Apixaban, edoxaban and rivaroxaban but not dabigatran are associated with higher mortality compared to vitamin-K antagonists: A retrospective German claims data analysis.

BACKGROUND: Vitamin-K antagonists (VKAs) have widely been replaced by non-VKA oral anticoagulants (NOACs). This includes Austria, Germany and Switzerland, where as VKA, instead of warfarin, the much longer-acting phenprocoumon is used, which was not compared to NOACs in clinical trials. METHODS: Using administrative data from a large German health insurance, we included all anticoagulation-naïve patients with a first prescription of a NOAC or VKA between 2012 and 2020. We analysed overall survival, major adverse cardiac and cerebrovascular events, major thromboembolic events and major bleeding. RESULTS: Overall, 570,137 patients were included (apixaban: 26.9%, dabigatran: 4.6%, edoxaban: 8.8%, rivaroxaban: 39.1% and VKA: 20.7% of these 99.4% phenprocoumon). In the primary analysis using a 1:1 propensity score matching-cohort (PSM-cohort), a significantly higher overall mortality was found for apixaban, edoxaban and rivaroxaban (all p < 0.001) but not for dabigatran (p = 0.13) compared to VKA. In this PSM-cohort, 5-year mortality was 22.7% for apixaban versus 12.7% for VKA, 19.5% for edoxaban versus 11.4% for VKA, 16.0% for rivaroxaban versus 12.3% for VKA (all p < 0.001) and 13.0% for dabigatran versus 12.8% for VKA (p = 0.06). The observed effect was confirmed in sensitivity analyses using un-weighted and three different weighted Fine-Gray regression models on the basis of the entire cohort. CONCLUSIONS: In this large real-world analysis, apixaban, edoxaban and rivaroxaban, but not dabigatran, were associated with worse survival compared to VKA. These findings, consistent with a few other studies including phenprocoumon, cast profound doubts on the unreflected, general use of NOACs. Randomized trials should assess whether phenprocoumon might actually be superior to NOACs.

Biomarker-based prediction of sinus rhythm in atrial fibrillation patients: the EAST-AFNET 4 biomolecule study.

BACKGROUND AND AIMS: In patients with atrial fibrillation (AF), recurrent AF and sinus rhythm during follow-up are determined by interactions between cardiovascular disease processes and rhythm-control therapy. Predictors of attaining sinus rhythm at follow-up are not well known. METHODS: To quantify the interaction between cardiovascular disease processes and rhythm outcomes, 14 biomarkers reflecting AF-related cardiovascular disease processes in 1586 patients in the EAST-AFNET 4 biomolecule study (71 years old, 46% women) were quantified at baseline. Mixed logistic regression models including clinical features were constructed for each biomarker. Biomarkers were interrogated for interaction with early rhythm control. Outcome was sinus rhythm at 12 months. Results were validated at 24 months and in external datasets. RESULTS: Higher baseline concentrations of three biomarkers were independently associated with a lower chance of sinus rhythm at 12 months: angiopoietin 2 (ANGPT2) (odds ratio [OR] 0.76 [95% confidence interval 0.65-0.89], p=0.001), bone morphogenetic protein 10 (BMP10) (OR 0.83 [0.71-0.97], p=0.017) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) (OR 0.73 [0.60-0.88], p=0.001). Analysis of rhythm at 24 months confirmed the results. Early rhythm control interacted with the predictive potential of NT-proBNP (pinteraction=0.033). The predictive effect of NT-proBNP was reduced in patients randomized to early rhythm control (usual care: OR 0.64 [0.51-0.80], p<0.001; early rhythm control: OR 0.90 [0.69-1.18], p=0.453). External validation confirmed that low concentrations of ANGPT2, BMP10 and NT-proBNP predict sinus rhythm during follow-up. CONCLUSIONS: Low concentrations of ANGPT2, BMP10 and NT-proBNP identify patients with AF who are likely to attain sinus rhythm during follow-up. The predictive ability of NT-proBNP is attenuated in patients receiving rhythm control.

Assessment of Days Alive Out of Hospital as a Possible End Point in Trials of Stroke Prevention for Atrial Fibrillation: A ROCKET AF Analysis.

