Ventricular rate in atrial fibrillation and the risk of heart failure and death.

AIMS: While clinical trials have suggested that a high ventricular rate is associated with increased risk of heart failure (HF) and mortality, all-comers studies are warranted. OBJECTIVE: To assess 1-year risk of new-onset diagnosed HF and all-cause mortality among rate-control treated patients presenting with atrial fibrillation (AF) on an electrocardiogram (ECG) according to ventricular rate. METHODS AND RESULTS: ECGs recorded at the Copenhagen General Practitioners Laboratory (2001-15) were used to identify patients with AF. Multivariate Cox proportional hazard regression models were used to compare risk of new-onset HF and all-cause mortality after first ECG presenting with AF according to ventricular rate on ECG [<60, 60-79, 80-99, and 100-110, > 110 beats per minute (bpm)]. We identified 7408 patients in treatment with rate control drugs at time of first ECG presenting with AF [median age 78 years (Q1,Q3 = 70-85 years)], 45.8% male, median ventricular rate 83 bpm, (Q1,Q3 = 71-101 bpm)]. During 1-year follow-up, 666 (9.0%) of all patients with AF developed HF and 858 (11.6%) died. Patients with AF ventricular rates 100-110 bpm and >110 bpm had a hazard ratio (HR) of 1.46 (CI: 1.10-1.95) and 2.41 (CI: 1.94-3.00) respectively for new-onset HF, compared with 60-79 bpm. Similarly, patients with AF ventricular rates 100-110 bpm and >110 bpm had a HR of 1.44 (CI: 1.13-1.82) and 1.34 (CI: 1.08-1.65) respectively for all-cause mortality, compared with 60-79 bpm. CONCLUSIONS: Ventricular rates ≥100 bpm among patients presenting with AF on ECG in treatment with rate control drugs were associated with greater risk of both new-onset HF and all-cause mortality.

Monogenic and Polygenic Contributions to Atrial Fibrillation Risk: Results From a National Biobank.

RATIONALE: Genome-wide association studies have identified over 100 genetic loci for atrial fibrillation (AF); recent work described an association between loss-of-function (LOF) variants in TTN and early-onset AF. OBJECTIVE: We sought to determine the contribution of rare and common genetic variation to AF risk in the general population. METHODS: The UK Biobank is a population-based study of 500 000 individuals including a subset with genome-wide genotyping and exome sequencing. In this case-control study, we included AF cases and controls of genetically determined white-European ancestry; analyses were performed using a logistic mixed-effects model adjusting for age, sex, the first 4 principal components of ancestry, empirical relationships, and case-control imbalance. An exome-wide, gene-based burden analysis was performed to examine the relationship between AF and rare, high-confidence LOF variants in genes with ≥10 LOF carriers. A polygenic risk score for AF was estimated using the LDpred algorithm. We then compared the contribution of AF polygenic risk score and LOF variants to AF risk. RESULTS: The study included 1546 AF cases and 41 593 controls. In an analysis of 9099 genes with sufficient LOF variant carriers, a significant association between AF and rare LOF variants was observed in a single gene, TTN (odds ratio, 2.71, P=2.50×10-8). The association with AF was more significant (odds ratio, 6.15, P=3.26×10-14) when restricting to LOF variants located in exons highly expressed in cardiac tissue (TTNLOF). Overall, 0.44% of individuals carried TTNLOF variants, of whom 14% had AF. Among individuals in the highest 0.44% of the AF polygenic risk score only 9.3% had AF. In contrast, the AF polygenic risk score explained 4.7% of the variance in AF susceptibility, while TTNLOF variants only accounted for 0.2%. CONCLUSIONS: Both monogenic and polygenic factors contribute to AF risk in the general population. While rare TTNLOF variants confer a substantial AF penetrance, the additive effect of many common variants explains a larger proportion of genetic susceptibility to AF.

The Importance and Role of Multiple Risk Factor Control in Type 2 Diabetes.

