Apixaban for Stroke Prevention in Subclinical Atrial Fibrillation.

BACKGROUND: Subclinical atrial fibrillation is short-lasting and asymptomatic and can usually be detected only by long-term continuous monitoring with pacemakers or defibrillators. Subclinical atrial fibrillation is associated with an increased risk of stroke by a factor of 2.5; however, treatment with oral anticoagulation is of uncertain benefit. METHODS: We conducted a trial involving patients with subclinical atrial fibrillation lasting 6 minutes to 24 hours. Patients were randomly assigned in a double-blind, double-dummy design to receive apixaban at a dose of 5 mg twice daily (2.5 mg twice daily when indicated) or aspirin at a dose of 81 mg daily. The trial medication was discontinued and anticoagulation started if subclinical atrial fibrillation lasting more than 24 hours or clinical atrial fibrillation developed. The primary efficacy outcome, stroke or systemic embolism, was assessed in the intention-to-treat population (all the patients who had undergone randomization); the primary safety outcome, major bleeding, was assessed in the on-treatment population (all the patients who had undergone randomization and received at least one dose of the assigned trial drug, with follow-up censored 5 days after permanent discontinuation of trial medication for any reason). RESULTS: We included 4012 patients with a mean (±SD) age of 76.8±7.6 years and a mean CHA2DS2-VASc score of 3.9±1.1 (scores range from 0 to 9, with higher scores indicating a higher risk of stroke); 36.1% of the patients were women. After a mean follow-up of 3.5±1.8 years, stroke or systemic embolism occurred in 55 patients in the apixaban group (0.78% per patient-year) and in 86 patients in the aspirin group (1.24% per patient-year) (hazard ratio, 0.63; 95% confidence interval [CI], 0.45 to 0.88; P = 0.007). In the on-treatment population, the rate of major bleeding was 1.71% per patient-year in the apixaban group and 0.94% per patient-year in the aspirin group (hazard ratio, 1.80; 95% CI, 1.26 to 2.57; P = 0.001). Fatal bleeding occurred in 5 patients in the apixaban group and 8 patients in the aspirin group. CONCLUSIONS: Among patients with subclinical atrial fibrillation, apixaban resulted in a lower risk of stroke or systemic embolism than aspirin but a higher risk of major bleeding. (Funded by the Canadian Institutes of Health Research and others; ARTESIA ClinicalTrials.gov number, NCT01938248.).

Direct Oral Anticoagulants for Stroke Prevention in Patients With Device-Detected Atrial Fibrillation: A Study-Level Meta-Analysis of the NOAH-AFNET 6 and ARTESiA Trials.

BACKGROUND: Device-detected atrial fibrillation (also known as subclinical atrial fibrillation or atrial high-rate episodes) is a common finding in patients with an implanted cardiac rhythm device and is associated with an increased risk of ischemic stroke. Whether oral anticoagulation is effective and safe in this patient population is unclear. METHODS: We performed a systematic review of MEDLINE and Embase for randomized trials comparing oral anticoagulation with antiplatelet or no antithrombotic therapy in adults with device-detected atrial fibrillation recorded by a pacemaker, implantable cardioverter defibrillator, cardiac resynchronization therapy device, or implanted cardiac monitor. We used random-effects models for meta-analysis and rated the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework (GRADE). The review was preregistered (PROSPERO CRD42023463212). RESULTS: From 785 citations, we identified 2 randomized trials with relevant clinical outcome data: NOAH-AFNET 6 (Non-Vitamin K Antagonist Oral Anticoagulants in Patients With Atrial High Rate Episodes; 2536 participants) evaluated edoxaban, and ARTESiA (Apixaban for the Reduction of Thrombo-Embolism in Patients With Device-Detected Sub-Clinical Atrial Fibrillation; 4012 participants) evaluated apixaban. Meta-analysis demonstrated that oral anticoagulation with these agents reduced ischemic stroke (relative risk [RR], 0.68 [95% CI, 0.50-0.92]; high-quality evidence). The results from the 2 trials were consistent (I2 statistic for heterogeneity=0%). Oral anticoagulation also reduced a composite of cardiovascular death, all-cause stroke, peripheral arterial embolism, myocardial infarction, or pulmonary embolism (RR, 0.85 [95% CI, 0.73-0.99]; I2=0%; moderate-quality evidence). There was no reduction in cardiovascular death (RR, 0.95 [95% CI, 0.76-1.17]; I2=0%; moderate-quality evidence) or all-cause mortality (RR, 1.08 [95% CI, 0.96-1.21]; I2=0%; moderate-quality evidence). Oral anticoagulation increased major bleeding (RR, 1.62 [95% CI, 1.05-2.50]; I²=61%; high-quality evidence). CONCLUSIONS: The results of the NOAH-AFNET 6 and ARTESiA trials are consistent with each other. Meta-analysis of these 2 large randomized trials provides high-quality evidence that oral anticoagulation with edoxaban or apixaban reduces the risk of stroke in patients with device-detected atrial fibrillation and increases the risk of major bleeding.

Risk of Stroke or Systemic Embolism According to Baseline Frequency and Duration of Subclinical Atrial Fibrillation: Insights From the ARTESiA Trial.

