Summary Atrial fibrillation is one of the major cardiovascular health problems: it is a common, chronic condition, affecting 2–3% of the population in Europe and the USA and requiring 1–3% of ...health-care expenditure as a result of stroke, sudden death, heart failure, unplanned hospital admissions, and other complications. Early diagnosis of atrial fibrillation, ideally before the first complication occurs, remains a challenge, as shown by patients who are only diagnosed with the condition when admitted to hospital for acute cardiac decompensation or stroke. Once diagnosed, atrial fibrillation requires chronic, multidimensional management in five domains (acute management, treatment of underlying and concomitant cardiovascular conditions, stroke prevention therapy, rate control, and rhythm control). The consistent provision of these treatment options to all patients with atrial fibrillation is difficult, despite recent improvements in organisation of care, knowledge about atrial fibrillation, and treatment options. Integrated care models that provide patient-centred care in, or close to, the patient's community while maintaining access to all specialist treatment options, emerge as the best approach to achieve consistent delivery of these chronic treatments to all patients with atrial fibrillation. Ongoing research efforts will establish when to initiate oral anticoagulation in patients with device-detected atrial high-rate episodes, quantify the prognostic effect of early and comprehensive rhythm control therapy, including atrial fibrillation ablation, and delineate optimum methods to reduce bleeding complications in patients treated with anticoagulation. Additionally, research efforts are needed to define different types of atrial fibrillation on the basis of the main causes of atrial fibrillation to pave the way for the clinical development of stratified atrial fibrillation therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Atrial fibrillation (AF) is an arrhythmia that can occur as the result of numerous different pathophysiological processes in the atria. Some aspects of the morphological and electrophysiological ...alterations promoting AF have been studied extensively in animal models. Atrial tachycardia or AF itself shortens atrial refractoriness and causes loss of atrial contractility. Aging, neurohumoral activation, and chronic atrial stretch due to structural heart disease activate a variety of signaling pathways leading to histological changes in the atria including myocyte hypertrophy, fibroblast proliferation, and complex alterations of the extracellular matrix including tissue fibrosis. These changes in electrical, contractile, and structural properties of the atria have been called "atrial remodeling." The resulting electrophysiological substrate is characterized by shortening of atrial refractoriness and reentrant wavelength or by local conduction heterogeneities caused by disruption of electrical interconnections between muscle bundles. Under these conditions, ectopic activity originating from the pulmonary veins or other sites is more likely to occur and to trigger longer episodes of AF. Many of these alterations also occur in patients with or at risk for AF, although the direct demonstration of these mechanisms is sometimes challenging. The diversity of etiological factors and electrophysiological mechanisms promoting AF in humans hampers the development of more effective therapy of AF. This review aims to give a translational overview on the biological basis of atrial remodeling and the proarrhythmic mechanisms involved in the fibrillation process. We pay attention to translation of pathophysiological insights gained from in vitro experiments and animal models to patients. Also, suggestions for future research objectives and therapeutical implications are discussed.
Kazem Rahimi and Paulus Kirchhof discuss the latest work from Faris Ghazal et al and how it may impact the way we currently detect Atrial Fibrillation in the general population.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective To clarify the impact of digoxin on death and clinical outcomes across all observational and randomised controlled trials, accounting for study designs and methods.Data sources and study ...selection Comprehensive literature search of Medline, Embase, the Cochrane Library, reference lists, and ongoing studies according to a prospectively registered design (PROSPERO: CRD42014010783), including all studies published from 1960 to July 2014 that examined treatment with digoxin compared with control (placebo or no treatment).Data extraction and synthesis Unadjusted and adjusted data pooled according to study design, analysis method, and risk of bias.Main outcome measures Primary outcome (all cause mortality) and secondary outcomes (including admission to hospital) were meta-analysed with random effects modelling.Results 52 studies were systematically reviewed, comprising 621 845 patients. Digoxin users were 2.4 years older than control (weighted difference 95% confidence interval 1.3 to 3.6), with lower ejection fraction (33% v 42%), more diabetes, and greater use of diuretics and anti-arrhythmic drugs. Meta-analysis included 75 study analyses, with a combined total of 4 006 210 patient years of follow-up. Compared with control, the pooled risk ratio for death with digoxin was 1.76 in unadjusted analyses (1.57 to 1.97), 1.61 in adjusted analyses (1.31 to 1.97), 1.18 in propensity matched studies (1.09 to 1.26), and 0.99 in randomised controlled trials (0.93 to 1.05). Meta-regression confirmed that baseline differences between treatment groups had a significant impact on mortality associated with digoxin, including markers of heart failure severity such as use of diuretics (P=0.004). Studies with better methods and lower risk of bias were more likely to report a neutral association of digoxin with mortality (P<0.001). Across all study types, digoxin led to a small but significant reduction in all cause hospital admission (risk ratio 0.92, 0.89 to 0.95; P<0.001; n=29 525).Conclusions Digoxin is associated with a neutral effect on mortality in randomised trials and a lower rate of admissions to hospital across all study types. Regardless of statistical analysis, prescription biases limit the value of observational data.