BACKGROUND: Days alive out of hospital (DAOH) is an objective and patient-centered net benefit end point. There are no assessments of DAOH in clinical trials of interventions for atrial fibrillation (AF), and it is not known whether this end point is of clinical utility in these populations. METHODS AND RESULTS: ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) was an international double-blind, double-dummy randomized clinical trial that compared rivaroxaban with warfarin in patients with atrial fibrillation at increased risk for stroke. We assessed DAOH using investigator-reported event data for up to 12 months after randomization in ROCKET AF. We assessed DAOH overall, by treatment group, and by subgroup, including age, sex, and comorbidities, using Poisson regression. The mean±SD number of days dead was 7.3±41.2, days hospitalized was 1.2±7.2, and mean DAOH was 350.7±56.2, with notable left skew. Patients with comorbidities had fewer DAOH overall. There were no differences in DAOH by treatment arm, with mean DAOH of 350.6±56.5 for those randomized to rivaroxaban and 350.7±55.8 for those randomized to warfarin (P=0.86). A sensitivity analysis found no difference in DAOH not disabled with rivaroxaban versus warfarin (DAOH not disabled, 349.2±59.5 days and 349.1 days±59.3 days, respectively, P=0.88). CONCLUSIONS: DAOH did not identify a treatment difference between patients randomized to rivaroxaban versus warfarin. This may be driven in part by the low overall event rates in atrial fibrillation anticoagulation trials, which leads to substantial left skew in measures of DAOH.

Safety and efficacy of long-term sodium channel blocker therapy for early rhythm control: the EAST-AFNET 4 trial.

AIMS: Clinical concerns exist about the potential proarrhythmic effects of the sodium channel blockers (SCBs) flecainide and propafenone in patients with cardiovascular disease. Sodium channel blockers were used to deliver early rhythm control (ERC) therapy in EAST-AFNET 4. METHODS AND RESULTS: We analysed the primary safety outcome (death, stroke, or serious adverse events related to rhythm control therapy) and primary efficacy outcome (cardiovascular death, stroke, and hospitalization for worsening of heart failure (HF) or acute coronary syndrome) during SCB intake for patients with ERC (n = 1395) in EAST-AFNET 4. The protocol discouraged flecainide and propafenone in patients with reduced left ventricular ejection fraction and suggested stopping therapy upon QRS prolongation >25% on therapy. Flecainide or propafenone was given to 689 patients [age 69 (8) years; CHA2DS2-VASc 3.2 (1); 177 with HF; 41 with prior myocardial infarction, coronary artery bypass graft, or percutaneous coronary intervention; 26 with left ventricular hypertrophy >15 mm; median therapy duration 1153 [237, 1828] days]. The primary efficacy outcome occurred less often in patients treated with SCB [3/100 (99/3316) patient-years] than in patients who never received SCB [SCBnever 4.9/100 (150/3083) patient-years, P < 0.001]. There were numerically fewer primary safety outcomes in patients receiving SCB [2.9/100 (96/3359) patient-years] than in SCBnever patients [4.2/100 (135/3220) patient-years, adjusted P = 0.015]. Sinus rhythm at 2 years was similar between groups [SCB 537/610 (88); SCBnever 472/579 (82)]. CONCLUSION: Long-term therapy with flecainide or propafenone appeared to be safe in the EAST-AFNET 4 trial to deliver effective ERC therapy, including in selected patients with stable cardiovascular disease such as coronary artery disease and stable HF. Clinical Trial Registration ISRCTN04708680, NCT01288352, EudraCT2010-021258-20, www.easttrial.org.

[Historical development of diagnosis of bradyarrhythmias : The early years of clinical electrophysiology in Germany]. / Historische Entwicklung der Diagnostik der bradykarden Rhythmusstörungen : Die frühen Jahre der Klinischen Elektrophysiologie in Deutschland.