BACKGROUND: In the ARTESiA trial (Apixaban for the Reduction of Thromboembolism in Patients With Device-Detected Subclinical Atrial Fibrillation), apixaban, compared with aspirin, reduced stroke or systemic embolism in patients with device-detected subclinical atrial fibrillation (SCAF). Clinical guidelines recommend considering SCAF episode duration when deciding whether to prescribe oral anticoagulation for this population. METHODS: We performed a retrospective cohort study in ARTESiA. Using Cox regression adjusted for CHA2DS2-VASc score and treatment allocation (apixaban or aspirin), we assessed frequency of SCAF episodes and duration of the longest SCAF episode in the 6 months before randomization as predictors of stroke risk and of apixaban treatment effect. RESULTS: Among 3986 patients with complete baseline SCAF data, 703 (17.6%) had no SCAF episode ≥6 minutes in the 6 months before enrollment. Among 3283 patients (82.4%) with ≥1 episode of SCAF ≥6 minutes in the 6 months before enrollment, 2542 (77.4%) had up to 5 episodes, and 741 (22.6%) had ≥6 episodes. The longest episode lasted <1 hour in 1030 patients (31.4%), 1 to <6 hours in 1421 patients (43.3%), and >6 hours in 832 patients (25.3%). Higher baseline SCAF frequency was not associated with increased risk of stroke or systemic embolism: 1.1% for 1 to 5 episodes versus 1.2%/patient-year for ≥6 episodes (adjusted hazard ratio, 0.89 [95% CI, 0.59-1.34]). In an exploratory analysis, patients with previous SCAF but no episode ≥6 minutes in the 6 months before enrollment had a lower risk of stroke or systemic embolism than patients with at least one episode during that period (0.5% versus 1.1%/patient-year; adjusted hazard ratio, 0.48 [95% CI, 0.27-0.85]). The frequency of SCAF did not modify the reduction in stroke or systemic embolism with apixaban (Pinteraction=0.1). The duration of the longest SCAF episode in the 6 months before enrollment was not associated with the risk of stroke or systemic embolism during follow-up (<1 hour: 1.0%/patient-year [reference]; 1-6 hours: 1.2%/patient-year [adjusted hazard ratio, 1.27 (95% CI, 0.85-1.90)]; >6 hours: 1.0%/patient-year [adjusted hazard ratio, 1.02 (95% CI, 0.63-1.66)]). SCAF duration did not modify the reduction in stroke or systemic embolism with apixaban (Ptrend=0.1). CONCLUSIONS: In ARTESiA, baseline SCAF frequency and longest episode duration were not associated with risk of stroke or systemic embolism and did not modify the effect of apixaban on reduction of stroke or systemic embolism. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01938248.

Anticoagulation in device-detected atrial fibrillation with or without vascular disease: a combined analysis of the NOAH-AFNET 6 and ARTESiA trials.

BACKGROUND AND AIMS: The optimal antithrombotic therapy in patients with device-detected atrial fibrillation (DDAF) is unknown. Concomitant vascular disease can modify the benefits and risks of anticoagulation. METHODS: These pre-specified analyses of the NOAH-AFNET 6 (n=2534 patients) and ARTESiA (n=4012 patients) trials compared anticoagulation to no anticoagulation in patients with DDAF with or without vascular disease, defined as prior stroke/transient ischemic attack, coronary or peripheral artery disease. Efficacy outcomes were the primary outcomes of both trials, a composite of stroke, systemic arterial embolism (SE), myocardial infarction, pulmonary embolism or cardiovascular death, and stroke or SE. Safety outcomes were major bleeding or major bleeding and death. RESULTS: In patients with vascular disease (NOAH-AFNET 6 56%, ARTESiA 46.0%), stroke, myocardial infarction, systemic or pulmonary embolism, or cardiovascular death occurred at 3.9%/patient-year with and 5.0%/patient-year without anticoagulation (NOAH-AFNET 6), and 3.2%/patient-year with and 4.4%/patient-year without anticoagulation (ARTESiA). Without vascular disease, outcomes were equal with and without anticoagulation (NOAH-AFNET 6 2.7%/patient-year, ARTESiA 2.3%/patient-year in both randomised groups). Meta-analysis found consistent results across both trials (I2heterogeneity=6%) with a trend for interaction with randomised therapy (pinteraction=0.08). Stroke/SE behaved similarly. Anticoagulation increased major bleeding in vascular disease patients (edoxaban 2.1%/patient-year, no anticoagulation 1.3%/patient-year; apixaban 1.7%/patient-year; no anticoagulation 1.1%/patient-year; incidence rate ratio 1.55 [1.10-2.20]) and without vascular disease (edoxaban 2.2%/patient-year; no anticoagulation 0.6%/patient-year; apixaban 1.4%/patient-year; no anticoagulation 1.1%/patient-year, incidence rate ratio 1.93 [0.72-5.20]). CONCLUSIONS: Patients with DDAF and vascular disease are at higher risk of stroke and cardiovascular events and may derive a greater benefit from anticoagulation than patients with DDAF without vascular disease.

Self-administered intranasal etripamil using a symptom-prompted, repeat-dose regimen for atrioventricular-nodal-dependent supraventricular tachycardia (RAPID): a multicentre, randomised trial.

