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Aims The global COVID-19 pandemic is caused by the SARS-CoV-2 virus entering human cells using angiotensin-converting enzyme 2 (ACE2) as a cell surface receptor. ACE2 is shed to the circulation, and a higher plasma level of soluble ACE2 (sACE2) might reflect a higher cellular expression of ACE2. The present study explored the associations between sACE2 and clinical factors, cardiovascular biomarkers, and genetic variability. Methods and results Plasma and DNA samples were obtained from two international cohorts of elderly patients with atrial fibrillation (n = 3999 and n = 1088). The sACE2 protein level was measured by the Olink Proteomics® Multiplex CVD II96 × 96 panel. Levels of the biomarkers high-sensitive cardiac troponin T (hs-cTnT), N-terminal probrain natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15), C-reactive protein, interleukin-6, D-dimer, and cystatin-C were determined by immunoassays. Genome-wide association studies were performed by Illumina chips. Higher levels of sACE2 were statistically significantly associated with male sex, cardiovascular disease, diabetes, and older age. The sACE2 level was most strongly associated with the levels of GDF-15, NT-proBNP, and hs-cTnT. When adjusting for these biomarkers, only male sex remained associated with sACE2. We found no statistically significant genetic regulation of the sACE2 level. Conclusions Male sex and clinical or biomarker indicators of biological ageing, cardiovascular disease, and diabetes are associated with higher sACE2 levels. The levels of GDF-15 and NT-proBNP, which are associated both with the sACE2 level and a higher risk for mortality and cardiovascular disease, might contribute to better identification of risk for severe COVID-19 infection.

Aims As health systems around the world increasingly look to measure and improve the value of care that they provide to patients, being able to measure the outcomes that matter most to patients is vital. To support the shift towards value-based health care in atrial fibrillation (AF), the International Consortium for Health Outcomes Measurement (ICHOM) assembled an international Working Group (WG) of 30 volunteers, including health professionals and patient representatives to develop a standardized minimum set of outcomes for benchmarking care delivery in clinical settings. Methods and results Using an online-modified Delphi process, outcomes important to patients and health professionals were selected and categorized into (i) long-term consequences of disease outcomes, (ii) complications of treatment outcomes, and (iii) patient-reported outcomes. The WG identified demographic and clinical variables for use as case-mix risk adjusters. These included baseline demographics, comorbidities, cognitive function, date of diagnosis, disease duration, medications prescribed and AF procedures, as well as smoking, body mass index (BMI), alcohol intake, and physical activity. Where appropriate, and for ease of implementation, standardization of outcomes and case-mix variables was achieved using ICD codes. The standard set underwent an open review process in which over 80% of patients surveyed agreed with the outcomes captured by the standard set. Conclusion Implementation of these consensus recommendations could help institutions to monitor, compare and improve the quality and delivery of chronic AF care. Their consistent definition and collection, using ICD codes where applicable, could also broaden the implementation of more patient-centric clinical outcomes research in AF.

Background Respiratory insufficiency with the need for mechanical ventilation (MV) is one of the most common indications for admission to intensive care units. However, little is known about the clinical outcomes of patients with acute myocardial infraction (AMI) complicated by cardiogenic shock (CS) who require mechanical ventilation (MV). The aim of this study was to identify the characteristics, risk factors, and outcomes associated with the provision of MV in this specific high-risk population. Methods Patients with CS complicating AMI and multivessel coronary artery disease from the CULPRIT-SHOCK trial were included. We explored clinical outcome within 30 days in patients not requiring MV, those with MV on admission, and those in whom MV was initiated within the first day after admission. Results Among 683 randomized patients included in the analysis, 17.4% received no MV, 59.7% were ventilated at admission and 22.8% received MV within or after the first day after admission. Patients requiring MV were younger, more frequently non-smokers, had higher body mass indices, presented more often with clinical signs of impaired organ perfusion including worse renal function, higher burden of coronary artery disease, were more likely to have experienced resuscitation within 24h before admission, had worse left ventricular function, and presented more often with non-ST-segment elevation myocardial infarction. The primary endpoint of all-cause death or need for renal replacement therapy occurred in 21.8% of patients without MV, in 53.3% of patients with MV at admission (adjusted odds ratio [aOR] 6.03, 95% confidence interval (CI) 3.17–11.47, p=0.002, compared to patients without) and 65.4% of patients with MV initiated within the first day after admission (aOR 8.09 95% CI 4.32–15.16, p Conclusions Requiring MV in patients with CS complicating AMI is common and independently associated with mortality after adjusting for covariates. Patients with delayed MV initiation appear to be at higher risk of adverse outcomes. Further research is necessary to identify the optimal timing of MV in this high-risk population. Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): Swiss National Foundation

