ECG Features Associated With Adverse Cardiovascular Outcomes in Patients With Atrial Fibrillation: A Combined AFFIRM and AF-CHF Analysis.

BACKGROUND: The association between standard parameters from a simple 12-lead ECG (i.e., QRS duration and PR, JT, and QT intervals) and adverse cardiovascular outcomes (cardiovascular mortality, all-cause mortality, arrhythmic mortality, and hospitalizations) in patients with a history of atrial fibrillation (AF) has not been previously studied. METHODS AND RESULTS: A pooled analysis of patient-level data was conducted on 5,436 patients, age 68.2 ± 8.3 years, 34.8% female, with a history of non-permanent AF randomized in AFFIRM and AF-CHF trials. The predictive value of ECG parameters was assessed in AF and sinus rhythm in multivariate Cox regression models. During a follow-up of 40.8 ± 16.3 months, QRS duration >120 milliseconds was independently associated with all-cause mortality (hazard ratio [HR] 1.46, 95% confidence interval [CI; 1.21-1.76] in AF, P < 0.001), cardiovascular mortality (HR 1.75, 95% CI (1.15-2.65) in sinus rhythm, P = 0.009; HR 1.56, 95% CI [1.27-1.93] in AF, P < 0.001), arrhythmic mortality (HR 1.90, 95% CI [1.09-3.32] in sinus, P = 0.024; HR 1.84, 95% CI [1.35-2.51] in AF, P < 0.001), any hospitalization (HR 1.15, 95% CI [1.02-1.29] in AF, P = 0.027), and cardiovascular hospitalization (HR 1.21, 95% CI [1.06-1.37] in AF; P = 0.004). Increased PR interval (>200 milliseconds) was independently associated with cardiovascular (HR 1.56, 95% CI [1.11-2.21], P = 0.010) and arrhythmic (HR 1.91, 95% CI [1.14-3.18], P = 0.004) mortality. The JT and QTc intervals were not predictive of mortality. CONCLUSIONS: Simple parameters from standard ECGs are significantly and independently associated with adverse cardiovascular outcomes in patients with a history of AF.

Improved outcomes in elderly patients with metastatic castration-resistant prostate cancer treated with the androgen receptor inhibitor enzalutamide: results from the phase III AFFIRM trial.

BACKGROUND: The randomized, double-blind phase III AFFIRM trial demonstrated that enzalutamide, an oral androgen receptor inhibitor, significantly prolonged overall survival (OS) [median 18.4 versus 13.6 months (hazard ratio, HR) 0.63 (95% confidence interval, CI, 0.53-0.75); P<0.001] compared with placebo in patients with metastatic castration-resistant prostate cancer who received prior docetaxel chemotherapy. PATIENTS AND METHODS: A post hoc analysis was carried out to assess the efficacy and safety of enzalutamide on outcomes in younger (<75 years) and elderly (≥75 years) patients in the AFFIRM population. Statistics are presented by age group (<75 years, ≥75 years) for efficacy outcomes of OS, radiographic progression-free survival (rPFS), time to prostate-specific antigen (PSA) progression, PSA response, and safety. RESULTS: OS was significantly improved with enzalutamide over placebo in patients<75 years [median not yet reached versus 13.6 months; HR 0.63 (95% CI 0.52-0.78), P<0.001] and in patients ≥75 years [median 18.2 versus 13.3 months; HR 0.61 (95% CI 0.43-0.86), P=0.004], respectively. rPFS was similarly improved in both the younger [HR 0.45 (95% CI 0.38-0.53), P<0.001] and elderly patient cohorts [HR 0.27 (95% CI 0.20-0.37), P<0.001] relative to placebo, as were time to PSA progression and PSA response. Adverse events (AEs) were similar between the two enzalutamide age groups, with the exception of an increase in patients≥75 years in the rates of all grade peripheral edema (22.1% versus 12.5%), fatigue (39.7% versus 31.6%), and diarrhea (26.6% versus 19.6%). The overall grade≥3 AE rates were low with no major difference in frequency or severity between age groups or treatment arms. Five patients were reported with seizure events; three patients<75 years and two patients ≥75 years. CONCLUSIONS: Enzalutamide significantly improves outcomes in both younger (<75 years) and elderly patients (≥75 years), with comparable safety and tolerability.

