Clinical trial designs to assess treatment effects on glomerular filtration rate decline.

Glomerular filtration rate (GFR) decline is used as surrogate endpoint for kidney failure. Interventions that reduce chronic kidney disease (CKD) progression often exert acute GFR reductions which differ from their long-term benefits and complicate the estimation of long-term benefit. Here, we assessed the utility of two alternative trial designs (wash-out design and active run-in randomized withdrawal design) that attempt to exclude the impact of acute effects. Post-hoc analyses of two clinical trials that characterized the effect of an intervention with acute reductions in GFR were conducted. The two trials included a wash-out period (EMPAREG-Outcome testing empagliflozin vs placebo) or an active run-in period with a randomized withdrawal (SONAR testing atrasentan vs placebo). We compared the drug effect on GFR decline calculated from the first on-treatment visit to the end-of-treatment (chronic effect in a standard randomized trial design) with GFR change calculated from randomization to end-of-wash-out, or GFR change from treatment specific baseline GFR values (GFR at start-of-run-in for placebo and end-of-run-in for atrasentan) until end-of-treatment. The effect of empagliflozin versus placebo on chronic GFR slope was 1.72 (95% confidence interval 1.49-1.94) mL/min/1.73m2 /year, similar to total GFR decline from baseline to the end of wash-out period using a linear mixed model 1.64 (1.44-1.85) mL/min/1.73m2 /year). The effect of atrasentan versus placebo on chronic GFR slope was 0.72 (0.32-1.11) mL/min/1.73m2 /year, similar to total slope from a single slope model when estimated from treatment specific baseline GFR values 0.77 (0.39-1.14) mL/min/1.73m2 /year). Statistical power of the two designs outperformed the standard randomized design. Thus, wash-out and active-run-in randomized-withdrawal trial designs are appropriate models to compute treatment effects on GFR decline.

Validity and Utility of a Hierarchical Composite End Point for Clinical Trials of Kidney Disease Progression: A Review.

Clinical trials in nephrology often use composite end points comprising clinical events, such as onset of ESKD and initiation of kidney function replacement therapy, along with a sustained large ( e.g. , ≥50%) decrease in GFR. Such events typically occur late in the disease course, resulting in large trials in which most participants do not contribute clinical events. In addition, components of the end point are considered of equal importance; however, their clinical significance varies. For example, kidney function replacement therapy initiation is likely to be clinically more meaningful than GFR decline of ≥50%. By contrast, hierarchical composite end points (HCEs) combine multiple outcomes and prioritize each patient's most clinically relevant outcome for inclusion in analysis. In this review, we consider the use of HCEs in clinical trials of CKD progression, emphasizing the potential to combine dichotomous clinical events such as those typically used in CKD progression trials, with the continuous variable of GFR over time, while ranking all components according to clinical significance. We consider maraca plots to visualize overall treatment effects and the contributions of individual components, discuss the application of win odds in kidney HCE trials, and review general design considerations for clinical trials for CKD progression with kidney HCE as an efficacy end point.

Roxadustat Versus Epoetin Alfa for Treating Anemia in Patients with Chronic Kidney Disease on Dialysis: Results from the Randomized Phase 3 ROCKIES Study.

BACKGROUND: Concerns regarding cardiovascular safety with current treatments for anemia in patients with dialysis-dependent (DD)-CKD have encouraged the development of alternatives. Roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, stimulates erythropoiesis by increasing endogenous erythropoietin and iron availability. METHODS: In this open-label phase 3 study, patients with DD-CKD and anemia were randomized 1:1 to oral roxadustat three times weekly or parenteral epoetin alfa per local clinic practice. Initial roxadustat dose depended on erythropoiesis-stimulating agent dose at screening for patients already on them and was weight-based for those not on them. The primary efficacy end point was mean hemoglobin change from baseline averaged over weeks 28‒52 for roxadustat versus epoetin alfa, regardless of rescue therapy use, tested for noninferiority (margin, -0.75 g/dl). Adverse events (AEs) were assessed. RESULTS: Among 2133 patients randomized (n=1068 roxadustat, n=1065 epoetin alfa), mean age was 54.0 years, and 89.1% and 10.8% were on hemodialysis and peritoneal dialysis, respectively. Mean (95% confidence interval) hemoglobin change from baseline was 0.77 (0.69 to 0.85) g/dl with roxadustat and 0.68 (0.60 to 0.76) g/dl with epoetin alfa, demonstrating noninferiority (least squares mean difference [95% CI], 0.09 [0.01 to 0.18]; P<0.001). The proportion of patients experiencing ≥1 AE and ≥1 serious AE was 85.0% and 57.6% with roxadustat and 84.5% and 57.5% with epoetin alfa, respectively. CONCLUSIONS: Roxadustat effectively increased hemoglobin in patients with DD-CKD, with an AE profile comparable to epoetin alfa. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Safety and Efficacy Study of Roxadustat to Treat Anemia in Patients With Chronic Kidney Disease, on Dialysis. CLINICALTRIALS: gov Identifier: NCT02174731.

