Safety of off-label dose reduction of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation.

AIM: To investigate the effects of off-label non-vitamin K oral anticoagulant (NOAC) dose reduction compared with on-label standard dosing in atrial fibrillation (AF) patients in routine care. METHODS: Population-based cohort study using data from the United Kingdom Clinical Practice Research Datalink, comparing adults with non-valvular AF receiving an off-label reduced NOAC dose to patients receiving an on-label standard dose. Outcomes were ischaemic stroke, major/non-major bleeding and mortality. Inverse probability of treatment weighting and inverse probability of censoring weighting on the propensity score were applied to adjust for confounding and informative censoring. RESULTS: Off-label dose reduction occurred in 2466 patients (8.0%), compared with 18 108 (58.5%) on-label standard-dose users. Median age was 80 years (interquartile range [IQR] 73.0-86.0) versus 72 years (IQR 66-78), respectively. Incidence rates were higher in the off-label dose reduction group compared to the on-label standard dose group, for ischaemic stroke (0.94 vs 0.70 per 100 person years), major bleeding (1.48 vs 0.83), non-major bleeding (6.78 vs 6.16) and mortality (10.12 vs 3.72). Adjusted analyses resulted in a hazard ratio of 0.95 (95% confidence interval [CI] 0.57-1.60) for ischaemic stroke, 0.88 (95% CI 0.57-1.35) for major bleeding, 0.81 (95% CI 0.67-0.98) for non-major bleeding and 1.34 (95% CI 1.12-1.61) for mortality. CONCLUSION: In this large population-based study, the hazards for ischaemic stroke and major bleeding were low, and similar in AF patients receiving an off-label reduced NOAC dose compared with on-label standard dose users, while non-major bleeding risk appeared to be lower and mortality risk higher. Caution towards prescribing an off-label reduced NOAC dose is therefore required.

Integrated management of atrial fibrillation in primary care: results of the ALL-IN cluster randomized trial.

AIMS: To evaluate whether integrated care for atrial fibrillation (AF) can be safely orchestrated in primary care. METHODS AND RESULTS: The ALL-IN trial was a cluster randomized, open-label, pragmatic non-inferiority trial performed in primary care practices in the Netherlands. We randomized 26 practices: 15 to the integrated care intervention and 11 to usual care. The integrated care intervention consisted of (i) quarterly AF check-ups by trained nurses in primary care, also focusing on possibly interfering comorbidities, (ii) monitoring of anticoagulation therapy in primary care, and finally (iii) easy-access availability of consultations from cardiologists and anticoagulation clinics. The primary endpoint was all-cause mortality during 2 years of follow-up. In the intervention arm, 527 out of 941 eligible AF patients aged ≥65 years provided informed consent to undergo the intervention. These 527 patients were compared with 713 AF patients in the control arm receiving usual care. Median age was 77 (interquartile range 72-83) years. The all-cause mortality rate was 3.5 per 100 patient-years in the intervention arm vs. 6.7 per 100 patient-years in the control arm [adjusted hazard ratio (HR) 0.55; 95% confidence interval (CI) 0.37-0.82]. For non-cardiovascular mortality, the adjusted HR was 0.47 (95% CI 0.27-0.82). For other adverse events, no statistically significant differences were observed. CONCLUSION: In this cluster randomized trial, integrated care for elderly AF patients in primary care showed a 45% reduction in all-cause mortality when compared with usual care.

Limited incremental predictive value of the frailty index and other vulnerability measures from routine care data for mortality risk prediction in older patients with COVID-19 in primary care.

BACKGROUND: During the COVID-19 pandemic, older patients in primary care were triaged based on their frailty or assumed vulnerability for poor outcomes, while evidence on the prognostic value of vulnerability measures in COVID-19 patients in primary care was lacking. Still, knowledge on the role of vulnerability is pivotal in understanding the resilience of older people during acute illness, and hence important for future pandemic preparedness. Therefore, we assessed the predictive value of different routine care-based vulnerability measures in addition to age and sex for 28-day mortality in an older primary care population of patients with COVID-19. METHODS: From primary care medical records using three routinely collected Dutch primary care databases, we included all patients aged 70 years or older with a COVID-19 diagnosis registration in 2020 and 2021. All-cause mortality was predicted using logistic regression based on age and sex only (basic model), and separately adding six vulnerability measures: renal function, cognitive impairment, number of chronic drugs, Charlson Comorbidity Index, Chronic Comorbidity Score, and a Frailty Index. Predictive performance of the basic model and the six vulnerability models was compared in terms of area under the receiver operator characteristic curve (AUC), index of prediction accuracy and the distribution of predicted risks. RESULTS: Of the 4,065 included patients, 9% died within 28 days after COVID-19 diagnosis. Predicted mortality risk ranged between 7-26% for the basic model including age and sex, changing to 4-41% by addition of comorbidity-based vulnerability measures (Charlson Comorbidity Index, Chronic Comorbidity Score), more reflecting impaired organ functioning. Similarly, the AUC of the basic model slightly increased from 0.69 (95%CI 0.66 - 0.72) to 0.74 (95%CI 0.71 - 0.76) by addition of either of these comorbidity scores. Addition of a Frailty Index, renal function, the number of chronic drugs or cognitive impairment yielded no substantial change in predictions. CONCLUSION: In our dataset of older COVID-19 patients in primary care, the 28-day mortality fraction was substantial at 9%. Six different vulnerability measures had little incremental predictive value in addition to age and sex in predicting short-term mortality.