Efficacy of amiodarone in patients with atrial fibrillation with and without left ventricular dysfunction: a pooled analysis of AFFIRM and AF-CHF trials.

INTRODUCTION: Despite amiodarone's established safety profile in the setting of heart failure, it is unknown whether its impact on cardiovascular outcomes in patients with atrial fibrillation is modulated by left ventricular function. METHODS AND RESULTS: A pooled analysis of 3,307 patients (age 68.0 ± 0.2 years; 31.1% female) enrolled in AFFIRM and AF-CHF trials was conducted to assess the effect of rhythm control with amiodarone on cardiovascular outcomes, according to left ventricular systolic function. In amiodarone-treated patients (N = 1,107), freedom from recurrent atrial fibrillation was 84% and 45% at 1 and 5 years, respectively, with no differences according to left ventricular function (P = 0.8754). Similarly, the adjusted proportion of time spent in atrial fibrillation (15.0 ± 1.8%) did not vary according to ventricular function (P = 0.6094). Over 40.0 ± 0.3 months of follow-up, 1,963 (59.4%) patients required at least one hospitalization, 1,401 (42.6%) of whom had cardiovascular-related hospitalizations. Adjusted all-cause and cardiovascular hospitalization rates were similar with amiodarone versus rate control in all patients and in subgroups with and without severe left ventricular dysfunction. A total of 729 (22.0%) patients died, 498 (15.1%) from cardiovascular causes. Adjusted all-cause and cardiovascular mortality rates were similar with amiodarone versus rate control overall and in subgroups with and without severe left ventricular dysfunction. CONCLUSION: Amiodarone's efficacy in maintaining sinus rhythm and reducing the burden of atrial fibrillation is similar in the presence or absence of severe left ventricular dysfunction. Rhythm control with amiodarone is associated with comparable hospitalization and mortality rates to rate control in patients with and without left ventricular dysfunction.

An update on enzalutamide in the treatment of prostate cancer.

Enzalutamide is an oral androgen receptor inhibitor that targets multiple steps in the androgen receptor signaling pathway. In the randomized phase III AFFIRM study, significant improvements in survival versus placebo were observed when enzalutamide was used as a treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) following prior treatment with docetaxel. Additional benefits included significant delay in time to first skeletal-related event, and improvement in several measures of pain and health-related quality of life. Treatment effects were consistent across all prespecified subgroups. The phase III PREVAIL study evaluated enzalutamide versus placebo in patients with mCRPC who had not received chemotherapy. Enzalutamide significantly decreased the risk of radiographic progression and death. There were also significant improvements in all secondary and prespecified exploratory endpoints, including delayed initiation of chemotherapy, reduction in risk of first skeletal-related event and a high percentage of patients with objective response compared with placebo. Enzalutamide was also studied in hormone naïve patients (as monotherapy) in a small, open-label phase II study in patients with prostate cancer who were eligible for androgen-deprivation therapy. A prostate-specific antigen (PSA) response, defined as ⩾80% decline in PSA level from baseline at week 25, was achieved in 92.5% of patients. Long-term follow up is ongoing. Despite differences between these three trials, enzalutamide displayed a favorable safety profile in all three patient populations. Similar rates of adverse events between the enzalutamide and placebo groups were observed in AFFIRM and PREVAIL, with fatigue, diarrhea, back pain and hot flashes being more common with enzalutamide than with placebo. Hypertension was reported at a higher rate in the enzalutamide group than in the placebo group in PREVAIL. Breast-related disorders associated with enzalutamide treatment were also reported in the Monotherapy trial. Few seizures were reported in any trial. Enzalutamide is being studied in several early disease state populations.

