Early Risks of Death, Stroke/Systemic Embolism, and Major Bleeding in Patients With Newly Diagnosed Atrial Fibrillation.

BACKGROUND: Atrial fibrillation is associated with increased risks of death, stroke/systemic embolism, and bleeding (incurred by antithrombotic therapy), which may occur early after diagnosis. METHODS: We assessed the risk of early events (death, stroke/systemic embolism, and major bleeding) over 12 months and their relation to the time after diagnosis of atrial fibrillation in 52 014 patients prospectively enrolled in the GARFIELD-AF registry (Global Anticoagulant Registry in the FIELD-Atrial Fibrillation) between March 2010 and August 2016. RESULTS: Over 12 months, 2140 patients died (mortality rate, 4.3; 95% CI, 4.2-4.5 per 100 person-years), of whom 288 (13.5%) died in the first month (6.8; 95% CI, 6.1-7.6). Over 12 months, 657 patients had a stroke/systemic embolism (1.3; 95% CI, 1.2-1.4) and 411 had a major bleeding (0.8; 95% CI, 0.8-0.9). During the first month, the rates (per 100 person-years) of stroke/systemic embolism and major bleed were 2.3 (95% CI, 1.9-2.8) and 1.5 (95% CI, 1.2-1.9), respectively. The elevated 1-month mortality rate was mostly attributable to cardiovascular mortality (3.5; 95% CI, 3.0-4.1), in particular, heart failure, sudden death, and acute coronary syndromes (1.0 [95% CI, 0.8-1.4], 0.6 [95% CI, 0.4-0.8], and 0.5 [95% CI, 0.3-0.8], respectively). Age, heart failure, prior stroke, history of cirrhosis, vascular disease, moderate-to-severe kidney disease, diabetes mellitus, and living in North or Latin America were independent predictors of a higher risk of early death, whereas anticoagulation and living in Europe or Asia were independent predictors of a lower risk of early death. A predictive model developed for the 1-month risk of death had a C-statistic of 0.81 (95% CI, 0.78-0.83). CONCLUSIONS: The increased hazard of early events, in particular, cardiovascular mortality, in newly diagnosed atrial fibrillation points to the importance of comprehensive care for such patients and should alert clinicians to detect warning signs of possible early mortality. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01090362.

A randomised controlled trial of extended anticoagulation treatment versus standard treatment for the prevention of recurrent venous thromboembolism (VTE) and post-thrombotic syndrome in patients being treated for a first episode of unprovoked VTE (the ExACT study).

Venous thromboembolism (VTE) is prevalent and impactful, with a risk of death, morbidity and recurrence. Post-thrombotic syndrome (PTS) is a common consequence and associated with impaired quality of life (QoL). The ExACT study was a non-blinded, prospective, multicentred randomised controlled trial comparing extended versus limited duration anticoagulation following a first unprovoked VTE (proximal deep vein thrombosis or pulmonary embolism). Adults were eligible if they had completed ≥3 months anticoagulation (remaining anticoagulated). The primary outcome was time to first recurrent VTE from randomisation. The secondary outcomes included PTS severity, bleeding, QoL and D-dimers. Two-hundred and eighty-one patients were recruited, randomised and followed up for 24 months (mean age 63, male:female 2:1). There was a significant reduction in recurrent VTE for patients receiving extended anticoagulation [2·75 vs. 13·54 events/100 patient years, adjusted hazard ratio (aHR) 0·20 (95% confidence interval (CI): 0·09 to 0·46, P < 0·001)] with a non-significant increase in major bleeding [3·54 vs. 1·18 events/100 patient years, aHR 2·99 (95% CI: 0·81-11·05, P = 0·10)]. Outcomes of PTS and QoL were no different between groups. D-dimer results (on anticoagulation) did not predict VTE recurrence. In conclusion, extended anticoagulation reduced VTE recurrence but did not reduce PTS or improve QoL and was associated with a non-significant increase in bleeding. Results also suggest very limited clinical utility of D-dimer testing on anticoagulated patients.

Supervised pulmonary hypertension exercise rehabilitation (SPHERe): study protocol for a multi-centre randomised controlled trial.