External validation of six COVID-19 prognostic models for predicting mortality risk in older populations in a hospital, primary care, and nursing home setting.

OBJECTIVES: To systematically evaluate the performance of COVID-19 prognostic models and scores for mortality risk in older populations across three health-care settings: hospitals, primary care, and nursing homes. STUDY DESIGN AND SETTING: This retrospective external validation study included 14,092 older individuals of ≥70 years of age with a clinical or polymerase chain reaction-confirmed COVID-19 diagnosis from March 2020 to December 2020. The six validation cohorts include three hospital-based (CliniCo, COVID-OLD, COVID-PREDICT), two primary care-based (Julius General Practitioners Network/Academisch network huisartsgeneeskunde/Network of Academic general Practitioners, PHARMO), and one nursing home cohort (YSIS) in the Netherlands. Based on a living systematic review of COVID-19 prediction models using Prediction model Risk Of Bias ASsessment Tool for quality and risk of bias assessment and considering predictor availability in validation cohorts, we selected six prognostic models predicting mortality risk in adults with COVID-19 infection (GAL-COVID-19 mortality, 4C Mortality Score, National Early Warning Score 2-extended model, Xie model, Wang clinical model, and CURB65 score). All six prognostic models were validated in the hospital cohorts and the GAL-COVID-19 mortality model was validated in all three healthcare settings. The primary outcome was in-hospital mortality for hospitals and 28-day mortality for primary care and nursing home settings. Model performance was evaluated in each validation cohort separately in terms of discrimination, calibration, and decision curves. An intercept update was performed in models indicating miscalibration followed by predictive performance re-evaluation. MAIN OUTCOME MEASURE: In-hospital mortality for hospitals and 28-day mortality for primary care and nursing home setting. RESULTS: All six prognostic models performed poorly and showed miscalibration in the older population cohorts. In the hospital settings, model performance ranged from calibration-in-the-large -1.45 to 7.46, calibration slopes 0.24-0.81, and C-statistic 0.55-0.71 with 4C Mortality Score performing as the most discriminative and well-calibrated model. Performance across health-care settings was similar for the GAL-COVID-19 model, with a calibration-in-the-large in the range of -2.35 to -0.15 indicating overestimation, calibration slopes of 0.24-0.81 indicating signs of overfitting, and C-statistic of 0.55-0.71. CONCLUSION: Our results show that most prognostic models for predicting mortality risk performed poorly in the older population with COVID-19, in each health-care setting: hospital, primary care, and nursing home settings. Insights into factors influencing predictive model performance in the older population are needed for pandemic preparedness and reliable prognostication of health-related outcomes in this demographic.

Managing the Increasing Burden of Atrial Fibrillation through Integrated Care in Primary Care: A Cost-Effectiveness Analysis.

Introduction: Integrated care for patients with atrial fibrillation (AF) in primary care reduced mortality compared to usual care. We assessed the cost-effectiveness of this approach. Methods: Dutch primary care practices were randomised to provide integrated care for AF patients or usual care. A cost-effectiveness analysis was performed from a societal perspective with a 2-year time horizon to estimate incremental costs and Quality Adjusted Life Years (QALYs). A sensitivity analysis was performed, imputing missing questionnaires for a large group of usual care patients. Results: 522 patients from 15 intervention practices were compared to 425 patients from 11 usual care practices. No effect on QALYs was seen, while mean costs indicated a cost reduction between €865 (95% percentile interval (PI) -€5730 to €3641) and €1343 (95% PI -€6534 to €3109) per patient per 2 years. The cost-effectiveness probability ranged between 36% and 54%. In the sensitivity analysis, this increased to 95%-99%. Discussion: Results should be interpreted with caution due to missing information for a large proportion of usual care patients. Conclusion: The higher costs from extra primary care consultations were likely outweighed by cost reductions for other resources, yet this study doesn't give sufficient clarity on the cost-effectiveness of integrated AF care.

Integrated care in patients with atrial fibrillation- a predictive heterogeneous treatment effect analysis of the ALL-IN trial.