PURPOSE OF REVIEW: The importance of composite risk factor control for reducing CVD risk in type 2 diabetes (T2DM) has gained increased attention and here we review the latest findings in the field. RECENT FINDINGS: The Steno-2 study was the first to show that early intensive risk factor control could improve risk factor status and halve the CVD risk in patients with diabetes with lasting impact. A range of observational studies have added further insight to the importance of multiple risk factor control showing an incremental association between number of risk factors controlled and reduction in CVD risk. Noteworthy, a Swedish population-based study recently showed that optimal risk factor status in patients with T2DM was associated with a CVD risk similar to the general population. Early intensive intervention to achieve optimal risk factor control reduces CVD risk and should be of principal focus in T2DM management.

Efficacy and safety of oral anticoagulants according to kidney function among patients with atrial fibrillation.

BACKGROUND AND AIMS: Patients with severely reduced kidney function have been excluded from randomized controlled trials and data on the safety and efficacy of direct oral anticoagulants (DOACs) according to kidney function remain sparse. The aim was to evaluate the safety and efficacy of the DOACs across subgroups of kidney function. METHODS: Using multiple Danish nationwide registers and laboratory databases, we included patients initiated on oral anticoagulants (OACs) with atrial fibrillation and available creatinine level and followed patients for 2 years to evaluate occurrence of stroke/thromboembolism (TE) and major bleeding. RESULTS: Among 26 686 included patients, 3667 (13.7%) had an estimated glomerular filtration rate (eGFR) of 30-49 mL/min/1.73 m2 and 596 (2.2%) had an eGFR below 30 mL/min/1.73 m2. We found no evidence of differences regarding the risk of stroke/TE between the OACs (P-value interaction >0.05 for all). Apixaban was associated with a lower 2-year risk of major bleeding compared to vitamin K antagonists (VKA) [hazard ratio 0.79, 95% confidence interval (CI) 0.67-0.93], and the risk difference was significantly larger among patients with reduced kidney function (P-value interaction 0.018). Rivaroxaban was associated with a higher risk of bleeding compared to apixaban (hazard ratio 1.78, 95%CI 1.32-2.39) among patients with eGFR 30-49 mL/min/1.73 m2. CONCLUSIONS: Overall, we found no differences regarding the risk of stroke/TE, but apixaban was associated with a 21% lower relative risk of major bleeding compared to VKA. This risk reduction was even greater when comparing apixaban to VKA among patients with eGFR 15-30 mL/min/1.73 m2, and when comparing apixaban to dabigatran and rivaroxaban among patients with eGFR 30-49 mL/min/1.73 m2.

Temporal changes in risk of cardiovascular events in people with newly diagnosed type 2 diabetes with and without cardiovascular disease.

AIMS: Examine temporal changes in the risk of cardiovascular events in people with newly diagnosed type 2 diabetes with and without cardiovascular disease (CVD). METHODS: 283,600 individuals with newly diagnosed type 2 diabetes and age-, sex-, and CVD-matched controls without diabetes were identified through Danish nationwide registries between 1997 and 2014. Using Cox regression models, we report the standardized absolute 5-year risk of cardiovascular death, myocardial infarction, stroke, and heart failure for people with diabetes and controls. RESULTS: Individuals with newly diagnosed diabetes were at increased risk of cardiovascular events compared to controls. From 1997-2002 to 2009-2014 reductions in cardiovascular events for people with diabetes were: cardiovascular death; 26.5% to 13.8% in people with CVD and from 7.3% to 3.2% in people without CVD, myocardial infarction; 13.1% to 6.5% in people with CVD and from 4.1% to 1.9% in people without CVD, stroke; 14.2% to 8.8% in people with CVD and from 4.9% to 2.2% in people without CVD, and heart failure; 21.0% to 13.8% in people with CVD and from 5.0% to 2.6% in people without CVD. The risk of cardiovascular events declined more among people with diabetes than controls. CONCLUSIONS: Newly diagnosed type 2 diabetes was associated with an increased risk of cardiovascular events, and the risk decreased significantly 1997-2014 in both people with and without CVD. Furthermore, the excess risk associated with type 2 diabetes decreased significantly during the study period.