BACKGROUND: Supervised cardio-pulmonary rehabilitation may be safe and beneficial for people with pulmonary hypertension (PH) in groups 1 (pulmonary arterial hypertension) and 4 (chronic thromboembolic disease), particularly as a hospital in-patient. It has not been tested in the most common PH groups; 2 (left heart disease), 3 (lung disease), or 5 (other disorders). Further it has not been evaluated in the UK National Health Service (NHS) out-patient setting, or with long-term follow-up. The aim of this randomised controlled trial (RCT) is to test the clinical and cost-effectiveness of a supervised exercise rehabilitation intervention with psychosocial support compared to best practice usual care for people with PH in the community/outpatient setting. METHODS: This multi-centre, pragmatic, two-arm RCT with embedded process evaluation aims to recruit 352 clinically stable adults with PH (groups 1-5) and WHO functional class II-IV. Participants will be randomised to either the Supervised Pulmonary Hypertension Exercise Rehabilitation (SPHERe) intervention or control. The SPHERe intervention consists of 1) individual assessment and familiarisation sessions; 2) 8-week, twice-weekly, supervised out-patient exercise training; 3) psychosocial/motivational support and education; 4) guided home exercise plan. The control intervention consists of best practice usual care with a single one-to-one practitioner appointment, and general advice on physical activity. Outcomes will be measured at baseline, 4 months (post-intervention) and 12 months by researchers blinded to treatment allocation. The primary outcome is the incremental shuttle walk test at 4 months. Secondary outcomes include health-related quality of life (HRQoL), time to clinical worsening and health and social care use. A purposive sample of participants (n = 20 intervention and n = 20 control) and practitioners (n = 20) will be interviewed to explore experiences of the trial, outcomes and interventions. DISCUSSION: The SPHERe study is the first multi-centre clinical RCT to assess the clinical and cost effectiveness of a supervised exercise rehabilitation intervention compared to usual care, delivered in the UK NHS, for people in all PH groups. Results will inform clinicians and commissioners as to whether or not supervised exercise rehabilitation is effective and should be routinely provided for people with PH. TRIAL REGISTRATION: ISRCTN no. 10608766, prospectively registered on 18th March 2019.

Estimated stroke risk, yield, and number needed to screen for atrial fibrillation detected through single time screening: a multicountry patient-level meta-analysis of 141,220 screened individuals.

BACKGROUND: The precise age distribution and calculated stroke risk of screen-detected atrial fibrillation (AF) is not known. Therefore, it is not possible to determine the number needed to screen (NNS) to identify one treatable new AF case (NNS-Rx) (i.e., Class-1 oral anticoagulation [OAC] treatment recommendation) in each age stratum. If the NNS-Rx is known for each age stratum, precise cost-effectiveness and sensitivity simulations can be performed based on the age distribution of the population/region to be screened. Such calculations are required by national authorities and organisations responsible for health system budgets to determine the best age cutoffs for screening programs and decide whether programs of screening should be funded. Therefore, we aimed to determine the exact yield and calculated stroke-risk profile of screen-detected AF and NNS-Rx in 5-year age strata. METHODS AND FINDINGS: A systematic review of Medline, Pubmed, and Embase was performed (January 2007 to February 2018), and AF-SCREEN international collaboration members were contacted to identify additional studies. Twenty-four eligible studies were identified that performed a single time point screen for AF in a general ambulant population, including people ≥65 years. Authors from eligible studies were invited to collaborate and share patient-level data. Statistical analysis was performed using random effects logistic regression for AF detection rate, and Poisson regression modelling for CHA2DS2-VASc scores. Nineteen studies (14 countries from a mix of low- to middle- and high-income countries) collaborated, with 141,220 participants screened and 1,539 new AF cases. Pooled yield of screening was greater in males across all age strata. The age/sex-adjusted detection rate for screen-detected AF in ≥65-year-olds was 1.44% (95% CI, 1.13%-1.82%) and 0.41% (95% CI, 0.31%-0.53%) for <65-year-olds. New AF detection rate increased progressively with age from 0.34% (<60 years) to 2.73% (≥85 years). Neither the choice of screening methodology or device, the geographical region, nor the screening setting influenced the detection rate of AF. Mean CHA2DS2-VASc scores (n = 1,369) increased with age from 1.1 (<60 years) to 3.9 (≥85 years); 72% of ≥65 years had ≥1 additional stroke risk factor other than age/sex. All new AF ≥75 years and 66% between 65 and 74 years had a Class-1 OAC recommendation. The NNS-Rx is 83 for ≥65 years, 926 for 60-64 years; and 1,089 for <60 years. The main limitation of this study is there are insufficient data on sociodemographic variables of the populations and possible ascertainment biases to explain the variance in the samples. CONCLUSIONS: People with screen-detected AF are at elevated calculated stroke risk: above age 65, the majority have a Class-1 OAC recommendation for stroke prevention, and >70% have ≥1 additional stroke risk factor other than age/sex. Our data, based on the largest number of screen-detected AF collected to date, show the precise relationship between yield and estimated stroke risk profile with age, and strong dependence for NNS-RX on the age distribution of the population to be screened: essential information for precise cost-effectiveness calculations.

Model-based evaluation of the long-term cost-effectiveness of systematic case-finding for COPD in primary care.

