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Objective Oral anticoagulant (OAC) prescription for stroke prevention in atrial fibrillation (AF) patients frequently does not follow current guidelines, with underuse in patients at high risk of stroke and substantial overuse in those at low risk. This review aims to systematically evaluate the effectiveness of interventions to improve appropriate OAC prescription in eligible AF patients for stroke prevention. Methods Systematic review of controlled and uncontrolled studies published up to July 2017 with interventions designed to improve appropriate OAC prescription for stroke prevention in eligible AF patients (according to risk assessment tool or guidelines). Categorization of intervention types was pre-specified. The main outcome was change in proportion of eligible AF patients prescribed OACs for stroke prevention. Results Twenty studies conducted in 392 settings were included (cluster randomized controlled trials, controlled trials and uncontrolled before-after designs; n = 29,868 patients at baseline). Fifteen studies reported significant improvements in appropriate prescription of OACs in AF patients. All interventions with a persuasive element (8/8); all studies targeting health care professional (HCP) education or guideline/protocol implementation (7/7); and all medical care programs (4/4) achieved significant increases in appropriate OAC prescription. Computerized decision support interventions (3/5) and reviews of prescribing (2/4) were less likely to report significant improvements in appropriate OAC prescription. Conclusion Interventions designed to improve appropriate prescription of OACs in eligible AF patients for stroke prevention can be effective. Successful approaches include education of HCPs; implementation of local guidelines; interdisciplinary medical care programs educating both HCPs and patients and persuasive interventions utilizing peer-group experts. Protocol registration: PROSPERO (CRD42016039654).

Management strategies for patients with atrial fibrillation (AF) in association with valvular heart disease (VHD) have been less informed by randomized trials, which have largely focused on ‘non-valvular AF’ patients. Thromboembolic risk also varies according to valve lesion and may also be associated with CHA2DS2-VASc score risk factor components, rather than only the valve disease being causal.Given the need to provide expert recommendations for professionals participating in the care of patients presenting with AF and associated VHD, a task force was convened by the European Heart Rhythm Association (EHRA) and European Society of Cardiology (ESC) Working Group (WG) on Thrombosis, with representation from the ESC WG on Valvular Heart Disease, Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), South African Heart (SA Heart) Association and Sociedad Latinoamericana de Estimulación Cardíaca y Electrofisiología (SOLEACE) with the remit to comprehensively review the published evidence, and to produce a consensus document on the management of patients with AF and associated VHD, with up-to-date consensus statements for clinical practice for different forms of VHD, based on the principles of evidence-based medicine.This is an executive summary of a consensus document which proposes that the term ‘valvular AF’ is outdated and given that any definition ultimately relates to the evaluated practical use of oral anticoagulation (OAC) type, we propose a functional EHRA (Evaluated Heartvalves, Rheumatic or Artificial) categorization in relation to the type of OAC use in patients with AF, as follows: (1) EHRA (Evaluated Heartvalves, Rheumatic or Artificial) type 1 VHD, which refers to AF patients with ‘VHD needing therapy with a vitamin K antagonist (VKA)’ and (2) EHRA (Evaluated Heartvalves, Rheumatic or Artificial) type 2 VHD, which refers to AF patients with ‘VHD needing therapy with a VKA or a non-VKA oral anticoagulant also taking into consideration CHA2DS2-VASc score risk factor components.

SummaryThere are exciting new developments in several areas of atrial fibrillation (AF) management that carry the hope of improving outcomes in AF patients. This paper is an executive summary that summarises the proceedings from the 3rd AFNET/EHRA consensus conference on atrial fibrillation, held in Sophia Antipolis from November 7th to 9th 2010, shortly after the release of the new ESC guidelines on AF. The conference was jointly organised by the German Atrial Fibrillation competence NETwork (AFNET) and the European Heart Rhythm Association (EHRA). This executive summary report covers four sections: 1. Risk factors and risk markers for AF, 2. Pathophysiological classification of AF, 3. Relevance of monitored AF duration for AF-related outcomes, and 4. Perspectives and needs for implementing better antithrombotic therapy.

Note: The review process for this editorial was handled by Christian Weber, Editor in Chief.

