Development and Validation of the DOAC Score: A Novel Bleeding Risk Prediction Tool for Patients With Atrial Fibrillation on Direct-Acting Oral Anticoagulants.

BACKGROUND: Current clinical decision tools for assessing bleeding risk in individuals with atrial fibrillation (AF) have limited performance and were developed for individuals treated with warfarin. This study develops and validates a clinical risk score to personalize estimates of bleeding risk for individuals with atrial fibrillation taking direct-acting oral anticoagulants (DOACs). METHODS: Among individuals taking dabigatran 150 mg twice per day from 44 countries and 951 centers in this secondary analysis of the RE-LY trial (Randomized Evaluation of Long-Term Anticoagulation Therapy), a risk score was developed to determine the comparative risk for bleeding on the basis of covariates derived in a Cox proportional hazards model. The risk prediction model was internally validated with bootstrapping. The model was then further developed in the GARFIELD-AF registry (Global Anticoagulant Registry in the Field-Atrial Fibrillation), with individuals taking dabigatran, edoxaban, rivaroxaban, and apixaban. To determine generalizability in external cohorts and among individuals on different DOACs, the risk prediction model was validated in the COMBINE-AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation) pooled clinical trial cohort and the Quebec Régie de l'Assurance Maladie du Québec and Med-Echo Administrative Databases (RAMQ) administrative database. The primary outcome was major bleeding. The risk score, termed the DOAC Score, was compared with the HAS-BLED score. RESULTS: Of the 5684 patients in RE-LY, 386 (6.8%) experienced a major bleeding event, within a median follow-up of 1.74 years. The prediction model had an optimism-corrected C statistic of 0.73 after internal validation with bootstrapping and was well-calibrated based on visual inspection of calibration plots (goodness-of-fit P=0.57). The DOAC Score assigned points for age, creatinine clearance/glomerular filtration rate, underweight status, stroke/transient ischemic attack/embolism history, diabetes, hypertension, antiplatelet use, nonsteroidal anti-inflammatory use, liver disease, and bleeding history, with each additional point scored associated with a 48.7% (95% CI, 38.9%-59.3%; P<0.001) increase in major bleeding in RE-LY. The score had superior performance to the HAS-BLED score in RE-LY (C statistic, 0.73 versus 0.60; P for difference <0.001) and among 12 296 individuals in GARFIELD-AF (C statistic, 0.71 versus 0.66; P for difference = 0.025). The DOAC Score had stronger predictive performance than the HAS-BLED score in both validation cohorts, including 25 586 individuals in COMBINE-AF (C statistic, 0.67 versus 0.63; P for difference <0.001) and 11 945 individuals in RAMQ (C statistic, 0.65 versus 0.58; P for difference <0.001). CONCLUSIONS: In individuals with atrial fibrillation potentially eligible for DOAC therapy, the DOAC Score can help stratify patients on the basis of expected bleeding risk.

Oral anticoagulation across diabetic subtypes in patients with newly diagnosed atrial fibrillation: A report from the GARFIELD-AF registry.

AIMS: This study aims to describe both management and prognosis of patients with diabetes mellitus (DM) and newly diagnosed atrial fibrillation (AF), overall as well as by antidiabetic treatment, and to assess the influence of oral anticoagulation (OAC) on outcomes by DM status. METHODS: The study population comprised 52 010 newly diagnosed patients with AF, 11 542 DM and 40 468 non-DM, enrolled in the GARFIELD-AF registry. Follow-up was truncated at 2 years after enrolment. Comparative effectiveness of OAC versus no OAC was assessed by DM status using a propensity score overlap weighting scheme and weights were applied to Cox models. RESULTS: Patients with DM [39.3% oral antidiabetic drug (OAD), 13.4% insulin ± OAD, 47.2% on no antidiabetic drug] had higher risk profile, OAC use, and rates of clinical outcomes compared with patients without DM. OAC use was associated in patients without DM and patients with DM with lower risk of all-cause mortality [hazard ratio 0.75 (0.69-0.83), 0.74 (0.64-0.86), respectively] and stroke/systemic embolism (SE) [0.69 (0.58-0.83), 0.70 (0.53-0.93), respectively]. The risk of major bleeding with OAC was similarly increased in patients without DM and those with DM [1.40 (1.14-1.71), 1.37 (0.99-1.89), respectively]. Patients with insulin-requiring DM had a higher risk of all-cause mortality and stroke/SE [1.91 (1.63-2.24)], [1.57 (1.06-2.35), respectively] compared with patients without DM, and experienced significant risk reductions of all-cause mortality and stroke/SE with OAC [0.73 (0.53-0.99); 0.50 (0.26-0.97), respectively]. CONCLUSIONS: In both patients with DM and patients without DM with AF, OAC was associated with lower risk of all-cause mortality and stroke/SE. Patients with insulin-requiring DM derived significant benefit from OAC.

