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Introduction: Sub-clinical AF has been reported in 10% of pacemaker patients (≥ 6 minutes, with 3 months of monitoring) and 16% of patients following cryptogenic stroke (≥ 30 seconds, with 1 month of monitoring). It is unknown how common sub-clinical AF is among other patient groups, including the elderly. These data are needed to give context to the detection of sub-clinical AF in clinical practice. Methods: We prospectively investigated the prevalence of sub-clinical AF among individuals ≥ 80 years, without known AF or symptoms of arrhythmia, attending primary care clinics. Subjects had a history of hypertension and at least one of the following: diabetes, BMI ≥ 30, sleep apnea, smoking, coronary disease, heart failure or left ventricular hypertrophy. Patients were recruited from 7 Ontario family practice clinics (n=119) and one general medicine clinic (n=10). Patients underwent 30 days of continuous, non-invasive ambulatory ECG monitoring using a device with automatic AF detection (Vitaphone 3100). The primary outcome was a composite of atrial flutter (AFL) or AF ≥ 6 minutes in duration. Those without AF were invited to complete an additional 30 days of monitoring. Results: Of 129 patients screened and consented, 100 patients initiated monitoring for an average monitoring duration of 36± 21 days. The mean (SD) age was 84 ± 3 years and systolic blood pressure was 138 ± 17 mmHg; 50% had coronary disease, 28% had diabetes and 6% had heart failure. Only 4% had a history of prior stroke. Thirty days of monitoring was completed by 57% of patients and 31% completed an additional 30 days. AFL or AF ≥ 30 seconds duration was documented in 19/100 patients; ≥ 6 minutes in 15; ≥ 30 minutes in 12; ≥ 6 hours in 8 and ≥ 24 hours in 2. Shorter episodes of atrial tachycardia lasting less than 30 seconds were observed in 47 patients. Conclusions: In this prospective, outpatient study, using non-invasive ECG monitoring, we found AFL or AF ≥ 6 minutes in 15% of elderly individuals with stroke risk factors. This high background prevalence of AFL/AF among elderly patients suggests a possible role for AF screening in this population; but also should be taken into consideration when interpreting the prevalence of AFL/AF in other populations.

Background: In patients with atrial fibrillation (AF) and normal renal function it has been reported that one oral factor-Xa inhibitor is associated with decreased efficacy compared to warfarin. In the RE-LY trial of patients with AF dabigatran, with approximately 80% renal elimination, was superior to warfarin for prevention of stroke and systemic embolism (SEE) with the 150 mg dose and non-inferior with the 110 mg dose and associated with significantly less major bleeding with the 110 mg dose. This is a post hoc analysis of the efficacy and safety of dabigatran vs. warfarin treatment in patients with normal renal function during the study. Methods: In the RE-LY trial among patients who received at least one dose of study medication, 17882 had creatinine measurements available at baseline, out of which 91% also had measurements after randomization. There were a total of 382 stroke/SEE, 280 ischemic strokes, and 1018 major bleed events during median follow-up of 1.8 years. The relations between outcomes, treatment, and renal function (Cockcroft-Gault estimated glomerular filtration rate (eGFR)) during follow-up were evaluated using Cox regression including treatment, eGFR as a continuous time dependent covariate, fitted using restricted cubic splines, and interaction. Hazard ratios (95% CI) comparing treatment effects were analyzed according to eGFR level. Results: In patients with normal renal function the relative risk of stroke/SEE was consistently lower in those treated with dabigatran as compared with warfarin. The patterns were similar for major bleeding with a trend of greater relative risk reduction with dabigatran as compared to warfarin at normal renal function. Conclusions: In patients with AF and normal renal function during treatment the efficacy of dabigatran compared to warfarin was consistent with the overall result of the RELY study. Both dabigatran doses were associated with lower risk of major bleeding in patients with normal renal function.

BACKGROUND:The role of trypanocidal therapy in patients with established Chagas´ cardiomyopathy is unproven.METHODS:We conducted a prospective, multicenter, randomized study involving 2854 patients with Chagas´ cardiomyopathy who received benznidazole or placebo for up to 80 days and were followed for a mean of 5.4 years. The primary outcome in the time-to-event analysis was the first event of any of the components of the composite outcome of death, resuscitated cardiac arrest, sustained ventricular tachycardia, insertion of a pacemaker or implantable cardioverter-defibrillator, cardiac transplantation, new heart failure, stroke, or other thromboembolic event.RESULTS:The primary outcome occurred in 394 patients (27.5%) in the benznidazole group and in 414 (29.1%) in the placebo group (hazard ratio, 0.93; 95% confidence interval [CI], 0.81 to 1.07; P=0.31). At baseline, a polymerase-chain-reaction (PCR) assay was performed on blood samples obtained from 1896 patients; 60.5% had positive results for Trypanosoma cruzi on PCR. The rates of conversion to negative PCR results (PCR conversion) were 66.2% in the benznidazole group and 33.5% in the placebo group at the end of treatment, 55.4% and 35.3%, respectively, at 2 years, and 46.7% and 33.1%, respectively, at 5 years or more (P

In Asian patients in RE-LY, dabigatran etexilate (DE) was as effective as warfarin, with a significantly lower bleeding risk. We evaluated the relationship between baseline renal function or CHADS2 score and efficacy or safety outcomes in these patients.Asian patients (n=2,782) were categorized according to baseline renal function or CHADS2 score, and efficacy and safety outcomes were analyzed for DE (110 mg and 150 mg b.i.d.) vs. warfarin. There was an increase in the rates of stroke/systemic embolism and major bleeding with worsening renal function and CHADS2 score. For stroke/systemic embolism (primary efficacy endpoint), there was no treatment interaction for dabigatran at either 110 or 150 mg b.i.d. compared with warfarin related to patients' baseline renal function (Pinteraction=0.56 for DE 110 mg and 0.62 for DE 150 mg vs. warfarin) or CHADS2 score (Pinteraction=0.68 for DE 110 mg and 0.31 for DE 150 mg vs. warfarin). For major bleeding, there was no treatment interaction by creatinine clearance category observed for either dose (Pinteraction=0.60 and 0.62 for DE 110 mg and DE 150 mg, respectively). Baseline CHADS2 score had no significant effect on bleeding event rates with DE vs. warfarin.Bleeding and stroke rates in Asian patients varied according to renal function and CHADS2 score, but the relative benefits of DE over warfarin were preserved when analyzed by subcategories.

