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Introduction Atrial Fibrillation (AF) is associated with increased risk of cardiovascular (CV) morbidity and mortality. Heart Failure (HF) represents the most common CV complication, more common than thromboembolic events. Purpose We aimed to determine clinical factors associated with HF hospitalization and mortality in a contemporary cohort of patients with AF without previous history of HF. Methods The Effective Anticoagulation with Factor Xa Next Generation in AF–Thrombolysis in Myocardial Infarction 48 (ENGAGE-AF TIMI 48) study tested the oral factor Xa inhibitor edoxaban in comparison with warfarin for the prevention of stroke or systemic embolism, in 21,105 patients with AF. We assessed the composite endpoint of HF hospitalization, death due to HF or sudden cardiac death in 8981 patients without a history of HF. Cox proportional hazard models were used to evaluate the significant clinical predictors associated with the endpoint of interest. Results Over a median follow-up of 2.8 years, 589 patients (6.5%) experienced the composite endpoint. Older patients, cardiovascular risk factors (hypertension, diabetes, heart valve disease), history of stroke and coronary artery disease, impaired renal function (ClCr ≤50 ml/min), heart rate at baseline and diuretic use were associated with increased risk of the composite endpoint (model c-statistic 0.66) (Figure 1). Outcomes were not affected by randomization to edoxaban or warfarin. In patients with available cardiac-derived biomarkers, elevated levels of both NT-proBNP and Troponin I were significantly associated with the endpoint after adjustment for the clinical predictors (Figure 1). The addition of the biomarkers to clinical predictors enhanced risk estimation (c-statistics 0.69, NRI 0.40, IDI 0.01, all p Figure 1 Conclusions HF hospitalization and mortality are important complications in AF patients without a history of HF. The addition of cardiac biomarkers to clinical characteristics enhances risk estimation. These findings may improve risk stratification.

Aims To investigate the relationship between body mass index (BMI) and outcomes in patients with atrial fibrillation (AF). Methods and results In the ENGAGE AF-TIMI 48 trial, patients with AF were randomized to warfarin (international normalized ratio 2.0–3.0) or edoxaban. The cohort (N = 21 028) included patients across BMI categories (kg/m2): underweight (18.5 kg/m2, while time in therapeutic range for warfarin improved significantly as BMI increased (P Conclusion An increased BMI was independently associated with a lower risk of stroke/SEE, better survival, but increased risk of bleeding. The efficacy and safety profiles of edoxaban were similar across BMI categories ranging from 18.5 to >40.

Background Patients with atrial fibrillation (AF) who interrupt anticoagulation are at high risk of thromboembolism and death. Methods and results Patients enrolled in the ENGAGE AF-TIMI 48 trial (randomized comparison of edoxaban vs. warfarin) who interrupted study anticoagulant for >3 days were identified. Clinical events (ischemic stroke/systemic embolism, major cardiac and cerebrovascular events [MACCE]) were analyzed from day 4 after interruption until day 34 or study drug resumption. During 2.8 years median follow-up, 13,311 (63%) patients interrupted study drug for >3 days. After excluding those who received open-label anticoagulation during the at-risk window, the population for analysis included 9148 patients. The rates of ischemic stroke/systemic embolism and MACCE post interruption were substantially greater than in patients who never interrupted (15.42 vs. 0.26 and 60.82 vs. 0.36 per 100 patient-years, respectively, p adj adj 2.75; 95% CI 2.02–3.74, p Conclusion Interruption of study drug was frequent in patients with AF and was associated with a substantial risk of major cardiac and cerebrovascular events over the ensuing 30 days. This risk was particularly high in patients who interrupted as a result of an adverse event; these patients deserve close monitoring and resumption of anticoagulation as soon as it is safe to do so.