INTRODUCTION: 'One-off' systematic case-finding for COPD using a respiratory screening questionnaire is more effective and cost-effective than routine care at identifying new cases. However, it is not known whether early diagnosis and treatment is beneficial in the longer term. We estimated the long-term cost-effectiveness of a regular case-finding programme in primary care. METHODS: A Markov decision analytic model was developed to compare the cost-effectiveness of a 3-yearly systematic case-finding programme targeted to ever smokers aged ≥50 years with the current routine diagnostic process in UK primary care. Patient-level data on case-finding pathways was obtained from a large randomised controlled trial. Information on the natural history of COPD and treatment effects was obtained from a linked COPD cohort, UK primary care database and published literature. The discounted lifetime cost per quality-adjusted life-year (QALY) gained was calculated from a health service perspective. RESULTS: The incremental cost-effectiveness ratio of systematic case-finding versus current care was £16 596 per additional QALY gained, with a 78% probability of cost-effectiveness at a £20 000 per QALY willingness-to-pay threshold. The base case result was robust to multiple one-way sensitivity analyses. The main drivers were response rate to the initial screening questionnaire and attendance rate for the confirmatory spirometry test. DISCUSSION: Regular systematic case-finding for COPD using a screening questionnaire in primary care is likely to be cost-effective in the long-term despite uncertainties in treatment effectiveness. Further knowledge of the natural history of case-found patients and the effectiveness of their management will improve confidence to implement such an approach.

The Push and Pull of Self-Managing Mild COPD: An Evaluation of Participant Experiences of a Nurse-Led Telephone Health Coaching Intervention.

Health coaching is a novel population intervention to support self-management but it is untested in people with mild disease. People with chronic obstructive pulmonary disease with mild dyspnea are a population excluded from supported self-management and whose illness might progress without intervention. We explored participants' experiences about how health coaching motivated behavior change. Interviews were conducted with 21 intervention and 10 control participants at 6 months, and 20 intervention participants at 12 months. Participants were identified from a randomized controlled trial of telephone health coaching. Data were analyzed using the framework method. Participants positively enacted behavior change to become more physically active. Participants took advantage of environmental affordances to pull themselves toward activity targets, or relied on being pushed to be more active by the health coach or significant others. Behavior change was maintained where efforts to be more active were built into the everyday lifeworld of participants.

Screening for Atrial Fibrillation: A Report of the AF-SCREEN International Collaboration.

Approximately 10% of ischemic strokes are associated with atrial fibrillation (AF) first diagnosed at the time of stroke. Detecting asymptomatic AF would provide an opportunity to prevent these strokes by instituting appropriate anticoagulation. The AF-SCREEN international collaboration was formed in September 2015 to promote discussion and research about AF screening as a strategy to reduce stroke and death and to provide advocacy for implementation of country-specific AF screening programs. During 2016, 60 expert members of AF-SCREEN, including physicians, nurses, allied health professionals, health economists, and patient advocates, were invited to prepare sections of a draft document. In August 2016, 51 members met in Rome to discuss the draft document and consider the key points arising from it using a Delphi process. These key points emphasize that screen-detected AF found at a single timepoint or by intermittent ECG recordings over 2 weeks is not a benign condition and, with additional stroke factors, carries sufficient risk of stroke to justify consideration of anticoagulation. With regard to the methods of mass screening, handheld ECG devices have the advantage of providing a verifiable ECG trace that guidelines require for AF diagnosis and would therefore be preferred as screening tools. Certain patient groups, such as those with recent embolic stroke of uncertain source (ESUS), require more intensive monitoring for AF. Settings for screening include various venues in both the community and the clinic, but they must be linked to a pathway for appropriate diagnosis and management for screening to be effective. It is recognized that health resources vary widely between countries and health systems, so the setting for AF screening should be both country- and health system-specific. Based on current knowledge, this white paper provides a strong case for AF screening now while recognizing that large randomized outcomes studies would be helpful to strengthen the evidence base.

Automated Software System to Promote Anticoagulation and Reduce Stroke Risk: Cluster-Randomized Controlled Trial.