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BFBNIB, CMK, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Abstract Background Atrial fibrillation (AF) and heart failure frequently coexist, commonly resulting in serious adverse events. With both conditions increasing in prevalence and justified concerns ...about treatment efficacy, it is vital to understand how the type of heart failure impacts on prognosis. Methods We performed a systematic review of studies examining cardiovascular outcomes in AF patients with heart failure and reduced ejection fraction (AF-HFrEF) compared to those with preserved ejection fraction (AF-HFpEF). The primary outcome was all-cause mortality, meta-analyzed using a random-effects model. Prospective registration: PROSPERO-CRD42014007305. Results Thirteen studies were included in the systematic review (n = 54,587) with 10 suitable for meta-analysis, including retrospective/prospective cohorts and sub-group analyses of randomized trials. AF-HFrEF was present in 49% and these patients were younger, more often male and with higher NYHA class than AF-HFpEF. Oral anticoagulation use was 55% versus 50% respectively (p < 0.001). All-cause mortality was significantly higher in AF-HFrEF; risk ratio (RR) 1.24, 95% CI 1.12–1.36, p < 0.001 (n = 45,100), with absolute death rates of 24% compared to 18% in AF-HFpEF over 2 years. There were no significant differences in incident stroke (RR 0.85, 95% CI 0.70–1.03, p = 0.094; n = 33,773) or heart failure hospitalization (RR 1.21, 95% CI 0.96–1.53, p = 0.115; n = 31,583). The risk of bias was generally low, but heterogeneity was substantial. Conclusions All-cause mortality is significantly higher in AF patients with HFrEF compared to HFpEF, although stroke risk and heart failure hospitalization are similar. Further studies are needed to address the prevention of adverse outcomes in all AF patients with heart failure, regardless of ejection fraction.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The Coronavirus disease 2019 (COVID-19) pandemic is overwhelming the healthcare systems. Identification of systemic reactions underlying COVID-19 will lead to new biomarkers and therapeutic targets ...for monitoring and early intervention in this viral infection. We performed targeted metabolomics covering up to 630 metabolites within several key metabolic pathways in plasma samples of 20 hospitalized COVID-19 patients and 37 matched controls. Plasma metabolic signatures specifically differentiated severe COVID-19 from control patients. The identified metabolic signatures indicated distinct alterations in both lipid and amino acid metabolisms in COVID-19 compared to control patient plasma. Systems biology-based analyses identified sphingolipid, tryptophan, tyrosine, glutamine, arginine, and arachidonic acid metabolism as mostly impacted pathways in COVID-19 patients. Notably, gamma-aminobutyric acid (GABA) was significantly reduced in COVID-19 patients and GABA plasma levels allowed for stratification of COVID-19 patients with high sensitivity and specificity. The data reveal large metabolic disturbances in COVID-19 patients and suggest use of GABA as potential biomarker and therapeutic target for the infection.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Cardiac implanted electronic devices (CIEDs), including pacemakers and implantable defibrillators that perform atrial sensing typically using an atrial electrode, frequently detect subclinical atrial ...high-rate episodes (AHREs). When the intracardiac electrograms are carefully examined, the majority of AHREs are atrial fibrillation (AF) or other atrial tachyarrhythmias, which have been shown to be associated with both an increased risk of stroke, and subsequent development of clinical AF. However, the absolute risk of stroke among patients with AHREs is less than might be expected for clinically diagnosed paroxysmal AF. In addition, a close temporal relationship between AHREs and stroke is seen in only 15% of strokes in patients with a CIED: the majority have either no AHREs before the stroke, or AHREs very distant from incident stroke, suggesting that AHREs might be more of a risk marker than a risk factor for stroke. Management of AHREs should not be the same as for clinical AF, and a degree of uncertainty underpins the rationale for much-needed, ongoing, randomized trials of oral anticoagulation in patients with CIED-detected AHREs. We propose a management algorithm that takes into account both the stroke risk and the AHRE burden, but highlights the current uncertainty and evidence gaps for this condition.
Abstract
Aims
It is recommended to perform atrial fibrillation ablation with continuous anticoagulation. Continuous apixaban has not been tested.