SummaryCoagulation markers may improve monitoring the risk of stroke and bleeding in patients with atrial fibrillation (AF) during anticoagulant treatment. We examined baseline levels of D-dimer and their association with stroke, cardiovascular death and major bleeding in 6,202 AF patients randomised to dabigatran or warfarin in the RE-LY trial. The effects of treatment on serial levels of D-dimer and coagulation factor (F) VIIa in 2,567 patients were also analysed. Baseline D-dimer levels were related to the rate of stroke/systemic embolism (SEE) with 0.64 % in the lowest quartile (Q1, as reference) (D-dimer < 298 μg/l), 1.38 % Q2 (D-dimer 298–473 μg/l), 1.71 % Q3 (D-dimer 474–822 μg/l) and 2.00 % in Q4 (D-dimer > 822 μg/l) (p=0.0007). Similar associations were shown for cardiovascular death and major bleeding. Addition of baseline D-dimer to established clinical risk factors improved prediction of stroke/SEE, cardiovascular death and major bleeding (C-index increased from 0.66 to 0.68, 0.71 to 0.73 and 0.66 to 0.67, respectively). Dabigatran provided a greater reduction of D-dimer levels than warfarin regardless of baseline anticoagulant treatment. Ontreatment levels of FVIIa were markedly reduced by warfarin (median 12.1–13.8 mU/ml) but significantly higher with dabigatran (median 39.4–49.0 mU/ml) at all-time points. Dabigatran is associated with greater reduction in D-dimer without the pronounced reduction of FVIIa seen with warfarin. These different effects on the coagulation system might explain the better efficacy and less intracranial bleeding observed with dabigatran compared with warfarin.Clinical Trial Registration: NCT00262600 (www.clinicaltrials.gov).Supplementary Material to this article is available online at www.thrombosis-online.com.

The new generation of non-vitamin K antagonist oral anticoagulants (NOACs) have been welcomed as a convenient alternative to warfarin. Three new oral anticoagulants, dabigatran etexilate, rivaroxaban and apixaban have been approved for the prevention of stroke and systemic embolism (SSE) in patients with atrial fibrillation (AF) and the prevention of venous thromboembolic events (VTEs) in patients who have undergone elective hip or knee replacement surgery. Dabigatran etexilate and rivaroxaban are also indicated for the treatment of VTE and the long-term prevention of recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE). A fourth agent, edoxaban, has been successfully tested for several indications but is not yet approved for use in North America or Europe. Building on these successes, new trials are planned to address remaining unmet needs and knowledge gaps. This paper examines the unresolved issues in anticoagulant therapy with a focus on planned and ongoing trials.

We read with great interest the article by Prutkin et al1 on rates and risk factors for infection associated with implantable cardioverter-defibrillator (ICD) implants. This study greatly improves our understanding of risk factors associated with ICD infections. However, we would like to voice our concerns about the choice of definitions used to make a presumptive diagnosis of ICD infection. Some criteria that were used to diagnose ICD infection (such as the International Classification of Disease, Ninth Revision, Clinical Modification code 996.61, infection caused by a cardiac device) are very reliable, and patients identified through these criteria very likely represent a true ICD infection. On the other hand, other criteria …

Background Heart failure (HF) is the commonest cause of hospitalization in older adults. Compared to routine hospitalization (RH), hospital at home (HaH)—substitutive hospital-level care in the patient’s home—improves outcomes and reduces costs in patients with general medical conditions. The efficacy of HaH in HF is unknown. Methods and Results We searched MEDLINE, Embase, CINAHL, and CENTRAL, for publications from January 1990 to October 2014. We included prospective studies comparing substitutive models of hospitalization to RH in HF. At least 2 reviewers independently selected studies, abstracted data, and assessed quality. We meta-analyzed results from 3 RCTs (n = 203) and narratively synthesized results from 3 observational studies (n = 329). Study quality was modest. In RCTs, HaH increased time to first readmission (mean difference (MD) 14.13 days [95% CI 10.36 to 17.91]), and improved health-related quality of life (HrQOL) at both, 6 months (standardized MD (SMD) -0.31 [-0.45 to -0.18]) and 12 months (SMD -0.17 [-0.31 to -0.02]). In RCTs, HaH demonstrated a trend to decreased readmissions (risk ratio (RR) 0.68 [0.42 to 1.09]), and had no effect on all-cause mortality (RR 0.94 [0.67 to 1.32]). HaH decreased costs of index hospitalization in all RCTs. HaH reduced readmissions and emergency department visits per patient in all 3 observational studies. Conclusions In the context of a limited number of modest-quality studies, HaH appears to increase time to readmission, reduce index costs, and improve HrQOL among patients requiring hospital-level care for HF. Larger RCTs are necessary to assess the effect of HaH on readmissions, mortality, and long-term costs.

Aspirin is used in combination with anticoagulant therapy in patients with atrial fibrillation (AF), but evidence of additional efficacy is not available.We compared ischemic events and bleeding in the SPORTIF III and IV randomized trials of anticoagulation with warfarin (international normalized ratio 2-3) or fixed-dose ximelagatran. Low-dose aspirin (100 mg/d) was allowed based on prevailing guidelines.The 14% of patients receiving aspirin more often had diabetes (27.5% vs 23%, P.01), coronary artery disease (69% vs 41%, P.01), previous stroke or transient ischemic attack (26% vs 20%, P.01), and left ventricular dysfunction (41% vs 36%, P.01). Addition of aspirin to either warfarin or ximelagatran was associated with no reduction in stroke or systemic embolism. Major bleeding occurred significantly more often with aspirin plus warfarin (3.9% per year) than with warfarin alone (2.3% per year, P.01), aspirin plus ximelagatran (2.0% per year), or ximelagatran alone (1.9% per year). The rate of myocardial infarction with aspirin and warfarin (0.6% per year) was not significantly different from that with ximelagatran alone (1.0% per year), warfarin alone (1.0% per year), or aspirin and ximelagatran (1.4% per year).Aspirin combined with anticoagulant therapy was associated with no reduction in stroke, systemic embolism, or myocardial infarction in patients with AF. Aspirin combined with warfarin was associated with an incremental rate of major bleeding of 1.6% per year. No increased major bleeding occurred with aspirin and ximelagatran. These results suggest that the risks associated with addition of aspirin to anticoagulation in patients with AF outweigh the benefit.