BACKGROUND AND PURPOSE: Oral anticoagulants (OAC) substantially reduce risk of stroke in atrial fibrillation, but uptake is suboptimal. Electronic health records enable automated identification of people at risk but not receiving treatment. We investigated the effectiveness of a software tool (AURAS-AF [Automated Risk Assessment for Stroke in Atrial Fibrillation]) designed to identify such individuals during routine care through a cluster-randomized trial. METHODS: Screen reminders appeared each time the electronic health records of an eligible patient was accessed until a decision had been taken over OAC treatment. Where OAC was not started, clinicians were prompted to indicate a reason. Control practices continued usual care. The primary outcome was the proportion of eligible individuals receiving OAC at 6 months. Secondary outcomes included rates of cardiovascular events and reports of adverse effects of the software on clinical decision-making. RESULTS: Forty-seven practices were randomized. The mean proportion-prescribed OAC at 6 months was 66.3% (SD=9.3) in the intervention arm and 63.9% (9.5) in the control arm (adjusted difference 1.21% [95% confidence interval -0.72 to 3.13]). Incidence of recorded transient ischemic attack was higher in the intervention practices (median 10.0 versus 2.3 per 1000 patients with atrial fibrillation; P=0.027), but at 12 months, we found a lower incidence of both all cause stroke (P=0.06) and hemorrhage (P=0.054). No adverse effects of the software were reported. CONCLUSIONS: No significant change in OAC prescribing occurred. A greater rate of diagnosis of transient ischemic attack (possibly because of improved detection or overdiagnosis) was associated with a reduction (of borderline significance) in stroke and hemorrhage over 12 months. CLINICAL TRIAL REGISTRATION: URL: http://www.isrctn.com. Unique Identifier: ISRCTN55722437.

Predicting risk of undiagnosed COPD: development and validation of the TargetCOPD score.

Chronic obstructive pulmonary disease (COPD) is greatly underdiagnosed worldwide and more efficient methods of case-finding are required. We developed and externally validated a risk score to identify undiagnosed COPD using primary care records.We conducted a retrospective cohort analysis of a pragmatic cluster randomised controlled case-finding trial in the West Midlands, UK. Participants aged 40-79 years with no prior diagnosis of COPD received a postal or opportunistic screening questionnaire. Those reporting chronic respiratory symptoms were assessed with spirometry. COPD was defined as presence of relevant symptoms with a post-bronchodilator forced expiratory volume in 1 s/forced vital capacity ratio below the lower limit of normal. A risk score was developed using logistic regression with variables available from electronic health records for 2398 participants who returned a postal questionnaire. This was externally validated among 1097 participants who returned an opportunistic questionnaire to derive the c-statistic, and the sensitivity and specificity of cut-points.A risk score containing age, smoking status, dyspnoea, prescriptions of salbutamol and prescriptions of antibiotics discriminated between patients with and without undiagnosed COPD (c-statistic 0.74, 95% CI 0.68-0.80). A cut-point of ≥7.5% predicted risk had a sensitivity of 68.8% (95% CI 57.3-78.9%) and a specificity of 68.8% (95% CI 65.8.1-71.6%).A novel risk score using routine data from primary care electronic health records can identify patients at high risk for undiagnosed symptomatic COPD. This score could be integrated with clinical information systems to help primary care clinicians target patients for case-finding.

Factors associated with work productivity among people with COPD: Birmingham COPD Cohort.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) are more likely to take time off work (absenteeism) and report poor performance at work (presenteeism) compared to those without COPD. Little is known about the modifiable factors associated with these work productivity outcomes. AIM: To assess the factors associated with work productivity among COPD patients. METHODS: Cross-sectional analysis of baseline data from a subsample (those in paid employment) of the Birmingham COPD Cohort study. Absenteeism was defined by self-report over the previous 12 months. Presenteeism was assessed using the Stanford Presenteeism Scale. Logistic regression analysis was used to assess the effects of sociodemographic, clinical and occupational characteristics on work productivity. RESULTS: Among 348 included participants, increasing dyspnoea was the only factor associated with both absenteeism and presenteeism (p for trend<0.01). Additionally, increasing history of occupational exposure to vapours, gases, dusts or fumes (VGDF) was independently associated with presenteeism (p for trend<0.01). CONCLUSIONS: This is the first study to identify important factors associated with poor work productivity among patients with COPD. Future studies should evaluate interventions aimed at managing breathlessness and reducing occupational exposures to VGDF on work productivity among patients with COPD.

Two-year outcomes of patients with newly diagnosed atrial fibrillation: results from GARFIELD-AF.

AIMS: The relationship between outcomes and time after diagnosis for patients with non-valvular atrial fibrillation (NVAF) is poorly defined, especially beyond the first year. METHODS AND RESULTS: GARFIELD-AF is an ongoing, global observational study of adults with newly diagnosed NVAF. Two-year outcomes of 17 162 patients prospectively enrolled in GARFIELD-AF were analysed in light of baseline characteristics, risk profiles for stroke/systemic embolism (SE), and antithrombotic therapy. The mean (standard deviation) age was 69.8 (11.4) years, 43.8% were women, and the mean CHA2DS2-VASc score was 3.3 (1.6); 60.8% of patients were prescribed anticoagulant therapy with/without antiplatelet (AP) therapy, 27.4% AP monotherapy, and 11.8% no antithrombotic therapy. At 2-year follow-up, all-cause mortality, stroke/SE, and major bleeding had occurred at a rate (95% confidence interval) of 3.83 (3.62; 4.05), 1.25 (1.13; 1.38), and 0.70 (0.62; 0.81) per 100 person-years, respectively. Rates for all three major events were highest during the first 4 months. Congestive heart failure, acute coronary syndromes, sudden/unwitnessed death, malignancy, respiratory failure, and infection/sepsis accounted for 65% of all known causes of death and strokes for <10%. Anticoagulant treatment was associated with a 35% lower risk of death. CONCLUSION: The most frequent of the three major outcome measures was death, whose most common causes are not known to be significantly influenced by anticoagulation. This suggests that a more comprehensive approach to the management of NVAF may be needed to improve outcome. This could include, in addition to anticoagulation, interventions targeting modifiable, cause-specific risk factors for death. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT01090362.