Retraction notice to "Pooled Analysis of Roxadustat for Anemia in Patients With Kidney Failure Incident to Dialysis." Kidney Int Rep. 2021;6:613-623.

[This retracts the article DOI: 10.1016/j.ekir.2020.12.018.].

Efficacy and Cardiovascular Safety of Roxadustat for Treatment of Anemia in Patients with Non-Dialysis-Dependent CKD: Pooled Results of Three Randomized Clinical Trials.

BACKGROUND AND OBJECTIVES: We evaluated the efficacy and cardiovascular safety of roxadustat versus placebo by analyzing data pooled from three phase 3 studies of roxadustat in patients with non-dialysis-dependent CKD and CKD-related anemia. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In the three phase 3, double-blind studies of roxadustat versus placebo evaluating the treatment of CKD-related anemia in patients not requiring dialysis, the primary efficacy end point was mean change from baseline in hemoglobin averaged over weeks 28-52, regardless of rescue therapy. The primary cardiovascular safety end point was a composite measure of major adverse cardiovascular events (MACE; all-cause mortality, myocardial infarction, stroke). MACE plus (MACE+; MACE plus unstable angina and heart failure requiring hospitalization) and all-cause mortality were key secondary safety end points. These safety end points were adjudicated. RESULTS: A total of 4277 patients with non-dialysis-dependent CKD were randomized (roxadustat, n=2391; placebo, n=1886). Baseline characteristics were comparable between groups; the mean (SD) hemoglobin was 9.1 (0.7) g/dl and mean eGFR was 20 (12) ml/min per 1.73 m2. Patients treated with roxadustat versus those treated with placebo showed a mean change from baseline in hemoglobin averaged over weeks 28-52, regardless of rescue therapy, of 1.9 versus 0.2 g/dl, a treatment difference of 1.7 (95% confidence interval [95% CI], 1.7 to 1.8). Roxadustat reduced the need for red blood cell transfusion in the first 52 weeks versus placebo (6.1 versus 20.4 per 100 patient-exposure years, respectively; hazard ratio [HR], 0.26; 95% CI, 0.21 to 0.32). There were no increased risks of MACE (HR, 1.10; 95% CI, 0.96 to 1.27), MACE+ (HR, 1.07; 95% CI, 0.94 to 1.21), all-cause mortality (HR, 1.08; 95% CI, 0.93 to 1.26), or individual MACE+ components in patients treated with roxadustat versus those treated with placebo. CONCLUSIONS: Roxadustat was more effective than placebo at increasing hemoglobin in patients with non-dialysis-dependent CKD and anemia, while decreasing transfusion rate and being noninferior to placebo with respect to risk of MACE. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: A Study of FG-4592 for the Treatment of Anemia in Chronic Kidney Disease Patients Not Receiving Dialysis, NCT01750190; Roxadustat in the Treatment of Anemia in Chronic Kidney Disease Patients Not Requiring Dialysis (ALPS), NCT01887600; Safety and Efficacy Study of Roxadustat to Treat Anemia in Patients With Chronic Kidney Disease (CKD), Not on Dialysis, NCT02174627.

Pooled Analysis of Roxadustat for Anemia in Patients With Kidney Failure Incident to Dialysis.

