Stop and Go: Barriers and Facilitators to Care Home Research.

Barriers to care home research have always existed, but have been thrown into sharp relief by the COVID-19 pandemic. Existing infrastructure failed to deliver the research, or outcomes, which care home residents deserved and we need to look, again, at how these barriers can be taken down. Barriers can be categorised as procedural (encountered before research starts), system (encountered during research) or resident-specific. To tackle these, research regulatory bodies need to adopt a standardised approach to how care home research is developed and designed, reviewed and regulated, and how such approaches can enable recruitment of as wide a range of residents and their representatives as possible, including those without the mental capacity to consent for research. Establishment of local, inter-disciplinary collaborations between universities, general practices, health and social care providers and care homes is another priority. This should be based on pre-existing models such as the 'Living lab' model developed in The Netherlands and now being implemented in the UK and Austria. These changes are critical to develop a sustainable research model. If well designed this will deliver better outcomes for residents and align with the individual and organisational priorities of those who care for them.

Enhanced activity of an ADAMTS-13 variant (R568K/F592Y/R660K/Y661F/Y665F) against platelet agglutination in vitro and in a murine model of acute ischemic stroke.

Essentials ADAMTS13 requires a substrate-induced conformational change to attain full activity in vitro. The efficacy of wild type ADAMTS13 in models of thrombosis/stroke may be enhanced by pre-activation. A pre-activated ADAMTS13 variant exhibits enhanced proteolysis of platelet agglutinates. This ADAMTS13 variant is protective in a murine model of stroke at a lower dose than WT ADAMTS13. SUMMARY: Background ADAMTS-13 circulates in a closed conformation, only achieving full proteolytic activity against von Willebrand factor (VWF) following a substrate-induced conformational change. A gain-of-function (GoF) ADAMTS-13 variant (R568K/F592Y/R660K/Y661F/Y665F) is conformationally preactivated. Objectives To establish how the hyperactivity of GoF ADAMTS-13 is manifested in experimental models mimicking the occlusive arterial thrombi present in acute ischemic stroke. Methods The ability of GoF ADAMTS-13 to dissolve VWF-platelet agglutinates was examined with an assay of ristocetin-induced platelet agglutination and in parallel-flow models of arterial thrombosis. A murine model of focal ischemia was used to assess the thrombolytic potential of GoF ADAMTS-13. Results Wild-type (WT) ADAMTS-13 required conformational activation to attain full activity against VWF-mediated platelet capture under flow. In this assay, GoF ADAMTS-13 had an EC50 value more than five-fold lower than that of WT ADAMTS-13 (0.73 ± 0.21 nm and 3.81 ± 0.97 nm, respectively). The proteolytic activity of GoF ADAMTS-13 against preformed platelet agglutinates under flow was enhanced more than four-fold as compared with WT ADAMTS-13 (EC50 values of 2.5 ± 1.1 nm and 10.2 ± 5.6 nm, respectively). In a murine stroke model, GoF ADAMTS-13 restored cerebral blood flow at a lower dose than WT ADAMTS-13, and partially retained the ability to recanalize vessels when administration was delayed by 1 h. Conclusions The limited proteolytic activity of WT ADAMTS-13 in in vitro models of arterial thrombosis suggests an in vivo requirement for conformational activation. The enhanced activity of the GoF ADAMTS-13 variant translates to a more pronounced protective effect in experimental stroke.

ADAMTS-13 and von Willebrand factor: a dynamic duo.

von Willebrand factor (VWF) is a key player in hemostasis, acting as a carrier for factor VIII and capturing platelets at sites of vascular damage. To capture platelets, it must undergo conformational changes, both within its A1 domain and at the macromolecular level through A2 domain unfolding. Its size and this function are regulated by the metalloproteinase ADAMTS-13. Recently, it has been shown that ADAMTS-13 undergoes a conformational change upon interaction with VWF, and that this enhances its activity towards its substrate. This review summarizes recent work on these conformational transitions, describing how they are controlled. It points to their importance in hemostasis, bleeding disorders, and the developing field of therapeutic application of ADAMTS-13 as an antithrombotic agent in obstructive microvascular thrombosis and in cardiovascular disease.