Under-prescribing of Prevention Drugs and Primary Prevention of Stroke and Transient Ischaemic Attack in UK General Practice: A Retrospective Analysis.

BACKGROUND: Stroke is a leading cause of death and disability; worldwide it is estimated that 16.9 million people have a first stroke each year. Lipid-lowering, anticoagulant, and antihypertensive drugs can prevent strokes, but may be underused. METHODS AND FINDINGS: We analysed anonymised electronic primary care records from a United Kingdom (UK) primary care database that covers approximately 6% of the UK population. Patients with first-ever stroke/transient ischaemic attack (TIA), ≥18 y, with diagnosis between 1 January 2009 and 31 December 2013, were included. Drugs were considered under-prescribed when lipid-lowering, anticoagulant, or antihypertensive drugs were clinically indicated but were not prescribed prior to the time of stroke or TIA. The proportions of strokes or TIAs with prevention drugs under-prescribed, when clinically indicated, were calculated. In all, 29,043 stroke/TIA patients met the inclusion criteria; 17,680 had ≥1 prevention drug clinically indicated: 16,028 had lipid-lowering drugs indicated, 3,194 anticoagulant drugs, and 7,008 antihypertensive drugs. At least one prevention drug was not prescribed when clinically indicated in 54% (9,579/17,680) of stroke/TIA patients: 49% (7,836/16,028) were not prescribed lipid-lowering drugs, 52% (1,647/3,194) were not prescribed anticoagulant drugs, and 25% (1,740/7,008) were not prescribed antihypertensive drugs. The limitations of our study are that our definition of under-prescribing of drugs for stroke/TIA prevention did not address patients' adherence to medication or medication targets, such as blood pressure levels. CONCLUSIONS: In our study, over half of people eligible for lipid-lowering, anticoagulant, or antihypertensive drugs were not prescribed them prior to first stroke/TIA. We estimate that approximately 12,000 first strokes could potentially be prevented annually in the UK through optimal prescribing of these drugs. Improving prescription of lipid-lowering, anticoagulant, and antihypertensive drugs is important to reduce the incidence and burden of stroke and TIA.

Comparison of international normalized ratio audit parameters in patients enrolled in GARFIELD-AF and treated with vitamin K antagonists.

Vitamin K antagonist (VKA) therapy for stroke prevention in atrial fibrillation (AF) requires monitoring of the international normalized ratio (INR). We evaluated the agreement between two INR audit parameters, frequency in range (FIR) and proportion of time in the therapeutic range (TTR), using data from a global population of patients with newly diagnosed non-valvular AF, the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF). Among 17 168 patients with 1-year follow-up data available at the time of the analysis, 8445 received VKA therapy (±antiplatelet therapy) at enrolment, and of these patients, 5066 with ≥3 INR readings and for whom both FIR and TTR could be calculated were included in the analysis. In total, 70 905 INRs were analysed. At the patient level, TTR showed higher values than FIR (mean, 56·0% vs 49·8%; median, 59·7% vs 50·0%). Although patient-level FIR and TTR values were highly correlated (Pearson correlation coefficient [95% confidence interval; CI], 0·860 [0·852-0·867]), estimates from individuals showed widespread disagreement and variability (Lin's concordance coefficient [95% CI], 0·829 [0·821-0·837]). The difference between FIR and TTR explained 17·4% of the total variability of measurements. These results suggest that FIR and TTR are not equivalent and cannot be used interchangeably.

Self-monitoring and self-management of oral anticoagulation.