Background Digoxin is widely used in patients with atrial fibrillation despite the lack of randomized controlled trials. Observational studies report conflicting results regarding its association with mortality, perhaps because of residual confounding by the presence of heart failure ( HF ). Methods and Results In the ENGAGE AF ‐ TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation‐Thrombolysis in Myocardial Infarction 48) trial, clinical outcomes of patients with atrial fibrillation with and without HF were examined by baseline digoxin use during a median follow‐up of 2.8 years. HF was defined at baseline as prior or current clinical stage C or D HF . Of 21 105 patients enrolled, 6327 (30%) were treated with digoxin at baseline. Among patients without HF (n=8981), digoxin use (20%) was independently associated with sudden cardiac death (adjusted hazard ratio, 1.51; 95% CI, 1.10–2.08), with no significant interaction by age, sex, left ventricular ejection fraction, renal function, or concomitant medications ( P >0.05 for each). Consistent results were observed using propensity matching (adjusted hazard ratio for sudden cardiac death, 1.90; 95% CI , 1.36–2.65). Among patients with HF (n=12 124), digoxin use (37%) was associated with an increase in all‐cause death, cardiovascular death, sudden cardiac death, and death caused by HF /cardiogenic shock ( P Conclusions In this observational analysis of patients with atrial fibrillation without investigator‐reported HF , digoxin use was significantly associated with sudden cardiac death. While residual confounding cannot be excluded, the association between digoxin use and worse clinical outcomes highlights the need to examine digoxin use, particularly when prescribed to control heart rate in patients with atrial fibrillation in a randomized trial. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 00781391.

Left Atrial (LA) dysfunction and left ventricular (LV) filling pressure are known predictors of cardiovascular (CV) outcome. However their prognostic relevance to predict CV events in Atrial Fibrillation (AF) population is not completely understood In a prospective echocardiographic substudy (971

Background Recent findings suggest that atrial fibrillation is associated with sudden cardiac death ( SCD ). We examined the incidence, characteristics, and factors associated with SCD in patients with atrial fibrillation. Methods and Results SCD was defined as witnessed death ≤60 minutes from the onset of new symptoms or unwitnessed death 1 to 24 hours after being observed alive, without another known cause of death. Predictors of SCD were examined using multivariate competing risks models. Over 2.8 years (median), 2349 patients died (40.5 per 1000 patient‐years), of which 1668 (71%) were cardiovascular deaths. SCD was the most common cause of cardiovascular death (n=749; median age 73 years; 70.6% male). Most SCD events occurred out of hospital (92.8%) and without prior symptoms (66.0%). Predictors of SCD included low ejection fraction, heart failure, and prior myocardial infarction ( P SCD , but not of other causes of death, included male sex, electrocardiographic left ventricular hypertrophy, higher heart rate, nonuse of beta blockers, and use of digitalis. The latter was associated with SCD in patients with or without heart failure (adjusted hazard ratio 1.55 [95% CI 1.29–1.86] and 1.56 [95% CI 1.14–2.11], respectively; P interaction =0.73). The rate of SCD was numerically but not statistically lower with edoxaban (1.20% per year with lower dose edoxaban; 1.28% per year with higher dose edoxaban) compared with warfarin (1.40% per year). Conclusion SCD is the most common cause of cardiovascular death in patients with atrial fibrillation and has several distinct predictors, some of which are modifiable. These findings may be considered in planning research and treatment strategies for patients with atrial fibrillation. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 00781391.

Background: Edoxaban (edo), a QD oral direct factor Xa inhibitor, is non-inferior to warfarin for preventing stroke or systemic embolism (SE) in mod-high risk pts with AF. Due to reduced protection from ischemic stroke in pts with CrCl >95 ml/min, the US FDA approved the higher dose edo regimen in pts with AF and a CrCl 15-95 ml/min (60mg QD if CrCl 50-95 ml/min; 30mg QD if CrCl 15-50 ml/min) without dose reduction for weight < 60 kg or use of P-glycoprotein (P-gp) inhibitors. We report here for the first time the clinical characteristics, efficacy and safety of the FDA-approved population. Methods: From the ENGAGE AF-TIMI 48 trial population, we excluded pts who received the lower-dose edo regimen (30/15 mg), had CrCl >95 ml/min, or were dose-reduced for weight≤ 60 kg or potent P-gp use. The 1° efficacy endpoint was stroke/SE and principal safety endpoint was major bleeding. Efficacy data are from the ITT cohort in the overall study period, unless otherwise specified. Results: There were 9387 pts with CrCl 15-95 ml/min randomized to either warfarin or edo 60/30 mg per the FDA label followed for 2.8 yrs (median). These pts were older (74 vs 64 yrs), more likely women (40 vs 33%), and had higher CHADS 2 and HAS-BLED scores compared to pts not included in the FDA label, but were balanced by randomization group. The annualized rate of stroke/SE on-treatment was 1.11% with edo vs. 1.72% with warfarin (HR vs. warfarin 0.64 [0.51-0.81], p Conclusion: Among high risk pts in the ENGAGE AF-TIMI 48 trial who represent the FDA approval population and dosing regimen of edo, treatment with edo 60/30 mg is superior to warfarin in the prevention of stroke/SE and reduces major bleeding, intracranial hemorrhage, and CV death.