INTRODUCTION: Erythropoiesis-stimulating agents are associated with increased cardiovascular risk when higher doses are used toward higher hematocrit targets. Patients new to dialysis are at higher risk for morbidity and mortality. Systematic evaluation of this population was predefined in the roxadustat clinical development program. Roxadustat is a hypoxia-inducible prolyl hydroxylase inhibitor. METHODS: Data were pooled from 3 phase 3, randomized, open-label, active-controlled trials. Eligible adults had kidney failure and initiated dialysis for 2 weeks to ≤ 4 months prior to randomization to roxadustat or epoetin alfa. Efficacy was assessed as mean change in hemoglobin from baseline averaged over weeks 28 to 52, regardless of rescue therapy. Key cardiovascular safety endpoints were major adverse cardiovascular events (MACE; all-cause mortality [ACM], myocardial infarction, and stroke), and MACE+ (MACE plus unstable angina or congestive heart failure requiring hospitalization), and ACM. RESULTS: This study included 1530 patients with kidney failure incident to dialysis. Mean (SD) changes in hemoglobin from baseline averaged over weeks 28 to 52, regardless of rescue therapy, were 2.12 (1.45) versus 1.91 (1.42) g/dl in the roxadustat and epoetin alfa groups (least-squares mean difference: 0.22; 95% CI, 0.05 to 0.40; P = 0.0130). Risks of MACE and MACE+ were lower in the roxadustat group (hazard ratio [HR], 0.70; 95% CI, 0.51 to 0.96) than the epoetin alfa group (HR, 0.66; 95% CI, 0.50 to 0.89); the HR for ACM was 0.76 (95% CI, 0.52 to 1.11). CONCLUSION: Roxadustat was at least as efficacious as epoetin alfa. Roxadustat had a lower risk of MACE/MACE+ in patients new to dialysis.

Roxadustat for Treating Anemia in Patients with CKD Not on Dialysis: Results from a Randomized Phase 3 Study.

BACKGROUND: Current anemia therapies for patients with non-dialysis-dependent CKD may require injection and medical visits. Roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, stimulates erythropoiesis and improves iron homeostasis. METHODS: In this double-blind phase 3 study, we randomized patients with non-dialysis-dependent CKD stages 3-5 and hemoglobin <10.0 g/dl (1:1) to thrice-weekly 70-mg oral roxadustat or placebo. Doses were titrated throughout the study based on hemoglobin levels. The primary efficacy end point was mean change from baseline in hemoglobin averaged over weeks 28-52 versus placebo, irrespective of rescue therapy use. We assessed patients for adverse events. RESULTS: The study included 2781 patients, 1393 who received roxadustat and 1388 who received placebo. Mean baseline hemoglobin was 9.1 g/dl for both groups. The mean change in hemoglobin from baseline was 1.75 g/dl (95% confidence interval [95% CI], 1.68 to 1.81) with roxadustat versus 0.40 g/dl (95% CI, 0.33 to 0.47) with placebo, (P<0.001). Among 411 patients with baseline elevated high-sensitivity C-reactive protein, mean change in hemoglobin from baseline was 1.75 g/dl (95% CI, 1.58 to 1.92) with roxadustat versus 0.62 g/dl (95% CI, 0.44 to 0.80) with placebo, (P<0.001). Roxadustat reduced the risk of red blood cell transfusion by 63% (hazard ratio, 0.37; 95% CI, 0.30 to 0.44). The most common adverse events with roxadustat and placebo, respectively, were ESKD (21.0% versus 20.5%), urinary tract infection (12.8% versus 8.0%), pneumonia (11.9% versus 9.4%), and hypertension (11.5% versus 9.1%). CONCLUSIONS: Roxadustat effectively increased hemoglobin in patients with non-dialysis-dependent CKD and reduced the need for red blood cell transfusion, with an adverse event profile comparable to that of placebo. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Safety and Efficacy Study of Roxadustat to Treat Anemia in Patients With CKD, Not on Dialysis, NCT02174627.

In Silico Predictions and In Vivo Results of Drug-Drug Interactions by Ketoconazole and Verapamil on AZD1305, a Combined Ion Channel Blocker and a Sensitive CYP3A4 Substrate.