Background/Introduction Apixaban use is increasing for stroke prevention in patients with atrial fibrillation (AF) and end stage renal disease (ESRD) on hemodialysis. There is uncertainty as to the optimal dose in this population in part related to the limited available pharmacokinetic (PK) data. Purpose We comprehensively evaluated the PK of apixaban collected over 1 month of apixaban dosing in 63 patients with AF and ESRD on hemodialysis. Methods Patients with AF and ESRD on hemodialysis were randomized to warfarin versus apixaban within the RENAL-AF trial with 5 mg BID dosing, except for 2.5 mg BID in those age ≥80 years or weight ≤60 kg. The 5 mg BID dose could be reduced to 2.5mg BID for minor bleeding. Day 1 PK data was collected on all patients pre- and post-hemodialysis. Day 3 and 1 month pre- and post-hemodialysis PK samples were collected in 49 patients. The timing of apixaban dosing and hemodialysis relative to PK samples was recorded. Dosing history, hemodialysis, and PK samples were chronologically integrated with patient specific data such as body size, age, race and gender. This dataset was combined with the ARISTOTLE dataset, and the published PK model from ARISTOTLE describing exposures in the AF population was updated to incorporate an additional clearance term for hemodialysis. The model estimated apixaban exposures (AUC) in RENAL-AF were compared to ARISTOLTE AUC values. Results There were 285 PK concentrations collected among 63 patients in the RENAL-AF trial. Patients had median age 69 years with 41% women (N=26) and a median weight of 84 kg (49, 157). The median AUCs for patients with ESRD on hemodialysis were 5,452 and 2,990 for patients treated with 5mg BID and 2.5mg BID doses, respectively. The median AUCs for patients treated with 5mg BID from ARISTOTLE increased from 2,802 for patients with class 1 CKD to 5,863 for class 4 CKD, while they increased from 2,392 for class 1 CKD to 2,881 for class 4 CKD in patients treated with 2.5mg BID. The median AUC for patients with ESRD on hemodialysis were within 50% of the exposure of patients from ARISTOTLE for all classes of CKD for the 2.5mg BID dose and for classes 2, 3A, 3B, and 4 CKD for the 5mg BID dose (Figure). Conclusions The steady state apixaban exposure data in patients with AF and ESRD on hemodialysis were modestly higher but consistent with the results of non-ESRD patients from ARISTOTLE, using 5 mg BID unless patients had age ≥80 years or weight ≤60 kg. Additional clinical outcomes data on the use of apixaban in patients with AF and ESRD on hemodialysis are needed. Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): Investigator sponsored grant from Bristol-Myers Squibb and Pfizer

Background The AUGUSTUS trial showed that patients with atrial fibrillation (AF) and acute coronary syndrome (ACS) and/or PCI treated with a P2Y12 inhibitor and apixaban resulted in less bleeding and comparable ischemic events compared with regimens that included a vitamin K antagonist (VKA), aspirin, or both. We assessed the effect of apixaban versus VKA and aspirin versus placebo according to patients' baseline risk of stroke and bleeding. Methods AUGUSTUS randomized 4614 patients in a two-by-two factorial design to open label apixaban or VKA and blinded aspirin or placebo. The primary endpoint was major or clinically relevant nonmajor (CRNM) bleeding over 6 months of follow-up. The effects were assessed stratified by baseline CHA2DS2-VASc and HAS-BLED score using Cox proportional hazards models. Results 4386 patients were included for this analysis. The median age was 71 (64–77) years, 29.4% were female, 81.7% had a CHA2DS2-VASc score≥3, and 66.8% a HAS-BLED score≥3. As shown in the table, rates of bleeding were lower with apixaban (vs VKA) irrespective of baseline bleeding risk (p-value interaction: 0.23). Aspirin (vs placebo) was associated with increased bleeding irrespective of baseline risk (p-value interaction: 0.88). Apixaban use was associated with a lower risk of death or hospitalization without a significant interaction with stroke risk (p-value of interaction=0.53). No differences were found for ischemic outcomes. Conclusion An antithrombotic regimen including a P2Y12 inhibitor and apixaban is associated with less bleeding and hospitalization compared to a regimen with VKA, aspirin, or both with results consistent across CHA2DS2-VASc, and HAS-BLED scores. Our findings support the use of apixaban and a P2Y12 inhibitor without aspirin during the first 6 months for most patients with AF and ACS and/or PCI, regardless of stroke and bleeding risk. Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): The Augustus trial was sponsored by Bristol-Myers Squibb and Pfizer, Inc

Background AUGUSTUS randomized patients with atrial fibrillation and ACS and/or PCI to apixaban or VKA and aspirin or placebo for 6 months on background P2Y12 inhibitor. Purpose To characterise the clinical outcomes in patients receiving clopidogrel or ticagrelor. Methods Patients enrolled in AUGUSTUS (n=4614) were grouped by P2Y12 inhibitor at randomization. Baseline characteristics were compared among groups. Rates of ISTH major or CRNM bleeding, definite/probable stent thrombosis (ST), stroke, MI, and death or ischaemic event were quantified and treatment groups were compared according to treatment with clopidogrel or ticagrelor. Results At randomization, patients were treated with clopidogrel (n=4165), ticagrelor (n=280), prasugrel (n=51) or no P2Y12 inhibitor (n=118). Median ages were 71, 69, 66 and 72 years (P Conclusions Apixaban is safer than VKA regardless of P2Y12 inhibitor used. Dropping aspirin reduces bleeding but is associated with numerically higher ST rates regardless of P2Y12 inhibitor used. These data support current recommendations for preferential use of NOAC vs. VKA and individualised choice of P2Y12 inhibitor and timing of aspirin cessation after PCI according to the patient's risks of bleeding and stent thrombosis. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Bristol-Myers Squibb/Pfizer