Comparison of bleeding risk scores in patients with atrial fibrillation: insights from the RE-LY trial.

BACKGROUND: Oral anticoagulation is the mainstay of stroke prevention in atrial fibrillation (AF), but must be balanced against the associated bleeding risk. Several risk scores have been proposed for prediction of bleeding events in patients with AF. OBJECTIVES: To compare the performance of contemporary clinical bleeding risk scores in 18 113 patients with AF randomized to dabigatran 110 mg, 150 mg or warfarin in the RE-LY trial. METHODS: HAS-BLED, ORBIT, ATRIA and HEMORR2 HAGES bleeding risk scores were calculated based on clinical information at baseline. All major bleeding events were centrally adjudicated. RESULTS: There were 1182 (6.5%) major bleeding events during a median follow-up of 2.0 years. For all the four schemes, high-risk subgroups had higher risk of major bleeding (all P < 0.001). The ORBIT score showed the best discrimination with c-indices of 0.66, 0.66 and 0.62, respectively, for major, life-threatening and intracranial bleeding, which were significantly better than for the HAS-BLED score (difference in c-indices: 0.050, 0.053 and 0.048, respectively, all P < 0.05). The ORBIT score also showed the best calibration compared with previous data. Significant treatment interactions between the bleeding scores and the risk of major bleeding with dabigatran 150 mg BD versus warfarin were found for the ORBIT (P = 0.0019), ATRIA (P < 0.001) and HEMORR2 HAGES (P < 0.001) scores. HAS-BLED score showed a nonsignificant trend for interaction (P = 0.0607). CONCLUSIONS: Amongst the current clinical bleeding risk scores, the ORBIT score demonstrated the best discrimination and calibration. All the scores demonstrated, to a variable extent, an interaction with bleeding risk associated with dabigatran or warfarin.

Conformational quiescence of ADAMTS-13 prevents proteolytic promiscuity.

Essentials Recently, ADAMTS-13 has been shown to undergo substrate induced conformation activation. Conformational quiescence of ADAMTS-13 may serve to prevent off-target proteolysis in plasma. Conformationally active ADAMTS-13 variants are capable of proteolysing the Aα chain of fibrinogen. This should be considered as ADAMTS-13 variants are developed as potential therapeutic agents. Click to hear Dr Zheng's presentation on structure function and cofactor-dependent regulation of ADAMTS-13 SUMMARY: Background Recent work has revealed that ADAMTS-13 circulates in a 'closed' conformation, only fully interacting with von Willebrand factor (VWF) following a conformational change. We hypothesized that this conformational quiescence also maintains the substrate specificity of ADAMTS-13 and that the 'open' conformation of the protease might facilitate proteolytic promiscuity. Objectives To identify a novel substrate for a constitutively active gain of function (GoF) ADAMTS-13 variant (R568K/F592Y/R660K/Y661F/Y665F). Methods Fibrinogen proteolysis was characterized using SDS PAGE and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Fibrin formation was monitored by turbidity measurements and fibrin structure visualized by confocal microscopy. Results ADAMTS-13 exhibits proteolytic activity against the Aα chain of human fibrinogen, but this is only manifest on its conformational activation. Accordingly, the GoF ADAMTS-13 variant and truncated variants such as MDTCS exhibit this activity. The cleavage site has been determined by LC-MS/MS to be Aα chain Lys225-Met226. Proteolysis of fibrinogen by GoF ADAMTS-13 impairs fibrin formation in plasma-based assays, alters clot structure and increases clot permeability. Although GoF ADAMTS-13 does not appear to proteolyse preformed cross-linked fibrin, its proteolytic activity against fibrinogen increases the susceptibility of fibrin to tissue-type plasminogen activator (t-PA)-induced lysis by plasmin and increases the fibrin clearance rate more than 8-fold compared with wild-type (WT) ADAMTS-13 (EC50 values of 3.0 ± 1.7 nm and 25.2 ± 9.7 nm, respectively) in in vitro thrombosis models. Conclusion The 'closed' conformation of ADAMTS-13 restricts its specificity and protects against fibrinogenolysis. Induced substrate promiscuity will be important as ADAMTS-13 variants are developed as potential therapeutic agents against thrombotic thrombocytopenic purpura (TTP) and other cardiovascular diseases.

