Jonathan P. Piccini

Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation

BACKGROUND The use of warfarin reduces the rate of ischemic stroke in patients with atrial fibrillation but requires frequent monitoring and dose adjustment. Rivaroxaban, an oral factor Xa inhibitor, may provide more consistent and predictable anticoagulation than warfarin. METHODS In a double-blind trial, we randomly assigned 14,264 patients with nonvalvular atrial fibrillation who were at increased risk for stroke to receive either rivaroxaban (at a daily dose of 20 mg) or dose-adjusted warfarin. The per-protocol, as-treated primary analysis was designed to determine whether rivaroxaban was noninferior to warfarin for the primary end point of stroke or systemic embolism. RESULTS In the primary analysis, the primary end point occurred in 188 patients in the rivaroxaban group (1.7% per year) and in 241 in the warfarin group (2.2% per year) (hazard ratio in the rivaroxaban group, 0.79; 95% confidence interval [CI], 0.66 to 0.96; P<0.001 for noninferiority). In the intention-to-treat analysis, the primary end point occurred in 269 patients in the rivaroxaban group (2.1% per year) and in 306 patients in the warfarin group (2.4% per year) (hazard ratio, 0.88; 95% CI, 0.74 to 1.03; P<0.001 for noninferiority; P=0.12 for superiority). Major and nonmajor clinically relevant bleeding occurred in 1475 patients in the rivaroxaban group (14.9% per year) and in 1449 in the warfarin group (14.5% per year) (hazard ratio, 1.03; 95% CI, 0.96 to 1.11; P=0.44), with significant reductions in intracranial hemorrhage (0.5% vs. 0.7%, P=0.02) and fatal bleeding (0.2% vs. 0.5%, P=0.003) in the rivaroxaban group. CONCLUSIONS In patients with atrial fibrillation, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism. There was no significant between-group difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. (Funded by Johnson & Johnson and Bayer; ROCKET AF ClinicalTrials.gov number, NCT00403767.).

Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment

AIMS Patients with non-valvular atrial fibrillation (AF) and renal insufficiency are at increased risk for ischaemic stroke and bleeding during anticoagulation. Rivaroxaban, an oral, direct factor Xa inhibitor metabolized predominantly by the liver, preserves the benefit of warfarin for stroke prevention while causing fewer intracranial and fatal haemorrhages. METHODS AND RESULTS We randomized 14 264 patients with AF in a double-blind trial to rivaroxaban 20 mg/day [15 mg/day if creatinine clearance (CrCl) 30-49 mL/min] or dose-adjusted warfarin (target international normalized ratio 2.0-3.0). Compared with patients with CrCl >50 mL/min (mean age 73 years), the 2950 (20.7%) patients with CrCl 30-49 mL/min were older (79 years) and had higher event rates irrespective of study treatment. Among those with CrCl 30-49 mL/min, the primary endpoint of stroke or systemic embolism occurred in 2.32 per 100 patient-years with rivaroxaban 15 mg/day vs. 2.77 per 100 patient-years with warfarin [hazard ratio (HR) 0.84; 95% confidence interval (CI) 0.57-1.23] in the per-protocol population. Intention-to-treat analysis yielded similar results (HR 0.86; 95% CI 0.63-1.17) to the per-protocol results. Rates of the principal safety endpoint (major and clinically relevant non-major bleeding: 17.82 vs. 18.28 per 100 patient-years; P = 0.76) and intracranial bleeding (0.71 vs. 0.88 per 100 patient-years; P = 0.54) were similar with rivaroxaban or warfarin. Fatal bleeding (0.28 vs. 0.74% per 100 patient-years; P = 0.047) occurred less often with rivaroxaban. CONCLUSION Patients with AF and moderate renal insufficiency have higher rates of stroke and bleeding than those with normal renal function. There was no evidence of heterogeneity in treatment effect across dosing groups. Dose adjustment in ROCKET-AF yielded results consistent with the overall trial in comparison with dose-adjusted warfarin.