Cardiovascular outcomes with GLP-1 receptor agonists vs. SGLT-2 inhibitors in patients with type 2 diabetes.

AIMS: We examined cardiovascular outcomes associated with initiation of glucagon-like peptide-1 receptor agonist (GLP-1RA) vs. sodium-glucose co-transporter-2 inhibitor (SGLT-2i) treatment in a real-world setting among patients with type 2 diabetes. METHODS AND RESULTS: This Danish nationwide registry-based cohort study included patients with type 2 diabetes with a first-ever prescription of either GLP-1RA or SGLT-2i from 2013 through 2015 with follow-up until end of 2018. All analyses were standardized with respect to age, sex, diabetes duration, comorbidity, and comedication. The main outcome was a composite of cardiovascular death, myocardial infarction, and stroke. Furthermore, the components of the composite outcome and hospitalization for heart failure were evaluated. Standardized average 3-year risks of outcomes and differences thereof were estimated using doubly robust estimation combining cause-specific Cox regression with propensity score regression. We identified 8913 new users of GLP-1RA and 5275 new users of SGLT-2i. The standardized 3-year risk associated with initiating GLP-1RA and SGLT-2i, respectively, was as follows: composite cardiovascular outcome, 5.6% [95% confidence interval (CI): 5.2-6.1] vs. 5.6% (95% CI: 4.8-6.3); cardiovascular mortality, 1.6% (95% CI: 1.3-1.9) vs. 1.5% (95% CI: 1.1-1.8); hospitalization for heart failure, 1.7% (95% CI: 1.5-2.0) vs. 1.8% (95% CI: 1.2-2.5); myocardial infarction, 2.1% (95% CI: 1.8-2.4) vs. 2.1% (95% CI: 1.5-2.6); and stroke, 2.5% (95% CI: 2.2-2.9) vs. 2.6% (95% CI: 2.2-3.1). CONCLUSION: In this nationwide study of patients with type 2 diabetes, initiating GLP-1RA vs. SGLT-2i was not found to be associated with significant differences in cardiovascular risk.

Switching from vitamin K antagonist to dabigatran in atrial fibrillation: differences according to dose.

AIMS: In atrial fibrillation (AF) patients 150 mg b.i.d. dabigatran is the standard dose, yet guidelines recommend 110 mg b.i.d. when bleeding risk is high. It is unknown to which extend these recommendations are followed in patients switching from vitamin K antagonist (VKA) to dabigatran. The aim of this study was to investigate if AF patients are switched from VKA to the appropriate dose of dabigatran. METHODS AND RESULTS: Using nationwide registries (22 August 2011 to 31 December 2012), we identified VKA-experienced AF patients with available creatinine values who switched to dabigatran. European guidelines criteria 2012 on dabigatran dosing were examined: age ≥80 years, HAS-BLED ≥3, estimated glomerular filtration rate (eGFR)<50 mL/min/1.73 m2, or use of interacting drugs. We identified 1626 VKA-experienced AF patients who switched to dabigatran 110 mg (820 patients) or 150 mg (806 patients). Patients who switched to 110 mg compared with 150 mg were older [median age 82 years (Q1-Q3: 77-86) vs. 68 years (Q1-Q3: 64-74)], more often females (54% vs. 35%), had a higher comorbidity burden, higher proportion with CHA2DS2-VASc score ≥2 (98% vs. 80%), and more with a HAS-BLED score ≥3 (46% vs. 28%). Patients switched to 110 mg had a higher absolute risk of mortality compared with patients switched to 150 mg. Overall, 26% were inappropriately dosed and 14% were switched to 110 mg although the higher dose was indicated. Furthermore, 39% of patients switched to 150 mg fulfilled one or more criteria for 110 mg, this mostly driven by high HAS-BLED scores (28.2% of patients on 150 mg). Female sex, age ≥80 years, eGFR < 50 mL/min/1.73 m2, drugs interacting with dabigatran, and prior bleeding were associated with switch to 110 mg. Patients inappropriately dosed had similar risk of mortality as patients appropriately dosed. CONCLUSION: Among VKA-experienced AF patients one in four were switched to a dabigatran dose contrary to guideline recommendations.