Background Edoxaban is a specific anti-Xa inhibitor that, in comparison to warfarin, has been found to be noninferior for the prevention of stroke or systemic embolism (SSE) and to reduce bleeding significantly in patients with nonvalvular atrial fibrillation (AF). The US Food and Drug Administration (FDA) approved the higher-dose edoxaban regimen (60/30 mg) in patients with AF and a creatinine clearance of ≤95 mL/min. We report for the first time the clinical characteristics, efficacy, and safety of the FDA-approved population in the ENGAGE AF–-TIMI 48 trial. Methods The patients included had been treated with either warfarin or edoxaban 60/30 mg and had a creatinine clearance of ≤95 mL/min. The primary efficacy was SSE, and the principal safety end point was major bleeding (International Society on Thrombosis and Haemostasis classification). Median follow-up was 2.8 years. Results Patients in the FDA-approved cohort were older, were more likely female, and had higher CHADS 2 and HAS-BLED scores, as compared with patients not included in the FDA label. The primary end point occurred in 1.63%/y with edoxaban vs 2.02%/y with warfarin (hazard ratio [HR] 0.81, 95% CI 0.67-0.97, P = .023). Edoxaban significantly reduced the rate of hemorrhagic stroke (HR 0.47, 95% CI 0.31-0.72, P P = .015). Ischemic stroke rates were similar between the treatment groups (1.31%/y vs 1.39%/y, P = .97). Major bleeding was significantly lower with edoxaban (3.16%/y vs 3.77%/y; HR 0.84, 95% CI 0.72-0.98, P = .023). Conclusion In the FDA-approved cohort of the ENGAGE AF–-TIMI 48 trial, treatment with edoxaban 60/30 mg was superior to warfarin in the prevention of SSE and significantly reduced cardiovascular death and bleeding, especially fatal bleeding and hemorrhagic stroke.

BACKGROUND: Atrial fibrillation (AF) and heart failure (HF) have emerged as the two epidemics of cardiovascular (CV) disease. The prevalence of AF increases with the severity of HF and contributes to HF disability. Among patients treated with vitamin K antagonists (VKAs), symptomatic HF is an independent risk factor for lower time in therapeutic range (TTR), which reduces the efficacy and safety of VKAs. METHODS: In the ENGAGE AF-TIMI 48 trial, both once-daily regimens of the direct oral factor Xa inhibitor edoxaban [high (HDE) and low dose (LDE)], were non inferior to warfarin (W) for prevention of stroke and systemic embolic events (SEE) in patients with AF and were associated with lower rates of bleeding. We evaluated the safety and the efficacy of edoxaban compared with W in patients with HF presenting with different severity of functional limitation (NYHA class). RESULTS: Among 21,105 patients enrolled 8,981(43%) had no history of HF, 9,489 (45%) had history of HF and a NYHA class I-II, whereas 2,635 (13%) had symptomatic HF with NYHA class III-IV. Patients with more severe HF symptoms had higher rates of stroke SEE, CV death and CV hospitalization (p CONCLUSION: The relative efficacy and safety of both edoxaban regimens, compared to well-managed W in AF patients with HF, was consistent irrespective of the severity of functional class.