BACKGROUND: Etripamil is a fast-acting, intranasally administered calcium-channel blocker in development for on-demand therapy outside a health-care setting for paroxysmal supraventricular tachycardia. We aimed to evaluate the efficacy and safety of etripamil 70 mg nasal spray using a symptom-prompted, repeat-dose regimen for acute conversion of atrioventricular-nodal-dependent paroxysmal supraventricular tachycardia to sinus rhythm within 30 min. METHODS: RAPID was a multicentre, randomised, placebo-controlled, event-driven trial, conducted at 160 sites in North America and Europe as part 2 of the NODE-301 study. Eligible patients were aged at least 18 years and had a history of paroxysmal supraventricular tachycardia with sustained, symptomatic episodes (≥20 min) as documented by electrocardiogram. Patients were administered two test doses of intranasal etripamil (each 70 mg, 10 min apart) during sinus rhythm; those who tolerated the test doses were randomly assigned (1:1) using an interactive response technology system to receive either etripamil or placebo. Prompted by symptoms of paroxysmal supraventricular tachycardia, patients self-administered a first dose of intranasal 70 mg etripamil or placebo and, if symptoms persisted beyond 10 min, a repeat dose. Continuously recorded electrocardiographic data were adjudicated, by individuals masked to patient assignment, for the primary endpoint of time to conversion of paroxysmal supraventricular tachycardia to sinus rhythm for at least 30 s within 30 min after the first dose, which was measured in all patients who administered blinded study drug for a confirmed atrioventricular-nodal-dependent event. Safety outcomes were assessed in all patients who self-administered blinded study drug for an episode of perceived paroxysmal supraventricular tachycardia. This trial is registered at ClinicalTrials.gov, NCT03464019, and is complete. FINDINGS: Between Oct 13, 2020, and July 20, 2022, among 692 patients randomly assigned, 184 (99 from the etripamil group and 85 from the placebo group) self-administered study drug for atrioventricular-nodal-dependent paroxysmal supraventricular tachycardia, with diagnosis and timing confirmed. Kaplan-Meier estimates of conversion rates by 30 min were 64% (63/99) with etripamil and 31% (26/85) with placebo (hazard ratio 2·62; 95% CI 1·66-4·15; p<0·0001). Median time to conversion was 17·2 min (95% CI 13·4-26·5) with the etripamil regimen versus 53·5 min (38·7-87·3) with placebo. Prespecified sensitivity analyses of the primary assessment were conducted to test robustness, yielding supporting results. Treatment-emergent adverse events occurred in 68 (50%) of 99 patients treated with etripamil and 12 (11%) of 85 patients in the placebo group, most of which were located at the administration site and were mild or moderate, and all of which were transient and resolved without intervention. Adverse events occurring in at least 5% of patients treated with etripamil were nasal discomfort (23%), nasal congestion (13%), and rhinorrhea (9%). No serious etripamil-related adverse events or deaths were reported. INTERPRETATION: Using a symptom-prompted, self-administered, initial and optional-repeat-dosing regimen, intranasal etripamil was well tolerated, safe, and superior to placebo for the rapid conversion of atrioventricular-nodal-dependent paroxysmal supraventricular tachycardia to sinus rhythm. This approach could empower patients to treat paroxysmal supraventricular tachycardia themselves outside of a health-care setting, and has the potential to reduce the need for additional medical interventions, such as intravenous medications given in an acute-care setting. FUNDING: Milestone Pharmaceuticals.

Left Atrial Appendage Occlusion during Cardiac Surgery to Prevent Stroke.

BACKGROUND: Surgical occlusion of the left atrial appendage has been hypothesized to prevent ischemic stroke in patients with atrial fibrillation, but this has not been proved. The procedure can be performed during cardiac surgery undertaken for other reasons. METHODS: We conducted a multicenter, randomized trial involving participants with atrial fibrillation and a CHA2DS2-VASc score of at least 2 (on a scale from 0 to 9, with higher scores indicating greater risk of stroke) who were scheduled to undergo cardiac surgery for another indication. The participants were randomly assigned to undergo or not undergo occlusion of the left atrial appendage during surgery; all the participants were expected to receive usual care, including oral anticoagulation, during follow-up. The primary outcome was the occurrence of ischemic stroke (including transient ischemic attack with positive neuroimaging) or systemic embolism. The participants, research personnel, and primary care physicians (other than the surgeons) were unaware of the trial-group assignments. RESULTS: The primary analysis population included 2379 participants in the occlusion group and 2391 in the no-occlusion group, with a mean age of 71 years and a mean CHA2DS2-VASc score of 4.2. The participants were followed for a mean of 3.8 years. A total of 92.1% of the participants received the assigned procedure, and at 3 years, 76.8% of the participants continued to receive oral anticoagulation. Stroke or systemic embolism occurred in 114 participants (4.8%) in the occlusion group and in 168 (7.0%) in the no-occlusion group (hazard ratio, 0.67; 95% confidence interval, 0.53 to 0.85; P = 0.001). The incidence of perioperative bleeding, heart failure, or death did not differ significantly between the trial groups. CONCLUSIONS: Among participants with atrial fibrillation who had undergone cardiac surgery, most of whom continued to receive ongoing antithrombotic therapy, the risk of ischemic stroke or systemic embolism was lower with concomitant left atrial appendage occlusion performed during the surgery than without it. (Funded by the Canadian Institutes of Health Research and others; LAAOS III ClinicalTrials.gov number, NCT01561651.).

Effects of a stepwise, structured LDL-C lowering strategy in patients post-acute coronary syndrome.