BACKGROUND: The introduction of point-of-care devices for the management of patients on oral anticoagulation allows self-testing by the patient at home. Patients who self-test can either adjust their medication according to a pre-determined dose-INR (international normalized ratio) schedule (self-management), or they can call a clinic to be told the appropriate dose adjustment (self-monitoring). Increasing evidence suggests self-testing of oral anticoagulant therapy is equal to or better than standard monitoring. This is an updated version of the original review published in 2010. OBJECTIVES: To evaluate the effects on thrombotic events, major haemorrhages, and all-cause mortality of self-monitoring or self-management of oral anticoagulant therapy compared to standard monitoring. SEARCH METHODS: For this review update, we re-ran the searches of the Cochrane Central Register of Controlled Trials (CENTRAL), 2015, Issue 6, the Cochrane Library, MEDLINE (Ovid, 1946 to June week 4 2015), Embase (Ovid, 1980 to 2015 week 27) on 1 July 2015. We checked bibliographies and contacted manufacturers and authors of relevant studies. We did not apply any language restrictions . SELECTION CRITERIA: Outcomes analysed were thromboembolic events, mortality, major haemorrhage, minor haemorrhage, tests in therapeutic range, frequency of testing, and feasibility of self-monitoring and self-management. DATA COLLECTION AND ANALYSIS: Review authors independently extracted data and we used a fixed-effect model with the Mantzel-Haenzel method to calculate the pooled risk ratio (RR) and Peto's method to verify the results for uncommon outcomes. We examined heterogeneity amongst studies with the Chi(2) and I(2) statistics and used GRADE methodology to assess the quality of evidence. MAIN RESULTS: We identified 28 randomised trials including 8950 participants (newly incorporated in this update: 10 trials including 4227 participants). The overall quality of the evidence was generally low to moderate. Pooled estimates showed a reduction in thromboembolic events (RR 0.58, 95% CI 0.45 to 0.75; participants = 7594; studies = 18; moderate quality of evidence). Both, trials of self-management or self-monitoring showed reductions in thromboembolic events (RR 0.47, 95% CI 0.31 to 0.70; participants = 3497; studies = 11) and (RR 0.69, 95% CI 0.49 to 0.97; participants = 4097; studies = 7), respectively; the quality of evidence for both interventions was moderate. No reduction in all-cause mortality was found (RR 0.85, 95% CI 0.71 to 1.01; participants = 6358; studies = 11; moderate quality of evidence). While self-management caused a reduction in all-cause mortality (RR 0.55, 95% CI 0.36 to 0.84; participants = 3058; studies = 8); self-monitoring did not (RR 0.94, 95% CI 0.78 to 1.15; participants = 3300; studies = 3); the quality of evidence for both interventions was moderate. In 20 trials (8018 participants) self-monitoring or self-management did not reduce major haemorrhage (RR 0.95, 95% CI, 0.80 to 1.12; moderate quality of evidence). There was no significant difference found for minor haemorrhage (RR 0.97, 95% CI 0.67 to 1.41; participants = 5365; studies = 13). The quality of evidence was graded as low because of serious risk of bias and substantial heterogeneity (I(2) = 82%). AUTHORS' CONCLUSIONS: Participants who self-monitor or self-manage can improve the quality of their oral anticoagulation therapy. Thromboembolic events were reduced, for both those self-monitoring or self-managing oral anticoagulation therapy. A reduction in all-cause mortality was observed in trials of self-management but not in self-monitoring, with no effects on major haemorrhage.

Patient self-management in primary care patients with mild COPD - protocol of a randomised controlled trial of telephone health coaching.

BACKGROUND: The prevalence of diagnosed chronic obstructive pulmonary disease (COPD) in the UK is 1.8%, although it is estimated that this represents less than half of the total disease in the population as much remains undiagnosed. Case finding initiatives in primary care will identify people with mild disease and symptoms. The majority of self-management trials have identified patients from secondary care clinics or following a hospital admission for exacerbation of their condition. This trial will recruit a primary care population with mild symptoms of COPD and use telephone health coaching to encourage self-management. METHODS/DESIGN: In this study, using a multi-centred randomised controlled trial (RCT) across at least 70 general practices in England, we plan to establish the effectiveness of nurse-led telephone health coaching to support self-management in primary care for people who report only mild symptoms of their COPD (MRC grade 1 and 2) compared to usual care. The intervention focuses on taking up smoking cessation services, increasing physical activity, medication management and action planning and is underpinned by behavioural change theory. In total, we aim to recruit 556 patients with COPD confirmed by spirometry with follow up at six and 12 months. The primary outcome is health related quality of life using the St Georges Respiratory Questionnaire (SGRQ). Spirometry and BMI are measured at baseline. Secondary outcomes include self-reported health behaviours (smoking and physical activity), physical activity measured by accelerometery (at 12 months), psychological morbidity, self-efficacy and cost-effectiveness of the intervention. Longitudinal qualitative interviews will explore how engaged participants were with the intervention and how embedded behaviour change was in every day practices. DISCUSSION: This trial will provide robust evidence about the effectiveness of a novel telephone health coaching intervention to promote behaviour change and prevent disease progression in patients with mild symptoms of dyspnoea in primary care. TRIAL REGISTRATION: Current controlled trials ISRCTN06710391 .