Aims Edoxaban is an oral, once-daily factor Xa inhibitor that is non-inferior to well-managed warfarin in patients with atrial fibrillation (AF) for the prevention of stroke and systemic embolic events (SEEs). We examined the efficacy and safety of edoxaban vs. warfarin in patients who were vitamin K antagonist (VKA) naive or experienced. Methods and results ENGAGE AF-TIMI 48 randomized 21 105 patients with AF at moderate-to-high risk of stroke to once-daily edoxaban vs. warfarin. Subjects were followed for a median of 2.8 years. The primary efficacy endpoint was stroke or SEE. As a pre-specified subgroup, we analysed outcomes for those with or without prior VKA experience (>60 consecutive days). Higher-dose edoxaban significantly reduced the risk of stroke or SEE in patients who were VKA naive [hazard ratio (HR) 0.71, 95% confidence interval (CI) 0.56–0.90] and was similar to warfarin in the VKA experienced (HR 1.01, 95% CI 0.82–1.24; P interaction = 0.028). Lower-dose edoxaban was similar to warfarin for stroke or SEE prevention in patients who were VKA naive (HR 0.92, 95% CI 0.73–1.15), but was inferior to warfarin in those who were VKA experienced (HR 1.31, 95% 1.08–1.60; P interaction = 0.019). Both higher-dose and lower-dose edoxaban regimens significantly reduced the risk of major bleeding regardless of prior VKA experience ( P interaction = 0.90 and 0.71, respectively). Conclusion In patients with AF, edoxaban appeared to demonstrate greater efficacy compared with warfarin in patients who were VKA naive than VKA experienced. Edoxaban significantly reduced major bleeding compared with warfarin regardless of prior VKA exposure.

Background: Recent findings suggest that atrial fibrillation is associated with sudden cardiac death (SCD). We examined the incidence, characteristics, and factors associated with SCD in patients with atrial fibrillation. Methods and Results: SCD was defined as witnessed death ≤60 minutes from the onset of new symptoms or unwitnessed death 1 to 24 hours after being observed alive, without another known cause of death. Predictors of SCD were examined using multivariate competing risks models. Over 2.8 years (median), 2349 patients died (40.5 per 1000 patient‐years), of which 1668 (71%) were cardiovascular deaths. SCD was the most common cause of cardiovascular death (n=749; median age 73 years; 70.6% male). Most SCD events occurred out of hospital (92.8%) and without prior symptoms (66.0%). Predictors of SCD included low ejection fraction, heart failure, and prior myocardial infarction (P

The effect of the barbiturate T2000 (1,3-dimethoxymethyl-5,5-diphenyl-barbituric acid; DMMDPB) on essential tremor, given in twice daily doses of 400 and 300 mg, was assessed in two brief, randomized, placebo-controlled, parallel-group, double-blinded, single-center trials in 12 and 22 patients, respectively. These trials represent the first clinical use of T2000 for a specific indication. The primary endpoint was the change in the mean scores of the treated and control groups based on the Fahn-Tolosa-Marin tremor scale. In the first study of 12 patients treated with 400 mg or placebo twice daily for 14 days, the mean change from baseline at day 14 was 19.3 (P < 0.0001) in the treated group and 9.0 (P = 0.0121) in the control group. Using a two-factor mixed ANOVA model to evaluate within group and between group changes, the effect of T2000 was significantly different from that of the placebo group (P = 0.03). In the second study of 22 patients treated with 300 mg of T2000 or placebo twice daily for 20 days, statistically significant changes were seen in treated patients compared to baseline, but the ANOVA model did not demonstrate a significant treatment effect of T2000 compared to placebo. When the treated groups from each study are compared, the 800-mg daily group is significantly different from the 600-mg daily group (P = 0.02). Some treated patients in each study, but no placebo patients, experienced marked improvement. These results support further evaluation of T2000 in the treatment of essential tremor.

The effects of amrinone, dobutamine, and a combination of the two drugs on peak positive left ventricular dP/dt and left ventricular performance were evaluated in 11 patients with chronic congestive heart failure. When administered alone, both dobutamine (10.9 micrograms/kg/min) and intravenous amrinone (1.9 mg/kg/min) significantly increased left ventricular dP/dt and performance. When compared with dobutamine alone, the addition of amrinone resulted in further increases in left ventricular dP/dt and cardiac index (to 1319 +/- 419 from 1202 +/- 376 mm Hg/sec, p less than .002, and to 3.56 +/- 0.78 from 3.04 +/- 0.67 liters/min/m2, p less than .01, respectively). The combination also induced a further reduction in left ventricular end-diastolic pressure (to 15.3 +/- 11.3 from 18.2 +/- 10.3 mm Hg, p less than .05) when compared with amrinone alone. The combination of dobutamine and amrinone increased heart rate slightly when compared with either drug alone, but did not further reduce systemic arterial pressure when compared with amrinone alone. The dose-response curve of left ventricular dP/dt and performance during titration of dobutamine with and without the addition of intravenous amrinone was evaluated in seven patients. The addition of amrinone to any dose of dobutamine produced higher cardiac index and lower systemic vascular resistance than dobutamine or amrinone alone. Thus, when compared with dobutamine alone in patients with chronic congestive heart failure, the addition of intravenous amrinone to dobutamine results in an additive improvement in left ventricular performance throughout the dose range.