The importance of the design of observational studies in comparative effectiveness research: Lessons from the GARFIELD-AF and ORBIT-AF registries.

Randomized controlled trials (RCTs) are considered the gold standard for estimating the effectiveness of a treatment. However, in many instances they are impractical to conduct because of time limitations, cost restrictions, or ethical reasons. As a consequence, non-randomized observational studies have an important role in comparative effectiveness and safety research since they can address issues that would not be possible using conventional RCT methodology. Observational studies can be strategically designed to reduce the risk of potential sources of bias by emulating the design principles of an equivalent but ideal randomized trial - the target trial - that would answer the research question of interest. In this article, we review some of the necessary components of observational studies required for valid causal inference within the framework of target trial emulation, so as to avoid common methodological pitfalls of study design. We discuss the assumptions of consistency, time-zero specification, exchangeability and positivity. To illustrate these concepts in a context where existing knowledge is well-established through clinical trials, we evaluate and compare the treatment effects of vitamin K antagonists (VKA) against no VKA (No VKA) on the treatment of atrial fibrillation from two real-world observational studies, namely the GARFIELD-AF and ORBIT-AF registries. Results are compared with those of published RCTs.

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.

The association between patterns of atrial fibrillation, anticoagulation, and cardiovascular events.

AIMS: Guidelines do not recommend to take pattern of atrial fibrillation (AF) into account for the indication of anticoagulation (AC). We assessed AF pattern and the risk of cardiovascular events during 2-years of follow-up. METHODS AND RESULTS: We categorized AF as paroxysmal, persistent, or permanent in 29 181 patients enrolled (2010-15) in the Global Anticoagulant Registry In the FIELD of AF (GARFIELD-AF). We used multivariable Cox regression to assess the risks of stroke/systemic embolism (SE) and death across patterns of AF, and whether this changed with AC on outcomes. Atrial fibrillation pattern was paroxysmal in 14 344 (49.2%), persistent in 8064 (27.6%), and permanent 6773 (23.2%) patients. Median CHA2DS2-VASc, GARFIELD-AF, and HAS-BLED scores assessing the risk of stroke/SE and/or bleeding were similar across AF patterns, but the risk of death, as assessed by the GARFIELD-AF risk calculator, was higher in non-paroxysmal than in paroxysmal AF patterns. During 2-year follow-up, after adjustment, non-paroxysmal AF patterns were associated with significantly higher rates of all-cause death, stroke/SE, and new/worsening congestive heart failure (CHF) than paroxysmal AF in non-anticoagulated patients only. In anticoagulated patients, a significantly higher risk of death but not of stroke/SE and new/worsening CHF persisted in non-paroxysmal compared with paroxysmal AF patterns. CONCLUSION: In non-anticoagulated patients, non-paroxysmal AF patterns were associated with higher risks of stroke/SE, new/worsening HF and death than paroxysmal AF. In anticoagulated patients, the risk of stroke/SE and new/worsening HF was similar across all AF patterns. Thus AF pattern is no longer prognostic for stroke/SE when patients are treated with anticoagulants. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362.

Predictors of NOAC versus VKA use for stroke prevention in patients with newly diagnosed atrial fibrillation: Results from GARFIELD-AF.