Use of non-vitamin K antagonist oral anticoagulants in atrial fibrillation patients: insights from a specialist atrial fibrillation clinic.

BACKGROUND: Non-vitamin K antagonist oral anticoagulants (NOACs) are broadly preferable to vitamin K antagonists (VKAs) for stroke prevention in non-valvular atrial fibrillation (AF) given their overall net clinical benefit. We report an audit of the profile of OAC usage and adverse events in patients attending a specialist AF clinic. METHODS: Patients attending our specialist AF clinic who were commenced on NOACs for SPAF between January 2013 and August 2014 were included and electronic medical records were retrospectively reviewed between August 2014 and November 2014, to collect demographic, clinical and outcome data. Outcomes included cerebrovascular and bleeding events, death, switching between NOACs or to VKA, dose changes, cessation of NOACs and the reasons for these. To provide perspective, descriptive comparisons were made with a historical cohort of warfarin users attending the specialist AF clinic prior to the introduction of NOACs. RESULTS: We report data on 813 patients as follows: (i) 233 consecutive patients (mean (standard deviation) age 74 (10) years, 45.1% female) initiated on NOACs, with median (interquartile range) CHA2 DS2 -VASc score 3 (2-5) and HAS-BLED score 1 (1-2); and (ii) a historical cohort of 580 patients on warfarin (mean (SD) age 75 (10) years, 42.1% female) with broadly similar demographics. Overall, 54.5% (127/233) were started on rivaroxaban, 22.7% (53/233) on dabigatran and 22.7% on apixaban. Two patients experienced a transient ischaemic attack; 31 patients (13%) contributed to 37 documented bleeding events of which five bleeds (in four patients, 1.7%) were classified as major. There were seven deaths; cause of death was not available for three and the others were not related to NOACs. Eighteen (7.7%) patients switched NOACs, 2 (0.9%) patients switched to warfarin and 8 (3.4%) had their NOACs stopped. There were no ischaemic strokes in the NOAC cohort, compared with nine in the warfarin cohort, with a similar rate of major bleeding (1.7% for NOACs and 1.6% for warfarin). There were more gastrointestinal haemorrhages in the NOAC cohort (3.4% vs. 0.7% with warfarin). CONCLUSION: In this specialist AF clinic, patients prescribed NOACs had a favourable adverse event profile with good efficacy for stroke prevention, with a low rate of cessation or switch to warfarin.

Plasma ADAMTS-13 levels and the risk of myocardial infarction: an individual patient data meta-analysis.

BACKGROUND: Low ADAMTS-13 levels have been repeatedly associated with an increased risk of ischemic stroke, but results concerning the risk of myocardial infarction are inconclusive. OBJECTIVES: To perform an individual patient data meta-analysis from observational studies investigating the association between ADAMTS-13 levels and myocardial infarction. METHODS: A one-step meta-analytic approach with random treatment effects was used to estimate pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) adjusted for confounding. Analyses were based on dichotomous exposures, with the 5th and 1st percentiles of ADAMTS-13 antigen levels as cut-off values. Quartile analyses, with the highest quartile as a reference category, were used to assess a graded association between levels and risk ('dose' relationship). Additionally, we assessed the risk of the combined presence of low ADAMTS-13 and high von Willebrand factor (VWF) levels. RESULTS: Five studies were included, yielding individual data on 1501 cases and 2258 controls (mean age of 49 years). Low ADAMTS-13 levels were associated with myocardial infarction risk, with an OR of 1.89 (95% CI 1.15-3.12) for values below the 5th percentile versus above, and an OR of 4.21 (95% CI 1.73-10.21) for values below the 1st percentile versus above. Risk appeared to be restricted to these extreme levels, as there was no graded association between ADAMTS-13 levels and myocardial infarction risk over quartiles. Finally, there was only a minor synergistic effect for the combination of low ADAMTS-13 and high VWF levels. CONCLUSIONS: Low ADAMTS-13 levels are associated with an increased risk of myocardial infarction.