Warfarin versus aspirin for prevention of cognitive decline in atrial fibrillation: randomized controlled trial (Birmingham Atrial Fibrillation Treatment of the Aged Study).

BACKGROUND AND PURPOSE: Atrial fibrillation is associated with decline of cognitive function. Observational evidence suggests that anticoagulation might protect against this decline. We report the first randomized controlled trial evidence on the effect of anticoagulation on cognitive function in elderly patients with atrial fibrillation. METHODS: A total of 973 patients aged≥75 years with atrial fibrillation were recruited from primary care and randomly assigned to warfarin (n=488; target international normalized ratio, 2-3) or aspirin (n=485; 75 mg/d). Neither participants nor investigators were masked to group assignment. Follow-up was for a mean of 2.7 years (SD, 1.2). Cognitive outcome was assessed using the Mini-Mental State Examination at 9-, 21-, and 33-month follow-up. Participants who had a stroke were censored from the analysis, which was by intention to treat with imputation for missing data. RESULTS: There was no difference between mean Mini-Mental State Examination scores in people assigned to warfarin or aspirin at 9 or 21 months. At 33-month follow-up, there was a nonsignificant difference of 0.56 in favor of warfarin that decreased to 0.49 (95% confidence interval, -0.01 to 0.98) after imputation. CONCLUSIONS: We found no evidence that anticoagulation confers clinically important protection over aspirin against cognitive decline as measured by the Mini-Mental State Examination in atrial fibrillation in the first 33 months of treatment other than that provided by preventing clinical stroke. CLINICAL TRIAL REGISTRATION URL: http://www.controlled-trials.com. Unique identifier: ISRCTN89345269.

TargetCOPD: a pragmatic randomised controlled trial of targeted case finding for COPD versus routine practice in primary care: protocol.

BACKGROUND: Many people with clinically significant chronic obstructive pulmonary disease (COPD) remain undiagnosed worldwide. There are a number of small studies which have examined possible methods of case finding through primary care, but no large RCTs that have adequately assessed the most cost-effective approach. METHODS/DESIGN: In this study, using a cluster randomised controlled trial (RCT) in 56 general practices in the West Midlands, we plan to investigate the effectiveness and cost-effectiveness of a Targeted approach to case finding for COPD compared with routine practice. Using an individual patient RCT nested in the Targeted arm, we plan also to compare the effectiveness and cost-effectiveness of Active case finding using a postal questionnaire (with supplementary opportunistic questionnaires), and Opportunistic-only case finding during routine surgery consultations.All ever-smoking patients aged 40-79 years, without a current diagnosis of COPD and registered with participating practices will be eligible. Patients in the Targeted arm who report positive respiratory symptoms (chronic cough or phlegm, wheeze or dyspnoea) using a brief questionnaire will be invited for further spirometric assessment to ascertain whether they have COPD or not. Post-bronchodilator spirometry will be conducted to ATS standards using an Easy One spirometer by trained research assistants.The primary outcomes will be new cases of COPD and cost per new case identified, comparing targeted case finding with routine care, and two types of targeted case finding (active versus opportunistic). A multilevel logistic regression model will be used to model the probability of detecting a new case of COPD for each treatment arm, with clustering of patients (by practice and household) accounted for using a multi-level structure.A trial-based analysis will be undertaken using costs and outcomes collected during the trial. Secondary outcomes include the feasibility, efficiency, long-term cost-effectiveness, patient and primary care staff views of each approach. DISCUSSION: This will be the largest RCT of its kind, and should inform how best to identify undiagnosed patients with COPD in the UK and other similar healthcare systems. Sensitivity analyses will help local policy-makers decide which sub-groups of the population to target first. TRIAL REGISTRATION: Current controlled trials ISRCTN14930255.

Self-monitoring of oral anticoagulation: systematic review and meta-analysis of individual patient data.