Assessing absolute stroke risk in patients with atrial fibrillation using a risk factor-based approach.

AIM: To assess the risk of stroke and thromboembolism in patients with atrial fibrillation (AF) based on risk factor combinations of the CHA2DS2-VASc score. METHODS AND RESULTS: Using nationwide Danish registries, patients with AF were included from 1997 to 2015 in this retrospective observational study. A multiple logistic regression, including interactions of history of stroke with age at AF, calendar year of AF, and the CHA2DS2-VASc score risk factors (congestive heart failure, hypertension, diabetes, vascular disease, and female sex) were used to predict the personalized risks of stroke within 1 year. A total of 147 842 patients with AF were included in the study cohort (median age 76 years, range 20-100 years, 51% females). Within the first year, 6% of the cohort were diagnosed with stroke. The predicted personalized 1-year absolute risk of stroke varied widely within each CHA2DS2-VASc score. To estimate the personalized risk of stroke an online calculator was created, the Calculator of Absolute Stroke Risk (CARS), which allows calculation of all the possible combinations of the CHA2DS2-VASc score (https://hjerteforeningen.shinyapps.io/riskvisrr/). CONCLUSION: Calculation of the individual risk using a risk factor-based approach as opposed to using average risk for a particular CHA2DS2-VASc score can improve risk estimates. Furthermore, CARS can assist in the communication of the stroke risk for a more evidence-based shared decision-making of whether to initiate oral anticoagulation therapy.

Temporal trends in patient characteristics, presumed causes, and outcomes following cardiogenic shock between 2005 and 2017: a Danish registry-based cohort study.

AIMS: Most cardiogenic shock (CS) studies focus on acute coronary syndrome (ACS). Contemporary data on temporal trends in patient characteristics, presumed causes, treatments, and outcomes of ACS- and in particular non-ACS-related CS patients are sparse. METHODS AND RESULTS: Using nationwide medical registries, we identified patients with first-time CS between 2005 and 2017. Cochrane-Armitage trend tests were used to examine temporal changes in presumed causes of CS, treatments, and outcomes. Among 14 363 CS patients, characteristics remained largely stable over time. As presumed causes of CS, ACS (37.1% in 2005 to 21.4% in 2017), heart failure (16.3% in 2005 to 12.0% in 2017), and arrhythmias (13.0% in 2005 to 10.9% in 2017) decreased significantly over time; cardiac arrest increased significantly (11.3% in 2005 to 24.5% in 2017); and changes in valvular heart disease were insignificant (11.5% in 2005 and 11.6% in 2017). Temporary left ventricular assist device, non-invasive ventilation, and extracorporeal membrane oxygenation use increased significantly over time; intra-aortic balloon pump and mechanical ventilation use decreased significantly. Over time, 30-day and 1-year mortality were relatively stable. Significant decreases in 30-day and 1-year mortality for patients presenting with ACS and arrhythmias and a significant increase in 1-year mortality in patients presenting with heart failure were seen. CONCLUSION: Between 2005 and 2017, we observed significant temporal decreases in ACS, heart failure, and arrhythmias as presumed causes of first-time CS, whereas cardiac arrest significantly increased. Although overall 30-day and 1-year mortality were stable, significant decreases in mortality for ACS and arrhythmias as presumed causes of CS were seen.

Rare Coding Variants Associated With Electrocardiographic Intervals Identify Monogenic Arrhythmia Susceptibility Genes: A Multi-Ancestry Analysis.