Gender differences in stroke prevention in atrial fibrillation in general practice: using the GRASP-AF audit tool.

BACKGROUND: Women represent a large proportion of patients with atrial fibrillation (AF) and tend to have higher risk of stroke. AIMS: This study examines gender differences in the utilisation of oral anticoagulation (OAC) and prognosis (i.e. stroke and death) in AF patients in UK general practice. DESIGN: Retrospective observational study. METHODS: The Guidance on Risk Assessment and Stroke Prevention in Atrial Fibrillation (GRASP-AF) tool was employed to identify AF patients from 11 general practices in Darlington, England. RESULTS: Two thousand two hundred and fifty-nine AF patients (mean±SD age 76 ± 12 years; 46% female) were identified. Based on CHA2 DS2 -VASc score 95% of women and 90% of men were at moderate-high risk of stroke. Women with moderate-high risk of stroke were treated with OAC less frequently than men (47% vs. 52%, p = 0.006). Overall rates of stroke and all-cause mortality were higher among women than men (p = 0.02 and p < 0.001). However, there was no significant gender difference in these outcomes in patients receiving OAC (p = 0.52 for stroke, p = 0.18 for death). Among people not receiving OAC where indicated, female gender was associated with an increased risk of stroke before (p = 0.01), and after (p = 0.04), adjustment for stroke risk factors. Women not receiving OAC had a higher risk of death on univariate regression analysis (p = 0.002), but not after adjustment for stroke risk factors (p = 0.53). CONCLUSION: Women with AF are at higher risk of stroke than men without OAC. The gender-related differences in risk of stroke disappear if OAC is used. Despite this, women are more likely not to receive OAC.

Dabigatran adherence in atrial fibrillation patients during the first year after diagnosis: a nationwide cohort study.

BACKGROUND: There is a perception among physicians that lack of routine monitoring with non-vitamin K antagonist oral anticoagulants (NOACs) may lead to poor adherence to medication. We studied adherence during the first year of usage in a cohort of patients with newly diagnosed non-valvular atrial fibrillation (AF) started on the NOAC, dabigatran etexilate. METHODS AND RESULTS: Nationwide Danish patient and prescription purchase registries were used to identify newly diagnosed AF patients taking dabigatran, comorbidities, and refill patterns under a twice-daily, one pill regimen. Adherence was characterized among remaining users (N = 2960) after 1 year using the proportion of days covered (PDC), gap rates and restart rates. The overall 1-year PDC was 83.9%, with 76.8% of patients having a 1-year PDC in excess of 80%. Patients with a CHA2 DS2 -VASc score ≥ 2 were more adherent to medication regimes than patients with a CHA2 DS2 -VASc score of 1 (PDC ratio, 1.12; 95% confidence interval [CI], 1.08-1.17) and generally patients with higher morbidity showed more adherence. Patients with prior bleeding were not less adherent to medication regimes than patients with no prior bleeding (PDC ratio, 1.02; 95% CI, 0.98-1.06). The overall gap rate was 1.4 gaps per year. There were no clear tendencies in gap rates among subgroups, although patients with higher morbidity tended to have slightly more, but shorter, gap periods. CONCLUSIONS: More than 75% of patients were showed > 80% adherence to medication regimes during the first year. Patients with higher morbidity, including patients with a higher risk of stroke or bleeding, exhibited better adherence. This improvement may be attributable to more regular contact with the healthcare system.