INTRODUCTION: Integrated care is effective in reducing all-cause mortality in patients with atrial fibrillation (AF) in primary care, though time and resource intensive. The aim of the current study was to assess whether integrated care should be directed at all AF patients equally. METHODS: The ALL-IN trial (n = 1,240 patients, median age 77 years) was a cluster-randomized trial in which primary care practices were randomized to provide integrated care or usual care to AF patients aged 65 years and older. Integrated care comprised of (i) anticoagulation monitoring, (ii) quarterly checkups and (iii) easy-access consultation with cardiologists. For the current analysis, cox proportional hazard analysis with all clinical variables from the CHA2DS2-VASc score was used to predict all-cause mortality in the ALL-IN trial. Subsequently, the hazard ratio and absolute risk reduction were plotted as a function of this predicted mortality risk to explore treatment heterogeneity. RESULTS: Under usual care, after a median of 2 years follow-up the absolute risk of all-cause mortality in the highest-risk quarter was 31.0%, compared to 4.6% in the lowest-risk quarter. On the relative scale, there was no evidence of treatment heterogeneity (p for interaction = 0.90). However, there was substantial treatment heterogeneity on the absolute scale: risk reduction in the lowest risk- quarter of risk 3.3% (95% CI -0.4% - 7.0) compared to 12.0% (95% CI 2.7% - 22.0) in the highest risk quarter. CONCLUSION: While the relative degree of benefit from integrated AF care is similar in all patients, patients with a high all-cause mortality risk have a greater benefit on an absolute scale and should therefore be prioritized when implementing integrated care.

Clinical consequences of off-label reduced dosing of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation: a systematic review and meta-analysis.

OBJECTIVE: Postmarketing observational studies report that a substantial percentage of patients with atrial fibrillation (AF) receive a reduced non-vitamin K antagonist oral anticoagulant (NOAC) dose without a clear indication. Recently, increasing evidence has become available to explore the clinical consequences of such off-label reduced dosing (OLRD). This study aims to systematically review and meta-analyse observational studies that report clinical outcomes associated with OLRD of NOACs compared with on-label non-reduced dosing (OLNRD) of NOACs in patients with AF. METHODS AND ANALYSIS: We performed a systematic literature review and meta-analysis of observational studies reporting clinical outcomes in AF patients with OLRD of an NOAC compared with AF patients with OLNRD of an NOAC. Using random effects meta-analyses, we estimated the risk of stroke/thromboembolism, bleeding and all-cause mortality. RESULTS: We included 19 studies with a total of 170 394 NOAC users. In these studies, the percentage of OLRD among patients with an indication for an on-label non-reduced NOAC dose ranged between 9% and 53%. 7 of these 19 studies met the predefined criteria for meta-analysis (n=80 725 patients). The pooled HR associated with OLRD of NOACs was 1.04 (95% CI 0.83 to 1.29; 95% prediction interval (PI) 0.60 to 1.79) for stroke/thromboembolism, 1.10 (95% CI 0.95 to 1.29; 95% PI 0.81 to 1.50) for bleeding and 1.22 (95% CI 0.81 to 1.84; 95% PI 0.55 to 2.70) for all-cause mortality. CONCLUSION: This meta-analysis shows no statistically significant increased risk of stroke/thromboembolism, nor a decreased bleeding risk, nor a difference in risk of all-cause mortality in patients with OLRD of NOACs. Future research may focus on differences between NOACs.

The Number of Concomitant Drugs and the Safety of Direct Oral Anticoagulants in Routine Care Patients with Atrial Fibrillation.

Background The benefit of direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs) on major bleeding was less prominent among atrial fibrillation (AF) patients with polypharmacy in post-hoc randomized controlled trials analyses. Whether this phenomenon also exists in routine care is unknown. The aim of the study is to investigate whether the number of concomitant drugs prescribed modifies safety and effectiveness of DOACs compared with VKAs in AF patients treated in general practice. Study Design Adult, nonvalvular AF patients with a first DOAC or VKA prescription between January 2010 and July 2018 were included, using data from the United Kingdom Clinical Practice Research Datalink. Primary outcome was major bleeding, secondary outcomes included types of major bleeding, nonmajor bleeding, ischemic stroke, and all-cause mortality. Effect modification was assessed using Cox proportional hazard regression, stratified for the number of concomitant drugs into three strata (0-5, 6-8, ≥9 drugs), and by including the continuous variable in an interaction term with the exposure (DOAC vs. VKA). Results A total of 63,600 patients with 146,059 person-years of follow-up were analyzed (39,840 person-years of DOAC follow-up). The median age was 76 years in both groups, the median number of concomitant drugs prescribed was 7. Overall, the hazard of major bleeding was similar between VKA-users and DOAC-users (hazard ratio [HR] 0.98; 95% confidence interval [CI] 0.87-1.11), though for apixaban a reduction in major bleeding was observed (HR 0.81; 95% CI 0.68-0.98). Risk of stroke was comparable, while risk of nonmajor bleeding was lower in DOAC users compared with VKA users (HR 0.92; 95% CI 0.88-0.97). We did not observe any evidence for an impact of polypharmacy on the relative risk of major bleeding between VKA and DOAC across our predefined three strata of concomitant drug use ( p -value for interaction = 0.65). For mortality, however, risk of mortality was highest among DOAC users, increasing with polypharmacy and independent of the type of DOAC prescribed ( p -value for interaction <0.01). Conclusion In this large observational, population-wide study of AF patients, risk of bleeding, and ischemic stroke were comparable between DOACs and VKAs, irrespective of the number of concomitant drugs prescribed. In AF patients with increasing polypharmacy, our data appeared to suggest an unexplained yet increased risk of mortality in DOAC-treated patients, compared with VKA recipients.