OBJECTIVE: Low-density lipoprotein cholesterol (LDL-C) lowering constitutes a cornerstone of secondary prevention of atherosclerotic cardiovascular disease (ASCVD), yet a considerable number of patients do not achieve guideline-recommended LDL­C targets. The 2016 European guidelines recommended titration of LDL­C lowering medication in a set number of steps, starting with oral medication. We aimed to investigate the effects of this stepwise approach in post-acute coronary syndrome (ACS) patients. METHODS: In a multicentre, prospective, non-randomised trial, we evaluated a three-step strategy aiming to reduce LDL­C to ≤ 1.8 mmol/l in post-ACS patients with prior ASCVD and/or diabetes mellitus. Steps, undertaken every 4-6 weeks, included: 1) start high-intensity statin (HIST); 2) addition of ezetimibe; 3) addition of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i). The primary outcome was the proportion of patients achieving LDL-C ≤ 1.8 mmol/l after Steps 1 and 2 (using oral medications alone). Secondary outcomes examined the prevalence of meeting the target throughout all steps ( https://onderzoekmetmensen.nl/nl/trial/21157 ). RESULTS: Out of 999 patients, 84% (95% confidence intervals (CI): 81-86) achieved the LDL­C target using only statin and/or ezetimibe. In an intention-to-treat analysis, the percentages of patients meeting the LDL­C target after each step were 69% (95% CI: 67-72), 84% (95% CI: 81-86), and 87% (95% CI: 85-89), respectively. There were protocol deviations for 23, 38 and 23 patients at each respective step. CONCLUSION: Through stepwise intensification of lipid-lowering therapy, 84% of very high-risk post-ACS patients achieved an LDL­C target of ≤ 1.8 mmol/l with oral medications alone. Addition of PCSK9i further increased this rate to 87% (95% CI: 85-89).

Efficacy and Safety of Appropriate Shocks and Antitachycardia Pacing in Transvenous and Subcutaneous Implantable Defibrillators: Analysis of All Appropriate Therapy in the PRAETORIAN Trial.

BACKGROUND: The PRAETORIAN trial (A Prospective, Randomized Comparison of Subcutaneous and Transvenous Implantable Cardioverter Defibrillator Therapy) showed noninferiority of subcutaneous implantable cardioverter defibrillator (S-ICD) compared with transvenous implantable cardioverter defibrillator (TV-ICD) with regard to inappropriate shocks and complications. In contrast to TV-ICD, S-ICD cannot provide antitachycardia pacing for monomorphic ventricular tachycardia. This prespecified secondary analysis evaluates appropriate therapy and whether antitachycardia pacing reduces the number of appropriate shocks. METHODS: The PRAETORIAN trial was an international, investigator-initiated randomized trial that included patients with an indication for implantable cardioverter defibrillator (ICD) therapy. Patients with previous ventricular tachycardia <170 bpm or refractory recurrent monomorphic ventricular tachycardia were excluded. In 39 centers, 849 patients were randomized to receive an S-ICD (n=426) or TV-ICD (n=423) and were followed for a median of 49.1 months. ICD programming was mandated by protocol. Appropriate ICD therapy was defined as therapy for ventricular arrhythmias. Arrhythmias were classified as discrete episodes and storm episodes (≥3 episodes within 24 hours). Analyses were performed in the modified intention-to-treat population. RESULTS: In the S-ICD group, 86 of 426 patients received appropriate therapy, versus 78 of 423 patients in the TV-ICD group, during a median follow-up of 52 months (48-month Kaplan-Meier estimates 19.4% and 17.5%; P=0.45). In the S-ICD group, 83 patients received at least 1 shock, versus 57 patients in the TV-ICD group (48-month Kaplan-Meier estimates 19.2% and 11.5%; P=0.02). Patients in the S-ICD group had a total of 254 shocks, compared with 228 shocks in the TV-ICD group (P=0.68). First shock efficacy was 93.8% in the S-ICD group and 91.6% in the TV-ICD group (P=0.40). The first antitachycardia pacing attempt successfully terminated 46% of all monomorphic ventricular tachycardias, but accelerated the arrhythmia in 9.4%. Ten patients with S-ICD experienced 13 electrical storms, versus 18 patients with TV-ICD with 19 electrical storms. Patients with appropriate therapy had an almost 2-fold increased relative risk of electrical storms in the TV-ICD group compared with the S-ICD group (P=0.05). CONCLUSIONS: In this trial, no difference was observed in shock efficacy of S-ICD compared with TV-ICD. Although patients in the S-ICD group were more likely to receive an ICD shock, the total number of appropriate shocks was not different between the 2 groups. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01296022.

Colchicine in Patients with Chronic Coronary Disease.

BACKGROUND: Evidence from a recent trial has shown that the antiinflammatory effects of colchicine reduce the risk of cardiovascular events in patients with recent myocardial infarction, but evidence of such a risk reduction in patients with chronic coronary disease is limited. METHODS: In a randomized, controlled, double-blind trial, we assigned patients with chronic coronary disease to receive 0.5 mg of colchicine once daily or matching placebo. The primary end point was a composite of cardiovascular death, spontaneous (nonprocedural) myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization. The key secondary end point was a composite of cardiovascular death, spontaneous myocardial infarction, or ischemic stroke. RESULTS: A total of 5522 patients underwent randomization; 2762 were assigned to the colchicine group and 2760 to the placebo group. The median duration of follow-up was 28.6 months. A primary end-point event occurred in 187 patients (6.8%) in the colchicine group and in 264 patients (9.6%) in the placebo group (incidence, 2.5 vs. 3.6 events per 100 person-years; hazard ratio, 0.69; 95% confidence interval [CI], 0.57 to 0.83; P<0.001). A key secondary end-point event occurred in 115 patients (4.2%) in the colchicine group and in 157 patients (5.7%) in the placebo group (incidence, 1.5 vs. 2.1 events per 100 person-years; hazard ratio, 0.72; 95% CI, 0.57 to 0.92; P = 0.007). The incidence rates of spontaneous myocardial infarction or ischemia-driven coronary revascularization (composite end point), cardiovascular death or spontaneous myocardial infarction (composite end point), ischemia-driven coronary revascularization, and spontaneous myocardial infarction were also significantly lower with colchicine than with placebo. The incidence of death from noncardiovascular causes was higher in the colchicine group than in the placebo group (incidence, 0.7 vs. 0.5 events per 100 person-years; hazard ratio, 1.51; 95% CI, 0.99 to 2.31). CONCLUSIONS: In a randomized trial involving patients with chronic coronary disease, the risk of cardiovascular events was significantly lower among those who received 0.5 mg of colchicine once daily than among those who received placebo. (Funded by the National Health Medical Research Council of Australia and others; LoDoCo2 Australian New Zealand Clinical Trials Registry number, ACTRN12614000093684.).