Arrhythmogenic Right Ventricular Dysplasia: A United States Experience

Background— Arrhythmogenic right ventricular dysplasia (ARVD) is an inherited cardiomyopathy characterized by right ventricular dysfunction and ventricular arrhythmias. The purpose of our study was to describe the presentation, clinical features, survival, and natural history of ARVD in a large cohort of patients from the United States. Methods and Results— The patient population included 100 ARVD patients (51 male; median age at presentation, 26 [interquartile range {IQR}, 18 to 38; range, 2 to 70] years). A familial pattern was observed in 32 patients. The most common presenting symptoms were palpitations, syncope, and sudden cardiac death (SCD) in 27%, 26%, and 23% of patients, respectively. Among those who were diagnosed while living (n=69), the median time between first presentation and diagnosis was 1 (range, 0 to 37) year. During a median follow-up of 6 (IQR, 2 to 13; range, 0 to 37) years, implantable cardioverter/defibrillators (ICD) were implanted in 47 patients, 29 of whom received an appropriate ICD discharge, including 3 patients who received the ICD for primary prevention. At follow-up, 66 patients were alive, of whom 44 had an ICD in place, 5 developed signs of heart failure, 2 had a heart transplant, and 18 were on drug therapy. Thirty-four patients died either at presentation (n=23: 21 SCD, 2 noncardiac deaths) or during follow-up (n=11: 10 SCD, 1 of biventricular heart failure), of whom only 3 were diagnosed while living and 1 had an ICD implanted. On Kaplan-Meier analysis, the median survival in the entire population was 60 years. Conclusions— ARVD patients present between the second and fifth decades of life either with symptoms of palpitations and syncope associated with ventricular tachycardia or with SCD. Diagnosis is often delayed. Once diagnosed and treated with an ICD, mortality is low. There is a wide variation in presentation and course of ARVD patients, which can likely be explained by the genetic heterogeneity of the disease.

Incidence and Prevalence of Atrial Fibrillation and Associated Mortality Among Medicare Beneficiaries, 1993–2007

Background— Atrial fibrillation (AF) is a common and costly problem among older persons. The frequency of AF increases with age, but representative national data about incidence and prevalence are limited. We examined the annual incidence, prevalence, and mortality associated with AF among older persons. Methods and Results— In a retrospective cohort study of Medicare beneficiaries 65 years and older diagnosed with AF between 1993 and 2007, we measured annual age- and sex-adjusted incidence and prevalence of AF and mortality following an AF diagnosis. Among 433 123 patients with incident AF, the mean age was 80 years, 55% were women, and 92% were white. The incidence of AF remained steady during the 14-year study period, ranging from 27.3 to 28.3 per 1000 person-years. Incidence rates were consistently higher among men and white beneficiaries. The prevalence of AF increased across the study period (mean, 5% per year) and was robust to sensitivity analyses. Among beneficiaries with incident AF in 2007, 36% had heart failure, 84% had hypertension, 30% had cerebrovascular disease, and 8% had dementia. Mortality after AF diagnosis declined slightly over time but remained high. In 2007, the age- and sex-adjusted mortality rates were 11% at 30 days and 25% at 1 year. Conclusions— Among older Medicare beneficiaries, incident AF is common and has remained relatively stable for more than a decade. Incident AF is associated with significant comorbidity and mortality; death occurs in one-quarter of beneficiaries within 1 year.

Response to Letter Regarding Article, “Renal Dysfunction as a Predictor of Stroke and Systemic Embolism in Patients With Nonvalvular Atrial Fibrillation: Validation of the R2CHADS2 Index in 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) and ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study Cohorts”

Background —We sought to define the factors associated with the occurrence of stroke and systemic embolism in a large, international atrial fibrillation (AF) trial. Methods and Results —In ROCKET AF, 14,264 patients with nonvalvular AF and creatinine clearance (CrCl) ≥30 mL/min were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards modeling was used to identify factors at randomization independently associated with the occurrence of stroke or non-central nervous system (CNS) embolism based on intention-to-treat analysis. A risk score was developed in ROCKET AF and validated in ATRIA, an independent AF patient cohort. Over a median follow-up of 1.94 years, 575 (4.0%) patients experienced primary endpoint events. Reduced CrCl was a strong, independent predictor of stroke and systemic embolism, second only to prior stroke or transient ischemic attack (TIA). Additional factors associated with stroke and systemic embolism included elevated diastolic blood pressure and heart rate, and vascular disease of the heart and limbs (C-index 0.635). A model including CrCl (R2CHADS2) improved net reclassification index (NRI) by 6.2% when compared with CHA2DS2VASc (C-statistic=0.578) and 8.2% when compared with CHADS2 (C-statistic=0.575). The inclusion of estimated glomerular filtration rate <60 and prior stroke or TIA in a model with no other covariates led to a C-statistic of 0.590. Validation of R2CHADS2 in an external, separate population improved NRI by 17.4% (95% CI 12.1-22.5%) relative to CHADS2. Conclusions —In patients with nonvalvular AF at moderate to high risk of stroke, impaired renal function is a potent predictor of stroke and systemic embolism. Stroke risk stratification in patients with AF should include renal function. Clinical Trial Registration Information —ClinicalTrials.gov; Unique identifier: [NCT00403767][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00403767&atom=%2Fcirculationaha%2Fearly%2F2012%2F12%2F03%2FCIRCULATIONAHA.112.107128.atom

Pulmonary Vein Isolation for the Maintenance of Sinus Rhythm in Patients with Atrial Fibrillation: a Meta-Analysis of Randomized Controlled Trials