Methods and results
We compared continuous apixaban ...(5 mg b.i.d.) to vitamin K antagonists (VKA, international normalized ratio 2–3) in atrial fibrillation patients at risk of stroke a prospective, open, multi-centre study with blinded outcome assessment. Primary outcome was a composite of death, stroke, or bleeding (Bleeding Academic Research Consortium 2–5). A high-resolution brain magnetic resonance imaging (MRI) sub-study quantified acute brain lesions. Cognitive function was assessed by Montreal Cognitive Assessment (MoCA) at baseline and at end of follow-up. Overall, 674 patients (median age 64 years, 33% female, 42% non-paroxysmal atrial fibrillation, 49 sites) were randomized; 633 received study drug and underwent ablation; 335 undertook MRI (25 sites, 323 analysable scans). The primary outcome was observed in 22/318 patients randomized to apixaban, and in 23/315 randomized to VKA {difference −0.38% 90% confidence interval (CI) −4.0%, 3.3%, non-inferiority P = 0.0002 at the pre-specified absolute margin of 0.075}, including 2 (0.3%) deaths, 2 (0.3%) strokes, and 24 (3.8%) ISTH major bleeds. Acute small brain lesions were found in a similar number of patients in each arm apixaban 44/162 (27.2%); VKA 40/161 (24.8%); P = 0.64. Cognitive function increased at the end of follow-up (median 1 MoCA unit; P = 0.005) without differences between study groups.
Conclusions
Continuous apixaban is safe and effective in patients undergoing atrial fibrillation ablation at risk of stroke with respect to bleeding, stroke, and cognitive function. Further research is needed to reduce ablation-related acute brain lesions.
We sought to describe the management of patients with atrial fibrillation (AF) in Europe after the release of the 2010 AF Guidelines of the European Society of Cardiology.
The PREFER in AF registry ...enrolled consecutive patients with AF from January 2012 to January 2013 in 461 centres in seven European countries. Seven thousand two hundred and forty-three evaluable patients were enrolled, aged 71.5 ± 11 years, 60.1% male, CHA2DS2VASc score 3.4 ± 1.8 (mean ± standard deviation). Thirty per cent patients had paroxysmal, 24.0% had persistent, 7.2% had long-standing persistent, and 38.8% had permanent AF. Oral anticoagulation was used in the majority of patients: 4799 patients (66.3%) received a vitamin K antagonist (VKA) as mono-therapy, 720 patients a combination of VKA and antiplatelet agents (9.9%), 442 patients (6.1%) a new oral anticoagulant drugs (NOAC). Antiplatelet agents alone were given to 808 patients (11.2%), no antithrombotic therapy to 474 patients (6.5%). Of 7034 evaluable patients, 5530 (78.6%) patients were adequately rate controlled (mean heart rate 60-100 bpm). Half of the patients (50.7%) received rhythm control therapy by electrical cardioversion (18.1%), pharmacological cardioversion (19.5%), antiarrhythmic drugs (amiodarone 24.1%, flecainide or propafenone 13.5%, sotalol 5.5%, dronedarone 4.0%), and catheter ablation (5.0%).
The management of AF patients in 2012 has adapted to recent evidence and guideline recommendations. Oral anticoagulant therapy with VKA (majority) or NOACs is given to over 80% of eligible patients, including those at risk for bleeding. Rate is often adequately controlled, and rhythm control therapy is widely used.
Summary Background Atrial fibrillation and heart failure often coexist, causing substantial cardiovascular morbidity and mortality. β blockers are indicated in patients with symptomatic heart failure ...with reduced ejection fraction; however, the efficacy of these drugs in patients with concomitant atrial fibrillation is uncertain. We therefore meta-analysed individual-patient data to assess the efficacy of β blockers in patients with heart failure and sinus rhythm compared with atrial fibrillation. Methods We extracted individual-patient data from ten randomised controlled trials of the comparison of β blockers versus placebo in heart failure. The presence of sinus rhythm or atrial fibrillation was ascertained from the baseline electrocardiograph. The primary outcome was all-cause mortality. Analysis was by intention to treat. Outcome data were meta-analysed with an adjusted Cox proportional hazards regression. The study is registered with Clinicaltrials.gov , number NCT0083244 , and PROSPERO, number CRD42014010012. Findings 18 254 patients were assessed, and of these 13 946 (76%) had sinus rhythm and 3066 (17%) had atrial fibrillation at baseline. Crude death rates over a mean follow-up of 1·5 years (SD 1·1) were 16% (2237 of 13 945) in patients with sinus rhythm and 21% (633 of 3064) in patients with atrial fibrillation. β-blocker therapy led to a significant reduction in all-cause mortality in patients with sinus rhythm (hazard ratio 0·73, 0·67–0·80; p<0·001), but not in patients with atrial fibrillation (0·97, 0·83–1·14; p=0·73), with a significant p value for interaction of baseline rhythm (p=0·002). The lack of efficacy for the primary outcome was noted in all subgroups of atrial fibrillation, including age, sex, left ventricular ejection fraction, New York Heart Association class, heart rate, and baseline medical therapy. Interpretation Based on our findings, β blockers should not be used preferentially over other rate-control medications and not regarded as standard therapy to improve prognosis in patients with concomitant heart failure and atrial fibrillation. Funding Menarini Farmaceutica Internazionale (administrative support grant).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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