Subcutaneous or Transvenous Defibrillator Therapy.

BACKGROUND: The subcutaneous implantable cardioverter-defibrillator (ICD) was designed to avoid complications related to the transvenous ICD lead by using an entirely extrathoracic placement. Evidence comparing these systems has been based primarily on observational studies. METHODS: We conducted a noninferiority trial in which patients with an indication for an ICD but no indication for pacing were assigned to receive a subcutaneous ICD or transvenous ICD. The primary end point was the composite of device-related complications and inappropriate shocks; the noninferiority margin for the upper boundary of the 95% confidence interval for the hazard ratio (subcutaneous ICD vs. transvenous ICD) was 1.45. A superiority analysis was prespecified if noninferiority was established. Secondary end points included death and appropriate shocks. RESULTS: A total of 849 patients (426 in the subcutaneous ICD group and 423 in the transvenous ICD group) were included in the analyses. At a median follow-up of 49.1 months, a primary end-point event occurred in 68 patients in the subcutaneous ICD group and in 68 patients in the transvenous ICD group (48-month Kaplan-Meier estimated cumulative incidence, 15.1% and 15.7%, respectively; hazard ratio, 0.99; 95% confidence interval [CI], 0.71 to 1.39; P = 0.01 for noninferiority; P = 0.95 for superiority). Device-related complications occurred in 31 patients in the subcutaneous ICD group and in 44 in the transvenous ICD group (hazard ratio, 0.69; 95% CI, 0.44 to 1.09); inappropriate shocks occurred in 41 and 29 patients, respectively (hazard ratio, 1.43; 95% CI, 0.89 to 2.30). Death occurred in 83 patients in the subcutaneous ICD group and in 68 in the transvenous ICD group (hazard ratio, 1.23; 95% CI, 0.89 to 1.70); appropriate shocks occurred in 83 and 57 patients, respectively (hazard ratio, 1.52; 95% CI, 1.08 to 2.12). CONCLUSIONS: In patients with an indication for an ICD but no indication for pacing, the subcutaneous ICD was noninferior to the transvenous ICD with respect to device-related complications and inappropriate shocks. (Funded by Boston Scientific; PRAETORIAN ClinicalTrials.gov number, NCT01296022.).

The genetic basis of apparently idiopathic ventricular fibrillation: a retrospective overview.

AIMS: During the diagnostic work-up of patients with idiopathic ventricular fibrillation (VF), next-generation sequencing panels can be considered to identify genotypes associated with arrhythmias. However, consensus for gene panel testing is still lacking, and variants of uncertain significance (VUS) are often identified. The aim of this study was to evaluate genetic testing and its results in idiopathic VF patients. METHODS AND RESULTS: We investigated 419 patients with available medical records from the Dutch Idiopathic VF Registry. Genetic testing was performed in 379 (91%) patients [median age at event 39 years (27-51), 60% male]. Single-gene testing was performed in 87 patients (23%) and was initiated more often in patients with idiopathic VF before 2010. Panel testing was performed in 292 patients (77%). The majority of causal (likely) pathogenic variants (LP/P, n = 56, 15%) entailed the DPP6 risk haplotype (n = 39, 70%). Moreover, 10 LP/P variants were found in cardiomyopathy genes (FLNC, MYL2, MYH7, PLN (two), TTN (four), RBM20), and 7 LP/P variants were identified in genes associated with cardiac arrhythmias (KCNQ1, SCN5A (2), RYR2 (four)). For eight patients (2%), identification of an LP/P variant resulted in a change of diagnosis. In 113 patients (30%), a VUS was identified. Broad panel testing resulted in a higher incidence of VUS in comparison to single-gene testing (38% vs. 3%, P < 0.001). CONCLUSION: Almost all patients from the registry underwent, albeit not broad, genetic testing. The genetic yield of causal LP/P variants in idiopathic VF patients is 5%, increasing to 15% when including DPP6. In specific cases, the LP/P variant is the underlying diagnosis. A gene panel specifically for idiopathic VF patients is proposed.

Device-related complications in subcutaneous versus transvenous ICD: a secondary analysis of the PRAETORIAN trial.

BACKGROUND: The subcutaneous implantable cardioverter-defibrillator (S-ICD) is developed to overcome lead-related complications and systemic infections, inherent to transvenous ICD (TV-ICD) therapy. The PRAETORIAN trial demonstrated that the S-ICD is non-inferior to the TV-ICD with regard to the combined primary endpoint of inappropriate shocks and complications. This prespecified secondary analysis evaluates all complications in the PRAETORIAN trial. METHODS AND RESULTS: The PRAETORIAN trial is an international, multicentre, randomized trial in which 849 patients with an indication for ICD therapy were randomized to receive an S- ICD (N = 426) or TV-ICD (N = 423) and followed for a median of 49 months. Endpoints were device-related complications, lead-related complications, systemic infections, and the need for invasive interventions. Thirty-six device-related complications occurred in 31 patients in the S-ICD group of which bleedings were the most frequent. In the TV-ICD group, 49 complications occurred in 44 patients of which lead dysfunction was most frequent (HR: 0.69; P = 0.11). In both groups, half of all complications were within 30 days after implantation. Lead-related complications and systemic infections occurred significantly less in the S-ICD group compared with the TV-ICD group (P < 0.001, P = 0.03, respectively). Significantly more complications required invasive interventions in the TV-ICD group compared with the S-ICD group (8.3% vs. 4.3%, HR: 0.59; P = 0.047). CONCLUSION: This secondary analysis shows that lead-related complications and systemic infections are more prevalent in the TV-ICD group compared with the S-ICD group. In addition, complications in the TV-ICD group were more severe as they required significantly more invasive interventions. This data contributes to shared decision-making in clinical practice.