BACKGROUND: Uptake of self-testing and self-management of oral anticoagulation [corrected] has remained inconsistent, despite good evidence of their effectiveness. To clarify the value of self-monitoring of oral anticoagulation, we did a meta-analysis of individual patient data addressing several important gaps in the evidence, including an estimate of the effect on time to death, first major haemorrhage, and thromboembolism. METHODS: We searched Ovid versions of Embase (1980-2009) and Medline (1966-2009), limiting searches to randomised trials with a maximally sensitive strategy. We approached all authors of included trials and requested individual patient data: primary outcomes were time to death, first major haemorrhage, and first thromboembolic event. We did prespecified subgroup analyses according to age, type of control-group care (anticoagulation-clinic care vs primary care), self-testing alone versus self-management, and sex. We analysed patients with mechanical heart valves or atrial fibrillation separately. We used a random-effect model method to calculate pooled hazard ratios and did tests for interaction and heterogeneity, and calculated a time-specific number needed to treat. FINDINGS: Of 1357 abstracts, we included 11 trials with data for 6417 participants and 12,800 person-years of follow-up. We reported a significant reduction in thromboembolic events in the self-monitoring group (hazard ratio 0·51; 95% CI 0·31-0·85) but not for major haemorrhagic events (0·88, 0·74-1·06) or death (0·82, 0·62-1·09). Participants younger than 55 years showed a striking reduction in thrombotic events (hazard ratio 0·33, 95% CI 0·17-0·66), as did participants with mechanical heart valve (0·52, 0·35-0·77). Analysis of major outcomes in the very elderly (age ≥85 years, n=99) showed no significant adverse effects of the intervention for all outcomes. INTERPRETATION: Our analysis showed that self-monitoring and self-management of oral coagulation is a safe option for suitable patients of all ages. Patients should also be offered the option to self-manage their disease with suitable health-care support as back-up. FUNDING: UK National Institute for Health Research (NIHR) Technology Assessment Programme, UK NIHR National School for Primary Care Research.

An international longitudinal registry of patients with atrial fibrillation at risk of stroke (GARFIELD): the UK protocol.

BACKGROUND: Atrial fibrillation (AF) is an independent risk factor for stroke and a significant predictor of mortality. Evidence-based guidelines for stroke prevention in AF recommend antithrombotic therapy corresponding to the risk of stroke. In practice, many patients with AF do not receive the appropriate antithrombotic therapy and are left either unprotected or inadequately protected against stroke. The purpose of the Global Anticoagulant Registry in the FIELD (GARFIELD) is to determine the real-life management and outcomes of patients newly diagnosed with non-valvular AF. METHODS/DESIGN: GARFIELD is an observational, international registry of newly diagnosed AF patients with at least one additional investigator-defined risk factor for stroke. The aim is to enrol 55,000 patients at more than 1000 centres in 50 countries worldwide. Enrolment will take place in five independent, sequential, prospective cohorts; the first cohort includes a retrospective validation cohort. Each cohort will be followed up for 2 years. The UK stands to be a significant contributor to GARFIELD, aiming to enrol 4,582 patients, and reflecting the care environment in which patients with AF are managed. The UK protocol will also focus on better understanding the validity of the two main stroke risk scores (CHADS2 and CHA2DS2VASC) and the HAS-BLED bleeding risk score, in the context of a diverse patient population. DISCUSSION: The GARFIELD registry will describe how therapeutic strategies, patient care, and clinical outcomes evolve over time. This study will provide UK-specific comprehensive data that will allow a range of evaluations both at a national level and in relation to global data and contribute to a better understanding of AF management in the UK. TRIAL REGISTRATION: ClinicalTrial.gov: NCT01090362.

Trial Protocol: a randomised controlled trial of extended anticoagulation treatment versus routine anticoagulation treatment for the prevention of recurrent VTE and post thrombotic syndrome in patients being treated for a first episode of unprovoked VTE (The ExACT Study).

BACKGROUND: Venous thromboembolism comprising pulmonary embolism and deep vein thrombosis is a common condition with an incidence of approximately 1 per 1,000 per annum causing both mortality and serious morbidity. The principal aim of treatment of a venous thromboembolism with heparin and warfarin is to prevent extension or recurrence of clot. However, the recurrence rate following a deep vein thrombosis remains approximately 10% per annum following treatment cessation irrespective of the duration of anticoagulation therapy. Patients with raised D-dimer levels after discontinuing oral anticoagulation treatment have also been shown to be at high risk of recurrence.Post thrombotic syndrome is a complication of a deep vein thrombosis which can lead to chronic venous insufficiency and ulceration. It has a cumulative incidence after 2 years of around 25% and it has been suggested that extended oral anticoagulation should be investigated as a possible preventative measure. METHODS/DESIGN: Patients with a first idiopathic venous thromboembolism will be recruited through anticoagulation clinics and randomly allocated to either continuing or discontinuing warfarin treatment for a further 2 years and followed up on a six monthly basis. At each visit D-dimer levels will be measured using a Roche Cobas h 232 POC device. In addition a venous sample will be taken for laboratory D-dimer analysis at the end of the study. Patients will be examined for signs and symptoms of PTS using the Villalta scale and complete VEINES and EQ5D quality of life questionnaires. DISCUSSION: The primary aim of the study is to investigate whether extending oral anticoagulation treatment (prior to discontinuing treatment) beyond 3-6 months for patients with a first unprovoked proximal deep vein thrombosis or pulmonary embolism prevents recurrence. The study will also determine the role of extending anticoagulation for patients with elevated D-dimer levels prior to discontinuing treatment and identify the potential of D-dimer point of care testing for identification of high risk patients within a primary care setting. TRIAL REGISTRATION: ISRCTN73819751.