Is female sex a risk factor for stroke and thromboembolism in patients with atrial fibrillation? A systematic review and meta-analysis.

BACKGROUND: Atrial fibrillation (AF) increases the risk of stroke, but this risk is not homogenous. Many risk factors contribute to stroke risk however, the evidence for female sex as a risk factor is less well-established. AIM: To perform a systematic review and meta-analysis of the available evidence to establish if female sex is a risk factor for stroke/thromboembolism among patients with AF. METHODS: A systematic literature search was conducted using Medline. The search term 'atrial fibrillation' was used in combination with 'stroke risk', 'thromboembolism', 'female' and 'gender differences' and returned 735 articles, of which 17 were appraised and included. Females with AF were compared with males with AF for the outcome of stroke/thromboembolism. RESULTS: Seventeen studies, 5 randomized-controlled trials and 12 prospective observational studies were included; 10 demonstrated an increased risk of stroke in women. Meta-analysis of the 17 studies revealed a 1.31-fold (95% confidence intervals (CIs) 1.18-1.46) elevated risk of stroke in women with AF; the risk appearing greatest for women aged ≥75 years. Only three studies compared entirely anticoagulated populations; stroke rates among these patients varied from 1.2-1.44% per-patient year for men and 2.08-2.43% per-patient year for women. Risk of stroke in women appeared similar regardless of oral anticoagulation therapy [risk ratio (95% CI 1.29 (1.09-1.52) and 1.49 (1.17-1.90) in non-anticogulated vs. anticoagulated/mixed cohorts, respectively). CONCLUSIONS: Women with AF are at increased risk of stroke, particularly elderly women. Comprehensive stroke risk assessment, including sex as a risk factor, should be undertaken in all AF patients.

Comparison of the CHADS2, CHA2DS2-VASc and HAS-BLED scores for the prediction of clinically relevant bleeding in anticoagulated patients with atrial fibrillation: the AMADEUS trial.

Many of the risk factors for stroke in atrial fibrillation (AF) are also important risk factors for bleeding. Wetested the hypothesis that the CHADS2 and CHA2DS2-VASc scores (used for stroke risk assessment) could be used to predict serious bleeding, and that these scores would compare well against the HAS-BLED score, which is a specific risk score designed for bleeding risk assessment. From the AMADEUS trial, we focused on the trial's primary safety outcome for serious bleeding, which was "any clinically relevant bleeding". The predictive value of HAS-BLED/CHADS2/CHA2DS2-VASc were compared by area under the curve (AUC, a measure of the c-index) and the Net Reclassification Improvement (NRI). Of 2,293 patients on VKA, 251 (11%) experienced at least one episode of "any clinically relevant bleeding" during an average 429 days follow up period. Incidence of "any clinically relevant bleeding" rose with increasing HAS-BLED/CHADS2/CHA2DS2-VASc scores, but was statistically significant only for HAS-BLED (p<0.0001). Only HAS-BLED demonstrated significant discriminatory performance for "any clinically relevant bleeding" (AUC 0.60, p<0.0001). There were significant AUC-differences between HAS-BLED (which had the highest AUC) and both CHADS2 (p<0.001) and CHA2DS2VASc (p=0.001). The HAS-BLED score also demonstrated significant NRI for the outcome of "any clinically relevant bleeding" when compared with CHADS2 (p=0.001) and CHA2DS2-VASc (p=0.04). In conclusion, the HAS-BLED score demonstrated significant discriminatory performance for "any clinically relevant bleeding" in anticoagulated patients with AF, whilst the CHADS2 and CHA2DS2-VASc scores did not. Bleeding risk assessment should be made using a specific bleeding risk score such as HAS-BLED, and the stroke risk scores such as CHADS2 or CHA2DS2-VASc scores should not be used.

Adjusted prognostic association of depression following myocardial infarction with mortality and cardiovascular events: individual patient data meta-analysis.