Early or Delayed Cardioversion in Recent-Onset Atrial Fibrillation.

BACKGROUND: Patients with recent-onset atrial fibrillation commonly undergo immediate restoration of sinus rhythm by pharmacologic or electrical cardioversion. However, whether immediate restoration of sinus rhythm is necessary is not known, since atrial fibrillation often terminates spontaneously. METHODS: In a multicenter, randomized, open-label, noninferiority trial, we randomly assigned patients with hemodynamically stable, recent-onset (<36 hours), symptomatic atrial fibrillation in the emergency department to be treated with a wait-and-see approach (delayed-cardioversion group) or early cardioversion. The wait-and-see approach involved initial treatment with rate-control medication only and delayed cardioversion if the atrial fibrillation did not resolve within 48 hours. The primary end point was the presence of sinus rhythm at 4 weeks. Noninferiority would be shown if the lower limit of the 95% confidence interval for the between-group difference in the primary end point in percentage points was more than -10. RESULTS: The presence of sinus rhythm at 4 weeks occurred in 193 of 212 patients (91%) in the delayed-cardioversion group and in 202 of 215 (94%) in the early-cardioversion group (between-group difference, -2.9 percentage points; 95% confidence interval [CI], -8.2 to 2.2; P = 0.005 for noninferiority). In the delayed-cardioversion group, conversion to sinus rhythm within 48 hours occurred spontaneously in 150 of 218 patients (69%) and after delayed cardioversion in 61 patients (28%). In the early-cardioversion group, conversion to sinus rhythm occurred spontaneously before the initiation of cardioversion in 36 of 219 patients (16%) and after cardioversion in 171 patients (78%). Among the patients who completed remote monitoring during 4 weeks of follow-up, a recurrence of atrial fibrillation occurred in 49 of 164 patients (30%) in the delayed-cardioversion group and in 50 of 171 (29%) in the early-cardioversion group. Within 4 weeks after randomization, cardiovascular complications occurred in 10 patients and 8 patients, respectively. CONCLUSIONS: In patients presenting to the emergency department with recent-onset, symptomatic atrial fibrillation, a wait-and-see approach was noninferior to early cardioversion in achieving a return to sinus rhythm at 4 weeks. (Funded by the Netherlands Organization for Health Research and Development and others; RACE 7 ACWAS ClinicalTrials.gov number, NCT02248753.).

Long-term outcome of targeted therapy of underlying conditions in patients with early persistent atrial fibrillation and heart failure: data of the RACE 3 trial.

AIMS: The Routine vs. Aggressive risk factor driven upstream rhythm Control for prevention of Early persistent atrial fibrillation (AF) in heart failure (HF) (RACE 3) trial demonstrated that targeted therapy of underlying conditions improved sinus rhythm maintenance at 1 year. We now explored the effects of targeted therapy on the additional co-primary endpoints; sinus rhythm maintenance and cardiovascular outcome at 5 years. METHODS AND RESULTS: Patients with early persistent AF and mild-to-moderate stable HF were randomized to targeted or conventional therapy. Both groups received rhythm control therapy according to guidelines. The targeted group additionally received four therapies: angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers (ARBs), statins, mineralocorticoid receptor antagonists (MRAs), and cardiac rehabilitation. The presence of sinus rhythm and cardiovascular morbidity and mortality at 5-year follow-up were assessed. Two hundred and sixteen patients consented for long-term follow-up, 107 were randomized to targeted and 109 to conventional therapy. At 5 years, MRAs [76 (74%) vs. 10 (9%) patients, P < 0.001] and statins [81 (79%) vs. 59 (55%), P < 0.001] were used more in the targeted than conventional group. Angiotensin-converting enzyme inhibitors/ARBs and physical activity were not different between groups. Sinus rhythm was present in 49 (46%) targeted vs. 43 (39%) conventional group patients at 5 years (odds ratio 1.297, lower limit of 95% confidence interval 0.756, P = 0.346). Cardiovascular mortality and morbidity occurred in 20 (19%) in the targeted and 15 (14%) conventional group patients, P = 0.353. CONCLUSION: In patients with early persistent AF and HF superiority of targeted therapy in sinus rhythm maintenance could not be preserved at 5-year follow-up. Cardiovascular outcome was not different between groups. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT00877643.

Antiarrhythmic drugs in patients with early persistent atrial fibrillation and heart failure: results of the RACE 3 study.