Background Sub-optimal self-care and non-adherence to treatments are important predictors of poor clinical outcomes in patients with heart failure. Task-sharing and technology have each contributed modest improvements, but the combined effect on outcomes is unknown. We aim to develop a complex intervention package to improve self-care predicated on task sharing and smartphone based remote monitoring among heart failure patients. Purpose As a formative step, we conducted a qualitative study among heart failure patients and their caregivers to explore self-care and to inform the development of a contextualized intervention package. Methods We conducted in-depth interviews among 22 patients admitted to in-patient wards with a clinical diagnosis of chronic heart failure (diagnosis made at least 1 month prior to index hospitalization) and 18 caregivers (n=40), sampled from 4 states in southern India. Patients were purposively sampled based on sex, socioeconomic status, health literacy and past one month's history of adherence to heart failure medications. The middle range theory of self-care informed the drafting of the interview guide. We recorded and transcribed interviews translated from 5 regional languages. We inductively coded the data from a social constructionist viewpoint, created categories, prepared memos, compared extreme cases, identified key emergent themes and their inter-relationships. Results Patients' mean age was 60.5 (±13.4), with representation from socioeconomic strata, urban and rural areas. Patients had a high pill burden [median 10; IQR (6, 31)] and 8 (44%) reported irregular adherence to prescribed medications in the last month. Key categories associated with sub-optimal self-care included “Passivity”, “Entrenched Belief systems”, “Negative Emotions/Affect”, “Ageing causes disease”, and “inability to control situations” across all socioeconomic strata. These themes appear to impair self-actualization that negatively impacts self efficacy/confidence and in turn self-care reciprocally (Refer Figure). Key facilitators of self-care were: Intrinsic patient distinctive facilitators (situational awareness, resilience) and extraneous facilitators (insurance/financial protection, positive caregiver relationships and ease of healthcare access). Patients and caregivers generally expressed their readiness to use mobile technology for remote monitoring and to be counseled by trained lay workers to address beliefs and be trained on self-care. Framework explaining self-care in HF Conclusions Findings from this formative study show opportunities for providers and community-based care workers to address task-sharing of beliefs by educating patients on self-care, including through the use of technology-based solutions. These findings regarding a self-care framework identify opportunities to improve self-care among heart failure patients using task-sharing and technology to support the patient-caregiver-provider triad. Acknowledgement/Funding India Alliance - Wellcome Trust and Department of Biotechnology

Background International guidelines vary in their recommendations for dual antiplatelet therapy (DAPT) use beyond 1 year post-myocardial infarction (MI). Purpose To identify predictors of DAPT use in patients ≥1 year post-MI prior to the publication of the DAPT score and the 2017 European Society of Cardiology (ESC) guidelines for DAPT in coronary artery disease. Methods TIGRIS (NCT01866904) was a prospective, multi-center (369 centers in 25 countries), observational study of patients 1 to 3 years post-MI between June 2013 and November 2014. We performed a multivariable logistic regression analysis to identify independent predictors of DAPT use at 396 days post-MI (365 + 31 days overrun period to allow intended DAPT discontinuation at 1 year). Patients on oral anticoagulation were excluded. Results Of 8464 patients enrolled (mean age 66 years, women 24%, ST-elevation MI 53%), 40% were on DAPT at 396 days post-MI (Figure). In the subset of patients on DAPT at 396 days post-MI, aspirin was combined with clopidogrel in 84%, prasugrel in 12%, and other antiplatelet agents in 4%. DAPT use at 396 days post-MI was independently associated with geographic region, age, PCI for the index MI, and a history of multivessel disease or angina (Table). Several variables included in the DAPT score and ESC guideline recommendations (diabetes, second prior MI, hypertension, peripheral artery disease, heart failure, smoking, and renal insufficiency) were not independent predictors of DAPT use at 396 days. Independent predictors of DAPT @396 days Variable at enrolment Patients Odds ratio (95% CI) P-value Region: Europe 3813 Reference group 0.01 North America 923 1.65 (0.56, 4.86) Latin America 1084 2.55 (1.19, 5.47) Asia and Australia 2644 3.01 (1.42, 6.36) Age DAPT use at 396 days post-MI by region Conclusion During the study period, DAPT use ≥1 year post-MI was prevalent and appeared to be influenced by regional practices. Further research is needed to determine whether the DAPT score and the 2017 ESC guidelines for dual antiplatelet therapy have changed long-term DAPT use practices. Acknowledgement/Funding AstraZeneca AB, Södertälje, Sweden

Background Approximately 10% of patients presenting with myocardial infarction (MI) do not have obstructive coronary artery disease (MINOCA). The role of antiplatelet therapy and outcomes in this group remain unclear. We assessed prognosis and the effect of an intensified clopidogrel regimen in MINOCA patients. Methods We analyzed data from the CURRENT-OASIS 7 trial, which randomized 25,086 patients with acute coronary syndromes (ACS) referred for early intervention to receive either double-dose (600mg day 1; 150mg days 2–7; then 75mg daily) or standard-dose (300mg day 1; then 75mg daily) clopidogrel. We evaluated clinical outcomes at 30-days in patients with versus without obstructive CAD and in relation to standard versus double-dose clopidogrel. Results Overall, 23,783 MI patients were included, of which 1,599 (6.7%) had MINOCA. MINOCA patients were younger, more frequently presented with non-ST-segment elevation MI and had fewer comorbidities. Rates of all-cause mortality (0.7% versus 2.4%, p=0.0046), cardiovascular mortality (0.6 versus 2.2%, p=0.0056), repeat MI (0.5% versus 2.3%, p=0.0009) and major bleedings (0.7% versus 2.5%, p=0.0001) were significantly lower among patients with MINOCA versus those with obstructive CAD. Compared with the standard-dose clopidogrel regimen, the double-dose regimen appeared to increase the risk of cardiovascular death, MI or stroke in MINOCA patients (0.8% versus 2.1%, hazard ratio (HR) 2.74, P=0.033). There was no difference in those with obstructive CAD (4.7% versus 4.4%, HR 0.93, P=0.226; P-for-interaction=0.023) (see Figure 1A). Major bleeding did not occur more frequently in MINOCA patients with double- versus standard-dose clopidogrel regimen (0.7% versus 0.6%, (HR 1.16 (95% CI 0.35–3.80), p=0.805), but their rate was higher In MI patients with obstructive CAD (2.7% versus 2.2% (HR 1.26 (95% CI 1.06–1.49), p=0.008) (Figure 1B). Figure 1A & B Conclusions Compared to MI patients with obstructive CAD, patients presenting with MINOCA represent a distinct cohort, which is generally younger, has a higher NSTEMI prevalence and fewer comorbidities. Their risk for adverse events, especially repeat MI, stroke, death, and bleeding, is low ( Acknowledgement/Funding The CURRENT-OASIS 7 trial was sponsored by Sanofi-Aventis and Bristol-Myers Squibb.

