In this issue: > Uninterrupted dabigatran vs. warfarin for AF ablation

> CIEDs for detecting and treating subclinical AF

> Seasonal trends in AF episodes and physical activity

> Choosing oral anticoagulation for stroke prevention in nonvalvular AF

> Ischaemic/haemorrhagic stroke with NOACs and warfarin in AF

> Cardioversion and quality of life/natural history of AF

> Non-major bleeding with apixaban vs. warfarin in AF

> US experience of LAA closure for stroke prevention in AF

> Causes of death in anticoagulated AF

> Bariatric surgery reduces new-onset AF risk

www.researchreview.com.au a RESEARCH REVIEW publication

1

Issue 36 - 2017Making Education Easy

AF = atrial fibrillation; CIED = cardiovascular implantable electronic devices;HR = hazard ratio; INR = international normalised ratio;LAA = left atrial appendage; NOAC = nonvitamin K oral anticoagulant;VKA = vitamin K antagonist.

Abbreviations used in this issue:

Welcome to issue 36 of Atrial Fibrillation Research Review.Research reporting fewer bleeding complications with uninterrupted dabigatran than with uninterrupted warfarin in patients undergoing AF ablation begins this issue. There is also a summary table to help with choosing oral anticoagulation for stroke prevention in nonvalvular AF, adapted from the two parts of an excellent consensus document. We have also included experiences from the US on LAA closure for preventing stroke in AF since the procedure was approved by the FDA in 2015. The final paper for this issue reports a reduced risk of new-onset AF in previously obese patients who have lost bodyweight following bariatric surgery.

Thank you for your feedback and suggestions – please keep them coming.

Kind Regards,

Dr Andrei Catanchinandrei.catanchin@researchreview.com.au

Uninterrupted dabigatran versus warfarin for ablation in atrial fibrillationAuthors: Calkins H et al., for the RE-CIRCUIT Investigators

Summary: Patients scheduled for catheter ablation of paroxysmal or persistent AF (n=704) were randomised to receive dabigatran 150mg twice daily or warfarin with a target INR of 2.0–3.0; 635 participants underwent ablation after 4–8 weeks of uninterrupted anticoagulation, which was continued for 8 weeks postablation. Compared with warfarin, dabigatran was associated with a lower incidence of major bleeding events during and up to 8 weeks postablation (primary endpoint; 1.6% vs. 6.9% [p<0.001]), fewer periprocedural pericardial tamponades, fewer groin haematomas and a similar incidence of minor bleeding events. One warfarin recipient experienced a thromboembolic event.

Comment: This important study strongly supports the periprocedural anticoagulation strategy some of us have been employing for some time (e.g. since Praxbind was released); AF ablation with uninterrupted Pradaxa. This approach could easily be applied to less invasive procedures (e.g. ablation for atrial flutter).

Reference: N Engl J Med; Published online March 19, 2017Abstract

The role of cardiovascular implantable electronic devices in the detection and treatment of subclinical atrial fibrillationAuthors: Hess PL et al.

Summary: These authors noted that most studies to date have explored the consequences of subclinical AF using CIEDs (cardiovascular implantable electronic devices) (CIEDs); however, three trials are to assess the time to a first AF diagnosis in patients receiving a CIED for AF detection. Estimated HRs for stroke, which are currently limited to patients with a prior CIED, vary between 0.87 and 9.40. Stroke risk pathogenesis may include proximately causal factors, upstream risk activators and risk markers. Although subclinical AF treatment may be a useful stroke prevention strategy, there is no direct evidence of benefit from oral anticoagulation. Two ongoing trials are assessing the risks and benefits of NOACs among participants with a previously implanted CIED who are at high stroke risk, but who have not had a prior diagnosis of clinical AF. If a clinical benefit is proven, then further research will be required to evaluate the cost effectiveness of screening for and the treatment of subclinical AF.

Comment: This review highlights an important current issue as we see increasingly more AF detected through various means – not only pacemakers/ICDs and loop recorders, but also the explosion of ‘wearable technology’ that can already (and will be increasingly able to) detect AF. What we do with this information remains to be determined.