Integrated management of atrial fibrillation including tailoring of anticoagulation in primary care: study design of the ALL-IN cluster randomised trial.

INTRODUCTION: In our ageing society, we are at the merge of an expected epidemic of atrial fibrillation (AF). AF management requires an integrated approach, including rate or rhythm control, stroke prevention with anticoagulation and treatment of comorbidities such as heart failure or type 2 diabetes. As such, primary care seems to be the logical healthcare setting for the chronic management of patients with AF. However, primary care has not yet played a dominant role in AF management, which has been in fact more fragmented between different healthcare providers. This fragmentation might have contributed to high healthcare costs. To demonstrate the feasibility of managing AF in primary care, studies are needed that evaluate the safety and (cost-)effectiveness of integrated AF management in primary care. METHODS AND ANALYSIS: The ALL-IN trial is a multicentre, pragmatic, cluster randomised, non-inferiority trial performed in primary care practices in a suburban region in the Netherlands. We aim to include a minimum of 1000 patients with AF aged 65 years or more from around 18 to 30 practices. Duration of the study is 2 years. Practices will be randomised to either the intervention arm (providing integrated AF management, involving a trained practice nurse and collaboration with secondary care) or the control arm (care as usual). The primary endpoint is all-cause mortality. Secondary endpoints are cardiovascular mortality, (non)-cardiovascular hospitalisation, major adverse cardiac events, stroke, major bleeding, clinically relevant non-major bleeding, quality of life and cost-effectiveness. ETHICS AND DISSEMINATION: The protocol was approved by the Medical Ethical Committee of the Isala Hospital Zwolle, the Netherlands. Patients in the intervention arm will be asked informed consent for participating in the intervention. Results are expected in 2019 and will be disseminated through both national and international journals and conferences. TRIAL REGISTRATION NUMBER: This trial is registered at the Netherlands Trial Register (NTR5532).

Effect of long-term GH replacement therapy on cardiovascular outcomes in isolated GH deficiency compared with multiple pituitary hormone deficiencies: a sub-analysis from the Dutch National Registry of Growth Hormone Treatment in Adults.

OBJECTIVE: Isolated GH deficiency (IGHD) could provide a model to investigate the influence of GH deficiency per se and the effect of GH replacement therapy without the influence from other pituitary hormone deficiencies or their treatment. The aim of this study is to address the questions about differences between IGHD and multiple pituitary hormone deficiencies (MPHDs) in clinical presentation and in responsiveness to GH treatment. DESIGN: A nationwide surveillance study was carried out to describe the difference in the clinical presentation and responsiveness to GH treatment of patients with IGHD and MPHDs. METHODS: The Dutch National Registry of GH Treatment in Adults was founded in 1998 to gain more insight into long-term efficacy and safety of GH therapy. Out of 2891 enrolled patients, 266 patients with IGHD at the start of GH treatment were identified and compared with 310 patients with MPHDs. Cardiovascular indices will be investigated at baseline and during long-term follow-up, including body composition, lipid profile, glucose metabolism, blood pressure, and morbidity. RESULTS: Patients with IGHD and MPHDs were demonstrated to be different entities at clinical presentation. Metabolically, patients with MPHDs had a larger waist circumference, lower HDL cholesterol level, and higher triglyceride level. The effect of GH treatment was comparable between patient groups. GH seems to protect against rising lipid levels and blood pressure, even after excluding patients using corresponding concomitant medication. The risk for cardiovascular disease or diabetes mellitus during follow-up was not different between patients with IGHD and MPHDs. CONCLUSIONS: Patients with IGHD had a less impaired metabolic profile than patients with MPHDs at baseline. Influence of other pituitary hormone replacement therapies on the effect of GH treatment is not demonstrated.