Background There is a growing prevalence of diabetes worldwide in patients in the general population, including those with prior myocardial infarction (MI). Purpose To describe the characteristics, health status, resource utilization and clinical adverse events of stable post-MI patients with diabetes. Methods The long-Term rIsk, clinical manaGement and healthcare Resource utilization of stable coronary artery dISease (TIGRIS) prospective observational study (NCT01866904) obtained data from 8985 stable patients 1–3 years post-MI from 369 centres in 25 countries, who provided diabetes status (no, yes, insulin-treated) and follow-up. Diabetes status, other patient characteristics, medications, medical history and healthcare resource utilization were recorded at enrolment. Health status was assessed at enrolment, 1 and 2 years by EQ-5D-3L and converted to an EQ-5D score. Deaths, cardiovascular (CV) events, bleeding events and related hospitalizations were recorded during 2 years of follow-up. Results Diabetes mellitus (DM) was prevalent at enrolment in 2966 (33%) patients of whom 872 (29%) were insulin-treated. Compared to patients without DM, those with DM had a higher mean body mass index (28.2 vs 26.6kg/m2) and heart rate (71 vs 67bpm), were more likely to have had ≥2 prior MIs (12% vs 10%), chronic kidney disease (10% vs 6%), peripheral artery disease (10% vs 5%), heart failure (15% vs 10%), anaemia (4% vs 2%), angina (12% vs 9%), stroke (6% vs 4%) and chronic obstructive pulmonary disease (9% vs 7%). Patients with DM reported more problems for each domain of the EQ-5D (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), which resulted in a lower mean EQ-5D utility score at enrolment (0.83±0.22 for no-diabetes vs 0.86±0.19 for diabetes). Moreover, they also had higher CV hospitalization rates in the 6 months prior to enrolment (6.4% vs 5%). All these measures were more marked in insulin-dependent diabetics. The incidences of all-cause death, CV death and the composite of CV death, MI and stroke were all significantly higher in patients with DM, especially those on insulin (see Figure). For CV death, MI and stroke the 2-year risk ratios, compared to patients without DM, were 2.64 (P Figure 1 Conclusions Within a global population of stable post-MI patients, those with DM (especially those on insulin) have poorer health status and EQ-5D utility score, higher hospitalization rates and worse clinical outcomes compared with those without DM. Thus, in cardiac clinics worldwide, patients with DM require particularly close attention. Acknowledgement/Funding The study was funded by AstraZeneca

Background Both levels of protein and lipid biomarkers have been found associated with cardiovascular outcomes in patients with stable coronary heart disease (CHD). There are few large-scale studies comparing the prognostic value of and interactions between these two groups of biomarkers in CHD. Methods In the 15,828 CHD patients included in the STABILITY trial 10,205 provided plasma samples at baseline allowing measurements of distinct ceramide and phospholipid species by mass spectrometry and markers of cardiac dysfunction (N-terminal pro-B-type natriuretic peptide [NT-proBNP]), high sensitivity cardiac troponin-T [cTnT-hs]), renal dysfunction (cystatin-C), oxidative stress (growth differentiation factor 15 [GDF-15]) by electro-immunoassays. During 3.7 years median follow-up, 1291 CVD, MI, and stroke events occurred. A previously developed ceramide and phospholipid species based risk score (CERT) and its associations to outcomes before and after adjustment were evaluated by Cox-regression models. Results The CERT model was significantly associated to all cardiovascular outcomes before and after adjustment for clinical characteristics and routine laboratory tests. However, the associations were attenuated after adjustment for other prognostic biomarkers. The data are summarized in Table 1 below. Table 1. HR per 1 SD increase in CERT HR (95% CI) p-value MACE Model 1 1.30 (1.24–1.37) Conclusion A ceramide/phospholipids based risk score is associated with the risk of fatal and non-fatal cardiovascular events in patients with stable CHD. The score is attenuated by adjustment for biomarkers indicating cardiorenal dysfunction and inflammatory activity and may be related to underlying mechanisms for adverse outcomes in stable CHD. Acknowledgement/Funding The original STABILITY study was funded by GlaxoSmithKline

Background Renal dysfunction is associated with increased risk of cardiovascular events in atrial fibrillation (AF). Estimated glomerular filtration rate (eGFR) can be calculated by different equations based on creatinine or cystatin C. We compared different methods of assessing eGFR and their association with cardiovascular (CV) death and major bleeding in 14,980 AF patients in the ARISTOTLE trial. Methods eGFR was calculated using equations based on creatinine (Cockcroft-Gault, MDRD, and CKD-EPI) and/or cystatin C (CKD-EPIcys and CKD-EPIcys+crea). In total five eGFR equations as well as a model based on the variables within the equations were assessed. Associations were evaluated by Spearman correlation, and discriminatory ability for CV-death and major bleeding by Harrell's c-index. Results Median age was 70.0 years, and 35.6% were women. Median eGFR (mL/min) were: Cockcroft-Gault 74.1, MDRD 66.5, CKD-EPI 68.5, CKD-EPIcys 74.2, and CKD-EPIcys+crea 72.6. Correlation ranged from 0.49 (Cockroft-Gault and CKD-EPIcys) to 0.99 (MDRD and CKD-EPI). Among the eGFR equations, those based on cystatin C yielded the highest c-indices for CV-death and major bleeding, 0.628 (CKD-EPIcys) and 0.612 (CKD-EPIcys+crea), respectively. A model based on the variables within the eGFR equations (age, sex, weight, creatinine, and cystatin C) yielded the highest discriminatory value for both outcomes, 0.673 and 0.656, respectively. Figure 1 Conclusions In patients with AF on anticoagulation, correlation between eGFR methods varied greatly. Cystatin C-based eGFR seem to provide the most robust balance in reflecting the risk of death and bleeding. However, a model based on the individual variables within the eGFR equations provided the highest discriminatory value. Acknowledgement/Funding The ARISTOTLE trial was funded by Bristol-Myers Squibb, Co Princeton, NJ and Pfizer Inc., New York, NY.