BACKGROUND: Alterations in electrocardiographic (ECG) intervals are well-known markers for arrhythmia and sudden cardiac death (SCD) risk. While the genetics of arrhythmia syndromes have been studied, relations between electrocardiographic intervals and rare genetic variation at a population level are poorly understood. METHODS: Using a discovery sample of 29 000 individuals with whole-genome sequencing from Trans-Omics in Precision Medicine and replication in nearly 100 000 with whole-exome sequencing from the UK Biobank and MyCode, we examined associations between low-frequency and rare coding variants with 5 routinely measured electrocardiographic traits (RR, P-wave, PR, and QRS intervals and corrected QT interval). RESULTS: We found that rare variants associated with population-based electrocardiographic intervals identify established monogenic SCD genes (KCNQ1, KCNH2, and SCN5A), a controversial monogenic SCD gene (KCNE1), and novel genes (PAM and MFGE8) involved in cardiac conduction. Loss-of-function and pathogenic SCN5A variants, carried by 0.1% of individuals, were associated with a nearly 6-fold increased odds of the first-degree atrioventricular block (P=8.4×10-5). Similar variants in KCNQ1 and KCNH2 (0.2% of individuals) were associated with a 23-fold increased odds of marked corrected QT interval prolongation (P=4×10-25), a marker of SCD risk. Incomplete penetrance of such deleterious variation was common as over 70% of carriers had normal electrocardiographic intervals. CONCLUSIONS: Our findings indicate that large-scale high-depth sequence data and electrocardiographic analysis identifies monogenic arrhythmia susceptibility genes and rare variants with large effects. Known pathogenic variation in conventional arrhythmia and SCD genes exhibited incomplete penetrance and accounted for only a small fraction of marked electrocardiographic interval prolongation.

Rivaroxaban Versus Apixaban for Stroke Prevention in Atrial Fibrillation: An Instrumental Variable Analysis of a Nationwide Cohort.

BACKGROUND: The comparative effectiveness of non-vitamin K antagonist oral anticoagulants (NOACs) is uncertain, as they have not been compared directly in randomized trials. Previous observational comparisons of NOACs are likely to be biased by unmeasured confounders. We sought to compare the efficacy and safety of rivaroxaban and apixaban for stroke prevention in patients with atrial fibrillation (AF), using practice variation in preference for NOAC as an instrumental variable. METHODS AND RESULTS: Patients started on apixaban or rivaroxaban after newly diagnosed AF were identified using Danish nationwide registries. Patients were categorized according to facility preferences for type of NOAC, independent of actual treatment, measured as fraction of the prior 20 patients with AF initiated on rivaroxaban in the same facility. Facility preference for NOAC was used as an instrumental variable. The occurrence of stroke/thromboembolism, major bleeding, myocardial infarction, and all-cause mortality over 2 years of follow-up were investigated using adjusted Cox regressions. We analyzed 6264 patients with AF initiated on rivaroxaban or apixaban. NOAC preference was strongly related to actual choice of treatment but not associated with any other measured baseline characteristics. Patients treated in facilities that had preference for rivaroxaban had more major bleeding: compared with patients treated in facilities that used rivaroxaban in 0% to 20% of cases, the adjusted hazard ratio for bleeding was 1.06 when treated in a facility with 25% to 40% use; 1.41 with 45% to 60% use; 1.51 with 65% to 80% use; and 1.81 with 0% to 100% use (Ptrend=0.01). Higher facility preference for rivaroxaban was not significantly associated with increased risk of stroke/thromboembolism (Ptrend=0.06), myocardial infarction (Ptrend=0.65), or all-cause mortality (Ptrend=0.89). When we used the instrumental variable to model the causal relationship between choice of NOAC and major bleeding, relative risk with rivaroxaban was 1.89 (95% CI, 1.06-2.72) compared with apixaban. CONCLUSIONS: Using instrumental variable estimation in a cohort of patients with AF, rivaroxaban was associated with higher risk of major bleeding compared with apixaban. No significant associations to other outcomes were found in main analyses.