SummaryAtrial fibrillation (AF) is a common complication of coronary artery bypass grafting (CABG). We sought to determine the diagnostic validity of plasma biomarkers of i) inflammation (marked by interleukin-6 [IL-6] and high-sensitivity C-reactive protein [hs-CRP]), ii) extracellular matrix remodelling (matrix metalloproteinase [MMP-9], tissue inhibitor of matrix metalloproteinase [TIMP-1]) and iii) the prothrombotic state (tissue factor and von Willebrand factor [vWF]) in the risk prediction of post-operative AF. Samples were obtained preoperatively from peripheral/femoral vein and from intracardiac chambers (right atrium [RA], the right atrial appendage [RAA], the left atrium [LA] and the left atrial appendage [LAA]) amongst 100 consecutive patients free of AF and inflammatory disease undergoing elective CABG. Biomarker concentrations were related to incident AF (30 days). At 30 days post CABG, 30 patients were proven to have had AF. Concentrations of tissue factor (TF) and vWF were unrelated to postoperative AF. Peripheral (p=0.018), and intracardiac levels (RAA (p=0.029) and LA (p=0.026)) of hs-CRP were associated with the presence of AF after CABG. Intracardiac levels of IL-6 in samples from the RAA (p=0.031), LA (p=0.042) and LAA (p=0.006), and MMP-9 in the LAA sample were also associated with AF (p=0.007). Our data suggest that an intra-cardiac inflammatory environment that is manifest peri-operatively may predispose to the development of post-operative AF. This intracardiac inflammatory state was reflected by increased peripheral hs-CRP levels. These differences may indicate local substrate abnormalities contributing to the development of AF post-operatively.

Haemost 2014; 111: 1167-1176. Atrial fibrillation (AF) currently affects nearly 2% of the general adult population, and its prevalence is rising (1, 2). Compared with individuals in sinus rhythm, AF patients have impaired quality of life, a five-fold increased risk of stroke, a threefold higher risk of heart failure and a twofold greater mortality (3). Hence, AF is a major health problem. Poor AF outcomes are highly preventable by timely and appropriately initiated medical treatment. Strokes related to AF are generally more severe and more often fatal or disabling than strokes of other aetiologies (4) but can be effectively prevented with oral anticoagulant therapy, either vitamin K antagonists or non-vitamin K antagonist oral anticoagulant drugs (NOACs) direct thrombin inhibitor dabigatran or direct factor Xa inhibitors rivaroxaban, apixaban and edoxaban. Compared to placebo, warfarin reduces the risk of stroke by 67% (5), and NOACs were at least as effective as warfarin or in some cases even better, altogether achieving a 19% relative risk reduction compared to warfarin (p

Anticoagulation intensity for elderly atrial fibrillation patients: Should we use a conventional INR target (2.0 to 3.0) or a lower range?

Bleeding risks with combination of oral anticoagulation plus antiplatelet therapy: Is clopidogrel any safer than aspirin when combined with warfarin?

SummaryVitamin K antagonists (e.g. warfarin) are commonly underutilised, due to limitations such as the need for monitoring, in high-risk atrial fibrillation (AF) patients. We therefore aimed to model the potential impact on clinical outcomes in patients with AF with the use of the novel oral anticoagulant (OAC) drugs, apixaban and dabigatran. We identified all high-risk (CHA2DS2-VASc score ≥2) patients with non-valvular AF and known one-year follow-up from the EuroHeart Survey on AF (EHS-AF). We modelled the expected numbers of clinical events on the novel OACs using published hazard ratios from their respective phase 3 clinical trials and calculated the numbers needed to treat and the mathematical net clinical benefit. Our analysis included 3,400 patients [39% females; mean (SD) age 67 (12) years; CHA2DS2-VASc score 3.0 (1.8)] of which 330 were excluded from the modelling analysis due to concomitant use of OAC and antiplatelet drugs. During one-year follow- up, 108 (3.2%) patients experienced thromboembolism, 51 (1.5%) major bleeds and 146 (4.3%) died. Compared to current treatments (i.e. warfarin, aspirin or nothing) the use of apixaban in highrisk patients would have potentially prevented an additional 17 deaths, 27 strokes and eight major bleeds within this cohort. With use of dabigatran 150 mg BID, 34 strokes could have been prevented and for dabigatran110 mg BID, 16 strokes and six major bleeds would be avoided. Extrapolation of the data from the EHS-AF to the whole of Europe would translate into the prevention of an additional 64,573 major cardiovascular events and deaths each year among patients with a CHA2DS2-VASc ≥2, by the use of apixaban, 43,235 with the use of dabigatran 150 mg bid and 27,272 with the use of dabigatran 110 mg bid. In conclusion, based on this modelling exercise, the utilisation of apixaban and dabigatran for thromboprophylaxis could provide a profound annual mathematical net clinical benefit on stroke and major bleeds, in European AF patients.Note: The editorial process for this paper was fully handled by Prof. C. Weber, Editor in Chief.