The objectives were to estimate and compare, in silico and in vivo, the effects of a strong and a moderate CYP3A4 inhibitor on AZD1305 pharmacokinetics. In silico, simulations were performed with the computer software Simcyp, and the predicted outcome was compared with the results observed in healthy male subjects. In silico, the geometric mean plasma exposure of AZD1305 + ketoconazole showed a 7.1-fold higher AUC and a 4.4-fold higher Cmax compared with AZD1305 alone. Coadministration with verapamil gave a 1.9-fold higher AUC and a 1.7-fold higher Cmax compared with AZD1305 alone. In vivo, the plasma exposure of AZD1305 + ketoconazole showed a 7.7-fold higher AUC and a 4.8 -fold higher Cmax compared with AZD1305 alone. Coadministration with verapamil gave a 2.2-fold higher AUC and a 2.0-fold higher Cmax compared with AZD1305 alone. The mean maximum QTcF increase from baseline was 407, 487, and 437 milliseconds for AZD1305, alone and in combination with verapamil or ketoconazole, respectively. Simcyp predicted the effects of ketoconazole and verapamil on the sensitive CYP3A4 substrate AZD1305 pharmacokinetics well. Both the in vivo study and the Simcyp predictions suggest a contraindication for strong CYP3A4 inhibitors and AZD1305 when given in combination.

Inverse Correlation between the Atrial Fibrillatory Rate and the Ventricular Repolarization Time: Observations at Baseline and after an Intravenous Infusion of a Combined Potassium and Sodium Current Blocker.

BACKGROUND: The atrial fibrillatory rate (AFR) and the ventricular rate and repolarization (QTcF) were studied at baseline and under the influence of the combined potassium and sodium current blocker AZD7009. METHODS: Ninety-two patients with atrial fibrillation (AF) were randomized to an intravenous infusion of AZD7009 or placebo. The atrial fibrillatory activity in lead V1 was extracted using spatiotemporal QRST cancellation. The exponential decay (ED) characterized the degree of atrial signal organization. RESULTS: The mean (SD) AFR at baseline was 396  ±  57 (range 253-584) and 410 ± 33 (range 363-469) bpm in patients randomized to AZD7009 and placebo, respectively. The AFR decreased within the first minutes of the AZD7009 infusion and reached its minimum of 235 ± 34 bpm after 18 minutes. On placebo, the AFR was unchanged. On AZD7009, the ED decreased from 1.2 ± 0.3 to reach its lowest level at 0.7 ± 0.2 after 14 minutes. The ventricular rate did not change significantly over time. The AFR was statistically significantly related to the ventricular repolarization at baseline, the QTcF being longer at lower AFR values, and this relationship remained during and after AZD7009. In the full multivariate linear regression model, including age, sex, left ventricular ejection fraction, QRS duration, heart rate, QTcF, AF episode duration, AF history duration, and right atrial or left atrial size, only QTcF and age were statistically significantly correlated with the AFR. The correlation remained when the uncorrected QT interval was used. CONCLUSIONS: The QTcF was inversely correlated with AFR, both at baseline and during administration of AZD7009. The AFR was not correlated with the ventricular rate.

Is the acetylcholine-regulated inwardly rectifying potassium current a viable antiarrhythmic target? Translational discrepancies of AZD2927 and A7071 in dogs and humans.

AIMS: We aimed at examining the acetylcholine-dependent inward-rectifier current (IKAch) as a target for the management of atrial fibrillation (AF). METHODS AND RESULTS: The investigative agents AZD2927 and A7071 concentration-dependently blocked IKACh in vitro with minimal off-target activity. In anaesthetized dogs (n = 17) subjected to 8 weeks of rapid atrial pacing (RAP), the left atrial effective refractory period (LAERP) was maximally increased by 50 ± 7.4 and 50 ± 4.8 ms following infusion of AZD2927 and A7071. Ventricular refractoriness and the QT interval were unaltered. During sustained AF, both drugs significantly reduced AF frequency and effectively restored sinus rhythm. AZD2927 successfully restored sinus rhythm at 10/10 conversion attempts and A7071 at 14/14 attempts, whereas saline converted 4/17 episodes only (P<0.001 vs. AZD2927 and A7071). In atrial flutter patients (n = 18) undergoing an invasive investigation, AZD2927 did not change LAERP, the paced QT interval, or ventricular refractoriness when compared with placebo. To address the discrepancy on LAERP by IKACh blockade in man and dog and the hypothesis that atrial electrical remodelling is a prerequisite for IKACh blockade being efficient, six dogs were studied after 8 weeks of RAP followed by sinus rhythm for 4 weeks to reverse electrical remodelling. In these dogs, both AZD2927 and A7071 were as effective in increasing LAERP as in the dogs studied immediately after the 8-week RAP period. CONCLUSION: Based on the present series of experiments, an important role of IKACh in human atrial electrophysiology, as well as its potential as a viable target for effective management of AF, may be questioned.