INTRODUCTION: A principal aim of the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) was to document changes in treatment practice for patients with newly diagnosed atrial fibrillation during an era when non-vitamin K antagonist oral anticoagulants (NOACs) were becoming more widely adopted. In these analyses, the key factors which determined the choice between NOACs and vitamin K antagonists (VKAs) are explored. METHODS: Logistic least absolute shrinkage and selection operator regression determined predictors of NOAC and VKA use. Data were collected from 24,137 patients who were initiated on AC ±â€¯antiplatelet (AP) therapy (NOAC [51.4%] or VKA [48.6%]) between April 2013 and August 2016. RESULTS: The most significant predictors of AC therapy were country, enrolment year, care setting at diagnosis, AF type, concomitant AP, and kidney disease. Patients enrolled in emergency care or in the outpatient setting were more likely to receive a NOAC than those enrolled in hospital (OR 1.16 [95% CI: 1.04-1.30], OR: 1.15 [95% CI: 1.05-1.25], respectively). NOAC prescribing seemed to be favored in lower-risk groups, namely, patients with paroxysmal AF, normotensive patients, and those with moderate alcohol consumption, but also the elderly and patients with acute coronary syndrome. By contrast, VKAs were preferentially used in patients with permanent AF, moderate to severe kidney disease, heart failure, vascular disease, and diabetes and with concomitant AP. CONCLUSION: GARFIELD-AF data highlight marked heterogeneity in stroke prevention strategies globally. Physicians are adopting an individualized approach to stroke prevention where NOACs are favored in patients with a lower stroke risk but also in the elderly and patients with acute coronary syndrome.

International longitudinal registry of patients with atrial fibrillation and treated with rivaroxaban: RIVaroxaban Evaluation in Real life setting (RIVER).

BACKGROUND: Real-world data on non-vitamin K oral anticoagulants (NOACs) are essential in determining whether evidence from randomised controlled clinical trials translate into meaningful clinical benefits for patients in everyday practice. RIVER (RIVaroxaban Evaluation in Real life setting) is an ongoing international, prospective registry of patients with newly diagnosed non-valvular atrial fibrillation (NVAF) and at least one investigator-determined risk factor for stroke who received rivaroxaban as an initial treatment for the prevention of thromboembolic stroke. The aim of this paper is to describe the design of the RIVER registry and baseline characteristics of patients with newly diagnosed NVAF who received rivaroxaban as an initial treatment. METHODS AND RESULTS: Between January 2014 and June 2017, RIVER investigators recruited 5072 patients at 309 centres in 17 countries. The aim was to enroll consecutive patients at sites where rivaroxaban was already routinely prescribed for stroke prevention. Each patient is being followed up prospectively for a minimum of 2-years. The registry will capture data on the rate and nature of all thromboembolic events (stroke / systemic embolism), bleeding complications, all-cause mortality and other major cardiovascular events as they occur. Data quality is assured through a combination of remote electronic monitoring and onsite monitoring (including source data verification in 10% of cases). Patients were mostly enrolled by cardiologists (n = 3776, 74.6%), by internal medicine specialists 14.2% (n = 718) and by primary care/general practice physicians 8.2% (n = 417). The mean (SD) age of the population was 69.5 (11.0) years, 44.3% were women. Mean (SD) CHADS2 score was 1.9 (1.2) and CHA2DS2-VASc scores was 3.2 (1.6). Almost all patients (98.5%) were prescribed with once daily dose of rivaroxaban, most commonly 20 mg (76.5%) and 15 mg (20.0%) as their initial treatment; 17.9% of patients received concomitant antiplatelet therapy. Most patients enrolled in RIVER met the recommended threshold for AC therapy (86.6% for 2012 ESC Guidelines, and 79.8% of patients according to 2016 ESC Guidelines). CONCLUSIONS: The RIVER prospective registry will expand our knowledge of how rivaroxaban is prescribed in everyday practice and whether evidence from clinical trials can be translated to the broader cross-section of patients in the real world. TRIAL REGISTRATION: Unique identifier: NCT02444221. Registerd 14 May 2015; Retrospectively Registered.

Characteristics of people living in Italy after a cancer diagnosis in 2010 and projections to 2020.