BACKGROUND: The association between depression after myocardial infarction and increased risk of mortality and cardiac morbidity may be due to cardiac disease severity. AIMS: To combine original data from studies on the association between post-infarction depression and prognosis into one database, and to investigate to what extent such depression predicts prognosis independently of disease severity. METHOD: An individual patient data meta-analysis of studies was conducted using multilevel, multivariable Cox regression analyses. RESULTS: Sixteen studies participated, creating a database of 10 175 post-infarction cases. Hazard ratios for post-infarction depression were 1.32 (95% CI 1.26-1.38, P<0.001) for all-cause mortality and 1.19 (95% CI 1.14-1.24, P<0.001) for cardiovascular events. Hazard ratios adjusted for disease severity were attenuated by 28% and 25% respectively. CONCLUSIONS: The association between depression following myocardial infarction and prognosis is attenuated after adjustment for cardiac disease severity. Still, depression remains independently associated with prognosis, with a 22% increased risk of all-cause mortality and a 13% increased risk of cardiovascular events per standard deviation in depression z-score.

Combined anticoagulation and antiplatelet therapy for high-risk patients with atrial fibrillation: a systematic review.

BACKGROUND: Previous research suggests uncertainty whether or not there is any additional benefit in adding antiplatelet therapy (APT) to anticoagulation therapy (ACT) in patients with high-risk atrial fibrillation (AF) in terms of reduction in vascular events, including stroke. The existing guidelines acknowledge an increased risk of bleeding associated with such a strategy; however, there is no consensus on the treatment pathway. OBJECTIVES: To determine, by undertaking a systematic review, if the addition of APT to ACT is beneficial compared with ACT alone in patients with AF who are considered to be at high risk of thromboembolic events (TEs). DATA SOURCES: Data sources included bibliographic databases {the Cochrane Library [Cochrane Central Register of Controlled Trials (CENTRAL)], MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, ClinicalTrials.gov, National Institute for Health Research (NIHR) Clinical Research Network Portfolio, Current Controlled Trials (CCT) and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP)}, reference lists from identified systematic reviews and relevant studies, and contact with clinical experts. Searches were from inception to September 2010 and did not use language restrictions or study design filters. REVIEW METHODS: Studies of any design were included to evaluate clinical effectiveness, including randomised controlled trials (RCTs), non-randomised comparisons, cohort studies, case series or registries, longitudinal studies, systematic reviews and meta-analyses, and conference abstracts published after 2008. Inclusion criteria consisted of a population with AF, at high-risk of TEs, aged ≥ 18 years, on combined ACT and APT compared with others on ACT alone or ACT plus placebo. Inclusion decisions, assessment of study quality and data extraction were undertaken using methods to minimise bias. RESULTS: Fifty-three publications were included, reporting five RCTs (11 publications), 18 non-randomised comparisons (24 publications) and 18 publications that reported reviews, which added no further data. There was variation in the population, types and doses of ACT and APT, definitions of outcomes, and length of follow-up between the studies. There was a paucity of directly randomised high-quality RCTs, whereas non-randomised comparisons were found to have significant confounding factors. No studies looked at the effect of ACT plus APT compared with ACT alone on vascular events in patients with AF following acute coronary syndrome (ACS) or percutaneous coronary intervention. In most studies, significant differences in event rates were not seen between the patients on combined therapy compared with those on ACT alone for outcomes such as stroke (including haemorrhagic and ischaemic strokes), rates of transient ischaemic attacks, composite end points of stroke and systemic embolism (SE), SE alone, acute myocardial infarction, mortality (vascular or all cause) or bleeding events. There was conflicting evidence regarding rates of major adverse events consisting of composite end points, although event rates were generally low. LIMITATIONS: An attempt was made to identify all of the available evidence around the subject despite the dearth of directly randomised studies using a robust review methodology. There was a paucity of directly randomised evidence to undertake a meta-analysis for the merits of one technology over another. The selection criteria were kept necessarily broad with regard to the population, intervention and comparator in order to capture all relevant studies. CONCLUSIONS: This systematic review suggests that there is still insufficient evidence to advocate a clear benefit of the addition of APT to ACT compared with ACT alone in reducing the risk of vascular events in a population of patients at high risk of TEs resulting from AF. It is recommended that a definitive prospective RCT needs to be undertaken in a population at high risk of atherosclerotic coronary artery and other vascular events in addition to being at high risk of AF-mediated TEs. From the UK context, at the time of writing, any future trial should compare adjusted-dose warfarin [international normalised ratio (INR) 2.0-3.0] plus aspirin (75-325 mg) with adjusted-dose warfarin (INR 2.0-3.0). However, given the emergence of newer anticoagulation agents (dabigatran, rivaroxaban and apixaban) this prioritisation may need to be revisited in the future to reflect current best clinical practice. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Atrial fibrillation as a risk factor for cognitive impairment: a semi-systematic review.