Rapid slowing of the atrial fibrillatory rate after administration of AZD7009 predicts conversion of atrial fibrillation.

BACKGROUND: Effects on the atrial fibrillatory rate (AFR) were studied during infusion with the combined potassium and sodium channel blocker AZD7009. METHODS AND RESULTS: Patients with persistent atrial fibrillation (AF) were randomized to AZD7009 or placebo. Thirty-five patients converted to sinus rhythm (SR) and were matched to 35 non-converters. The mean AFR before conversion was 231 fibrillations per minute (fpm), having decreased by 41%; in non-converters, it was 296 fpm at the end of infusion, having decreased by 26%. The rate of decrease was greater in converters at 5 min, -88 vs. -66 fpm (p=0.02), and at 10 min, -133 vs. -111 fpm (p=0.048). The AFR-SD and the exponential decay decreased. A small left atrial area was the only baseline predictor of conversion to SR. CONCLUSIONS: AZD7009 produced a significantly more rapid decrease of the AFR in converters than in non-converters, but the AFR at baseline was not predictive of conversion.

Assessment of ventricular repolarization variability with the DeltaT50 method improves identification of patients with congenital long QT syndromes.

BACKGROUND: We analyzed ventricular repolarization variability in genotyped long QT syndrome (LQTS) patients and in healthy volunteers (HV). METHOD: The deltaT50, that is, the temporal variability of ventricular repolarization at 50% of the T-wave downslope, was analyzed every 15th minute on 175 and 390 Holter electrocardiogram (ECG) recordings from HV and genotyped LQTS patients, respectively. The average deltaT50 and QTcF were calculated in each subject. RESULTS: DeltaT50 was 2.26 ± 0.71 ms (mean ± SD) in the HV and 5.74 ± 2.30 ms in the LQTS population (P < 0.0001). The sensitivity and specificity of QTcF (cutoff value 450 ms) to discriminate between the LQTS patients and the HV were 51.5% and 98.9%, and for deltaT50 (cutoff value 3 ms) 93.9% and 88.6%, respectively. The combination of both variables improved the diagnosis of the LQTS patients even further. Subgroups of LQTS patients at higher risk of cardiac events (with LQTS3, JLN, QTc > 500 ms or symptoms) had higher deltaT50 than subgroups at lower risk (with LQTS1, QTc < 450 ms or without symptoms). The variation in deltaT50 between day and night was concordant with the risk of symptoms; patients with LQTS1 had higher deltaT50 in the daytime and patients with LQTS3 had higher deltaT50 during the night. CONCLUSION: DeltaT50 more accurately distinguished between LQTS patients and HV than QTcF and was higher in LQTS patients with a higher risk of cardiac events. DeltaT50 can be used together with QTcF to improve the diagnosis in patients with the LQTS phenotype and tentatively also be of value for risk assessment in such patients.

Decrease of the atrial fibrillatory rate, increased organization of the atrial rhythm and termination of atrial fibrillation by AZD7009.

BACKGROUND: The atrial fibrillatory rate (AFR), on AZD7009 as compared to placebo, was investigated as a potential biomarker for electrophysiological effect in early antiarrhythmic drug development. METHODS: Patients with permanent AF received infusions of AZD7009 and placebo in an exploratory two-way, single-blind, randomized cross-over study. The ECG was continuously recorded, and following QRST cancellation the AFR, its standard deviation (SD), the exponential decay and the atrial electrogram amplitude were determined as 3-min averages. RESULTS: The mean AFR rapidly decreased by 43% from baseline (394 ± 38 to 225 ± 61 fibrillations/min, p=0.0003) on AZD7009, but not on placebo. The SD of the AFR and the exponential decay decreased in parallel. In 2 of 8 patients, termination of AF occurred after the AFR had decreased by 58% and 53%, respectively. CONCLUSIONS: The AFR may potentially serve as a biomarker of electrophysiological effects in early evaluation of rhythm control agents.

DeltaT50--a new method to assess temporal ventricular repolarization variability.