BACKGROUND: Estimates of cancer prevalence are widely based on limited duration, often including patients living after a cancer diagnosis made in the previous 5 years and less frequently on complete prevalence (i.e., including all patients regardless of the time elapsed since diagnosis). This study aims to provide estimates of complete cancer prevalence in Italy by sex, age, and time since diagnosis for all cancers combined, and for selected cancer types. Projections were made up to 2020, overall and by time since diagnosis. METHODS: Data were from 27 Italian population-based cancer registries, covering 32% of the Italian population, able to provide at least 7 years of registration as of December 2009 and follow-up of vital status as of December 2013. The data were used to compute the limited-duration prevalence, in order to estimate the complete prevalence by means of the COMPREV software. RESULTS: In 2010, 2,637,975 persons were estimated to live in Italy after a cancer diagnosis, 1.2 million men and 1.4 million women, or 4.6% of the Italian population. A quarter of male prevalent cases had prostate cancer (n = 305,044), while 42% of prevalent women had breast cancer (n = 604,841). More than 1.5 million people (2.7% of Italians) were alive since 5 or more years after diagnosis and 20% since ≥15 years. It is projected that, in 2020 in Italy, there will be 3.6 million prevalent cancer cases (+ 37% vs 2010). The largest 10-year increases are foreseen for prostate (+ 85%) and for thyroid cancers (+ 79%), and for long-term survivors diagnosed since 20 or more years (+ 45%). Among the population aged ≥75 years, 22% will have had a previous cancer diagnosis. CONCLUSIONS: The number of persons living after a cancer diagnosis is estimated to rise of approximately 3% per year in Italy. The availability of detailed estimates and projections of the complete prevalence are intended to help the implementation of guidelines aimed to enhance the long-term follow-up of cancer survivors and to contribute their rehabilitation needs.

Excess mortality related to circulatory system diseases and diabetes mellitus among Italian AIDS patients vs. non-AIDS population: a population-based cohort study using the multiple causes-of-death approach.

BACKGROUND: Chronic diseases, chiefly cancers and circulatory system diseases (CSDs), have become the leading non-AIDS-related causes of death among HIV-infected people, as in the general population. After our previous report of an excess mortality for several non-AIDS-defining cancers, we now aim to assess whether people with AIDS (PWA) experience also an increased mortality for CSDs and diabetes mellitus (DM), as compared to the non-AIDS general population (non-PWA). METHODS: A nationwide, population-based, retrospective cohort study was conducted including 5285 Italians, aged 15-74 years, who were diagnosed with AIDS between 2006 and 2011. Multiple cause-of-death (MCoD) data, i.e. all conditions reported in death certificates, were retrieved through record-linkage with the National Register of Causes of Death up to 2011. Using MCoD data, sex- and age-standardized mortality ratios (SMRs) with 95% confidence intervals (CIs) were calculated by dividing the observed number of PWA reporting a specific disease among MCoD to the expected number, estimated on the basis of mortality rates (based on MCoD) of non-PWA. RESULTS: Among 1229 deceased PWA, CSDs were mentioned in 201 (16.4%) certificates and DM in 46 (3.7%) certificates among the various causes of death. These values corresponded to a 13-fold higher mortality related to CSDs (95% CI 10.8-14.4) and DM (95% CI: 9.5-17.4) as compared to 952,019 deceased non-PWA. Among CSDs, statistically significant excess mortality emerged for hypertension (23 deaths, SMR = 6.3, 95% CI: 4.0-9.4), ischemic heart diseases (39 deaths, SMR = 6.1, 95% CI: 4.4-8.4), other forms of heart diseases (88 deaths, SMR = 13.4, 95% CI: 10.8-16.5), and cerebrovascular diseases (42 deaths, SMR = 13.4, 95% CI: 9.7-18.2). The SMRs were particularly elevated among PWA aged < 50 years and those infected through drug injection. CONCLUSIONS: The use of MCoD data disclosed the fairly high mortality excess related to several CSDs and DM among Italian PWA as compared to non-PWA. Study findings also indicate to start preventive strategies for such diseases at a younger age among AIDS patients than in the general population and with focus on drug users.

Multiple cause-of-death data among people with AIDS in Italy: a nationwide cross-sectional study.

BACKGROUND: Multiple cause-of-death (MCOD) data allow analyzing the contribution to mortality of conditions reported on the death certificate that are not selected as the underlying cause of death. Using MCOD data, this study aimed to fully describe the cause-specific mortality of people with AIDS (PWA) compared to people without AIDS. METHODS: We conducted a nationwide investigation based on death certificates of 2,515 Italian PWA and 123,224 people without AIDS who had died between 2006 and 2010. The conditions most frequently associated with PWA mortality, compared to people without AIDS, were identified using an age-standardized proportion ratio (ASPR) calculated as the ratio between the age-standardized proportion of a specific cause among PWA and the same proportion among people without AIDS. RESULTS: The most frequently reported conditions at death among PWA were infectious/parasitic diseases (52%), digestive (36%), respiratory (33%), and circulatory (32%) system diseases, and neoplasms (29%). All AIDS-defining conditions resulted highly associated (ASPR significantly greater than unity) with PWA deaths. Significant associations also emerged for leishmaniasis (ASPR = 188.0), encephalitis/myelitis/encephalomyelitis (ASPR = 14.3), dementia (ASPR = 13.1), chronic viral hepatitis (ASPR = 13.1), liver fibrosis/cirrhosis (ASPR = 4.4), pneumonia (ASPR = 4.4), anal (ASPR = 12.1) and liver (ASPR = 1.9) cancers, and Hodgkin's disease (ASPR = 3.1). CONCLUSIONS: Study findings identified the contribution of several non-AIDS-defining conditions on PWA mortality, emphasizing the need of preventive public health interventions targeting this population.