Background In ARISTOTLE, patients with atrial fibrillation and ≥2 dose-reduction criteria [age ≥80 years, weight ≤60 kg, and creatinine ≥1.5 mg/dL (133 μmol/L)] were randomized to apixaban 2.5 mg twice daily (b.i.d) or warfarin. Purpose To determine whether the apixaban dose adjustment in ARISTOTLE resulted in similar efficacy and safety compared to warfarin. Methods The effects of apixaban 2.5 mg b.i.d versus warfarin on stroke or systemic embolism, major bleeding and death in ARISTOTLE patients with ≥2 dose-reduction criteria were compared with the effects of apixaban 5 mg b.i.d in patients with 0 or 1 dose-reduction criterion. Results Of 751 (4.1%) patients with ≥2 dose-reduction criteria, 386 were assigned to apixaban 2.5 mg b.i.d and 365 to warfarin. Compared to patients with 0 or 1 dose reduction criteria (n=17,322), these patients had a higher risks of stroke/systemic embolism (HR =1.78; 95% CI [1.24–2.57]), major bleeding (HR =1.73; 95% CI [1.28–2.32]) and death (HR=3.21; 95% CI [2.69–3.83]), irrespective of whether they were assigned to apixaban or warfarin. The benefits of apixaban 2.5 mg b.i.d compared with warfarin on stroke or systemic embolism, major bleeding, and death in patients with ≥2 dose-reduction criteria were consistent with that of apixaban 5 mg b.i.d in patients with either 0 or 1 dose-reduction criteria (Figure). Conclusions While they are at higher overall risk, patients with appropriate dose reduction criteria have consistent benefits with apixaban 2.5 mg b.i.d. over warfarin. Additional analyses investigating the relationship between apixaban dose and both apixaban plasma concentrations and levels of thrombosis biomarkers are underway. Acknowledgement/Funding Bristol-Myers Squibb and Pfizer, Inc.

Background Older patients with atrial fibrillation (AF) often have multiple chronic conditions adding complexity to treatment decisions. However, regarding older AF patients, the association between multimorbidity and quality of care has not been explored previously in a non-selected nationwide cohort. Purpose To investigate the association between morbidity burden and the treatment with oral anticoagulation therapy (OAC) and rhythm-control strategies in patients >65 years of age with incident AF in Denmark. Methods Using Danish nationwide registers, we identified all Danish AF patients >65 years of age hospitalized for incident AF between 2010 and 2016. Using logistic regression models, we estimated the association between morbidity burden (5 comorbidities) and the likelihood of receiving AF specific treatments. Estimates were reported as odds ratios with 95% confidence intervals (OR, 95% CI) with Results A total of 49,802 AF patients were eligible for inclusion, with a median age of 77.5 years (Interquartile range [IQR] 71.8–83.8) and 24,983 (50.2%) were male. A total of 25,181 (50.6%) patients had 5 comorbidities. The median CHA2DS2-VASc score ranged from 3 (IQR 2–3) to 5 (IQR 4–5) in patients with 5 comorbidities, respectively. Increasing morbidity burden was associated with decreasing odds of being treated with OAC therapy with the lowest odds in patients with >5 comorbidities (OR 0.39, 95% CI 0.34–0.45) compared with AF patients with Morbidity burden was associated with increased odds of being prescribed anti-arrhythmic medication with the highest odds in patients with >5 comorbidities (OR 2.50 95% CI 2.08–2.99). In contrast, having >5 comorbidities was associated with decreased odds of AF related procedures (OR 0.32, 95% CI 0.23–0.43) compared to patients with Forest plot of OAC initiation factors Conclusion Morbidity burden is strongly associated with OAC initiation and rhythm-control strategies in older patients with incident AF. Older AF patients with multimorbidity are less likely to be treated with OAC although these are the patients who benefit most from treatment. Therefore, initiatives and quality improvement programs should be done to close this important gap between clinical trials and clinical practice.

Aims: In atrial fibrillation (AF), mortality remains high despite effective anticoagulation. A model predicting the risk of death in these patients is currently not available. We developed and validated a risk score for death in anticoagulated patients with AF including both clinical information and biomarkers. Methods and results: The new risk score was developed and internally validated in 14 611 patients with AF randomized to apixaban vs. warfarin for a median of 1.9 years. External validation was performed in 8548 patients with AF randomized to dabigatran vs. warfarin for 2.0 years. Biomarker samples were obtained at study entry. Variables significantly contributing to the prediction of all-cause mortality were assessed by Cox-regression. Each variable obtained a weight proportional to the model coefficients. There were 1047 all-cause deaths in the derivation and 594 in the validation cohort. The most important predictors of death were N-terminal pro B-type natriuretic peptide, troponin-T, growth differentiation factor-15, age, and heart failure, and these were included in the ABC (Age, Biomarkers, Clinical history)-death risk score. The score was well-calibrated and yielded higher c-indices than a model based on all clinical variables in both the derivation (0.74 vs. 0.68) and validation cohorts (0.74 vs. 0.67). The reduction in mortality with apixaban was most pronounced in patients with a high ABC-death score. Conclusion: A new biomarker-based score for predicting risk of death in anticoagulated AF patients was developed, internally and externally validated, and well-calibrated in two large cohorts. The ABC-death risk score performed well and may contribute to overall risk assessment in AF.