The introduction of His bundle electrography by Benjamin Scherlag (New York) in 1969, together with programmed stimulation of the heart by Philip Coumel (Paris) in 1967, and Hein Wellens (Amsterdam) in 1972, were decisive turning points on the way to invasive electrophysiology and the development of an independent, now distinctly interventional subspecialty of cardiology. The main topic of the 1970s was bradycardic arrhythmias, promoted by pacemaker therapy, which had been introduced just over 10 years earlier. The recording of the potentials of the bundle of His and other recording locations in the atria and ventricles allowed a differentiated assessment of the excitation process and the refractory periods. High-rate atrial stimulation to determine sinus node recovery time and premature stimulation to determine sinoatrial conduction time were developed to analyze sinoatrial node function. This article describes the introduction of His bundle electrography in a gradually increasing number of centers in Germany and their scientific contribution.

A Randomized Controlled Trial Comparing Apixaban With the Vitamin K Antagonist Phenprocoumon in Patients on Chronic Hemodialysis: The AXADIA-AFNET 8 Study.

BACKGROUND: Non-vitamin K oral anticoagulants have become the standard therapy for preventing stroke and ischemic thromboembolism in most patients with atrial fibrillation (AF). The effectiveness and safety of non-vitamin K oral anticoagulants in patients on hemodialysis is not well known. METHODS: From June 2017 through May 2022, AXADIA-AFNET 8 (Compare Apixaban and Vitamin K Antagonists in Patients With Atrial Fibrillation and End-Stage Kidney Disease), an investigator-initiated PROBE (prospective randomized open blinded end point) outcome assessment trial, randomized patients with AF on chronic hemodialysis to either apixaban (2.5 mg BID) or the vitamin K antagonist (VKA) phenprocoumon (international normalized ratio, 2.0 to 3.0). The composite primary safety outcome was defined by a first event of major bleeding, clinically relevant nonmajor bleeding, or all-cause death. The primary efficacy outcome was a composite of ischemic stroke, all-cause death, myocardial infarction, and deep vein thrombosis or pulmonary embolism. Our hypothesis was that apixaban is noninferior to VKA. RESULTS: Thirty-nine sites randomized 97 patients (30% women; mean age 75 years; mean CHA2DS2-VASc [congestive heart failure, hypertension, age ≥75 years, diabetes, stroke or transient ischemic attack, vascular disease, age 65 to 74 years, female sex] score, 4.5; baseline characteristics balanced between groups): 48 to apixaban and 49 to VKA. The median follow-up time was 429 days (range, 37 to 1370) versus 506 days (range, 101 to 1379), respectively. Adherence to apixaban was >80% in 44 of 48 patients; the median time in therapeutic range on VKA was 50.7%. Composite primary safety outcome events occurred in 22 patients (45.8%) on apixaban and in 25 patients (51.0%) on VKA (hazard ratio, 0.93 [95% CI, 0.53-1.65]; Pnoninferiority=0.157). Composite primary efficacy outcome events occurred in 10 patients (20.8%) on apixaban and in 15 patients (30.6%) on VKA (P=0.51; log rank). There were no significant differences regarding individual outcomes (all-cause mortality, 18.8% versus 24.5%; major bleeding, 10.4% versus 12.2%; and myocardial infarction, 4.2% versus 6.1%, respectively). CONCLUSIONS: In this randomized trial comparing apixaban and VKA in patients with AF on hemodialysis with long follow-up, no differences were observed in safety or efficacy outcomes. Even on oral anticoagulation, patients with AF on hemodialysis remain at high risk of cardiovascular events. Larger randomized trials are needed to determine the optimal anticoagulation regimen for patients with AF on hemodialysis. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02933697.

Early Rhythm Control in Patients With Atrial Fibrillation and High Comorbidity Burden.