Background— Many patients with implanted cardioverter defibrillators (ICDs) receive adjunctive antiarrhythmic drug therapy, most commonly amiodarone or sotalol. The effects of these drugs on defibrillation energy requirements have not been previously assessed in a randomized controlled trial. Methods and Results— The Optimal Pharmacological Therapy in Cardioverter Defibrillator Patients (OPTIC) trial was a randomized clinical trial evaluating the efficacy of amiodarone plus β-blocker and sotalol versus β-blocker alone for reduction of ICD shocks. Within OPTIC, a prospectively designed substudy evaluated the effects of the 3 treatment arms on defibrillation energy requirements. Defibrillation thresholds (DFTs) were measured (binary step-down protocol) at baseline and again after 8 to 12 weeks of therapy in 94 patients, of whom 29 were randomized to receive β-blocker therapy (control group), 35 to amiodarone plus β-blocker, and 30 to sotalol. In the control group, the mean DFT decreased from 8.77±5.15 J at baseline to 7.13±3.43 J ( P =0.027); in the amiodarone group, DFT increased from 8.53±4.29 to 9.82±5.84 J ( P =0.091). In the sotalol group, DFT decreased from 8.09±4.81 to 7.20±5.30 J ( P =0.21). DFT changes in the β-blocker and the amiodarone group were significantly different ( P =0.006). In all patients, adequate safety margins for defibrillation were maintained. No clinical variable predicted baseline DFT or changes in DFT on therapy. Conclusion— Although amiodarone increased DFT, the effect size with modern ICD systems is very small. Therefore, DFT reassessment after the institution of antiarrhythmic drug therapy with amiodarone or sotalol is not routinely required.

Background— Several randomized trials have compared atrial-based (dual-chamber or atrial) pacing with ventricular pacing in patients with bradycardia. No trial has shown a mortality reduction, and only 1 small trial suggested a reduction in stroke. The goal of this review was to determine whether atrial-based pacing prevents major cardiovascular events. Methods and Results— A systematic review was performed of publications since 1980. For inclusion, trials had to compare an atrial-based with a ventricular-based pacing mode; use a randomized, controlled, parallel design; and have data on mortality, stroke, heart failure, or atrial fibrillation. Individual patient data were obtained from 5 of the 8 identified studies, representing 95% of patients in the 8 trials, and a total of 35 000 patient-years of follow-up. There was no significant heterogeneity among the results of the individual trials. There was no significant reduction in mortality (hazard ratio [HR], 0.95; 95% confidence interval [CI], 0.87 to 1.03; P =0.19) or heart failure (HR, 0.89; 95% CI, 0.77 to 1.03; P =0.15) with atrial-based pacing. There was a significant reduction in atrial fibrillation (HR, 0.80; 95% CI, 0.72 to 0.89; P =0.00003) and a reduction in stroke that was of borderline significance (HR, 0.81; 95% CI, 0.67 to 0.99; P =0.035). There was no convincing evidence that any patient subgroup received special benefit from atrial-based pacing. Conclusions— Compared with ventricular pacing, the use of atrial-based pacing does not improve survival or reduce heart failure or cardiovascular death. However, atrial-based pacing reduces the incidence of atrial fibrillation and may modestly reduce stroke.

Azimilide hydrochloride (azimilide), an investigational antiarrhythmic drug, has shown variable efficacy in preventing atrial fibrillation (AF). This study was designed to assess its efficacy in maintaining sinus rhythm in patients with paroxysmal AF and heart disease. Patients with symptomatic paroxysmal AF were screened for 1 month by transtelephonic monitoring. After recording 1 episode of AF in the screening period, they were randomized to receive azimilide 125 mg or placebo once daily. Patients were stratified by the presence or absence of congestive heart failure or coronary heart disease (CHF/CHD). A maximum of 220 patients without CHF/CHD were randomized, with the remainder having CHF/CHD. Patients with CHF/CHD were monitored for 3 days during loading. The primary efficacy analysis was the time to the first symptomatic recurrence of AF in the CHF/CHD group. Secondary analyses were the time to the first recurrence in the entire population and the time to the first recurrence in those with significant structural heart disease. The median time to recurrence of AF in the CHF/CHD group was 10 days in the 2 treatment arms. Nonsignificant trends were seen toward efficacy of azimilide in the CHF/CHD group (hazard ratio 1.28, 95% confidence interval 0.97 to 1.70, p=0.087), structural heart disease group (hazard ratio 1.22, 95% confidence interval 0.96 to 1.56, p=0.11), and overall group (hazard ratio 1.22, 95% confidence interval 1.00 to 1.49, p=0.053). No patient died. In conclusion, azimilide showed a nonsignificant trend toward efficacy in maintaining sinus rhythm in patients with AF.

Azimilide dihydrochloride (azimilide) is an investigational antiarrhythmic drug that has been tested in patients with a variety of arrhythmias. In patients with atrial fibrillation, it has shown excellent efficacy in some previous trials and minimal efficacy in others.Patients who had symptomatic atrial fibrillation for48 hours but6 months were eligible for this multicenter, randomized, placebo-controlled clinical trial. Patients were admitted to a hospital and randomly assigned to receive either azimilide 125 mg or a matched placebo twice daily for 3 days and then once daily. Patients who were in sinus rhythm spontaneously or had sinus rhythm restored by electric cardioversion on day 4 were discharged from the hospital. Recurrence of atrial fibrillation was documented by electrocardiogram. In the primary efficacy analysis, time to recurrence in the 2 treatment groups was compared with the log-rank test in the subgroup of patients with structural heart disease. Safety was assessed as deaths, adverse events, and serious adverse events.A total of 446 patients were randomized in the study; 314 were in the subgroup with structural heart disease. The median time to arrhythmia recurrence in both treatment groups with structural heart disease was 13 days, and the difference between treatments was not significant (P = .4596, n = 314). The relative risk for recurrence (placebo:azimilide) was 1.104 (95% CI 0.849-1.436). There was 1 death in the placebo group and 3 in the azimilide group.Azimilide did not demonstrate clinically important or statistically significant efficacy in reducing the risk for arrhythmia recurrence in patients with structural heart disease who were in atrial fibrillation and converted to sinus rhythm.