Aims Atrial fibrillation (AF) is associated with an increased risk of stroke, which is currently estimated by clinical characteristics. The cardiac biomarkers N-terminal fragment B-type natriuretic peptide (NT-proBNP) and cardiac troponin high-sensitivity (cTn-hs) are independently associated with risk of stroke in AF. Our objective was to develop and validate a new biomarker-based risk score to improve prognostication of stroke in patients with AF. Methods and results A new risk score was developed and internally validated in 14 701 patients with AF and biomarkers levels determined at baseline, median follow-up of 1.9 years. Biomarkers and clinical variables significantly contributing to predicting stroke or systemic embolism were assessed by Cox-regression and each variable obtained a weight proportional to the model coefficients. External validation was performed in 1400 patients with AF, median follow-up of 3.4 years. The most important predictors were prior stroke/transient ischaemic attack, NT-proBNP, cTn-hs, and age, which were included in the ABC ( A ge, B iomarkers, C linical history) stroke risk score. The ABC-stroke score was well calibrated and yielded higher c-indices than the widely used CHA2DS2-VASc score in both the derivation cohort (0.68 vs. 0.62, P < 0.001) and the external validation cohort (0.66 vs. 0.58, P < 0.001). Moreover, the ABC-stroke score consistently provided higher c-indices in several important subgroups. Conclusion A novel biomarker-based risk score for predicting stroke in AF was successfully developed and internally validated in a large cohort of patients with AF and further externally validated in an independent AF cohort. The ABC-stroke score performed better than the presently used clinically based risk score and may provide improved decision support in AF. ClinicalTrials. gov identifier NCT00412984, [NCT00799903][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00799903&atom=%2Fehj%2F37%2F20%2F1582.atom

Aims Although non-vitamin K antagonist oral anticoagulants are recommended for stroke prevention in patients with non-valvular atrial fibrillation (NVAF) based on clinical trial results, there is a need for safety and efficacy data from unselected patients in everyday clinical practice. XANTUS investigated the safety and efficacy of the Factor Xa inhibitor rivaroxaban in routine clinical use in the NVAF setting. Methods and results Consecutive consenting patients with NVAF newly started on rivaroxaban were eligible and were followed up at ∼3-month intervals for 1 year, or for at least 30 days after permanent discontinuation. All adverse events (AEs) were recorded as AEs or serious AEs; major outcomes (including major bleeding, symptomatic thromboembolic events [stroke, systemic embolism, transient ischaemic attack, and myocardial infarction], and all-cause death) were centrally adjudicated. There were 6784 patients treated with rivaroxaban at 311 centres in Europe, Israel, and Canada. Mean patient age was 71.5 years (range 19–99), 41% were female, and 9.4% had documented severe or moderate renal impairment (creatinine clearance

Despite the demonstrable success of oral anticoagulants in reducing the rate of stroke in patients with atrial fibrillation, they continue to be seriously underutilized. Indications for their use as stated in the guidelines incorporate a number of risk score algorithms, the most widely used being the CHA2DS2-VASc score. Nonetheless there are several limitations to the various scores currently in clinical use and a critique of these is the focus of this review. In this review we discuss the pathophysiology of atrial fibrillation and its role in thromboembolic stroke risk. We amalgamate this with the basis of major professional society anticoagulation recommendations with regards to the strengths and limitations of current risk stratification strategies and discuss gaps in our current evidence base and next steps to address those gaps.

Women with stable coronary artery disease have better clinical outcomes than men, but this association is modified by degree of depression : insights from the STABILITY trial

Aims Microvascular obstruction (MVO) is the underlying cause for the no-reflow phenomenon in ST-segment elevation myocardial infarction (STEMI). The association between MVO assessed by cardiac magnetic resonance imaging (CMR) and prognosis has not been convincingly demonstrated. We sought to determine the relationship between MVO assessed early after primary percutaneous coronary intervention (PCI) in STEMI and all-cause mortality, hospitalization for heart failure (HF), and reinfarction. Methods and results We performed a pooled analysis using individual patient data from seven randomized primary PCI trials in which MVO was assessed within 7 days after reperfusion by CMR using late gadolinium enhancement imaging (n = 1688). Clinical follow-up was performed for at least 6 months after the index event. Median time to CMR after STEMI was 3 days [interquartile range (IQR) 2-4], and median duration of clinical follow-up was 365 days (IQR 188-374). Microvascular obstruction was present in 960 (56.9%) of patients, and median MVO (percent left ventricular myocardial mass) was 0.47% (IQR 0.00-2.54). A graded response was present between the extent of MVO (per 1.0% absolute increase) and subsequent mortality [Cox adjusted hazard ratio (HR) 1.14, 95% confidence interval (CI) 1.09-1.19, P

Aims The risk of stroke in patients with atrial fibrillation (AF) increases with age. In the ARISTOTLE trial, apixaban when compared with warfarin reduced the rate of stroke, death, and bleeding. We evaluated these outcomes in relation to patient age. Methods and results A total of 18 201 patients with AF and a raised risk of stroke were randomized to warfarin or apixaban 5 mg b.d. with dose reduction to 2.5 mg b.d. or placebo in 831 patients with ≥2 of the following criteria: age ≥80 years, body weight ≤60 kg, or creatinine ≥133 μmol/L. We used Cox models to compare outcomes in relation to patient age during 1.8 years median follow-up. Of the trial population, 30% were 0.11 for all). Results were also consistent for the 13% of patients ≥80 years. No significant interaction with apixaban dose was found with respect to treatment effect on major outcomes. Conclusion The benefits of apixaban vs. warfarin were consistent in patients with AF regardless of age. Owing to the higher risk at older age, the absolute benefits of apixaban were greater in the elderly.