BACKGROUND: The randomized EAST-AFNET4 (Early Treatment of Atrial Fibrillation for Stroke Prevention Trial-Atrial Fibrillation Network) demonstrated that early rhythm control (ERC) reduces adverse cardiovascular outcomes in patients with recently diagnosed atrial fibrillation and stroke risk factors. The effectiveness and safety of ERC in patients with multiple cardiovascular comorbidities is not known. METHODS: These prespecified subanalyses of EAST-AFNET4 compared the effectiveness and safety of ERC with usual care (UC) stratified into patients with higher (CHA2DS2-VASc score ≥4) and lower comorbidity burden. Sensitivity analyses ignored sex (CHA2DS2-VA score). RESULTS: EAST-AFNET4 randomized 1093 patients with CHA2DS2-VASc score ≥4 (74.8±6.8 years, 61% female) and 1696 with CHA2DS2-VASc score <4 (67.4±8.0 years, 37% female). ERC reduced the composite primary efficacy outcome of cardiovascular death, stroke, or hospitalization for worsening of heart failure or for acute coronary syndrome in patients with CHA2DS2-VASc score ≥4 (ERC, 127/549 patients with events; UC, 183/544 patients with events; hazard ratio [HR], 0.64 [0.51-0.81]; P < 0.001) but not in patients with CHA2DS2-VASc score <4 (ERC, 122/846 patients with events; UC, 133/850 patients with events; HR, 0.93 [0.73-1.19]; P=0.56, Pinteraction=0.037). The primary safety outcome (death, stroke, or serious adverse events of rhythm control therapy) was not different between study groups in patients with CHA2DS2-VASc score ≥4 (ERC, 112/549 patients with events; UC, 132/544 patients with events; HR, 0.84 [0.65, 1.08]; P=0.175), but occurred more often in patients with CHA2DS2-VASc scores <4 randomized to ERC (ERC, 119/846 patients with events; UC, 91/850 patients with events; HR, 1.39 [1.05-1.82]; P=0.019, Pinteraction=0.008). Life-threatening events or death were not different between groups (CHA2DS2-VASc score ≥4, ERC, 84/549 patients with event, UC, 96/544 patients with event; CHA2DS2-VASc scores <4, ERC, 75/846 patients with event, UC, 73/850 patients with event). When female sex was ignored for the creation of higher and lower risk groups (CHA2DS2-VA score), the Pinteraction was not significant for the primary efficacy outcome (P=0.25), but remained significant (P=0.044) for the primary safety outcome. CONCLUSIONS: Patients with recently diagnosed atrial fibrillation and CHA2DS2-VASc score ≥4 should be considered for ERC to reduce cardiovascular outcomes, whereas those with fewer comorbidities may have less favorable outcomes with ERC. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01288352. URL: https://www.clinicaltrialsregister.eu; Unique identifier: 2010-021258-20. URL: https://www.isrctn.com/; Unique identifier: ISRCTN04708680.

Presenting Pattern of Atrial Fibrillation and Outcomes of Early Rhythm Control Therapy.

BACKGROUND: Whether atrial fibrillation (AF) pattern or timing of AF therapy modifies the effectiveness of early rhythm control (ERC) is not known. OBJECTIVES: This study sought to compare clinical characteristics and outcomes in patients presenting with different AF patterns on ERC vs usual care. METHODS: The effects of ERC were compared in first-diagnosed AF (FDAF), paroxysmal AF (paroxAF), and persistent AF (persAF) in this prespecified analysis of the EAST-AFNET 4 (Early treatment of atrial fibrillation for stroke prevention) trial. Associations between AF pattern and primary outcomes (first primary outcome: cardiovascular death, stroke, and hospitalization for heart failure and acute coronary syndrome; second primary outcome: nights spent in hospital per year) were compared over a mean follow-up of 5.1 years. Changes in health-related quality of life were assessed by the EQ-5D. RESULTS: FDAF patients (n = 1,048, enrolled 7 days after diagnosing AF) were slightly older (71 years of age, 48.0% female) than patients with paroxAF (n = 994, 70 years of age, 50.0% female) and persAF (n = 743, 70 years of age, 38.0% female). ERC reduced the primary outcome in all 3 AF patterns. Hospitalizations for acute coronary syndrome were highest in FDAF (incidence rate ratio [IRR]: 1.50; 95% CI: 0.83-2.69; P for interaction = 0.032) compared with paroxAF (IRR: 0.64; 95% CI: 0.32-1.25) and persAF (IRR: 0.50; 95% CI: 0.25-1.00). FDAF patients spent more nights in hospital (IRR: 1.38; 95% CI: 1.12-1.70; P for interaction = 0.004) than paroxAF (IRR: 0.84; 95% CI: 0.67-1.03), and persAF (IRR: 1.02; 95% CI: 0.80-1.30) patients. ERC improved health-related quality of life (EQ-5D score) in patients with paroxAF and persAF but not in patients with FDAF (P = 0.019). CONCLUSIONS: ERC reduces the first primary composite outcome in all AF patterns. Patients with FDAF are at high risk for hospitalization and acute coronary syndrome, particularly on ERC. (Early treatment of atrial fibrillation for stroke prevention trial; ISRCTN04708680; Early Treatment of Atrial Fibrillation for Stroke Prevention Trial [EAST]; NCT01288352; Early treatment of Atrial fibrillation for Stroke prevention Trial [EAST]; EudraCT2010-021258-20).