Reference: JAMA Cardiol 2017;2(3):324–31Abstract

Atrial FibrillationResearch ReviewTM

@ CardioreviewsVisit https://twitter.com/cardioreviews

Follow RESEARCH REVIEW Australia on Twitter now

Claim CPD/CME points Click here for more info.

Click here to subscribe free and update your subscription to Research Review RESEARCH REVIEW – The Australian Perspective Since 2007

www.researchreview.com.au a RESEARCH REVIEW publication

2

Atrial Fibrillation Research ReviewTM

Comment: This fascinating study correlates daily physical activity and daily AF burden with a clear seasonal variation (less activity and more AF in winter, cyclical over 3.5 years) in almost 1000 patients, average age 68 years, with cardiac devices. While it’s possible that AF led to reduced activity, this wasn’t reflected in hospitalisation data and it’s more likely the reverse is true, although direct causality cannot be inferred from this analysis.

Reference: Int J Cardiol 2017;234:48–52Abstract

Seasonal trends in atrial fibrillation episodes and physical activity collected daily with a remote monitoring system for cardiac implantable electronic devicesAuthors: Censi F et al.

Summary: Remotely transmitted AF and daily physical activity monitoring data were analysed for 988 HomeGuide trial participants implanted with a pacemaker or implantable defibrillator. Seasonal trends were seen for both physical activity and AF incidence with an inverse correlation. A first-order autoregressive model revealed a regression coefficient of daily activity to AF incidence of –0.64 (p<0.0001); the cross-correlation coefficient reached its maximum values at ±180 day lags. Compared with summer months, winter months were associated with a 14.4% greater AF incidence and 14.7% less physical activity (p<0.0001 for both). A power spectral analysis showed weekly periodicity in physical activity, but not AF incidence, that corresponded to rest during festivities.

Summary table: First choice Second choice Notes

Stable vascular disease NOAC monotherapy NOAC plus aspirin No specific NOAC preference

Percutaneous coronary intervention/stents

Low-dose NOAC recommended during concurrent anti platelet therapy

Dabigatran has good evidence for the low dose, further data are awaited for the other NOACs

Cardioversion Warfarin standard of care “NOACs are safe and effective alternatives, with practical advantages...” NOACs likely equivalent

Catheter ablation Uninterrupted warfarin standard of care Uninterrupted NOAC RECIRCUIT had not been released at the time of writing; warfarin and dabigatran are reversible

Valvular AF (mechanical valves, moderate–severe mitral stenosis) Warfarin standard of care

Other valve disease Apixaban/rivaroxaban Dabigatran

Warfarin with time in therapeutic range >70% Warfarin continuation is reasonable Change to NOAC No specific NOAC preference

CHA2DS2VASc score 1 (2 in females) Consider dabigatran/apixaban

Single episode AF Treat as for recurrent AF May wait until AF recurs in borderline cases No specific NOAC preference

Verapamil Apixaban/rivaroxaban Dabigatran

Previous stroke NOAC Warfarin

Acute stroke on anticoagulation Measure anticoagulation intensity and consider thrombolysis Catheter thrombectomy

After stroke/transient ischaemic attack Anticoagulant after exclude haemorrhage ‘1-3-6-12 rule’

High risk of gastrointestinal bleeding Apixaban 5mg twice daily or dabigatran 110mg twice daily

Dabigatran 150mg twice daily or rivaroxaban 20mg Avoid concurrent antiplatelet use

Creatinine clearance 30–50 mL/min Apixaban 5/2.5mg twice daily or rivaroxaban 15mg Dabigatran 110mg twice daily

Haemodialysis No anticoagulation NOACs not recommended

Age >75 years Apixaban Dabigatran 110mg twice daily or rivaroxaban

Hypertension Any NOAC No specific NOAC preference

Adherence issues Probably NOAC; see paper No specific NOAC preference

Choosing a particular oral anticoagulant and dose for stroke prevention in individual patients with non-valvular atrial fibrillation: parts 1 & 2Authors: Diener H-C et al.

Summary/comment: This excellent consensus document (in two parts) suggests answers to the frequently posed question ‘which NOAC/dose is best for my patient?’ and merits further reading.