Item does not contain fulltext AIMS: We assessed the effect of concomitant aspirin use on the efficacy and safety of apixaban compared with warfarin in patients with atrial fibrillation (AF). METHODS AND RESULTS: In ARISTOTLE, 18 201 patients were randomized to apixaban 5 mg twice daily or warfarin. Concomitant aspirin use was left to the discretion of the treating physician. In this predefined analysis, simple and marginal structured models were used to adjust for baseline and time-dependent confounders associated with aspirin use. Outcome measures included stroke or systemic embolism, ischaemic stroke, myocardial infarction, mortality, major bleeding, haemorrhagic stroke, major or clinically relevant non-major bleeding, and any bleeding. On Day 1, 4434 (24%) patients were taking aspirin. Irrespective of concomitant aspirin use, apixaban reduced stroke or systemic embolism [with aspirin: apixaban 1.12% vs. warfarin 1.91%, hazard ratio (HR) 0.58, 95% confidence interval (CI) 0.39-0.85 vs. without aspirin: apixaban 1.11% vs. warfarin 1.32%, HR 0.84, 95% CI 0.66-1.07; P interaction = 0.10] and caused less major bleeding than warfarin (with aspirin: apixaban 3.10% vs. warfarin 3.92%, HR 0.77, 95% CI 0.60-0.99 vs. without aspirin: apixaban 1.82% vs. warfarin 2.78%, HR without aspirin 0.65, 95% CI 0.55-0.78; P interaction = 0.29). Similar results were seen in the subgroups of patients with and without arterial vascular disease. CONCLUSION: Apixaban had similar beneficial effects on stroke or systemic embolism and major bleeding compared with warfarin, irrespective of concomitant aspirin use.

Aim Studies have reported less favourable outcomes in women compared with men after primary percutaneous coronary intervention (PCI) in ST-segment elevation myocardial infarction (STEMI). Whether sex-specific differences in the magnitude or prognostic impact of infarct size or post-infarction cardiac function explain this finding is unknown. Methods and results We pooled patient-level data from 10 randomized primary PCI trials in which infarct size was measured within 1 month (median 4 days) by either cardiac magnetic resonance imaging or technetium-99m sestamibi single-photon emission computed tomography. We assessed the association between sex, infarct size, and left ventricular ejection fraction (LVEF) and the composite rate of death or heart failure (HF) hospitalization within 1 year. Of 2632 patients with STEMI undergoing primary PCI, 587 (22.3%) were women. Women were older than men and had a longer delay between symptom onset and reperfusion. Infarct size did not significantly differ between women and men, and women had higher LVEF. Nonetheless, women had a higher 1-year rate of death or HF hospitalization compared to men, and while infarct size was a strong independent predictor of 1-year death or HF hospitalization (P Conclusions In this large-scale, individual patient-level pooled analysis of patients with STEMI undergoing primary PCI, women had a higher 1-year rate of death or HF hospitalization compared to men, a finding not explained by sex-specific differences in the magnitude or prognostic impact of infarct size or by differences in post-infarction cardiac function.

This editorial refers to ‘Edoxaban versus warfarin in vitamin K antagonist-experienced and naive patients with atrial fibrillation’, by M.L. O'Donoghue et al. , on page doi: 10.1093/eurheartj/ehv014. Relative to warfarin, non-vitamin K oral anticoagulants (NOACs) are at least as good at preventing stroke or systemic embolism, cause less haemorrhagic stroke, and result in modestly lower mortality.1 Thus, the European Society of Cardiology has recommended NOACs in place of vitamin K antagonists (VKAs) in most patients with atrial fibrillation (class IIa, level of evidence A).2 According to one report, the use of NOACs in the USA has increased to > 60% of prescriptions for patients being initiated on oral anticoagulation.3 However, patients already treated with VKAs are usually not switched to NOACs.4 The low rates of switching from VKAs to NOACs relate to multiple factors including patient preference, medication cost, and clinical factors such as severe renal impairment. There is a common perception that a patient who is stable on a VKA will derive less benefit from a NOAC than a “VKA-naive”, patient who has not been previously treated with a VKA. The question remains whether or not this perception is supported by evidence. Not only does prior use of a VKA influence decisions to use a NOAC, but so does the degree of International Normalized Ratio (INR) control on a VKA, as measured by the time in therapeutic range (TTR). The prevailing opinion is that switching to a NOAC is less beneficial for patients on a VKA with a high TTR. In the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W) trial, patients who were at centres …

Aims Despite the known benefits of regular exercise, the reasons why many coronary heart disease (CHD) patients engage in little physical activity are not well understood. This study identifies factors associated with low activity levels in individuals with chronic CHD participating in the STABILITY study, a global clinical outcomes trial evaluating the lipoprotein phospholipaseA2 inhibitor darapladib. Methods and results Prior to randomization, 15 486 (97.8%) participants from 39 countries completed a lifestyle questionnaire. Total physical activity was estimated from individual subject self-reports of hours spend each week on mild, moderate, and vigorous exercise, corresponding approximately to 2, 4, and 8 METS, respectively. Multivariate logistic regression evaluated clinical and demographic variables for the lowest compared with higher overall exercise levels, and for individuals who decreased rather than maintained or increased activity since diagnosis of CHD. The least active 5280 subjects (34%) reported exercise of ≤24MET.h/week. A total of 7191 subjects (46%) reported less exercise compared with before diagnosis of CHD. The majority of participants were either ‘not limited’ or ‘limited a little’ walking 100 m (84%), climbing one flight of stairs (82%), or walking 1 km/½ mile (68%), and