Thyroid Dysfunction under Amiodarone in Patients with and without Congenital Heart Disease: Results of a Nationwide Analysis.

Background: Amiodarone has a profound adverse toxicity profile. Large population-based analyses quantifying the risk of thyroid dysfunction (TD) in adults with and without congenital heart disease (ACHD) are lacking. Methods: All adults registered with a major German health insurer (≈9.2 million members) with amiodarone prescriptions were analyzed. Occurrence of amiodarone-associated TD was assessed. Results: Overall, 48,891 non-ACHD (37% female; median 73 years) and 886 ACHD (34% female; median 66 years) received amiodarone. Over 184,787 patient-years, 10,875 cases of TD occurred. The 10-year risk for TD was 38% in non-ACHD (35% ACHD). Within ACHD, compared to amiodarone-naïve patients, the hazard ratio (HR) for TD was 3.9 at 4 years after any amiodarone exposure. TD was associated with female gender (HR 1.42, p < 0.001) and younger age (HR 0.97 per 10 years, p = 0.009). Patients with congenital heart disease were not at increased risk (HR 0.98, p = 0.80). Diagnosis of complex congenital heart disease, however, was a predictor for TD (HR 1.56, p = 0.02). Amiodarone was continued in 47% of non-ACHD (38% ACHD), and 2.3% of non-ACHD (3.5% ACHD) underwent thyroid surgery/radiotherapy. Conclusions: Amiodarone-associated TD is common and comparable in non-ACHD and ACHD. While female gender and younger age are predictors for TD, congenital heart disease is not necessarily associated with an elevated risk.

Systematic, early rhythm control strategy for atrial fibrillation in patients with or without symptoms: the EAST-AFNET 4 trial.

AIMS: Clinical practice guidelines restrict rhythm control therapy to patients with symptomatic atrial fibrillation (AF). The EAST-AFNET 4 trial demonstrated that early, systematic rhythm control improves clinical outcomes compared to symptom-directed rhythm control. METHODS AND RESULTS: This prespecified EAST-AFNET 4 analysis compared the effect of early rhythm control therapy in asymptomatic patients (EHRA score I) to symptomatic patients. Primary outcome was a composite of death from cardiovascular causes, stroke, or hospitalization with worsening of heart failure or acute coronary syndrome, analyzed in a time-to-event analysis. At baseline, 801/2633 (30.4%) patients were asymptomatic [mean age 71.3 years, 37.5% women, mean CHA2DS2-VASc score 3.4, 169/801 (21.1%) heart failure]. Asymptomatic patients randomized to early rhythm control (395/801) received similar rhythm control therapies compared to symptomatic patients [e.g. AF ablation at 24 months: 75/395 (19.0%) in asymptomatic; 176/910 (19.3%) symptomatic patients, P = 0.672]. Anticoagulation and treatment of concomitant cardiovascular conditions was not different between symptomatic and asymptomatic patients. The primary outcome occurred in 79/395 asymptomatic patients randomized to early rhythm control and in 97/406 patients randomized to usual care (hazard ratio 0.76, 95% confidence interval [0.6; 1.03]), almost identical to symptomatic patients. At 24 months follow-up, change in symptom status was not different between randomized groups (P = 0.19). CONCLUSION: The clinical benefit of early, systematic rhythm control was not different between asymptomatic and symptomatic patients in EAST-AFNET 4. These results call for a shared decision discussing the benefits of rhythm control therapy in all patients with recently diagnosed AF and concomitant cardiovascular conditions (EAST-AFNET 4; ISRCTN04708680; NCT01288352; EudraCT2010-021258-20).