AIMS: Maintaining sinus rhythm in patients with persistent atrial fibrillation (AF) is challenging. We explored the efficacy of class I and III antiarrhythmic drugs (AADs) in patients with persistent AF and mild to moderate heart failure (HF). METHODS AND RESULTS: In the RACE 3 trial, patients with early persistent symptomatic AF and short history of mild to moderate HF with preserved or reduced left ventricular ejection fraction (LVEF) were randomized to targeted or conventional therapy. Both groups received AF and HF guideline-driven treatment. Additionally, the targeted-group received mineralocorticoid receptor antagonists, statins, angiotensin-converting enzyme inhibitors and/or receptor blockers, and cardiac rehabilitation. Class I and III AADs could be instituted in case of symptomatic recurrent AF. Eventually, pulmonary vein isolation could be performed. Primary endpoint was sinus rhythm on 7-day Holter after 1-year. Included were 245 patients, age 65 ± 9 years, 193 (79%) men, AF history was 3 (2-6) months, HF history 2 (1-4) months, 72 (29.4%) had HF with reduced LVEF. After baseline electrical cardioversion (ECV), 190 (77.6%) had AF recurrences; 108 (56.8%) received class I/III AADs; 19 (17.6%) flecainide, 36 (33.3%) sotalol, 3 (2.8%) dronedarone, 50 (46.3%) amiodarone. At 1-year 73 of 108 (68.0%) patients were in sinus rhythm, 44 (40.7%) without new AF recurrences. Maintenance of sinus rhythm was significantly better with amiodarone [n = 29/50 (58%)] compared with flecainide [n = 6/19 (32%)] and sotalol/dronedarone [n = 9/39 (23%)], P = 0.0064. Adverse events occurred in 27 (25.0%) patients, were all minor and reversible. CONCLUSION: In stable HF patients with early persistent AF, AAD treatment was effective in nearly half of patients, with no serious adverse effects reported.

Effect of alirocumab on cardiovascular outcomes after acute coronary syndromes according to age: an ODYSSEY OUTCOMES trial analysis.

AIMS: Lowering low-density lipoprotein cholesterol (LDL-C) reduces cardiovascular risk irrespective of age, but the evidence is less strong for older patients. METHODS AND RESULTS: This prespecified analysis from ODYSSEY OUTCOMES compared the effect of alirocumab vs. placebo in 18 924 patients with recent acute coronary syndrome (ACS) according to age. We examined the effect of assigned treatment on occurrence of the primary study outcome, a composite of coronary heart disease death, myocardial infarction, ischaemic stroke, or unstable angina requiring hospitalization [major adverse cardiovascular event (MACE)] and all-cause death. Relative risk reductions were consistent for patients ≥65 vs. <65 years for MACE [hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.68-0.91 vs. 0.89, 0.80-1.00; Pinteraction = 0.19] and all-cause death [HR 0.77, 0.62-0.95 vs. 0.94, 0.77-1.15; Pinteraction = 0.46], and consistent for MACE when dichotomizing at age 75 years (HR 0.85, 0.64-1.13 in ≥75 vs. 0.85, 0.78-0.93 in <75, Pinteraction = 0.19). When considering age as a continuous variable in regression models, advancing age increased risk of MACE, as well as the absolute reduction in MACE with alirocumab, with numbers-needed-to-treat for MACE at 3 years of 43 (25-186) at age 45 years, 26 (15-97) at age 75 years, and 12 (6-81) for those at age 85 years. Although adverse events were more frequent in older patients, there were no differences between alirocumab and placebo. CONCLUSION: In patients with recent ACS, alirocumab improves outcomes irrespective of age. Increasing absolute benefit but not harm with advancing age suggests that LDL-C lowering is an important preventive intervention for older patients after ACS.

Individual Treatment Effect Estimation of 2 Doses of Dabigatran on Stroke and Major Bleeding in Atrial Fibrillation.

BACKGROUND: We aimed to estimate absolute benefit and harm from treatment with dabigatran in individual patients with atrial fibrillation, and to select the optimal dose for each individual. METHODS: We derived and validated a prediction model for ischemic stroke/systemic embolism and major bleeding in patients with atrial fibrillation from the 3 treatment arms of the RE-LY trial (Randomized Evaluation of Long-Term Anticoagulation Therapy With Dabigatran Etexilate) (n=11 955 in derivation cohort, n=6158 in validation cohort). Readily available patient characteristics were included in Fine and Gray competing risk models (sex, age, smoking, antiplatelet drugs, previous vascular disease, diabetes mellitus, blood pressure, estimated glomerular filtration rate, and hemoglobin). Five-year risks for ischemic stroke/systemic embolism and major bleeding were estimated without anticoagulation therapy, and compared with high- and low-dose dabigatran. RESULTS: Model calibration was good, and discrimination was adequate with a c-statistic of 0.65 (95% CI, 0.62-0.70) for ischemic stroke/systemic embolism and 0.69 (95% CI, 0.66-0.71) for major bleeding. The 5-year absolute risk reduction for ischemic stroke/systemic embolism with dabigatran 150 mg twice daily ranged from <10% in 20% of patients to >25% in 14% of patients, and the 5-year absolute risk increase for major bleeding ranged from <5% in 53% of patients to 15% to 20% in 1% of patients. Comparing high-dose to low-dose dabigatran, the net benefit (absolute risk reduction minus absolute risk increase) was positive for 46% of patients. CONCLUSIONS: The absolute treatment benefits and harms of dabigatran in atrial fibrillation can be estimated based on readily available patient characteristics. Such treatment effect estimations can be used for shared decision making before starting dabigatran treatment and to determine the optimal dose. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00262600.

Bleeding and New Cancer Diagnosis in Patients With Atherosclerosis.