Acute and chronic hemodynamic and clinical responses to milrinone, a new oral inotrope-vasodilator agent, were evaluated prospectively in 37 patients with severe congestive heart failure. The majority of patients (n = 31) had not responded to prior vasodilator therapy, with a substantial number (n = 8) requiring intravenous inotropic support at the time of initial study. All patients showed acute hemodynamic improvement with oral milrinone, and an optimal maintenance dose was chosen for each patient during dose-ranging studies (average dose 48 mg/day). Milrinone was discontinued before follow-up hemodynamic study in 12 patients (because of worsening congestive heart failure in 6 patients, sudden death in 3 patients, arrhythmia in 1 patient and refusal by 2 patients).Hemodynamic effects of milrinone both acutely and after chronic therapy (average 37 days) were compared in the remaining 25 patients. Acutely, mean cardiac index increased from 1.9 ± 0.5 to 2.5 ± 0.5 liters/min per m2(p < 0.001), and mean pulmonary capillary wedge pressure decreased from 28 ± 9 to 18 ± 8 mm Hg (p < 0.001). When oral milrinone was readministered after chronic therapy, mean cardiac index increased from 1.9 < 0.5 to 2.5 < 1.7 liters/min per m2(p < 0.001), and pulmonary capillary wedge pressure decreased from 27 ± 8 to 20 ± 8 mm Hg (p < 0.001) at 1 hour.New York Heart Association functional class improved in 18 of the 25 patients treated over a long-term period (mean 5.5 ± 2.3 months). No major adverse side effects were observed with chronic therapy; however, 23 patients developed fluid retention requiring increased doses of diuretic drugs. The cumulative survival rate at 6 months for the entire group was 34%. Hence, milrinone appears to produce sustained hemodynamic and clinical improvement in many patients with severe refractory chronic heart failure, but overall mortality remains high.

To determine the magnitude and time course of the optimal acute hemodynamic response to oral milrinone, an ascending dose range study was performed in 34 patients with severe chronic congestive heart failure (2.5 to 10 mg, n = 21; 7.5 to 15 mg, n = 13). With the 7.5- and 10-mg doses in both groups, cardiac index increased 26%, pulmonary capillary wedge pressure decreased 25% and systemic vascular resistance decreased 20%, with peak effect at 90 minutes. The hemodynamic improvement with 10 mg was sufficient to normalize cardiac index in 29% of patients. There was a clear dose-response relation, with the largest increases of cardiac index seen with the 15-mg dose (1.67 +/- 0.10 to 2.31 +/- 0.11; p less than 0.005). This dose-response relation was confirmed by the correlation of drug levels and change in cardiac index. However, some patients had significant hypotension and tachycardia with the 15-mg dose. Thus, although 10 mg appears to be optimal for most patients, the dose of milrinone should be individualized for all patients.

We measured systemic hemodynamics, regional blood flow, and neurohormonal parameters in 13 patients with severe chronic congestive heart failure before and after 1 month of therapy with oral milrinone, a bipyridine cardiotonic agent. After milrinone there were significant reductions in pulmonary wedge pressure (27 ± 2 to 19 ± 3 mm Hg; P < 0.02) and systemic vascular resistance (1866 ± 152 to 1393 ± 93 dyne · sec/cm5; P < 0.05) that were associated with increases in cardiac index (1.85 ± 0.15 to 2.47 ± 0.20 L/min/m2; P < 0.02). There was a marked improvement in forearm blood flow (1.98 ± 0.14 to 3.02 ± 0.16 ml/min/dl; P < 0.01) and a reduction in forearm vascular resistance (45 ± 3 to 30 ± 3 U; P