Anticoagulation, therapy of concomitant conditions, and early rhythm control therapy: a detailed analysis of treatment patterns in the EAST - AFNET 4 trial.

AIMS: Treatment patterns were compared between randomized groups in EAST-AFNET 4 to assess whether differences in anticoagulation, therapy of concomitant diseases, or intensity of care can explain the clinical benefit achieved with early rhythm control in EAST-AFNET 4. METHODS AND RESULTS: Cardiovascular treatment patterns and number of visits were compared between randomized groups in EAST-AFNET 4. Oral anticoagulation was used in >90% of patients during follow-up without differences between randomized groups. There were no differences in treatment of concomitant conditions between groups. The type of rhythm control varied by country and centre. Over time, antiarrhythmic drugs were given to 1171/1395 (84%) patients in early therapy, and to 202/1394 (14%) in usual care. Atrial fibrillation (AF) ablation was performed in 340/1395 (24%) patients randomized to early therapy, and in 168/1394 (12%) patients randomized to usual care. 97% of rhythm control therapies were within class I and class III recommendations of AF guidelines. Patients randomized to early therapy transmitted 297 166 telemetric electrocardiograms (ECGs) to a core lab. In total, 97 978 abnormal ECGs were sent to study sites. The resulting difference between study visits was low (0.06 visits/patient/year), with slightly more visits in early therapy (usual care 0.39 visits/patient/year; early rhythm control 0.45 visits/patient/year, P < 0.001), mainly due to visits for symptomatic AF recurrences or recurrent AF on telemetric ECGs. CONCLUSION: The clinical benefit of early, systematic rhythm control therapy was achieved using variable treatment patterns of antiarrhythmic drugs and AF ablation, applied within guideline recommendations.

Termination Based on Event Accrual in Per Protocol Versus Intention to Treat in the ROCKET AF Trial.

Background In event-driven clinical trials, study termination is based on accrual of a target number of primary efficacy events. For noninferiority trials in which superiority is conditionally examined, the ideal cohort in which to track event accrual is unclear. We used data from the ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial to determine the effect of primary efficacy-event tracking in the per-protocol cohort during the on-treatment period versus the intention-to-treat (ITT) cohort during the ITT period. Methods and Results ROCKET AF was terminated after accruing 429 primary efficacy events (stroke or systemic embolism) in the per-protocol cohort during the on-treatment period for noninferiority. We identified the date on which 429 events occurred in the ITT cohort during the ITT period. We performed noninferiority and superiority analyses based on hypothetical study termination on this date. ROCKET AF would have terminated 226 days earlier if events were tracked during the ITT period. Similar to the main trial findings, rivaroxaban would have met noninferiority versus warfarin for the primary efficacy end point (hazard ratio [HR], 0.77; 95% CI, 0.62-0.96; P<0.001). In contrast to the main trial findings, rivaroxaban would have met superiority for the primary efficacy end point (HR, 0.82; 95% CI, 0.68-0.99; P=0.038). In both termination scenarios, rivaroxaban was associated with a lower risk of intracranial hemorrhage and similar risk of other safety end points. Conclusions Clinical trial termination based on event accrual in the ITT cohort versus the per-protocol cohort may have important implications on trial results depending on rates of study drug discontinuation and event rates off treatment.

Pharmacotherapy for diabetes and stroke risk: Results from ROCKET AF.