Outcomes Among Patients With Atrial Fibrillation and Appropriate Anticoagulation Control.

BACKGROUND: Atrial fibrillation (AF) patients on a vitamin K antagonist (VKA) with time in therapeutic range (TTR) ≥70% are not recommended to switch to a direct oral anticoagulant according to guidelines. OBJECTIVES: This study sought to assess future TTR and risk of stroke/thromboembolism and major bleeding among AF patients on VKA with TTR ≥70%. METHODS: The authors used Danish nationwide registries to identify AF patients on VKA from 1997 to 2011 with available international normalized ratio values. Patients were included 6 months after VKA initiation, divided according to TTR, and followed for 12 months after inclusion. Cox proportional hazard models estimated hazard ratios (HRs). TTR was examined both as a baseline variable and as a time-dependent covariate in the Cox models. RESULTS: Of the 4,772 included AF patients still on VKA 6 months after initiation, 1,691 (35.4%) had a TTR ≥70%, and 3,081 (65.6%) had a TTR <70%. Among patients with prior TTR ≥70% still on treatment 12 months after inclusion, only 513 (55.7%) still had a TTR ≥70%. Compared with prior TTR ≥70%, prior TTR <70% was not associated with a higher risk of stroke/thromboembolism (HR: 1.14; 95% confidence interval [CI]: 0.77 to 1.70) or major bleeding (HR: 1.12; 95% CI: 0.84 to 1.49). When the authors estimated TTR time-dependently during follow-up, TTR <70% was associated with an increased risk of stroke/thromboembolism (HR: 1.91; 95% CI: 1.30 to 2.82) and major bleeding (HR: 1.34; 95% CI: 1.02 to 1.76). CONCLUSIONS: Among AF patients on VKA, almost one-half of patients with prior TTR ≥70% had TTR <70% during the following year. Prior TTR ≥70% per se had limited long-term prognostic value.

Antithrombotic Therapy and First Myocardial Infarction in Patients With Atrial Fibrillation.

BACKGROUND: Patients with atrial fibrillation (AF) have increased risk of thromboembolic events such as stroke and myocardial infarction (MI). Although it has been established that the efficacy of anticoagulation is superior to that of antiplatelet agents for stroke prophylaxis in AF, the optimal antithrombotic treatment remains uncertain for primary protection against MI. OBJECTIVES: The authors investigated the incidence of first-time MI in patients with AF according to antithrombotic treatment and estimated the risk of stroke and bleeding. METHODS: Subjects with first-time AF diagnosed from 1997 to 2012 without history of coronary artery disease were identified using Danish nationwide administrative registries. Subjects were divided into time varying exposure groups according to antithrombotic treatment. The relative risks of outcomes were estimated by Poisson regression models. RESULTS: A total of 71,959 patients (median 75 years of age; females: 47%). At baseline, 37,539 patients (52%) were treated with vitamin K antagonist (VKA) monotherapy, 25,458 (35%) with acetylsalicylic acid (ASA) monotherapy and 8,962 (13%) with dual-therapy (VKA + ASA). The incidence of MI was 3% (n = 2,275). Relative to the VKA-treated group, the associated risk of MI was significantly higher for ASA (incidence rate ratio [IRR]: 1.54; 95% confidence interval [CI]: 1.40 to 1.68) and dual-therapy (IRR: 1.22; 95% CI: 1.06 to 1.40). The bleeding risk was significantly higher for dual-therapy (IRR: 1.93; 95% CI: 1.81 to 2.07). The risk of stroke relative to that of VKA therapy was significantly higher for both ASA (IRR: 2.00; 95% CI: 1.88 to 2.12) and dual-therapy (IRR: 1.30; 95% CI: 1.18 to 1.43). CONCLUSIONS: VKA monotherapy in patients with AF was associated with a lower risk of first-time MI and stroke than ASA monotherapy. Combination of ASA and VKA therapy was not associated with a lower risk of MI but was associated with increased bleeding risk.