Reference: Eur Heart J 2017;38(12):852–9 & 860–8Abstract (part 1); Abstract (part 2)

PBS codes: Non-valvular atrial fibrillation – 4269. Other PBS codes differ – please refer to PBS Schedule.

Before prescribing, please review full Product Information available from Bristol-Myers Squibb Australia Pty Ltd by calling 1800 067 567.MINIMUM PRODUCT INFORMATION ELIQUIS® (apixaban) 2.5 mg and 5 mg tablets. Indications: For use in adult patients for VTE prevention after elective total hip or total knee replacement surgery; stroke and systemic embolism prevention with non-valvular atrial fibrillation (NVAF) with at least one additional factor for stroke; treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE); prevention of recurrent DVT and PE. Contraindications: Hypersensitivity to apixaban or tablet excipients; clinically significant active bleeding (intracranial, GI); impairment of haemostasis; hepatic disease associated with coagulopathy and clinically relevant bleeding risk, severe hepatic impairment (Child-Pugh C); severe renal impairment CrCl < 25 mL/min; organ lesion or conditions at risk of clinically significant major bleeding; strong inhibitors of both CYP3A4 and P-gp, concomitant anticoagulant treatments. See PI for details. Precautions: Haemorrhage risk: existing conditions with increased bleeding risk; fall in haemoglobin or blood pressure – search for bleeding site; discontinue if severe haemorrhage or complications; consider treatment. Increased risk of thrombotic events after premature discontinuation when transitioning to warfarin (consider coverage with another anticoagulant); valvular heart disease; active cancer; acute pulmonary embolism in haemodynamically unstable patients or patients who require thrombolysis or pulmonary embolectomy; patients with provoked VTE; ischaemic stroke; renal or hepatic impairment; elevated liver enzymes or bilirubin; strong inducers of both CYP3A4 and P-gp; concomitant NSAIDs; other anti-platelets or antithrombotic agents not recommended; spinal/epidural anaesthesia or puncture; indwelling catheters; neuraxial blockade; hip fracture surgery; pregnancy; lactation; children; elderly patients on concomitant acetylsalicylic acid; effects on clotting tests. See PI for details. Interactions with other Medicines: inducers and inhibitors of both CYP3A4 and P-gp. See PI for details. Adverse Effects: Most common: anaemia, haemorrhage (including eye, GI, rectal, gingival), haematoma, haematuria, epistaxis, contusion, nausea, menorrhagia. Others include: thrombocytopenia, hypotension, haemorrhage: intra-abdominal, haemorrhoidal, mouth, vaginal, urogenital, operative, vessel/catheter/incision site, post-procedural bleeding, haematochezia, liver enzymes increased or abnormal, bilirubin increased, wound secretion, haemoptysis, hypersensitivity. See PI for details. Dosage and Administration: VTE prevention: 2.5 mg twice daily. Start 12 to 24 hours after surgery. Take for 32-38 days in hip replacement and 10-14 days for knee replacement. NVAF: 5 mg twice daily; 2.5 mg twice daily in patients with at least two of the following characteristics: ≥ 80 yrs; ≤ 60 kg; serum creatinine ≥ 133 µmol/L. DVT/PE treatment: 10 mg twice daily for 7 days, followed by 5 mg twice daily. Prevention of recurrent DVT/PE: 2.5 mg twice daily after at least 6 months of treatment for DVT/PE. See PI for details. V11115. Bristol-Myers Squibb Australia Pty Ltd. ABN 33 004 333 322. Level 2, 4 Nexus Court, Mulgrave VIC 3170 Australia. Pfizer Australia Pty Ltd. 38–42 Wharf Road, West Ryde NSW 2114 Australia. ®Registered trademark.References: 1. ELIQUIS approved Product Information. 2. Granger CB et al. N Engl J Med 2011; 365: 981–992. 3. Agnelli G et al. N Engl J Med 2013; 369: 799–808. McCann Health 10707780. 432AU1700380-01. PP-ELI-AUS-0430. April 2017.