HLA-G 3'UTR Polymorphisms Predict Drug-Induced G3-4 Toxicity Related to Folinic Acid/5-Fluorouracil/Oxaliplatin (FOLFOX4) Chemotherapy in Non-Metastatic Colorectal Cancer.

Polymorphisms in drug-metabolizing enzymes might not completely explain inter-individual differences in toxicity profiles of patients with colorectal cancer (CRC) that receive folinic acid/5-fluorouracil/oxaliplatin (FOLFOX4). Recent data indicate that the immune system could contribute to FOLFOX4 outcomes. In light of the immune inhibitory nature of human leukocyte antigen-G (HLA-G), a non-classical major histocompatibility complex (MHC) class I molecule, we aimed to identify novel genomic markers of grades 3 and 4 (G3-4) toxicity related to FOLFOX4 therapy in patients with CRC. We retrospectively analyzed data for 144 patients with stages II-III CRC to identify HLA-G 3' untranslated region (3'UTR) polymorphisms and related haplotypes and evaluate their impact on the risk of developing G3-4 toxicities (i.e., neutropenia, hematological/non-hematological toxicity, neurotoxicity) with logistic regression. The rs1610696-G/G polymorphism was associated with increased risk of G3-4 neutropenia (OR = 3.76, p = 0.015) and neurotoxicity (OR = 8.78, p = 0.016); rs371194629-Ins/Ins was associated with increased risk of neurotoxicity (OR = 5.49, p = 0.027). HLA-G 3'UTR-2, which contains rs1610696-G/G and rs371194629-Ins/Ins polymorphisms, was associated with increased risk of G3-4 neutropenia (OR = 3.92, p = 0.017) and neurotoxicity (OR = 11.29, p = 0.009). A bootstrap analysis confirmed the predictive value of rs1610696 and rs371194629, but the UTR-2 haplotype was validated only for neurotoxicity. This exploratory study identified new HLA-G 3'UTR polymorphisms/haplotypes as potential predictive markers of G3-4 toxicities in CRC.

Risk factors for early mortality after AIDS in the cART era: A population-based cohort study in Italy.

BACKGROUND: Despite the dramatically improved survival due to combination antiretroviral therapies (cART), life expectancy of people with HIV/AIDS remains lower than that of the general population. This study aimed to estimate, at a population level, the survival experience of Italian people with AIDS (PWA) and to quantify the prognostic role of selected factors at diagnosis in the risk of early mortality (i.e., within six months from AIDS diagnosis). METHODS: A population-based, retrospective-cohort study was conducted among Italian PWA diagnosed between 1999 and 2009 and recorded in the national AIDS registry. The vital status, up to December 2010, of 14,552 PWA was ascertained through a record linkage procedure with the Italian mortality database. Survival probabilities were estimated through Kaplan-Meier method. To identify risk factors for early mortality from any cause, odds ratios (ORs) and corresponding 95% confidence intervals (CIs), adjusted for major confounders, were computed using multivariate logistic regression models. RESULTS: Of the 5,706 deaths registered among the 14,552 PWA included in the study, 2,757 (18.9%) occurred within six months from AIDS diagnosis. The probability of surviving six months increased from 81.2% in PWA diagnosed in 1999-2000 to 82.9% in 2009, while the 5-year survival augmented from 60.7% in PWA diagnosed in 1999-2000 to 65.4% for PWA diagnosed in 2005-2006. Elevated risks of early mortality were associated to older age (OR = 5.28; 95% CI: 4.41-6.32 for age ≥60 vs. <35 years), injecting drug use (OR = 1.71; 95% CI: 1.53-1.91 vs. heterosexual intercourse), and CD4 count <50 cells/mm(3) at AIDS diagnosis (OR = 1.87, 95% CI: 1.55-2.27 vs. ≥350). Elevated ORs for early mortality also emerged for PWA diagnosed with primary brain lymphoma (OR = 11.66, 95% CI: 7.32-18.57), or progressive multifocal leukoencephalopathy (OR = 4.21, 95% CI: 3.37-5.27). CONCLUSIONS: Our study documented, among Italian PWA, the high - though slightly decreasing - frequency of early mortality in the full cART era. These findings indicate the need for enduring and ameliorating preventive actions aimed at timely HIV testing among all individuals at risk for HIV infection and/or those who present diseases known to be related with HIV infection.