BACKGROUND: Patients treated with antithrombotic drugs are at risk of bleeding. Bleeding may be the first manifestation of underlying cancer. METHODS: We examined new cancers diagnosed in relation to gastrointestinal or genitourinary bleeding among patients enrolled in the COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies) and determined the hazard of new cancer diagnosis after bleeding at these sites. RESULTS: Of 27 395 patients enrolled (mean age, 68 years; women, 21%), 2678 (9.8%) experienced any (major or minor) bleeding, 713 (2.6%) experienced major bleeding, and 1084 (4.0%) were diagnosed with cancer during a mean follow-up of 23 months. Among 2678 who experienced bleeding, 257 (9.9%) were subsequently diagnosed with cancer. Gastrointestinal bleeding was associated with a 20-fold higher hazard of new gastrointestinal cancer diagnosis (7.4% versus 0.5%; hazard ratio [HR], 20.6 [95% CI, 15.2-27.8]) and 1.7-fold higher hazard of new nongastrointestinal cancer diagnosis (3.8% versus 3.1%; HR, 1.70 [95% CI, 1.20-2.40]). Genitourinary bleeding was associated with a 32-fold higher hazard of new genitourinary cancer diagnosis (15.8% versus 0.8%; HR, 32.5 [95% CI, 24.7-42.9]), and urinary bleeding was associated with a 98-fold higher hazard of new urinary cancer diagnosis (14.2% versus 0.2%; HR, 98.5; 95% CI, 68.0-142.7). Nongastrointestinal, nongenitourinary bleeding was associated with a 3-fold higher hazard of nongastrointestinal, nongenitourinary cancers (4.4% versus 1.9%; HR, 3.02 [95% CI, 2.32-3.91]). CONCLUSIONS: In patients with atherosclerosis treated with antithrombotic drugs, any gastrointestinal or genitourinary bleeding was associated with higher rates of new cancer diagnosis. Any gastrointestinal or genitourinary bleeding should prompt investigation for cancers at these sites. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01776424.

Stroke Outcomes in the COMPASS Trial.

BACKGROUND: Strokes were significantly reduced by the combination of rivaroxaban plus aspirin in comparison with aspirin in the COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies). We present detailed analyses of stroke by type, predictors, and antithrombotic effects in key subgroups. METHODS: Participants had stable coronary artery or peripheral artery disease and were randomly assigned to receive aspirin 100 mg once daily (n=9126), rivaroxaban 5 mg twice daily (n=9117), or rivaroxaban 2.5 mg twice daily plus aspirin (n=9152). Patients who required anticoagulation or had a stroke within 1 month, previous lacunar stroke, or intracerebral hemorrhage were excluded. RESULTS: During a mean follow-up of 23 months, fewer patients had strokes in the rivaroxaban plus aspirin group than in the aspirin group (83 [0.9% per year] versus 142 [1.6% per year]; hazard ratio [HR], 0.58; 95% CI, 0.44-0.76; P<0.0001). Ischemic/uncertain strokes were reduced by nearly half (68 [0.7% per year] versus 132 [1.4% per year]; HR, 0.51; 95% CI, 0.38-0.68; P<0.0001) by the combination in comparison with aspirin. No significant difference was noted in the occurrence of stroke in the rivaroxaban alone group in comparison with aspirin: annualized rate of 0.7% (HR, 0.82; 95% CI, 0.65-1.05). The occurrence of fatal and disabling stroke (modified Rankin Scale, 3-6) was decreased by the combination (32 [0.3% per year] versus 55 [0.6% per year]; HR, 0.58; 95% CI, 0.37-0.89; P=0.01). Independent predictors of stroke were prior stroke, hypertension, systolic blood pressure at baseline, age, diabetes mellitus, and Asian ethnicity. Prior stroke was the strongest predictor of incident stroke (HR, 3.63; 95% CI, 2.65-4.97; P<0.0001) and was associated with a 3.4% per year rate of stroke recurrence on aspirin. The effect of the combination in comparison with aspirin was consistent across subgroups with high stroke risk, including those with prior stroke. CONCLUSIONS: Low-dose rivaroxaban plus aspirin is an important new antithrombotic option for primary and secondary stroke prevention in patients with clinical atherosclerosis. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01776424.

Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease.

BACKGROUND: We evaluated whether rivaroxaban alone or in combination with aspirin would be more effective than aspirin alone for secondary cardiovascular prevention. METHODS: In this double-blind trial, we randomly assigned 27,395 participants with stable atherosclerotic vascular disease to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg once daily). The primary outcome was a composite of cardiovascular death, stroke, or myocardial infarction. The study was stopped for superiority of the rivaroxaban-plus-aspirin group after a mean follow-up of 23 months. RESULTS: The primary outcome occurred in fewer patients in the rivaroxaban-plus-aspirin group than in the aspirin-alone group (379 patients [4.1%] vs. 496 patients [5.4%]; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.86; P<0.001; z=-4.126), but major bleeding events occurred in more patients in the rivaroxaban-plus-aspirin group (288 patients [3.1%] vs. 170 patients [1.9%]; hazard ratio, 1.70; 95% CI, 1.40 to 2.05; P<0.001). There was no significant difference in intracranial or fatal bleeding between these two groups. There were 313 deaths (3.4%) in the rivaroxaban-plus-aspirin group as compared with 378 (4.1%) in the aspirin-alone group (hazard ratio, 0.82; 95% CI, 0.71 to 0.96; P=0.01; threshold P value for significance, 0.0025). The primary outcome did not occur in significantly fewer patients in the rivaroxaban-alone group than in the aspirin-alone group, but major bleeding events occurred in more patients in the rivaroxaban-alone group. CONCLUSIONS: Among patients with stable atherosclerotic vascular disease, those assigned to rivaroxaban (2.5 mg twice daily) plus aspirin had better cardiovascular outcomes and more major bleeding events than those assigned to aspirin alone. Rivaroxaban (5 mg twice daily) alone did not result in better cardiovascular outcomes than aspirin alone and resulted in more major bleeding events. (Funded by Bayer; COMPASS ClinicalTrials.gov number, NCT01776424 .).