Background—Catheter ablation is an established yet evolving nonpharmacologic intervention for the maintenance of sinus rhythm in patients with atrial fibrillation (AF). The efficacy and safety of pulmonary vein isolation (PVI) compared with medical therapy remain in question. Methods and Results—We conducted a meta-analysis of all randomized, controlled trials comparing PVI and medical therapy for the maintenance of sinus rhythm. The primary end point in this analysis was freedom from recurrent AF at 12 months. The relative efficacy of PVI was estimated using random-effects modeling according to intention to treat. We identified 6 trials that randomized a total of 693 patients with AF to PVI or control. PVI was associated with markedly increased odds of freedom from AF at 12 months of follow-up (n=266/344 [77%] versus n=102/346 [29%]; odds ratio, 9.74; 95% CI, 3.98 to 23.87). When we excluded the trial that only enrolled patients with persistent AF (Q-statistic, 2.485; P=0.647 after exclusion), PVI was associated with even greater odds of AF-free survival (15.78; 95% CI, 10.07 to 24.73). PVI was associated with a decreased hospitalization for cardiovascular causes (14 versus 93 per 100 person-years; rate ratio, 0.15; 95% CI, 0.10 to 0.23). Among those randomly assigned to PVI, 17% required a repeat PVI ablation before 12 months. The rate of major complications was 2.6% (n=9/344) in the catheter ablation group. Conclusions—Compared with a nonablation treatment strategy, PVI results in dramatically increased freedom from AF at 1 year. Although the procedure can be associated with major complications, the risk of these complications is comparable to other interventional procedures.

Clinical Features of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Associated With Mutations in Plakophilin-2

Background— Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited cardiomyopathy characterized by right ventricular dysfunction and ventricular arrhythmias. A recent study reported mutations in PKP2, encoding the desmosomal protein plakophilin-2, associated with ARVD/C. The purpose of our study was to validate the frequency of PKP2 mutations in another large series of ARVD/C patients and to examine the phenotypic characteristics associated with PKP2 mutations. Methods and Results— DNA from 58 ARVD/C patients was sequenced to determine the presence of mutations in PKP2. Clinical features of ARVD/C were compared between 2 groups of patients: those with a PKP2 mutation and those with no detectable PKP2 mutation. Thirteen different PKP2 mutations were identified in 25 (43%) of the patients. Six of these mutations have not been reported previously; 4 occurred in multiple, apparently unrelated, families. The mean age at presentation was lower among those with a PKP2 mutation (28±11 years) than in those without (36±16 years) (P<0.05). The age at median cumulative symptom-free survival (32 versus 42 years) and at the median cumulative arrhythmia-free survival (34 versus 46 years) was lower among patients with a PKP2 mutation than among those without a PKP2 mutation (P<0.05). Inducibility of ventricular arrhythmias on an electrophysiology study, diffuse nature of right ventricular disease, and presence of prior spontaneous ventricular tachycardia were identified as predictors of implanted cardioverter/defibrillator (ICD) intervention only among patients without a PKP2 mutation (P<0.05). Conclusions— Our study highlights the clinical relevance of PKP2 mutations in ARVD/C. Presence of a PKP2 mutation in ARVD/C correlates with earlier onset of symptoms and arrhythmia. Patients with a PKP2 mutation experience ICD interventions irrespective of the classic risk factors determining ICD intervention in ARVD/C patients.

Outcomes After Cardioversion and Atrial Fibrillation Ablation in Patients Treated With Rivaroxaban and Warfarin in the ROCKET AF Trial

OBJECTIVES This study sought to investigate the outcomes following cardioversion or catheter ablation in patients with atrial fibrillation (AF) treated with warfarin or rivaroxaban. BACKGROUND There are limited data on outcomes following cardioversion or catheter ablation in AF patients treated with factor Xa inhibitors. METHODS We compared the incidence of electrical cardioversion (ECV), pharmacologic cardioversion (PCV), or AF ablation and subsequent outcomes in patients in a post hoc analysis of the ROCKET AF (Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation) trial. RESULTS Over a median follow-up of 2.1 years, 143 patients underwent ECV, 142 underwent PCV, and 79 underwent catheter ablation. The overall incidence of ECV, PCV, or AF ablation was 1.45 per 100 patient-years (n = 321; 1.44 [n = 161] in the warfarin arm, 1.46 [n = 160] in the rivaroxaban arm). The crude rates of stroke and death increased in the first 30 days after cardioversion or ablation. After adjustment for baseline differences, the long-term incidence of stroke or systemic embolism (hazard ratio [HR]: 1.38; 95% confidence interval [CI]: 0.61 to 3.11), cardiovascular death (HR: 1.57; 95% CI: 0.69 to 3.55), and death from all causes (HR: 1.75; 95% CI: 0.90 to 3.42) were not different before and after cardioversion or AF ablation. Hospitalization increased after cardioversion or AF ablation (HR: 2.01; 95% CI: 1.51 to 2.68), but there was no evidence of a differential effect by randomized treatment (p value for interaction = 0.58). The incidence of stroke or systemic embolism (1.88% vs. 1.86%) and death (1.88% vs. 3.73%) were similar in the rivaroxaban-treated and warfarin-treated groups. CONCLUSIONS Despite an increase in hospitalization, there were no differences in long-term stroke rates or survival following cardioversion or AF ablation. Outcomes were similar in patients treated with rivaroxaban or warfarin. (An Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation [ROCKET AF]; NCT00403767).