Head and neck and esophageal cancers after liver transplant: results from a multicenter cohort study. Italy, 1997-2010.

This study quantified the risk of head and neck (HN) and esophageal cancers in 2770 Italian liver transplant (LT) recipients. A total of 186 post-transplant cancers were diagnosed-including 32 cases of HN cancers and nine cases of esophageal carcinoma. The 10-year cumulative risk for HN and esophageal carcinoma was 2.59%. Overall, HN cancers were nearly fivefold more frequent in LT recipients than expected (standardized incidence ratios - SIR=4.7, 95% CI: 3.2-6.6), while esophageal carcinoma was ninefold more frequent (SIR=9.1, 95% CI: 4.1-17.2). SIRs ranged from 11.8 in LT with alcoholic liver disease (ALD) to 1.8 for LT without ALD for HN cancers, and from 23.7 to 2.9, respectively, for esophageal carcinoma. Particularly elevated SIRs in LT with ALD were noted for carcinomas of tongue (23.0) or larynx (13.7). Our findings confirmed and quantified the large cancer excess risk in LT recipients with ALD. The risk magnitude and the prevalence of ALD herein documented stress the need of timely and specifically organized programs for the early diagnosis of cancer among LT recipients, particularly for high-risk recipients like those with ALD.

Time trends of cancer incidence in Setif, Algeria, 1986-2010: an observational study.

BACKGROUND: Incidence rates of various cancers are increasing in Arab countries and are expected to reach those of industrialized ones in few decades. This paper aimed to describe the incidence rates of most common cancers--and/or of those cancer preventable through modifiable behaviors--recorded in the province of Setif, Algeria from 1986 through 2010. METHODS: Cancer diagnoses for the 1986-2010 period were provided by the population-based Cancer Registry of Setif, disentangled by site, morphology, age (quinquennia), sex, and calendar period. The corresponding population was obtained from the Algerian Institute of Statistics. Age-standardized rates (world population) (ASR-WR) were computed by calendar period (five quinquennias from 1986-1990 to 2006-2010), while annual percent changes (APCs) were computed for the period 1996-2010. RESULTS: During the 2006-2010 period, ASR-WR for all cancer sites were 106.4/100,000 in men and 110.3 in women. The four leading cancers were: lung (18.0%); colon-rectum (9.6%); bladder (9.1%); and prostate (6.5%) in men; breast (36.4%); colon-rectum (8.5%); cervix uteri (6.0%); and thyroid (6.0%) in women. Between 1996-2010, overall cancer incidence increased statistically significantly (p < 0.05) in both men (APC = +2.5%) and women (APC = +3.7%). Statistically significant decreasing trends were observed for nasopharyngeal carcinoma (APC = -3.4%) in men, and for cervical (APC = -4.2%) and gallbladder (APC = -3.2%) cancers in women. Statistically significant increasing trends were observed for most common cancers both in men (lung:+1.8%, colon-rectum:+5.4%, prostate:+4.3%, liver:+8.9%, and bladder:+5.9%) and women (breast:+8.2%, colon-rectum:+4.5%, lung:+10.0%, liver:+5.4%, thyroid:+5.3%, and larynx:+13.8%). CONCLUSIONS: International recommendations against cancer must be strongly promoted in Setif after taking into account epidemiological transition, lifestyle, and environmental changes.

Changes in the nature and outcome of notifications to HM Coroner from the Norfolk and Norwich University Hospital, UK, before and after the introduction of a medical examiner service: 2018 versus 2022.