SummaryThe concept of net clinical benefit has been used to quantify the balance between risk of ischaemic stroke (IS) and risk of intracranial haemorrhage (ICH) with the use oral anticoagulant therapy (OAC) in the setting of non-valvular atrial fibrillation (AF), and has shown that patients at highest risk of stroke and thromboembolism gain the greatest benefit from OAC with warfarin. There are no data for the new OACs, that is, dabigatran, rivaroxaban and apixaban, as yet. We calculated the net clinical benefit balancing IS against ICH using data from the Danish National Patient Registry on patients with non-valvular AF between 1997–2008, for dabigatran, rivaroxaban and apixaban on the basis of recent clinical trial outcome data for these new OACs. In patients with CHADS2=0 but at high bleeding risk, apixaban and dabigatran 110 mg bid had a positive net clinical benefit. At CHA2DS2-VASc=1, apixaban and both doses of dabigatran (110 mg and 150 mg bid) had a positive net clinical benefit. In patients with CHADS2 score≥1 or CHA2DS2-VASc≥2, the three new OACs (dabigatran, rivaroxaban and apixaban) appear superior to warfarin for net clinical benefit, regardless of risk of bleeding. When risk of bleeding and stroke are both high, all three new drugs appear to have a greater net clinical benefit than warfarin. In the absence of head-to-head trials for these new OACs, our analysis may help inform decision making processes when all these new OACs become available to clinicians for stroke prevention in AF. Using ‘real world’ data, our modelling analysis has shown that when the risk of bleeding and stroke are both high, all three new drugs appear to have a greater net clinical benefit compared to warfarin.The editorial process for this article was fully handled by Prof. Christian Weber, Editor-in-Chief.

SummaryIt was the aim of this study to determine the efficacy and safety of vitamin K antagonists (VKAs) and acetylsalicylic acid (ASA) in patients with non-valvular atrial fibrillation (AF), with separate analyses according to predicted thromboembolic and bleeding risk. By individual levellinkage of nationwide registries, we identified all patients discharged with non-valvular AF in Denmark (n=132,372). For every patient, the risk of stroke and bleeding was calculated by CHADS2, CHA2DS2-VASc, and HAS-BLED. During follow-up, treatment with VKA and ASA was determined time-dependently. VKA consistently lowered the risk of thromboembolism compared to ASA and no treatment; the combination of VKA+ASA did not yield any additional benefit. In patients at high thromboembolic risk, hazard ratios (95% confidence interval) for thromboembolism were: 1.81 (1.73–1.90), 1.14 (1.06–1.23), and 1.86 (1.78–1.95) for ASA, VKA+ASA, and no treatment, respectively, compared to VKA. The risk of bleeding was increased with VKA, ASA, and VKA+ASA compared to no treatment, the hazard ratios were: 1.0 (VKA; reference), 0.93 (ASA; 0.89–0.97), 1.64 (VKA+ASA; 1.55–1.74), and 0.84 (no treatment; 0.81–0.88), respectively. There was a neutral or positive net clinical benefit (ischaemic stroke vs. intracranial haemorrhage) with VKA alone in patients with a CHADS2 score of ≥ 0, and CHA2DS2-VASc score of ≥ 1. This large cohort study confirms the efficacy of VKA and no effect of ASA treatment on the risk of stroke/thromboembolism. Also, the risk of bleeding was increased with both VKA and ASA treatment, but the net clinical benefit was clearly positive, in favour of VKA in patients with increased risk of stroke/thromboembolism.