BACKGROUND: Increased beat-to-beat variability in cardiac repolarization time is a tentative risk marker of drug-induced torsades de pointes. We developed a new, automatic method based on the temporal variability of the T-wave down slope to assess this variability. METHOD AND RESULTS: Leads V(1) to V(6) of resting electrocardiograms were recorded in 42 healthy subjects (18-68 years, 22 men). The temporal variability at 50% of the T-wave down slope, deltaT50 (1.5 ± 0.41 milliseconds; range, 0.86-2.66 milliseconds), was measured with an accuracy of 1 millisecond on at least 9 pairs of electrocardiogram complexes with a signal-to-noise ratio more than 10 and changes in the R-R interval less than 150 milliseconds. The correlation between repeated measurements of deltaT50 was high. DeltaT50 was measured without corrections for age, sex, heart rate, T-wave amplitude, signal-to-noise ratio, R-R variability, and QTcF because none of these factors explained more than 4% of the within-subject deltaT50 variability. CONCLUSION: The beat-to-beat repolarization variability was measured with high fidelity with the deltaT50 method and was a robust measure in healthy volunteers.

QT response after a test dose and during maintenance therapy with AZD1305 in patients with atrial fibrillation: a double-blind, randomized, placebo-controlled trial.

BACKGROUND AND OBJECTIVE: AZD1305 is an investigational antiarrhythmic agent that prolongs refractoriness through combined potassium and sodium channel inhibition. This study aimed to explore the utility of a test dose in predicting QT interval corrected according to Fridericia's formula (QTcF) during subsequent maintenance treatment with AZD1305. METHODS: This was a randomized, double-blind, parallel-group, placebo-controlled trial carried out at multiple hospital cardiac facilities in Denmark, Norway, Poland, Slovakia, and Sweden. Patients with documented atrial fibrillation (AF) but currently in stable sinus rhythm for ≥2 hours and ≤90 days were eligible for inclusion. Patients were randomized in a 1 : 1 : 1 ratio to receive AZD1305 extended-release or matching placebo tablets as follows: group A - test dose 250 mg, evening dose 125 mg on day 1, maintenance dose 125 mg twice daily; group B - test dose 500 mg, placebo evening dose, maintenance dose 125 mg twice daily; placebo group - placebo test and maintenance dose. Maintenance dosing was for 9 days. QTcF >550 ms at any time during the in-patient phase or >500 ms after discharge (day 4) were predefined study drug discontinuation criteria. The main outcome measure was the relationship between QTcF following the test dose and during maintenance treatment. RESULTS: Sixty-five patients were randomized (n = 21, 22, and 22 in group A, group B, and the placebo group, respectively). AZD1305 dose-dependently increased QTcF. There was a positive, linear correlation between the change in QTcF during the first 6 hours after the test dose and during the maintenance phase. Three patients, all from group B, discontinued treatment on day 1 due to QTcF >550 ms. All other patients completed the study without events related to QT prolongation. There was a trend for reduced AF recurrence with AZD1305 compared with placebo. CONCLUSION: In this exploratory study a test dose predicted the QT response during maintenance treatment with AZD1305 and may thus be employed in further studies. [ClinicalTrials.gov Identifier: NCT00643448].

Pharmacological cardioversion of atrial fibrillation--a double-blind, randomized, placebo-controlled, multicentre, dose-escalation study of AZD1305 given intravenously.

AIM: AZD1305 is a combined ion channel blocker developed for the treatment of atrial fibrillation (AF). The aim of this study was to determine whether AZD1305 was effective in converting AF to sinus rhythm (SR). METHODS AND RESULTS: Patients with AF episodes of duration 3 h to 3 months were randomized in a 3:1 ratio to receive a maximum 30 min intravenous infusion of AZD1305 or matching placebo. The primary efficacy endpoint was the proportion of patients converting within 90 min of the start of infusion, after which patients who had not converted were to undergo direct current (DC) cardioversion. Four ascending AZD1305 dose groups were assigned sequentially, with dose rates of 50, 100, 130, and 180 mg/h. A total of 171 patients were randomized. Pharmacological conversion was achieved in 0 of 43 patients (0%) in the placebo group, and in 2 of 26 (8%; P= 0.14 vs. placebo), 8 of 45 (18%; P= 0.006), 17 of 45 (38%; P< 0.001), and 6 of 12 patients (50%; P< 0.001) in AZD1305 dose groups 1-4, respectively. Maximum QTcF (QT interval corrected according to Fridericia's formula) generally increased dose-dependently up to a plateau, although there was wide variation between patients. Two patients experienced torsade de pointes (TdP): one patient without symptoms in dose group 3, and one patient requiring DC defibrillation in dose group 4. Both patients recovered without sequelae. CONCLUSIONS: AZD1305 was effective in converting AF to SR, but was associated with QT prolongation and TdP. The benefit-risk profile was judged as unfavourable and the AZD1305 development programme was discontinued. CLINICAL TRIAL REGISTRATION: http://clinicaltrials.gov identifier NCT00915356.

Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation: the HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) score.

OBJECTIVES: The purpose of this study was to investigate predictors of bleeding in a cohort of anticoagulated patients and to evaluate the predictive value of several bleeding risk stratification schemas. BACKGROUND: The risk of bleeding during antithrombotic therapy in patients with atrial fibrillation (AF) is not homogeneous, and several clinical risk factors have been incorporated into clinical bleeding risk stratification schemas. Current risk stratification schemas for bleeding during anticoagulation therapy have been based on complex scoring systems that are difficult to apply in clinical practice, and few have been derived and validated in AF cohorts. METHODS: We investigated predictors of bleeding in a cohort of 7,329 patients with AF participating in the SPORTIF (Stroke Prevention Using an ORal Thrombin Inhibitor in Atrial Fibrillation) III and V clinical trials and evaluated the predictive value of several risk stratification schemas by multivariate analysis. Patients were anticoagulated orally with either adjusted-dose warfarin (target international normalized ratio 2 to 3) or fixed-dose ximelagatran 36 mg twice daily. Major bleeding was centrally adjudicated, and concurrent aspirin therapy was allowed in patients with clinical atherosclerosis. RESULTS: By multivariate analyses, significant predictors of bleeding were concurrent aspirin use (hazard ratio [HR]: 2.10; 95% confidence interval [CI]: 1.59 to 2.77; p < 0.001); renal impairment (HR: 1.98; 95% CI: 1.42 to 2.76; p < 0.001); age 75 years or older (HR: 1.63; 95% CI: 1.23 to 2.17; p = 0.0008); diabetes (HR: 1.47; 95% CI: 1.10 to 1.97; p = 0.009), and heart failure or left ventricular dysfunction (HR: 1.32; 95% CI: 1.01 to 1.73; p = 0.041). Of the tested schemas, the new HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) score performed best, with a stepwise increase in rates of major bleeding with increasing HAS-BLED score (p(trend) <0.0001). The c statistic for bleeding varied between 0.50 and 0.67 in the overall entire cohort and 0.68 among patients naive to warfarin at baseline (n = 769). CONCLUSIONS: This analysis identifies diabetes and heart failure or left ventricular dysfunction as potential risk factors for bleeding in AF beyond those previously recognized. Of the contemporary bleeding risk stratification schemas, the new HAS-BLED scheme offers useful predictive capacity for bleeding over previously published schemas and may be simpler to apply.

Identifying patients at high risk for stroke despite anticoagulation: a comparison of contemporary stroke risk stratification schemes in an anticoagulated atrial fibrillation cohort.

BACKGROUND AND PURPOSE: The risk of stroke in patients with atrial fibrillation (AF) is not homogeneous, and various clinical risk factors have informed the development of stroke risk stratification schemes (RSS). Among anticoagulated cohorts, the emphasis should be on the identification of patients who remain at high risk for stroke despite anticoagulation. METHODS: We investigated predictors of thromboembolism (TE) risk in an anticoagulated AF clinical trial cohort (n = 7329 subjects) and tested the predictive value of contemporary RSS in this cohort: CHADS2, Framingham, NICE 2006, American College of Cardiology/American Heart Association/European Society of Cardiology 2006, the 8th American College of Chest Physicians guidelines and the CHA2DS2-VASc schemes. RESULTS: On multivariate analysis, significant predictors of TE were stroke/TIA (hazard ratio [HR], 2.24; P < 0.001), age 75 years or older (HR, 1.77; P = 0.0002), coronary artery disease (HR, 1.52; P = 0.0047), and smoking (HR, 2.10; P = 0.0005), whereas reported alcohol use (HR, 0.70; P = 0.02) was protective. Comparison of contemporary RSS demonstrated variable classification of AF patients into risk strata, although c-statistics for TE were broadly similar among the RSS tested and varied between 0.575 (NICE 2006) and 0.647 (CHA2DS2-VASc). CHA2DS2-VASc classified 94.2% as being at high risk, whereas most other RSS categorized two-thirds as being at high risk. Of the 184 TE events, 181 (98.4%) occurred in patients identified as being at high risk by the CHA2DS2-VASc schema. There was a stepwise increase in TE with increasing CHA2DS2-VASc score (P (trend) < 0.0001), which had the highest HR (3.75) among the tested schemes. The negative predictive value (ie, the percent categorized as "not high risk" actually being free from TE) for CHA2DS2-VASc was 99.5%. CONCLUSIONS: Coronary artery disease and smoking are additional risk factors for TE in anticoagulated AF patients, whereas alcohol use appears protective. Of the contemporary stroke RSS, the CHA2DS2-VASc scheme correctly identified the greatest proportion of AF patients at high risk, despite the similar predictive ability of most RSS evidenced by the c-statistic.