It is unclear if atrial fibrillation (AF) is an independent risk factor for cognitive impairment. This review evaluates the available evidence and provides an overview of the association between AF and cognitive function. Electronic database searches, January 1990 to December 2012, identified 271 studies comparing the incidence of cognitive impairment and/or dementia in patients with/without AF. Cognitive function was diagnosed by a physician using the mini-mental state examination (MMSE) or other established diagnostic criteria. Studies with <20 participants and without direct comparison to controls in sinus rhythm were excluded. There were no restrictions on the basis of age, language or study design. Full texts of 11 studies were obtained. Eight studies (three cross-sectional, two case-control and three prospective cohorts) reported an association between cognitive decline and AF. Among cross-sectional studies, patients with AF had a 1.7 (95% CI 1.2-2.5) to 3.3 (95% CI 1.6-6.5) greater risk of cognitive impairment, and a 2.3-fold (95% CI 1.4-3.7) increased risk of dementia, compared to patients in sinus rhythm. There was marked heterogeneity in the design, size and quality of studies and reporting of the data which precluded formal meta-analysis. Eight studies reported an association between AF and cognitive impairment and/or dementia, but the magnitude of risk varied. Further large-scale prospective studies are needed to establish whether AF is a risk factor for cognitive decline, utilizing objective measures of cognitive function and neuropsychological testing, and to investigate the potential benefit of anticoagulation on reducing cognitive impairment and development of dementia.

Routine versus aggressive upstream rhythm control for prevention of early atrial fibrillation in heart failure: background, aims and design of the RACE 3 study.

BACKGROUND: Rhythm control for atrial fibrillation (AF) is cumbersome because of its progressive nature caused by structural remodelling. Upstream therapy refers to therapeutic interventions aiming to modify the atrial substrate, leading to prevention of AF. OBJECTIVE: The Routine versus Aggressive upstream rhythm Control for prevention of Early AF in heart failure (RACE 3) study hypothesises that aggressive upstream rhythm control increases persistence of sinus rhythm compared with conventional rhythm control in patients with early AF and mild-to-moderate early systolic or diastolic heart failure undergoing electrical cardioversion. DESIGN: RACE 3 is a prospective, randomised, open, multinational, multicenter trial. Upstream rhythm control consists of angiotensin converting enzyme inhibitors and/or angiotensin receptor blockers, mineralocorticoid receptor antagonists, statins, cardiac rehabilitation therapy, and intensive counselling on dietary restrictions, exercise maintenance, and drug adherence. Conventional rhythm control consists of routine rhythm control therapy without cardiac rehabilitation therapy and intensive counselling. In both arms, every effort is made to keep patients in the rhythm control strategy, and ion channel antiarrhythmic drugs or pulmonary vein ablation may be instituted if AF relapses. Total inclusion will be 250 patients. If upstream therapy proves to be effective in improving maintenance of sinus rhythm, it could become a new approach to rhythm control supporting conventional pharmacological and non-pharmacological rhythm control.