† In adult patients with NVAF and at least one additional risk factor for stroke1

‡In adult patients with symptomatic proximal DVT or PE3

ELIQUIS PROTECTS PATIENTS WITH NVAF, DVT AND PE FROM THROMBOEMBOLIC EVENTS†‡1–3

NVAF, non-valvular atrial fibrillation; SE, systemic embolism; DVT, deep vein thrombosis; PE, pulmonary embolism; RRR, relative risk reduction. eliquis.com.au

SUPERIOR REDUCTION IN STROKE/SE IN NVAF vs WARFARIN 21% RRR (p=0.01)†1,2

SUPERIOR REDUCTION

IN MAJOR BLEEDING

IN NVAF vs WARFARIN

31% RRR (p<0.001)†1,2

SUPERIOR REDUCTION IN MAJOR BLEEDING IN DVT/PE vs ENOXAPARIN/ WARFARIN 69% RRR (p<0.001)‡3

COMPARABLE

PREVENTION

OF RECURRENT

DVT/PE OR DVT/PE-

RELATED DEATH

vs ENOXAPARIN/

WARFARIN

(p<0.001 non-inferiority)‡3

PBS Information: Authority required (STREAMLINED). Refer to PBS Schedule for full authority information.

www.researchreview.com.au a RESEARCH REVIEW publication

3

Atrial Fibrillation Research ReviewTM

Non-major bleeding with apixaban versus warfarin in patients with atrial fibrillationAuthors: Bahit MC et al.Summary: These authors reported on nonmajor bleeding and clinical outcomes for 18,140 ARISTOTLE trial participants with AF who received ≥1 dose of study drug. The nonmajor bleeding rate was greater than the major bleeding rate (12.1% vs. 3.8%) and, similar to major bleeding, was less frequent among apixaban recipients than warfarin recipients (6.4 vs. 9.4 per 100 patient-years; adjusted HR 0.69 [95% CI 0.63–0.75]). Haematuria (16.4%), epistaxis (14.8%), gastrointestinal bleeding (13.3%), haematoma (11.5%) and bruising/ecchymosis (10.1%) were the most frequent forms of nonmajor bleeds. Apixaban and warfarin recipients who experienced nonmajor bleeds had similar medical or surgical intervention rates (24.7% vs. 24.5%), but there were trends for warfarin recipients to be more likely to change their antithrombotic therapy (58.6% vs. 50.0%) or permanently discontinue study drug (5.1% vs. 3.6% [p=0.10]). Independent associations were seen between clinically relevant nonmajor bleeding and increased risks of overall death (adjusted HR 1.70 [95% CI 1.32–2.18]) and subsequent major bleeding (2.18 [1.56–3.04]).

Comment: It’s easy to accept nonmajor bleeding as ‘part of taking an anticoagulant’; however, as this study shows, even ‘minor’ bleeding is not benign and predicts adverse outcomes including mortality. Nonmajor bleeding was significantly less frequent with apixaban than warfarin.

Reference: Heart 2017;103(8):623–8Abstract

Post-approval U.S. experience with left atrial appendage closure for stroke prevention in atrial fibrillationAuthors: Reddy VY et al.Summary: Acute procedural performance and complication rates were reported for all 3822 LAA closure procedures performed in the US for stroke prevention in patients with nonvalvular AF since FDA approval in March 2015. The implantation success rate was 95.6% and the median procedure time was 50 minutes. Of the 382 physicians performing these implantations, 71% were new, nonclinical trial implanters who performed 50% of the procedures. The procedural complication rates were 1.02% for pericardial tamponade (three cases were fatal), 0.078% for procedure-related stroke, 0.24% for device embolisation and 0.078% for procedure-related mortality.

Comment: The bulk of ‘real-world data’ in AF has been about NOACs. Catheter-directed LAA closure is not only an alternative to warfarin but an alternative to anticoagulation, and has been performed in Australia for almost 10 years, based on the original WATCHMAN device studies. In this US analysis, we see overall acceptable results, but methods are not quite ideal.