A randomized invasive cardiac electrophysiology study of the combined ion channel blocker AZD1305 in patients after catheter ablation of atrial flutter.

BACKGROUND: This study assessed the cardiac electrophysiological and hemodynamic effects of an intravenous infusion of the combined ion channel blocker AZD1305. METHODS: After successful ablation of atrial flutter, patients were randomized to receive placebo (n = 12) or AZD1305 (n = 38) in 4 ascending dose groups. Electrophysiological and hemodynamic measurements were performed before and commencing 20 minutes after start of infusion. RESULTS: Left atrial effective refractory period increased dose and the primary outcome measure increased dose and plasma concentration dependently, with a mean increase of 55 milliseconds in dose group 3. There was a corresponding increase in right atrial effective refractory period of 84 milliseconds. The right ventricular effective refractory period and the paced QT interval also increased dose and concentration dependently, by 59 and 70 milliseconds, respectively, in dose group 3. There were indications of moderate increases of atrial, atrioventricular nodal, and ventricular conduction times. No consistent changes in intracardiac pressures were observed, but there was a small transient decrease in systolic blood pressure. Adverse events were consistent with the study population and procedure, and there were no signs of proarrhythmia despite marked delay in ventricular repolarization in some individuals. CONCLUSIONS: AZD1305 shows electrophysiological characteristics indicative of potential antiarrhythmic efficacy in atrial fibrillation.

Responsiveness of AF6, a new, short, validated, atrial fibrillation-specific questionnaire--symptomatic benefit of direct current cardioversion.

OBJECTIVES: To measure the effects on symptoms of electrical cardioversion (DC) in patients with atrial fibrillation (AF) by means of a new, short, validated, AF-specific questionnaire, the AF6. METHODS: One hundred eleven patients (67 ± 12 years, 89 men) were screened before and 12 ± 3 days after DC using AF6, covering 'breathing difficulties at rest', 'breathing difficulties on exertion', 'limitations in day-to-day life due to atrial fibrillation', 'feeling of discomfort due to atrial fibrillation', 'tiredness due to atrial fibrillation', and 'worry/anxiety due to atrial fibrillation'. A single global score was calculated. The Toronto AF Symptoms and Severity Check List (AFSS) and the generic SF-36 were also administered. Patients in sinus rhythm at 12 ± 3 days (n = 56) were defined as responders and patients in AF (n = 55) as non-responders. RESULTS: The mean single global score decreased in all patients (18 ± 12.4 to 13 ± 11.6, p < 0.0001) and in responders (22 ± 14 vs. 12 ± 12, p < 0.01) but not in non-responders (14 ± 9 vs. 14 ± 11, N.S). The AFSS frequency scores decreased from 14.5 ± 7.7 to 9.5 ± 7.8 in responders, p = 0.001, but not in non-responders. There was a strong correlation between changes in the AF6 and the SF-36 regarding four of the six items. Effect sizes of AF6 ranged from 0 to 0.52 in all patients, in responders from 0.10 to 0.85 and in non-responders from -0.23 to 0.34, the highest figures consistently referring to 'tiredness due to atrial fibrillation'. CONCLUSIONS: The symptom scores measured by AF6 decreased significantly, especially in responders. AF6 demonstrated adequate responsiveness to change, and effect sizes were mostly moderate, in responders moderate to high.