This editorial refers to ‘Peri-interventional management of novel oral anticoagulants in daily care: results from the prospective Dresden NOAC registry’[‡][1], by J. Beyer-Westendorf et al. , on page 1888. The new oral anticoagulants (NOACs) are attractive alternatives to vitamin K antagonists (VKAs) for patients requiring long-term anticoagulation. NOACs are at least as effective and safe as warfarin while allowing convenient fixed dosing regimens.1,2 Moreover, due to their rapid onset and offset of action,3 NOACs have the potential to simplify the peri-procedural management of patients requiring interruption of anticoagulant treatment for elective interventions. Beyer-Westendorf and colleagues now report thrombotic and bleeding outcomes during the first 30 days after an elective procedure from a prospective registry of 2179 patients receiving long-term NOAC therapy for atrial fibrillation (81%), venous thrombo-embolism (17%), or other indications (2%).4 During an 18-month period, 595 patients underwent a total of 863 elective procedures. Most patients were taking rivaroxaban (76%) or dabigatran (23.5%), and only a minority (0.5%) was taking apixaban. Patients who underwent procedures without interruption of NOAC therapy did not experience major bleeding and had a non-major clinically relevant bleed rate of < 5%. Patients who underwent a procedure with interruption of NOAC therapy and who received bridging anticoagulation [40% of patients; most commonly with low molecular weight heparin (LMWH)] had similar rates of thrombotic events compared with those who did not receive bridging (1.6% vs. … [1]: #fn-3

Although many studies have shown that implantable cardioverter defibrillator (ICD) therapy improves the survival of patients with significant left ventricular dysfunction, the magnitude of effectiveness of ICD therapy in clinically defined subgroups remains uncertain. Similarly, although studies have shown an improvement in patients' hemodynamics and quality of life with cardiac resynchronization therapy (CRT), there is a continuing uncertainty about the effect of CRT on patients' survival and the magnitude of improvement in quality of life with this therapy. On August 24, 2004, an ad hoc group of experts representing clinical cardiovascular medicine, biostatistics, economics, and health policy were joined by representatives of the Food and Drug Administration, Centers for Medicare and Medicaid Services (Baltimore, Md), Agency for Healthcare Research and Quality (Rockville, Md), and the device industry for a 1-day round table to review the available clinical trial evidence on the effect of ICD therapy in the primary prevention of sudden cardiac death and the effect of CRT in patients with congestive heart failure. The meeting was organized by the Duke Clinical Research Institute, Durham, NC, and funded in part by the Agency for Healthcare Research and Quality. This document summarizes the evidence reviewed at that meeting and the discussions of that evidence.

OBJECTIVES This study was designed to identify all randomized clinical trial data evaluating angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for the prevention of atrial fibrillation (AF), to estimate the magnitude of this effect and to identify patient subgroups most likely to benefit. BACKGROUND Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) reduce morbidity and mortality in patients with heart failure, vascular disease, and hypertension. Several reports suggest that they may also prevent the development of AF. METHODS A systematic review of the literature was performed to identify all reports of the effect of ACEIs or ARBs on the development of AF. Eligible studies had to be randomized, controlled, parallel-design human trials of an ACEI or ARB that collected data on the development of AF. RESULTS A total of 11 studies, which included 56,308 patients, were identified: 4 in heart failure, 3 in hypertension, 2 in patients following cardioversion for AF, and 2 in patients following myocardial infarction. Overall, ACEIs and ARBs reduced the relative risk of AF by 28% (95% confidence interval [CI] 15% to 40%, p = 0.0002). Reduction in AF was similar between the two classes of drugs (ACEI: 28%, p = 0.01; ARB: 29%, p = 0.00002) and was greatest in patients with heart failure (relative risk reduction [RRR] = 44%, p = 0.007). Overall, there was no significant reduction in AF in patients with hypertension (RRR = 12%, p = 0.4), although one trial found a significant 29% reduction in patients with left ventricular (LV) hypertrophy. In patients following cardioversion, there appears to be a large effect (48% RRR), but the confidence limits are wide (95% CI 21% to 65%). CONCLUSIONS Both ACEIs and ARBs appear to be effective in the prevention of AF. This benefit appears to be limited to patients with systolic left ventricular dysfunction or LV hypertrophy. The use of these drugs following cardioversion appears promising but requires further study.

Objectives: To assess the efficacy of the administration of magnesium as a method for the prevention of postoperative atrial fibrillation (AF) and to evaluate its influence on hospital length of stay (LOS) and mortality. Methods: Literature search and meta-analysis of the randomised control studies published since 1966. Results: 20 randomised trials were identified, enrolling a total of 2490 patients. Study sample size varied between 20 and 400 patients. Magnesium administration decreased the proportion of patients developing postoperative AF from 28% in the control group to 18% in the treatment group (odds ratio 0.54, 95% confidence interval (CI) 0.38 to 0.75). Data on LOS were available from seven trials (1227 patients). Magnesium did not significantly affect LOS (weighted mean difference −0.07 days of stay, 95% CI −0.66 to 0.53). The overall mortality was low (0.7%) and was not affected by magnesium administration (odds ratio 1.22, 95% CI 0.39 to 3.77). Conclusion: Magnesium administration is an effective prophylactic measure for the prevention of postoperative AF. It does not significantly alter LOS or in-hospital mortality.

The effect of left atrial (LA) dimension on the recurrence of atrial fibrillation (AF) has been examined in small studies. We evaluated the effect of LA dimension on the occurrence of AF using 2- and 4-year echocardiographic data in a large cohort of patients with new onset AF.The Canadian Registry of AF (CARAF) enrolled subjects with AF at the first electrocardiographically confirmed diagnosis. Patients were classified at 2 and 4 years as no recurrent AF (No RAF), paroxysmal AF (PAF), or chronic AF (CAF) based on clinical symptoms and electrocardiographic documentation. The association between baseline, 2-, and 4-year LA dimensions with occurrence of AF as determined by echocardiography was evaluated using a multivariate analysis.The No RAF group (n = 176) had a significantly smaller LA dimension (36.9 +/- 6.8 mm) at baseline compared to the CAF group (n = 227) (42.8 +/- 7.5 mm, P.0001). The No RAF and PAF (n = 153) groups did not have a significant change in LA dimension at 2 or 4 years. Only those with CAF had a significant increase in LA dimension at 2 and 4 years, +1.39 mm (95% CI 0.01-2.8) and +3.48 mm (95% CI 1.8-5.2), respectively.A larger baseline LA dimension is associated with progression to CAF. Patients with no or paroxysmal recurrence had no change in LA dimension over a 4-year period. These findings have implications in tailoring modes of therapy in patients with AF.