Prophylactic Implantable Defibrillator in Patients With Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia and No Prior Ventricular Fibrillation or Sustained Ventricular Tachycardia

Background— The role of implantable cardioverter-defibrillator (ICD) in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia and no prior ventricular fibrillation (VF) or sustained ventricular tachycardia is an unsolved issue. Methods and Results— We studied 106 consecutive patients (62 men and 44 women; age, 35.6±18 years) with arrhythmogenic right ventricular cardiomyopathy/dysplasia who received an ICD based on 1 or more arrhythmic risk factors such as syncope, nonsustained ventricular tachycardia, familial sudden death, and inducibility at programmed ventricular stimulation. During follow-up of 58±35 months, 25 patients (24%) had appropriate ICD interventions and 17 (16%) had shocks for life-threatening VF or ventricular flutter. At 48 months, the actual survival rate was 100% compared with the VF/ventricular flutter–free survival rate of 77% (log-rank P=0.01). Syncope significantly predicted any appropriate ICD interventions (hazard ratio, 2.94; 95% confidence interval, 1.83 to 4.67; P=0.013) and shocks for VF/ventricular flutter (hazard ratio, 3.16; 95% confidence interval, 1.39 to 5.63; P=0.005). The positive predictive value of programmed ventricular stimulation was 35% for any appropriate ICD intervention and 20% for shocks for VF/ventricular flutter, with a negative predictive value of 70% and 74%. None of the 27 asymptomatic patients with isolated familial sudden death had appropriate ICD therapy. Twenty patients (19%) had inappropriate ICD interventions, and 18 (17%) had device-related complications. Conclusions— One fourth of patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia and no prior sustained ventricular tachycardia or VF had appropriate ICD interventions. Syncope was an important predictor of life-saving ICD intervention and is an indication for ICD. Prophylactic ICD may not be indicated in asymptomatic patients because of their low arrhythmic risk regardless of familial sudden death and programmed ventricular stimulation findings. Programmed ventricular stimulation had a low predictive accuracy for ICD therapy.

Comparative Efficacy of Dronedarone and Amiodarone for the Maintenance of Sinus Rhythm in Patients With Atrial Fibrillation

OBJECTIVES We sought to compare the efficacy and safety of dronedarone versus amiodarone for the prevention of recurrent atrial fibrillation (AF). BACKGROUND Dronedarone is a noniodinated amiodarone congener developed to maintain sinus rhythm. Few data are available to directly compare the efficacy and safety of dronedarone versus amiodarone. METHODS We conducted a systematic overview of all randomized controlled trials in which the authors evaluated dronedarone or amiodarone for the prevention of AF. The effect of amiodarone versus dronedarone was summarized by the use of indirect comparison meta-analysis and normal logistic meta-regression models. RESULTS We identified 4 placebo-controlled trials of dronedarone, 4 placebo-controlled trials of amiodarone, and 1 trial of dronedarone versus amiodarone. By using random-effects modeling, we found that there was a significant estimated reduction in recurrent AF with amiodarone versus placebo (odds ratio [OR]: 0.12; 95% confidence interval [CI]: 0.08 to 0.19) but not dronedarone versus placebo (OR: 0.79; 95% CI: 0.33 to 1.87). A normal logistic regression model incorporating all trial evidence found amiodarone superior to dronedarone (OR: 0.49; 95% CI: 0.37 to 0.63; p < 0.001) for the prevention of recurrent AF. In contrast, these models also found a trend toward greater all-cause mortality (OR: 1.61; 95% CI: 0.97 to 2.68; p = 0.066) and greater overall adverse events requiring drug discontinuation with amiodarone versus dronedarone (OR: 1.81; 95% CI: 1.33 to 2.46; p < 0.001). CONCLUSIONS Dronedarone is less effective than amiodarone for the maintenance of sinus rhythm, but has fewer adverse effects. For every 1,000 patients treated with dronedarone instead of amiodarone, we estimate approximately 228 more recurrences of AF in exchange for 9.6 fewer deaths and 62 fewer adverse events requiring discontinuation of drug.