A medical examiner (ME) system was introduced to England and Wales in 2019 intended to ensure appropriate notification of cases to HM Coroner (HMC). The aim of the study is to determine and compare: (a) the nature of notifications to HMC for Norfolk from the Norfolk and Norwich University Hospital (NNUH) in 2018 compared with 2022; (b) to determine the outcome of those notifications and (c) to establish patterns of change in the number and nature of such notifications. HMC and ME datasets were interrogated to determine differences between notifications to HMC and outcomes in 2018 compared with 2022. From deaths at NNUH (2018 - n = 2605; 2022 - n = 2969), there were significantly fewer HMC notifications in 2022 compared with 2018 (25.3% vs. 17.6%). A decrease in notifications was noted for persons undergoing any 'treatment or procedure of a medical or similar nature' (24.0% vs. 16.2%) p < 0.0014. An increase in notifications was noted for neglect, including self-neglect (3.3% vs. 12.2%) p < 0.001. Of the coronial outcomes, there were significant increases in the numbers of post-mortem (PM) examinations (29.3% vs. 35.5%) p = 0.0276 and inquests (26.0% vs. 31.4%) p = 0.0485). There was a significant decrease in no further action by HMC (5.7 vs. 2.3) p = 0.0485. The study shows that the introduction of the medical examiner service has resulted in significant change in the nature of HMC notification categories. The notifications appear to be more appropriate, with an increased proportion of inquests and PM examinations and with a reduction in 100 A or 'no further action' outcomes.

Clinical Outcomes in Older Patients with Atrial Fibrillation: Insights from the GARFIELD-AF Registry.

BACKGROUND: Oral anticoagulants (OAC) are underutilized in older patients with atrial fibrillation, despite proven clinical benefits. Our objective was to investigate baseline characteristics, treatment patterns, and impact of anticoagulation upon clinical outcomes with respect to age. METHODS: Adults with newly diagnosed atrial fibrillation were recruited into the prospective observational registry, GARFIELD-AF, and followed up for 24 months. Adjusted hazard ratios (HR) were obtained via Cox proportional-hazards models with applied weights, to quantify the association of age with clinical outcomes. Comparative effectiveness of OAC vs No OAC and non-vitamin K oral anticoagulants (NOAC) vs vitamin K antagonists (VKA) were assessed using a propensity score with an overlap weighting scheme. RESULTS: Of 52,018 patients, 32.6% were 65-74 years of age, 29.3% were 75-84 years, and 7.9% were ≥85 years. OAC treatment was associated with a numerical reduction in all-cause mortality among those aged 65-74 years (HR; 95% confidence interval) (0.86; 0.69-1.06) and aged 75-84 years (0.89; 0.75-1.05) and a significant reduction in patients ≥85 years (0.77; 0.63-0.95) vs no OAC. Similarly, OACs were associated with a decrease in stroke: 65-74 (0.51; 0.35-0.76) and ≥85 years (0.58; 0.34-0.99) and a numerical decrease in 75-84 years (0.84; 0.59-1.18). No increase in major bleeding was observed in patients aged ≥85 treated with OACs. Compared with VKA, NOACs were associated with a significant reduction in all-cause mortality in patients aged <65 and 65-74, with numerical reductions in those aged 75-84 and ≥85 years. CONCLUSIONS: Older patients using OACs saw lower all-cause mortality and stroke risk; NOACs had less mortality and major bleeding compared with VKAs.

Impact of patient selection in clinical trials: application of ROCKET AF and ARISTOTLE criteria in GARFIELD-AF.

BACKGROUND: The extent to which differences in results from Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) and Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial (ROCKET) atrial fibrillation (AF)-the landmark trials for the approval of apixaban and rivaroxaban, respectively, for non-valvular AF-were influenced by differences in their protocols is debated. The potential influence of selection criteria on trial results was assessed by emulating these trials in data from the Global Anticoagulant Registry in the Field (GARFIELD)-AF registry. METHODS: Vitamin K antagonist (VKA) and non-vitamin K oral antagonist (NOAC) users from GARFIELD-AF were selected according to eligibility for the original ARISTOTLE or ROCKET AF trials. A propensity score overlap weighted Cox model was used to emulate trial randomisation between treatment groups. Adjusted HRs for stroke or systemic embolism (SE) within 2 years of enrolment were calculated for each NOAC versus VKA. RESULTS: Among patients on apixaban, rivaroxaban and VKA, 2570, 3560 and 8005 were eligible for ARISTOTLE, respectively, and 1612, 2005 and 4368, respectively, for ROCKET AF. When selecting for ARISTOTLE criteria, apixaban users had significantly lower stroke/SE risk versus VKA (HR 0.57; 95% CI 0.34 to 0.94) while no reduction was observed with rivaroxaban (HR 0.98; 95% CI 0.68 to 1.40). When selecting for ROCKET AF criteria, safety and efficacy versus VKA were similar across the NOACs. CONCLUSION: Apixaban and rivaroxaban showed similar results versus VKA in high-risk patients selected according to ROCKET AF criteria, whereas differences emerged when selecting for the more inclusive ARISTOTLE criteria. Our results highlight the importance of trial selection criteria in interpreting trial results and underline the problems faced in comparing treatments across rather than within clinical trials.