Carotid sinus syndrome (CSS) is an under recognized cause of recurrent unexplained syncope and potentially of recurrent falls in the elderly. The mechanisms that lead to syncope in patients with CSS remain debated. However, evidence for both peripheral and central alterations have been recently reported. The diagnosis of CSS is challenging and a high clinical suspicion is usually needed to make the diagnosis. Clinical presentation may be typical and characterized by a clear association between accidental manipulation of the carotid sinus and the presentation of syncope. On the other hand, recurrent unexplained syncope and unexplained falls may be the clinical presentation of patients with CSS without a specific trigger. Carotid sinus hypersensitivity documented by carotid sinus massage (CSM) may be the only finding indicating the possibility of CSS as the cause of syncope. In older patients with recurrent unexplained syncope and a negative diagnostic work-up, carotid sinus massage both in the supine and upright positions is recommended. CSS may present primarily as a cardioinhibitory response or a true vasodepressor response. Therapy should address any underlying pathology if present, and be directed to either prevent cardioinhibition, vasodepression or both alterations. A variety of medical therapies have been used with unclear effects. No appropriately designed controlled clinical trials have been performed comparing pacing with medical therapy. Nonetheless, available information indicates that pacing may have a strong beneficial effect and prevents recurrence of syncope in patients with CSS. The present paper critically reviews the latest insights in the pathophysiology, diagnosis and management of CSS.

Background Advances in primary and secondary prevention of sudden death have led to a wide array of potentially beneficial therapies. Identification of patients most likely to benefit would be of use when considering costly interventions such as an implantable defibrillator. We sought to determine the effect of advancing age on the mode of death in the Amiodarone Trialists Metanalysis. Methods and results Patients (n = 6252; age, 61.2±10.5 years; 83% men) were included in an analysis of predictors of sudden death (SD) and all-cause death (ACD), based on baseline variables at enrollment. Patients were divided into 5 age groups: ≤50 years, 51 to 60 years, 61 to 70 years, 71 to 80 years, and >80 years. During a mean of 16.8±10.3 months of follow-up, there were 1023 deaths, with an annual overall mortality rate of 11.7%. Both sudden death and nonsudden death rates increased with age, although the increase of nonsudden death with age was more dramatic. The overall proportion of death that was sudden (SD/ACD ratio) was 0.41, falling from 0.51 before age 50 years to 0.26 after age 80 years (P = .002 for trend). The SD/ACD ratio was not affected by sex, New York Heart Association Class, or left ventricular ejection fraction. Conclusions Although the incidence of sudden death increases with age, the proportion of death that is sudden diminishes markedly. This finding may influence the yield of interventions targeted at prevention of sudden death.

The epidemiology of AF is a challenging and surprising area of medical knowledge. The prevalence of AF may be not changing despite the common perception. It is possible that being earlier disease of the middle age, and because of changing etiology and successful treatment of underlying vascular conditions, AF is shifting to the elderly population. In this population, it becomes more clinically significant, and increasingly leads to disability and death. Screening procedures for silent AF likely are underimplemented and may change understanding of AF epidemiology significantly. Hypertension may be the most common primary etiology of AF, and the possibility of effective primary prevention of AF by strict control of hypertension needs to be evaluated adequately.

Background— The Canadian Trial of Physiological Pacing (CTOPP) reported that the risk of stroke or cardiovascular death was similar between patients receiving ventricular versus physiological pacemakers at the end of the original follow-up period of 3 years. However, the occurrence of atrial fibrillation was significantly less frequent with physiological pacemakers. To assess a potential delayed benefit of physiological pacing, follow-up of patients in this study was extended to 6 years. Methods and Results— A total of 1474 patients requiring a pacemaker for symptomatic bradycardia were randomized to receive ventricular and 1094 to physiological pacemakers. The primary outcome was stroke or cardiovascular death. The study was completed in July 1998, and follow-up was extended to July 2001. At a mean follow-up of 6.4 years, there was no difference between treatment groups in the primary outcome of cardiovascular death or stroke. There was no significant difference in total mortality or stroke between groups. There was a significantly lower rate of development of atrial fibrillation in the physiological group, with a relative risk reduction of 20.1% (CI, 5.4 to 32.5; P =0.009). Conclusions— The CTOPP extended study does not show a difference in cardiovascular death or stroke, or in total mortality, or in stroke between patients implanted with ventricular or physiological pacemakers over a mean follow-up of >6 years. However, there is a persistent significant reduction in the development of atrial fibrillation with physiological pacing.

There is an increased risk of stroke and other cardiovascular events in patients with atrial fibrillation (AF). Three meta-analyses of randomized clinical trials (RCTs) comparing oral anticoagulants (OAC) with aspirin (ASA) arrived at different conclusions regarding the relative efficacy of these agents to prevent ischemic stroke in AF patients. This article summarizes a recently published individual patient meta-analysis of all published RCTs comparing OAC and ASA in AF. In total, 4052 patients randomized to OAC or ASA were similar regarding important prognostic factors. Patients receiving OAC had a significantly lower risk of any stroke (hazard ratio [HR] 0.54 [95% CI 0.43-0.71]), ischemic stroke (HR 0.48 [0.37-0.63]), or cardiovascular events (HR 0.71 [0.59-0.85]). Patients receiving OAC were more likely to experience major bleeding (HR 1.71 [1.21-2.41]). The benefit of OAC was most prominent in patients at a high risk of stroke and other cardiovascular events, such as patients with hypertension, diabetes, or previous cerebrovascular events. Overall, OAC improves outcomes for cardiovascular events in AF patients but modestly increases the absolute risk of major bleeding. Since high-risk AF patients appear to benefit most from OAC, determining stroke risk in AF patients is very important.

Atrial fibrillation (AF) is a common arrhythmia that is associated with an increased risk for vascular events, particularly stroke. Two different therapies have been extensively evaluated for prevention of vascular events in AF: oral anticoagulation (such as warfarin), and aspirin. Placebo-controlled trials of warfarin have been performed and summarized in a meta-analysis. There is clear evidence of a benefit, with a relative risk reduction in stroke of 67% and in total vascular events of 42%. Aspirin also has been studied and is effective, but with a more modest benefit (relative risk reduction of 22%). Several studies have compared warfarin and aspirin, and showed a clear benefit in favor of warfarin for reduction of vascular events and stroke. Compared to aspirin, the risk of major hemorrhage with oral anticoagulation is increased by 70% to 100%. Current practice guidelines recommend oral anticoagulation therapy for high-risk patients with AF, unless there is an increased risk for bleeding. Nonetheless, oral anticoagulation therapy with drugs such as warfarin is difficult for both patients and physicians because of the increased risk for bleeding and the need for ongoing monitoring of coagulation status. Many patients do not receive anticoagulation therapy despite its proven benefits. (J Cardiovasc Electrophysiol, Vol. 14, pp. S52-S55, September 2003, Suppl.)