Contra: “Anti-platelet therapy is an alternative to oral anticoagulation for atrial fibrillation”

Thromb Haemost 2009; 101: 415–416 Patients with atrial fibrillation (AF) have a substantial risk of stroke and thromboembolism compared with age-matched people in sinus rhythm, which varies with associated comorbidities and risk factors (1, 2). When a stroke occurs in patients with AF, the severity of the stroke is much greater, as is mortality and disability compared to those in sinus rhythm (3). Unsurprisingly, the biggest challenge facing physicians caring for patients with AF is the prevention of stroke and thromboembolism, whether as primary or secondary prevention. Examination of stroke rates from the non-warfarin arms of trial cohorts and one epidemiological study have informed the development of stroke risk stratification schema for AF (4). More than a dozen stroke risk stratification schemes for AF patients have been proposed, but all have modest predictive value for stroke (1, 5). These risk stratification schemes are used in many guidelines, which generally recommend anti-thrombotic therapy with warfarin for AF patients at ‘high-risk’ of stroke and aspirin for those at ‘low-risk’. For those patients who fall into the ‘moderate-risk’ category (usually those with one single stroke risk factor), either aspirin or warfarin is recommended, due to the lack of evidence in favour of either drug, as well as the close margin between stroke reduction and bleeding risk of anticoagulation with warfarin. Thus, many guidelines recommend that anti-thrombotic therapy is decided on an individual basis. However, such an approach is confounded by new trial evidence from the Birmingham Atrial Fibrillation Treatment of the Aged Study (BAFTA) showing the substantial benefits – even in subjects aged >75 – of warfarin over aspirin for stroke prevention (1.8% vs. 3.8% events per year, respectively: relative risk [RR] 0.48, 95% confidence interval [CI] 0.28–0.80), with no difference in rates of major haemorrhage between warfarin or aspirin (6). The merits or otherwise of why warfarin should really be the drug of choice for stroke prevention in elderly patients with AF have recently been debated in this journal (7, 8). It is said that guidelines begat guidelines, and in real-life clinical practice, such guidelines on anti-thrombotic therapy for AF are often not adhered to (9). In the Euro Heart Survey, prescription of antithrombotic therapy was based on the type of AF and availability of warfarin monitoring clinic, rather than the stroke risk profile per se (9). The type of AF should not be a consideration, given that paroxysmal AF has a similar stroke risk to persistent or permanent AF, in the presence of risk factors, and such patients would derive much benefit from anticoagulation (10). In the current issue of Thrombosis and Haemostasis, Rietbrock et al. (11) evaluate the incidence of stroke in routine clinical practice among >51,000 chronic AF patients aged ≥40 years taking either aspirin or warfarin, by examining the United Kingdom General Practice Research Database from 1987 onwards. Virtually all the patients had been treated with warfarin or aspirin, with almost 10,000 patients who had received both (either concomitantly or separately). They compared non-use (never) with both ‘current use’ (defined as the time from the prescription date until three months after the expected duration of use) and ‘past use’ (defined as the period of time starting three months after the expected end of a prescription) and found that current use of warfarin was associated with a 38% (RR 0.62, 95% CI 0.54–0.71) reduction in stroke compared to past use after adjustment for age, sex, and stroke risk profile. Compared to no warfarin use, current and past use were both associated with a significant reduction in stroke rate, by 67% (RR 0.33, 95% CI 0.30–0.35) and 44% (RR 0.56, 95% CI 0.50–0.63), respectively. The benefits were more evident amongst the elderly, whereby the risk of stroke was reduced by 45% in elderly warfarin users (aged 75 years or older) and by 14% in younger users. As emphasised by the BAFTA trial (6), elderly patients with AF should not be denied warfarin thromboprophylaxis, given the impressive benefits of stroke prevention with anticoagulation in elderly AF patients. In contrast, there was no difference in the rate of stroke between current and past use of aspirin (RR 1.04, 95% CI 0.94 – 1.15). Thus, the stroke risk reduction with warfarin in routine clinical practice is similar to that achieved in clinical trials, in a UK general practice cohort involving >30,000 elderly AF patients, demonstrating that the evidence from clinical trials can translate into real-life clinical practice. Indeed, current or past use of aspirin did not seem to matter, and in fact, there were no significant changes in the rates of stroke were observed with dis© 2009 Schattauer GmbH, Stuttgart