BACKGROUND: Insulin use may be a better predictor of stroke risk and morbidity and mortality than diabetes in patients with atrial fibrillation (AF). OBJECTIVES: Determine if the increased risk of stroke observed in patients with AF and diabetes is restricted to those treated with insulin. METHODS: We analyzed the association between diabetes and treatment and the occurrence of stroke/systemic embolism, myocardial infarction (MI), all-cause death, vascular death, composite outcomes, and bleeding risk in the ROCKET AF trial. RESULTS: In a cohort of 14,264 patients, there were 40.3% (n = 5746) with diabetes, 5.9% (n = 842) on insulin, 18.9% (n = 2697) on oral medications, and 11.9% (n = 1703) diet-controlled. Compared to those without diabetes, patients with non-insulin-treated diabetes had increased risks of stroke (hazard ratio [HR] 1.33, 95% confidence interval [CI] 1.06-1.68), MI (HR 1.64, 95% CI 1.17-2.30), all-cause death (HR 1.26, 95% CI 1.08-1.46), vascular death (HR 1.33, 95% CI 1.11-1.60), and composite outcomes (HR 1.37, 95% CI 1.18-1.157). Patients with insulin-treated diabetes had a significantly higher risk of MI (HR 2.31, 95% CI 1.33-4.01) and composite outcomes (HR 1.57, 95% CI 1.19-2.08) compared to those without diabetes. There were no significant differences between insulin-treated and non-insulin-treated diabetes for any outcome. CONCLUSION: Among patients with AF and diabetes, there were no significant differences in outcomes in insulin-treated diabetes compared to non-insulin-treated diabetes.

Early Rhythm Control Therapy in Patients With Atrial Fibrillation and Heart Failure.

BACKGROUND: Even on optimal therapy, many patients with heart failure and atrial fibrillation experience cardiovascular complications. Additional treatments are needed to reduce these events, especially in patients with heart failure and preserved left ventricular ejection fraction. METHODS: This prespecified subanalysis of the randomized EAST-AFNET4 trial (Early Treatment of Atrial Fibrillation for Stroke Prevention Trial) assessed the effect of systematic, early rhythm control therapy (ERC; using antiarrhythmic drugs or catheter ablation) compared with usual care (allowing rhythm control therapy to improve symptoms) on the 2 primary outcomes of the trial and on selected secondary outcomes in patients with heart failure, defined as heart failure symptoms New York Heart Association II to III or left ventricular ejection fraction [LVEF] <50%. RESULTS: This analysis included 798 patients (300 [37.6%] female, median age 71.0 [64.0, 76.0] years, 785 with known LVEF). The majority of patients (n=442) had heart failure and preserved LVEF (LVEF≥50%; mean LVEF 61±6.3%), the others had heart failure with midrange ejection fraction (n=211; LVEF 40%-49%; mean LVEF 44 ± 2.9%) or heart failure with reduced ejection fraction (n=132; LVEF<40%; mean LVEF 31±5.5%). Over the 5.1-year median follow-up, the composite primary outcome of cardiovascular death, stroke, or hospitalization for worsening of heart failure or for acute coronary syndrome occurred less often in patients randomly assigned to ERC (94/396; 5.7 per 100 patient-years) compared with patients randomly assigned to usual care (130/402; 7.9 per 100 patient-years; hazard ratio, 0.74 [0.56-0.97]; P=0.03), not altered by heart failure status (interaction P value=0.63). The primary safety outcome (death, stroke, or serious adverse events related to rhythm control therapy) occurred in 71 of 396 (17.9%) patients with heart failure randomly assigned to ERC and in 87 of 402 (21.6%) patients with heart failure randomly assigned to usual care (hazard ratio, 0.85 [0.62-1.17]; P=0.33). LVEF improved in both groups (LVEF change at 2 years: ERC 5.3±11.6%, usual care 4.9±11.6%, P=0.43). ERC also improved the composite outcome of death or hospitalization for worsening of heart failure. CONCLUSIONS: Rhythm control therapy conveys clinical benefit when initiated within 1 year of diagnosing atrial fibrillation in patients with signs or symptoms of heart failure. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01288352. URL: http://www.controlled-trials.com; Unique identifier: ISRCTN04708680. URL: https://www.clinicaltrialsregister.eu; Unique identifier: 2010-021258-20.

Prognostic markers of all-cause mortality in patients with atrial fibrillation: data from the prospective long-term registry of the German Atrial Fibrillation NETwork (AFNET).