Objective: This study was undertaken to determine the association between amiodarone therapy and risk of complications of cardiac surgery in patients in the randomized placebo-controlled, double-blind Canadian Amiodarone Myocardial Infarction Arrhythmia Trial. Methods: Prospectively collected data regarding postoperative complications in 82 patients who underwent cardiac surgery during Canadian Amiodarone Myocardial Infarction Arrhythmia Trial participation were analyzed; 36 patients were randomly assigned to receive amiodarone and 46 were assigned to receive placebo. Of the patients randomly assigned to receive amiodarone, 24 patients continued amiodarone treatment to within 7 days of the operation (active amiodarone group) and 12 patients had the amiodarone discontinued at least 7 days before the operation (discontinued amiodarone group). Results: The baseline characteristics of the three groups were similar. The risks of ventricular fibrillation, atrial fibrillation, and respiratory complications were similar. The risk of requiring an intra-aortic balloon pump was significantly increased by amiodarone (34.8% vs 16.7% vs 8.7% for active amiodarone, discontinued amiodarone, and placebo groups, respectively, P =.024). There was no significant difference in the use of temporary pacing. Neither the mean duration of stay in the intensive care unit nor the 7- and 30-days mortalities were affected by amiodarone. Conclusions: Patients receiving long-term amiodarone treatment after myocardial infarction had a higher rate of intra-aortic balloon use after cardiac surgery. There was no increased risk of pulmonary complications, need for pacing, or death. J Thorac Cardiovasc Surg 2003;125:633-7

Post-operative atrial fibrillation is very common. It is associated with increased length of ICU and hospital stay, and costs of post-operative care of patients after cardiac surgery. More then seventy trials on the pharmacological and non-pharmacological interventions were conducted since 1970's. Meta-analysis of these trials, together with detailed analysis of the largest of these trials suggested that conventional beta-blockers, sotalol, amiodarone and bi-atrial overdrive pacing are effective in prevention of post-operative atrial fibrillation. Amiodarone and bi-atrial pacing may decrease the length of hospital stay.

Background Many patients undergoing coronary artery bypass graft (CABG) surgery have risk factors for both atrial fibrillation (AF) and stroke. The left atrial appendage (LAA) is a main source of thrombus coming from the left atrium. LAA occlusion should be tested as a means to reduce future cerebral ischemic events in these patients. Methods The Left Atrial Appendage Occlusion Study (LAAOS) is a randomized clinical trial designed to evaluate the feasibility, safety, and efficacy of LAA occlusion for prevention of ischemic stroke in patients undergoing CABG. The target population consists of patients at risk of AF and stroke who are having routine CABG surgery. The main study will be a prospective, controlled, unblinded trial. Patients at risk of future development of AF, or having AF, will be randomly assigned to undergo or not undergo LAA occlusion. A total of 2500 patients will be randomly assigned and followed for 5 years for the primary outcome of stroke. This study of 2500 patients will have 90% power to detect a relative reduction of 20% in stroke, from a 5-year incidence of 20% in the control group to 16% in the intervention group. Currently, a pilot trial is underway that will enroll 100 patients to assess feasibility, safety, and rates of successful LAA occlusion as assessed by postoperative transesophageal echocardiography. The most suitable surgical technique will also be assessed during the pilot trial. In the pilot study, the main outcomes are safety and rate of successful obliteration of the LAA after surgical occlusion. Conclusions The clinical trial designed to evaluate LAA occlusion at the time of routine CABG surgery is currently in the pilot phase. (Am Heart J 2003;145:174-8.)

BackgroundThe uptake of guideline recommendations that improve heart failure (HF) outcomes remains suboptimal. We reviewed implementation interventions that improve physician adherence to these recommendations, and identified contextual factors associated with implementation success.MethodsWe searched databases from January 1990 to November 2017 for studies testing interventions to improve uptake of class I HF guidelines. We used the Cochrane Effective Practice and Organisation of Care and Process Redesign frameworks for data extraction. Primary outcomes included: proportion of eligible patients offered guideline-recommended pharmacotherapy, self-care education, left ventricular function assessment and/or intracardiac devices. We reported clinical outcomes when available.ResultsWe included 38 studies. Provider-level interventions (n=13 studies) included audit and feedback, reminders and education. Organisation-level interventions (n=18) included medical records system changes, multidisciplinary teams, clinical pathways and continuity of care. System-level interventions (n=3) included provider/institutional incentives. Four studies assessed multi-level interventions. We could not perform meta-analyses due to statistical/conceptual heterogeneity. Thirty-two studies reported significant improvements in at least one primary outcome. Clinical pathways, multidisciplinary teams and multifaceted interventions were most consistently successful in increasing physician uptake of guidelines. Among randomised controlled trials (RCT) (n=10), pharmacist and nurse-led interventions improved target dose prescriptions. Eleven studies reported clinical outcomes; significant improvements were reported in three, including a clinical pathway, a multidisciplinary team and a multifaceted intervention. Baseline assessment of barriers, staff training, iterative intervention development, leadership commitment and policy/financial incentives were associated with intervention effectiveness. Most studies (n=20) had medium risk of bias; nine RCTs had low risk of bias.ConclusionOur study is limited by the quality and heterogeneity of the primary studies. Clinical pathways, multidisciplinary teams and multifaceted interventions appear to be most consistent in increasing guideline uptake. However, improvements in process outcomes were rarely accompanied by improvements in clinical outcomes. Our work highlights the need for improved research methodology to reliably assess the effectiveness of implementation interventions.

Despite major advances in the management of heart failure with angiotensin-converting–enzyme inhibitors, beta-blockers, and resynchronization therapy, there are more than 1 million hospitalizations for heart failure in the United States each year, and mortality remains high.1 As compared with the general population, patients with heart failure have an increased risk of stroke and of systemic thromboembolic events, which are believed to arise from within the heart as a result of left ventricular stasis, endocardial dysfunction, and a systemic hypercoagulable state.2 Heart failure is a risk factor for atrial fibrillation, which, even if asymptomatic, further increases the risk of stroke.3 Consequently, . . .