Reference: J Am Coll Cardiol 2017;69(3):253–61Abstract

Ischaemic and haemorrhagic stroke associated with non-vitamin K antagonist oral anticoagulants and warfarin use in patients with atrial fibrillationAuthors: Staerk L et al.Summary: NOACs were compared with VKAs for stroke/thromboembolism or intracranial bleeding risk in a Danish cohort of 43,229 patients registered with AF, including 42% VKA recipients, 29% dabigatran recipients, 13% rivaroxaban recipients and 16% apixaban recipients, with respective mean CHA2DS2VASc scores of 2.9, 2.7, 3.0 and 3.1. Over follow-up of 2 years, there were 1054 stroke/thromboembolic events and 261 intracranial bleeds. Compared with the standardised 1-year absolute risk of stroke/thromboembolism for VKAs of 2.01%, the respective absolute risk differences for dabigatran, rivaroxaban and apixaban did not differ significantly. In contrast, compared with the standardised 1-year absolute risk of intracranial bleeding with VKAs of 0.60%, dabigatran and apixaban were associated with significantly lower absolute risk differences (–0.34% [95% CI –0.47% to – 0.21%] and –0.20% [–0.38% to –0.01%]), but the absolute risk difference for rivaroxaban was not significantly different.

Comment: In this large Danish real-world registry, NOAC efficacy was similar to warfarin but times in therapeutic range and INRs are not provided and we know this country performs exceptionally well in this respect. The other important information not provided relates to dosing of the NOACs, specifically the appropriateness of low-dose prescribing.

Reference: Eur Heart J 2017;38(12):907–15Abstract

Cardioversion and subsequent quality of life and natural history of atrial fibrillationAuthors: Pokorney SD et al., for the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) InvestigatorsSummary: These researchers analysed data from patients who had undergone cardioversion and propensity-matched noncardioverted patients in a 3:1 ratio from the prospective ORBIT-AF registry. Among 9642 patients, 8% underwent 906 cardioversions over median follow-up of 12 months. Compared with noncardioverted patients, cardioverted patients had higher rates of 1-year cardiovascular-related hospitalisation (43% vs. 21%; adjusted HR 2.2 [95% CI 1.8–2.8]) and sinus rhythm at both first and second follow-up visits (36% vs. 27% [p=0.042]); the findings for first-time cardioverted patients were similar. Neither symptom improvement nor symptomatic progression differed significantly between cardioverted and noncardioverted patients (34% vs. 42% and 15% vs. 4%). Cardioversion was associated with AF progression after cardioversion and after first cardioversion (respective odds ratios 1.6 [95% CI 1.2–2.2] and 2.7 [p<0.001]). Only 18% of patients who were not previously on an antiarrhythmic started such treatment postcardioversion, <5% underwent ablation, and 22% stopped their antiarrhythmic agent.

Comment: These findings are not necessarily surprising; cardioversion as rhythm control is usually temporary and additional strategies are required (antiarrhythmic drugs and/or catheter ablation). However, cardioversion can be very useful even in the short term (e.g. to help determine symptoms or confirm asymptomatic AF) and this can guide ongoing management.

Reference: Am Heart J 2017;185:59–66Abstract

Independent commentary by Dr Andrei Catanchin,a cardiologist/electrophysiologist specialising in the management of AF and other arrhythmias at Epworth HealthCare in Melbourne. He performs catheter ablation, implants pacemakers and ICDs (defibrillators) and his research interests include alternatives to warfarin (e.g. NOACs) in AF management. Dr Catanchin is a Senior Lecturer with the University of Melbourne, teaches at all levels and regularly presents at local and national meetings.

Atrial FibrillationResearch ReviewTM

www.researchreview.com.au a RESEARCH REVIEW publication

4

Atrial Fibrillation Research ReviewTM

This publication is endorsed by ACN according to our Continuing Professional Development Endorsed Course Standards. It has been allocated 1 CPD hour(s) according to the Nursing and Midwifery Board

of Australia – Continuing Professional Development Standard.