AIMS: Atrial fibrillation (AF) is associated with a high risk of cardiovascular and non-cardiovascular death, even on anticoagulation. It is controversial, which conditions-including concomitant diseases and AF itself-contribute to this mortality. To further clarify these questions, major determinants of long-term mortality and their contribution to death were quantified in an unselected cohort of AF patients. METHODS AND RESULTS: We established a large nationwide registry comprising 8833 AF-patients with a median follow-up of 6.5 years (45 345 patient-years) and central adjudication of adverse events. Baseline characteristics of the patients were evaluated as predictors of mortality using Cox regression and C-indices for determination of predictive power. Annualized mortality was highest in the first year (6.2%) and remained high thereafter (5.2% in men and 5.5% in women). Thirty-eight percent of all deaths were cardiovascular, mainly due to heart failure or sudden death. Sex-specific age was the strongest predictor of mortality, followed by concomitant cardiovascular and non-cardiovascular conditions. These factors accounted for 25% of the total mortality beyond age and sex and for 84% of the mortality differences between AF types. Thus, the electrical phenotype of the disease at baseline contributed only marginally to prediction of mortality. CONCLUSION: Mortality is high in AF patients and arises primarily from heart failure, peripheral artery disease, chronic obstructive lung disease, chronic kidney disease, and diabetes mellitus, which, therefore, should be targeted to lower mortality. Parameters related to the electrical manifestation of AF did not have an independent impact on long-term mortality in our representative cohort.

Sex-specific differences and long-term outcome of patients with coronary artery disease and chronic kidney disease: the Coronary Artery Disease and Renal Failure (CAD-REF) Registry.

BACKGROUND: Cardiovascular morbidity and mortality are closely linked to chronic kidney disease (CKD). Sex-specific long-term outcome data of patients with coronary artery disease (CAD) and CKD are scarce. METHODS: In the prospective observational multicenter Coronary Artery Disease and REnal Failure (CAD-REF) Registry, 773 (23.1%) women and 2,579 (76.9%) men with angiographically documented CAD and different stages of CKD were consecutively enrolled and followed for up to 8 years. Long-term outcome was evaluated using survival analysis and multivariable Cox-regression models. RESULTS: At enrollment, women were significantly older than men, and suffered from more comorbidities like CKD, hypertension, diabetes mellitus, and multivessel coronary disease. Regarding long-term mortality, no sex-specific differences were observed (Kaplan-Meier survival estimates: 69% in women vs. 69% in men, plog-rank = 0.7). Survival rates decreased from 89% for patients without CKD at enrollment to 72% for patients with CKD stages 1-2 at enrollment and 49% for patients with CKD stages 3-5 at enrollment (plog-rank < 0.001). Cox-regression analysis revealed that sex or multivessel coronary disease were no independent predictors of long-term mortality, while age, CKD stages 3-5, albumin/creatinine ratio, diabetes, valvular heart disease, peripheral artery disease, and left-ventricular ejection fraction were predictors of long-term mortality. CONCLUSIONS: Sex differences in CAD patients mainly exist in the cardiovascular risk profile and the extent of CAD. Long-term mortality was not depended on sex or multivessel disease. More attention should be given to treatment of comorbidities such as CKD and peripheral artery disease being independent predictors of death. Clinical Trail Registration ClinicalTrials.gov Identifier: NCT00679419.

The RACE to the EAST. In pursuit of rhythm control therapy for atrial fibrillation-a dedication to Harry Crijns.

The RACE trial was one of the first landmark trials to establish whether restoring and maintaining sinus rhythm could reduce morbidity and mortality in patients with atrial fibrillation (AF). Its neutral outcome shaped clinical decision-making for almost 20 years. However, there were two important treatment-related factors associated with mortality of rhythm control therapy at that time: One was safety of antiarrhythmic drug therapy, and the other one withdrawal of anticoagulation after restoration of sinus rhythm. Both concerns have been overcome, and, moreover, important knowledge considering the importance of time for the treatment of AF has been gained. These insights led to the concept of the EAST-AFNET 4 trial, and after more than two decades in the pursuit of ongoing therapeutic improvement, early rhythm control therapy has demonstrated to reduce a composite of cardiovascular death, stroke, and hospitalization for worsening of HF or acute coronary syndrome, by 21% (first primary outcome, absolute reduction 1.1 per 100 patient-years). For this entire period, Harry Crijns characterized the treatment of AF patients, and contributed decisively to realizing the benefit of rhythm control therapy. It is almost easier to list the clinical trials without Harry's involvement than to list those which he co-designed and led.