To the editor: Dabigatran is a new oral direct thrombin inhibitor approved to prevent stroke in atrial fibrillation. It has no antidote, and management of severe bleeding is uncertain. A participant in RE-LY (randomized trial that compared dabigatran with warfarin[1][1]) unintentionally underwent

Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non-valvular atrial fibrillation from the RE-LY trial : reply to a rebuttal

Diabetes mellitus (DM) is frequent among patients with atrial fibrillation (AF). The RE-LY trial permits evaluation of patient characteristics, outcomes and the effectiveness of dabigatran etexilate among diabetic individuals.Patient characteristics and outcomes were compared between diabetic and non-diabetic patients and the relative efficacy of each dose of dabigatran (150 mg bid and 110 mg bid) versus warfarin was evaluated.Of 18,113 patients in RE-LY, 4221 patients (23.3%) had DM. Patients with DM were younger (70.9 vs. 71.7 years), more likely to have hypertension (86.6% vs. 76.5%), coronary artery disease (37.4% vs. 24.9%) and peripheral vascular disease (5.6% vs. 3.2%); (all p0.01). Time in therapeutic range for warfarin-treated patients was 65% for diabetic versus 68% for non-diabetic patients (p0.001). Regardless of assigned treatment, stroke or systemic embolism was more common among patients with DM (1.9% per year vs. 1.3% per year, p0.001). DM was also associated with an increased risk of death (5.1% per year vs. 3.5% per year, p0.001) and major bleeding (4.2% per year vs. 3.0% per year, p0.001). The absolute reduction in stroke or systemic embolism with dabigatran compared to warfarin was greater among patients with DM than those without DM (dabigatran 110 mg: 0.59% per year vs. 0.05% per year; dabigatran 150 mg: 0.89% per year vs. 0.51% per year).Compared to non-DM patients, AF patients with DM derive a greater absolute risk reduction in embolic events when treated with dabigatran. ClinicalTrials.gov Identifier: NCT00262600.

Background Radiation therapy (RT) may pose acute and long-term risks for patients with cardiac implantable electronic devices (CIEDs), including pacemakers (PMs) and implantable cardioverter-defibrillators (ICDs). However, the frequency of these problems has not been accurately defined. Objective The purpose of this study was to determine the prevalence of CIEDs among patients requiring RT and report the common CIED-related problems when patients are managed according to a standard clinical care path. Methods In a single tertiary-care center, we prospectively screened all patients requiring RT and identified patients with ICDs or PMs. We collected clinical data about their cancer, RT treatment plan, and CIED. Radiation dose to the device was estimated in all patients, and any device malfunction during RT was documented. Results Of the 34,706 consecutive patients receiving RT, 261 patients (0.8%, mean age 77.9 ± 9.4 years) had an implantable cardiac device: 54 (20.7%) ICDs and 207 (79.3%) PMs. The site of RT was head and neck (27.4%), chest (30.0%), and abdomen/pelvis (32.6%). Using our care path, 63.2% of patients required continuous cardiac monitoring, 14.6% required device reprogramming, 18.8% required magnet application during RT, and 3.4% required device repositioning to the contralateral side before RT. Four patients (1.5%) had inappropriate device function during RT: 3 experienced hemodynamically tolerated ventricular pacing at the maximum sensor rate, and 1 experienced a device power-on-reset. No patient died or suffered permanent device failure. Conclusion Nearly 1% of patients receiving RT in this series has a PM or ICD. However, with a systematic policy of risk assessment and patient management, significant device-related complications are rare.

International audience; Defibrillation testing by induction and termination of ventricular fibrillation is widely done at the time of implantation of implantable cardioverter defibrillators (ICDs). We aimed to compare the efficacy and safety of ICD implantation without defibrillation testing versus the standard of ICD implantation with defibrillation testing. In this single-blind, randomised, multicentre, non-inferiority trial (Shockless IMPLant Evaluation [SIMPLE]), we recruited patients aged older than 18 years receiving their first ICD for standard indications at 85 hospitals in 18 countries worldwide. Exclusion criteria included pregnancy, awaiting transplantation, particpation in another randomised trial, unavailability for follow-up, or if it was expected that the ICD would have to be implanted on the right-hand side of the chest. Patients undergoing initial implantation of a Boston Scientific ICD were randomly assigned (1:1) using a computer-generated sequence to have either defibrillation testing (testing group) or not (no-testing group). We used random block sizes to conceal treatment allocation from the patients, and randomisation was stratified by clinical centre. Our primary efficacy analysis tested the intention-to-treat population for non-inferiority of no-testing versus testing by use of a composite outcome of arrhythmic death or failed appropriate shock (ie, a shock that did not terminate a spontaneous episode of ventricular tachycardia or fibrillation). The non-inferiority margin was a hazard ratio (HR) of 1·5 calculated from a proportional hazards model with no-testing versus testing as the only covariate; if the upper bound of the 95% CI was less than 1·5, we concluded that ICD insertion without testing was non-inferior to ICD with testing. We examined safety with two, 30 day, adverse event outcome clusters. The trial is registered with ClinicalTrials.gov, number NCT00800384. Between Jan 13, 2009, and April 4, 2011, of 2500 eligible patients, 1253 were randomly assigned to defibrillation testing and 1247 to no-testing, and followed up for a mean of 3·1 years (SD 1·0). The primary outcome of arrhythmic death or failed appropriate shock occurred in fewer patients (90 [7% per year]) in the no-testing group than patients who did receive it (104 [8% per year]; HR 0·86, 95% CI 0·65-1·14; pnon-inferiority

We agree with Professor Haft, in response to our article,1 that the prognostic significance of atrial arrhythmias lasting 17 000 electrograms for AF episodes lasting ≥6 …

Background increasing age is associated with a higher prevalence of atrial fibrillation (AF), and higher risks of stroke and bleeding. We report the effects of apixaban versus acetylsalicylic acid (ASA) in older patients (≥75 years and ≥85 years) compared with younger patients with AF unsuitable for vitamin K antagonists. Methods AVERROES (Apixaban Versus ASA to Prevent Stroke In AF Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment) trial (n = 5,599) included 1,898 patients ≥75 years and 366 patients ≥85 years. We compared the baseline characteristics and effects of apixaban compared with aspirin on clinical outcomes by age. Results compared with aspirin, apixaban was more efficacious for preventing strokes and systemic embolism in patients ≥85 years (absolute rate [AR] 1%/year on apixaban versus 7.5%/year on aspirin; hazard ratio [HR] 0.14, 95% confidence interval [CI] 0.02-0.48) compared with younger patients (AR 1.7%/year on apixaban versus 3.4%/year on aspirin; HR 0.50, 95% CI 0.35-0.69) (P-value for interaction = 0.05). Major haemorrhage was higher in patients ≥85 years compared with younger patients but similar with apixaban versus aspirin in both young and older individuals (4.9%/year versus 1.0%/year on aspirin and 4.7%/year versus 1.2%/year on apixaban) with no significant treatment-by-age interaction (P-value = 0.65). Conclusions older patients with AF are at particularly high risk of stroke if given aspirin and have substantially greater relative and absolute benefits from apixaban compared with younger patients with no greater risk of haemorrhage. Clinical trial registration ClinicalTrials.gov number: NCT00496769. URL: https://clinicaltrials.gov/ct2/show/NCT00496769.