For more information click here

Bariatric surgery and the risk of new-onset atrial fibrillation in Swedish obese subjectsAuthors: Jamaly S et al.Summary: The impact of bariatric surgery on new-onset AF risk was explored in the prospective SOS (Swedish Obese Subjects) cohort study of 2000 obese individuals with sinus rhythm and no history of AF who underwent bariatric surgery matched to 2021 obese control subjects who received usual care. Median follow-up was 19 years. Compared with controls, the patients who underwent bariatric surgery had a significantly lower rate of first-time AF (12.4% vs. 16.8%; HR 0.71 [95% CI 0.60–0.83]). The benefit was greater for younger versus older patients (p=0.001 for interaction) and those with a higher versus lower diastolic blood pressure (p=0.028 for interaction).

Comment: In the last few years we have seen that effective treatment of obesity can reduce AF and its symptoms – here we have evidence that weight reduction may actually act as ‘primary prevention’ of AF, in this case via bariatric surgery, which effectively achieved sustained weight reduction of 25% at 1 year, 17% at 10 years and 18% at 20 years (compared with no reduction in controls).

Reference: J Am Coll Cardiol 2016;68(23):2497–504Abstract

Causes of death in anticoagulated patients with atrial fibrillationAuthors: Gómez-Outes A et al.Summary: This meta-analysis compared causes of death in patients receiving NOACs or warfarin for preventing stroke and systemic embolism in 71,683 patients with AF from four trials (134,046 patient-years of follow-up). The adjusted mortality rate was 4.72% per year. Cardiac deaths accounted for 46% of all deaths, whereas nonhaemorrhagic stroke/systemic embolism and haemorrhage-related deaths accounted for 5.7% and 5.6%, respectively. Compared with patients who survived, those who died more frequently had a history of heart failure (odds ratio 1.75 [95% CI 1.25–2.44]), permanent/persistent AF (1.38 [1.25–1.52]) and diabetes (1.37 [1.11–1.68]), and were more frequently male, older and had a lower creatinine clearance. There was a small, but significant, reduction in all-cause mortality with NOACs versus warfarin that was mainly driven by fewer fatal bleeds (difference –0.42% per year).

Comment: The majority of deaths in AF patients are not directly related to the AF itself (although we know anticoagulation reduces mortality). Rather, the associated medical conditions are responsible; e.g. heart failure, advanced age, diabetes and renal impairment. NOACs are associated with lower mortality than warfarin, predominantly due to less major bleeding.

Reference: J Am Coll Cardiol 2016;68(23):2508–21Abstract

© 2017 RESEARCH REVIEW

www.researchreview.com.au a RESEARCH REVIEW publication

5

Atrial Fibrillation Research ReviewTM

Research Reviews are prepared with an independent commentary from relevant specialists. To become a reviewer please email geoff@researchreview.com.au.Research Review Australia Pty Ltd is an independent Australian publisher. Research Review receives funding from a variety of sources including Government depts., health product companies, insurers and other organisations with an interest in health. Journal content is created independently of sponsor companies with assistance from leading local specialists. Privacy Policy: Research Review will record your email details on a secure database and will not release them to anyone without your prior approval. Research Review and you have the right to inspect, update or delete your details at any time. Disclaimer: This publication is not intended as a replacement for regular medical education but to assist in the process. The reviews are a summarised interpretation of the published study and reflect the opinion of the writer rather than those of the research group or scientific journal. It is suggested readers review the full trial data before forming a final conclusion on its merits. Research Review publications are intended for Australian health professionals.

Australian Research Review subscribers can claim CPD/CME points for time spent reading our reviews from a wide range of local medical and nursing colleges. Find out more on our CPD page.

Practice ReviewTM

Cardiology

This review covers news and issues relevant to clinical practice in cardiology. It will bring you the latest updates, both locally and from around the globe, in relation to topics such as new and updated treatment guidelines, changes to medicines reimbursement and licensing, educational, medicolegal issues, professional body

news and more.

Click here to vist www.researchreview.com.au

to subscribe free and update your subscription to

receive Cardiology Practice Review.

This online educational activity is endorsed by the Australian Nursing and Midwifery Federation (ANMF) Federal Office.

Completion attracts 1 CPD hour.

For more information click here

Australian Cardiovascular Nursing Collegehttp://www.acnc.net.au

RESEARCH REVIEW – The Australian Perspective Since 2007