Efficacy outcomes by baseline prostate-specific antigen quartile in the AFFIRM trial.

BACKGROUND: Enzalutamide significantly prolonged the survival of men with metastatic castration-resistant prostate cancer (PCa) after docetaxel in the randomised, phase 3, double-blind, placebo-controlled, multinational Patients with Progressive Castration-Resistant Prostate Cancer Previously Treated with Docetaxel-Based Chemotherapy (AFFIRM) trial (NCT00974311). Prostate-specific antigen (PSA) is commonly used as a marker of PCa disease burden, and the relationship of baseline PSA level to consequent treatment effect is of clinical interest. OBJECTIVE: Exploratory analysis to evaluate any differences in patient characteristics and efficacy outcomes by baseline PSA level in the AFFIRM trial. DESIGN, SETTING, AND PARTICIPANTS: Post hoc subanalysis of all randomised patients (n=1199) from the AFFIRM trial. INTERVENTION: Participants were randomly assigned in a two-to-one ratio to receive oral enzalutamide 160 mg/d or placebo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The major clinical efficacy end points were overall survival (OS), radiographic progression-free survival (rPFS), and time to PSA progression (TTPP) versus placebo; baseline characteristics, treatment duration, and subsequent antineoplastic therapy were compared by baseline PSA quartile. RESULTS AND LIMITATIONS: Baseline PSA quartiles corresponded to the following PSA groups: <40 ng/ml (n=299), 40 to <111 ng/ml (n=300), 111 to <406 ng/ml (n=300), and ≥406 ng/ml (n=300). Enzalutamide consistently improved OS, rPFS, and TTPP compared with placebo across all subgroups, regardless of baseline PSA level. Hazard ratios for improvements in OS were 0.55 (95% confidence interval [CI], 0.36-0.85), 0.69 (95% CI, 0.47-1.02), 0.73 (95% CI, 0.53-1.01), and 0.53 (95% CI, 0.39-0.73) for PSA groups 1-4, respectively. The post hoc design of this analysis was not statistically powered to assess the relationship between baseline PSA and clinical efficacy outcomes. CONCLUSIONS: This post hoc analysis of the AFFIRM trial demonstrates consistent benefits in OS, rPFS, and TTPP with enzalutamide regardless of baseline disease severity, as assessed by PSA. PATIENT SUMMARY: Exploratory post hoc analysis of the AFFIRM trial showed that enzalutamide improves overall survival, radiographic progression-free survival, and time to prostate-specific antigen progression compared with placebo regardless of baseline disease severity, as assessed by prostate-specific antigen. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00974311.

Evidence for the efficacy of enzalutamide in postchemotherapy metastatic castrate-resistant prostate cancer.

The treatment of metastatic castrate-resistant prostate cancer (mCRPC) has evolved rapidly with the recent approval of a number of treatments and agents, including docetaxel, sipuleucel T, abiraterone, cabazitaxel, and enzalutamide. Enzalutamide (previously MDV-3100) is a novel oral androgen receptor inhibitor that targets multiple steps in the androgen receptor signaling pathway. The randomized phase III AFFIRM study demonstrated significant improvements in a number of efficacy endpoints, including the primary endpoint of overall survival and secondary endpoints of progression-free survival, and time to prostate-specific antigen progression in patients with progressive mCRPC who had received prior treatment with docetaxel. Enzalutamide was well tolerated and there were comparable incidences of grade 3 or greater adverse events reported for the enzalutamide and placebo control arms in AFFIRM. Unlike some other treatments for mCRPC, enzalutamide does not require administration with steroids. The ongoing randomized phase III PREVAIL trial will investigate the efficacy and safety of enzalutamide in chemotherapy-naïve patients with mCRPC. Additional trials are investigating the use of enzalutamide in a number of disease settings.