Background The primary aim of this study was to compare quality-of-life outcome between patients randomized to implantable cardioverter defibrillator (ICD) therapy and patients randomized to amiodarone treatment in the Canadian Implantable Defibrillator Study (CIDS). A secondary aim was to evaluate the effects on quality-of-life outcomes of receiving shocks from the device. Methods Quality of life was assessed in 317 English-speaking participants by use of the Rand Corporation's 38-item Mental Health Inventory (MHI) and the Nottingham Health Profile (NHP). Assessments were done in the hospital at baseline and with mailed questionnaires after 2, 6, and 12 months of follow-up. Sixty-two percent of patients completed the follow-up assessments at 6 and 12 months. Results Repeated measures analysis of variance revealed significant time by treatment group interaction effect on total MHI and the psychological distress and psychological well-being sub-scales, and on 5 of the 7 NHP scales (energy, physical mobility, emotional reactions, sleep disturbance, and lifestyle impairment) (P

Background The impact of atrial fibrillation (AF) and its treatment on health-related quality of life (QOL) is not well understood. We assessed QOL in patients with symptomatic AF participating in the Canadian Trial of Atrial Fibrillation. Methods Self-report QOL questionnaires including the Short-Form-36 (SF-36), symptom checklist (SCL) and AF Severity Scale (AFSS) were completed at baseline and 3, and 12 months after randomization. Results The study group was aged 65 ± 10 years and 59% were male. By design, 50% of patients were randomized to amiodarone (n = 132), 25% to sotalol (n = 66), and 25% to propafenone (n = 66). Most patients had normal left ventricular function (89%). Physical (41.9 ± 9.3 to 43.7 ± 9.2, P =.001) and mental health (47.5 ± 10.5 to 49.0 ± 9.8, P =.023) summary measures from the SF-36 improved significantly from baseline to 3 months. Arrhythmia symptom frequency and severity (SCL) also improved markedly from baseline to 3 months (symptom frequency 20.4 ± 9.4 to 16.2 ± 9.5 and symptom severity 16.7 ± 8.2 to 12.9 ± 7.4, both P

Background Azimilide is a novel classification III antiarrhythmic agent that blocks both IKrand IKsand shows evidence of efficacy in patients with atrial fibrillation or flutter. Its effect on paroxysmal supraventricular tachycardia (PSVT) has not been reported. Methods and Results One hundred ninety-three patients with symptomatic PSVT were enrolled in 4 double-blind, randomized, placebo-controlled clinical trials with almost identical trial design (supraventricular arrhythmia-1 [SVA-1], SVA-2, SVA-3, and SVA-4), performed as a separate stratum of studies that also included a stratum of patients with atrial fibrillation or flutter. Patients received oral azimilide (100 mg in SVA-1 and SVA-3, 35 or 75 mg in SVA-2, and 125 mg in SVA-4) or matching placebo twice daily for 3 days (loading period), followed by once-daily dosing (maintenance period). The primary outcome variable was the first recording of a symptomatic supraventricular arrhythmia (either PSVT, atrial fibrillation, or atrial flutter) recorded on a transtelephonic electrocardiographic event recorder. The duration of study was 270 days in SVA-1 and SVA-2 and 180 days in SVA-3 and SVA-4. Combined analysis results of the PSVT stratum from the 4 studies showed a dose-response relationship in prolongation of time to recurrence (P = .02). In the combined 100-mg daily dose, the hazard ratio (placebo:azimilide) was 2.35 (P = .023). The hazard ratio for the 125-mg daily dose measured 1.28 (P = not significant). However, the time to recurrence was prolonged when the patients receiving 100 and 125 mg daily were combined and compared with placebo (P = .02). There were no deaths and 1 case of torsades de pointes. Conclusion These trial results suggest a significant dose-related suppression of PSVT with azimilide, with a low risk of serious adverse events. (Am Heart J 2002;143:643-9.)

The purpose of this study was to assess the effect of azimilide, a Class III antiarrhythmic drug, on ECG conduction intervals recorded during sinus rhythm in patients with a history of symptomatic atrial fibrillation or atrial flutter. In Phase I clinical pharmacology studies, azimilide was associated with prolongation of the QT and QTc intervals on electrocardiograms recorded during sinus rhythm in normal subjects, but the effect of azimilide on the target population of patients with atrial fibrillation has not been reported in detail previously. Patients with a history of atrial fibrillation, atrial flutter, or both were randomly assigned to receive placebo or azimilide twice daily for 3 days and then qd thereafter. Azimilide doses of 50 mg, 100 mg, or 125 mg were tested. The RR, PR, QRS, QT, QTc(Bazett), and QTc(Fridericia) intervals were measured from electrocardiograms recorded at baseline and on Day 4 of test therapy. Increasing azimilide doses were associated with significant increases in the RR, QT, QTc(Bazett), and QTc(Fridericia) compared with changes in the placebo group based on the F-test for differences among treatment groups and the test for a dose response. In the azimilide 125 mg dose group, the mean change in RR was significantly greater than the mean change in the placebo group (+61.4 ms in the azimilide 125 mg group vs. -14.1 ms in the placebo group). The mean change in QT was significantly greater in the azimilide 125 mg group than the mean change in the placebo group (+44.2 ms in the azimilide 125 mg group vs. -1.0 ms in the placebo group). The mean change in QTc using both correction methods was significantly greater in the azimilide 125 mg group than the mean change in the respective placebo group: QTc(Bazett) +31.6 ms in the azimilide 125 mg group versus +2.1 ms in the placebo group and QTc(Fridericia) +35.8 in the azimilide 125 mg group versus +1.0 ms in the placebo group. It was concluded that in patients with a history of atrial fibrillation or flutter, azimilide was associated with statistically significant increases in RR, QT, QTc(Bazett), and QTc(Fridericia) when patients were in sinus rhythm.