized Clinical Trial

JAMA Neurology

RCT (n=7112) found HAVOC score, left atrial diameter (LAD), and premature atrial contraction frequency predicted subsequent clinical AF. Among subgroup with LAD >4.6 cm (9% overall population), risk of ischaemic stroke was lower in rivaroxaban vs. aspirin group (1.7 vs 6.5%/year).

 

Effectively Initiating and Maintaining Anticoagulation in Patients With Atrial Fibrillation: Lessons Learned From Research and Practice

Circulation

With availability of DOACs, authors have seen large increases in anticoagulation (AC) rates, but considerable gaps in guideline adherence remain among high-risk patients. Article shares practical strategies to address common barriers to initiating/maintaining AC in this group.

 

Oral anticoagulation among atrial fibrillation patients with anaemia: an observational cohort study

European Heart Journal

Observational cohort-study of 18,734 anaemic AF patients suggests treatment with oral anticoagulants increased rate of major bleeding and reduced time in therapeutic range with no reduction in risk of stroke/thromboembolism particularly among patients with moderate/severe anaemia.

 

Risk factors for thromboembolic and bleeding events in anticoagulated patients with atrial fibrillation: the prospective, multicentre observational PREvention oF thromboembolic events - European Registry in Atrial Fibrillation (PREFER in AF)

BMJ Open

Study of 5310 pts receiving a VKA and 3156 pts receiving a NOAC found that abnormal liver function, prior stroke or TIA, labile INR, therapy with antiplatelet or NSAIDs, heart failure and age ≥75 yrs were independently associated with thromboembolic and major bleeding events.

 

Direct oral anticoagulation and mortality in moderate to high-risk atrial fibrillation

Heart

Retrospective analysis of patients (n=11,314) with non-valvular atrial fibrillation reports DOAC therapy was associated with a significantly lower risk of death compared with no oral anticoagulation: 7.6% vs 11.1% per year respectively (HR=0.69, p<0.001).

 

 

 

The above records have been identified by UKMi and feature in the NICE Medicines Awareness Service. Further details on this service can be found at:

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

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