GARFIELD-AF: risk profiles, treatment patterns and 2-year outcomes in patients with atrial fibrillation in Germany, Austria and Switzerland (DACH) compared to 32 countries in other regions worldwide.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is a worldwide non-interventional study of stroke prevention in patients with non-valvular AF. METHODS AND RESULTS: 52,080 patients with newly diagnosed AF were prospectively enrolled from 2010 to 2016. 4121 (7.9%) of these patients were recruited in DACH [Germany (n = 3567), Austria (n = 465) and Switzerland (n = 89) combined], and 47,959 patients were from 32 countries in other regions worldwide (ORW). Hypertension was most prevalent in DACH and ORW (85.3% and 75.6%, respectively). Diabetes, hypercholesterolaemia, carotid occlusive disease and vascular disease were more prevalent in DACH patients vs ORW (27.6%, 49.4%, 5.8% and 29.0% vs 21.7%, 40.9%, 2.8% and 24.5%). The use of non-vitamin K antagonist oral anticoagulants (NOACs) increased more in DACH over time. Management of vitamin K antagonists was suboptimal in DACH and ORW (time in therapeutic range of INR ≥ 65% in 44.6% and 44.4% of patients or ≥ 70% in 36.9% and 36.0% of patients, respectively). Adjusted rates of cardiovascular mortality and MI/ACS were higher in DACH while non-haemorrhagic stroke/systemic embolism was lower after 2-year follow-up. CONCLUSIONS: Similarities and dissimilarities in AF management and clinical outcomes are seen in DACH and ORW. The increased use of NOAC was associated with a mismatch of risk-adapted anticoagulation (over-and-undertreatment) in DACH. Suboptimal control of INR requires educational activities in both regional groups. Higher rates of cardiovascular death in DACH may reflect the higher risk profile of these patients and lower rates of non-haemorrhagic stroke could be associated with increased NOAC use.

Rhythm versus rate control in patients with newly diagnosed atrial fibrillation - Observations from the GARFIELD-AF registry.

Background: Investigate real-world outcomes of early rhythm versus rate control in patients with recent onset atrial fibrillation. Methods: The Global Anticoagulant Registry in the FIELD-AF (GARFIELD-AF) is an international multi-centre, non-interventional prospective registry of newly diagnosed (≤6 weeks' duration) atrial fibrillation patients at risk for stroke. Patients were stratified according to treatment initiated at baseline (≤48 days post enrolment), and outcome risks evaluated by overlap propensity weighted Cox proportional-hazards models. Results: Of 45,382 non-permanent atrial fibrillation patients, 23,858 (52.6 %) received rhythm control and 21,524 (47.4 %) rate control. Rhythm-controlled patients had lower median age (68.0 [Q1;Q3: 60.0;76.0] versus 73.0 [65.0;79.0]), fewer histories of stroke/transient ischemic attack/systemic embolism (9.4 % versus 13.0 %), and lower expected probabilities of death (median GARFIELD-AF death score 4.0 [2.3;7.5] versus 5.1 [2.8;9.2]). The two groups had the same median CHA2DS2-VASc scores (3.0 [2.0;4.0]) and similar proportions of anticoagulated patients (rhythm control: 66.0 %, rate control: 65.5 %). The propensity-score-weighted hazard ratios of rhythm vs rate control (reference) were 0.85 (95 % CI: 0.79-0.92, p-value < 0.0001) for all-cause mortality, 0.84 (0.72-0.97, p-value 0.020) for non-haemorrhagic stroke/systemic embolism and 0.90 (0.78-1.04, p-value 0.164) for major bleeding. Conclusion: Rhythm control strategy was initiated in about half of the patients with newly diagnosed non-valvular non-permanent atrial fibrillation. After balancing confounders, significantly lower risks of all-cause mortality and non-haemorrhagic stroke were observed in patients who received early rhythm control.