AimsAtrial fibrillation (AF) is common among patients with impaired renal function. Apixaban, a novel oral anticoagulant with partial renal excretion, was compared with warfarin and reduced the rate stroke, death and bleeding in the ARISTOTLE trial. We evaluated these outcomes in relation to renal function.Methods and resultsBaseline glomerular filtration rate (GFR) was estimated using the Cockcroft–Gault and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations as well as cystatin C measurements. According to baseline Cockcroft–Gault, there were 7518 patients (42%) with an estimated GFR (eGFR) of >80 mL/min, 7587 (42%) between >50 and 80 mL/min, and 3017 (15%) with an eGFR of ≤50 mL/min. The rate of cardiovascular events and bleeding was higher at impaired renal function (≤80 mL/min). Apixaban was more effective than warfarin in preventing stroke or systemic embolism and reducing mortality irrespective of renal function. These results were consistent, regardless of methods for GFR estimation. Apixaban was associated with less major bleeding events across all ranges of eGFRs. The relative risk reduction in major bleeding was greater in patients with an eGFR of ≤50 mL/min using Cockcroft–Gault {hazard ratio (HR) 0.50 [95% confidence interval (CI) 0.38–0.66], interaction P = 0.005} or CKD-EPI equations [HR 0.48 (95% CI 0.37–0.64), interaction P = 0.003].ConclusionIn patients with AF, renal impairment was associated with increased risk of cardiovascular events and bleeding. When compared with warfarin, apixaban treatment reduced the rate of stroke, death, and major bleeding, regardless of renal function. Patients with impaired renal function seemed to have the greatest reduction in major bleeding with apixaban.

Aims Controversy exists regarding the early use of glycoprotein IIb/IIIa inhibitors (GPIs) in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). The Assessment of Pexelizumab in Acute Myocardial Infarction (APEX-AMI) trial provides a unique opportunity to examine early vs. late or non-use of GPIs in a large STEMI cohort treated with PCI. Methods and results In the APEX-AMI trial, 3969 of 5707 patients received one of three GPIs at the operator's discretion (abciximab, eptifibatide, tirofiban). Of GPI-treated patients, the median time from symptom onset to GPI administration was 180 min (25th, 75th percentile: 130, 258); 1125 received the agent prior to arriving in the catheterization laboratory [pre-sheath; GPI to sheath insertion: 37 min (16, 66)], whereas 2844 patients were treated after arrival in the catheterization laboratory [in-lab; sheath insertion to GPI: 16 min (10, 27)]. The pre-sheath use of GPIs was associated with a significantly lower hazard of 90-day mortality [adjusted hazard ratio (HR) 0.68, 95% confidence interval (CI) 0.48–0.95, P = 0.025] and of 90-day composite of death/CHF/shock (adjusted HR 0.81, 95% CI 0.65–1.00, P = 0.054). In-hospital severe and moderate bleeding was not related to the use of GPIs. Conclusion This retrospective analysis from a large patient cohort with acute STEMI undergoing PCI suggests that pharmacological pre-treatment of PCI with GPIs, particularly abciximab, was associated with significantly lower occurrence of 90-day clinical outcomes and supports the pre-procedural administration of GPIs in this clinical setting. Clinical trial registration information: URL: . Unique identifier: NCT00091637.

Aims To examine the extent of delay from initial hospital presentation to fibrinolytic therapy or primary percutaneous coronary intervention (PCI), characteristics associated with prolonged delay, and changes in delay patterns over time in patients with ST-segment elevation myocardial infarction (STEMI). Methods and results We analysed data from 5170 patients with STEMI enrolled in the Global Registry of Acute Coronary Events from 2003 to 2007. The median elapsed time from first hospital presentation to initiation of fibrinolysis was 30 min (interquartile range 18–60) and to primary PCI was 86 min (interquartile range 53–135). Over the years under study, there were no significant changes in delay times to treatment with either strategy. Geographic region was the strongest predictor of delay to initiation of fibrinolysis >30 min. Patient's transfer status and geographic location were strongly associated with delay to primary PCI. Patients treated in Europe were least likely to experience delay to fibrinolysis or primary PCI. Conclusion These data suggest no improvements in delay times from hospital presentation to initiation of fibrinolysis or primary PCI during our study period. Geographic location and patient transfer were the strongest predictors of prolonged delay time, suggesting that improvements in modifiable healthcare system factors can shorten delay to reperfusion therapy even further.

The financial ‘meltdown’ that began in 2008 dramatically underscores the need for significant global changes in our fundamental institutions and interactions, and the field of medicine is no exception. Global ‘flattening’ encompassed by modern information and communication networks has increased our awareness of major health disparities at almost every level. At the same time, however, we have unprecedented access to knowledge that allows people to live longer and healthier lives. The field of cardiovascular medicine is particularly illustrative of this paradox. Despite decades of unprecedented improvements in prevention, treatment, and outcomes, cardiovascular medicine now faces a major global upswing in disease impact, driven by global demographic and cultural trends. Moreover, given the discipline's emphasis on technological and pharmacological treatments, it accounts for a major portion of healthcare costs. Outstanding emerging examples of local, national, and global collaboration among cardiovascular practitioners, however, suggest rapidly growing awareness of these challenges, as well as new opportunities for addressing them.1 In this article, we argue that leaders in the field of cardiovascular medicine have a fundamental responsibility to create, develop, and implement a global knowledge network that exemplifies the learning health system of the future. Numerous studies document the effects of cardiovascular disease (CVD), as well as the impact of its treatment and prevention, on rates of death and disability among the world's population. As life expectancies increase globally, the prevalence of ischaemic heart disease and heart failure will continue to grow even as age-specific risk drops due to application of existing measures for treatment and prevention.2,3 New and striking increases in obesity and diabetes mellitus threaten to compound the effects of age, creating a dramatic surge in CVD prevalence and potentially offsetting gains achieved through reductions in smoking and by the use of effective treatments aimed at lowering lipid …