Alessandro Capucci

Subclinical Atrial Fibrillation and the Risk of Stroke

BACKGROUND One quarter of strokes are of unknown cause, and subclinical atrial fibrillation may be a common etiologic factor. Pacemakers can detect subclinical episodes of rapid atrial rate, which correlate with electrocardiographically documented atrial fibrillation. We evaluated whether subclinical episodes of rapid atrial rate detected by implanted devices were associated with an increased risk of ischemic stroke in patients who did not have other evidence of atrial fibrillation. METHODS We enrolled 2580 patients, 65 years of age or older, with hypertension and no history of atrial fibrillation, in whom a pacemaker or defibrillator had recently been implanted. We monitored the patients for 3 months to detect subclinical atrial tachyarrhythmias (episodes of atrial rate >190 beats per minute for more than 6 minutes) and followed them for a mean of 2.5 years for the primary outcome of ischemic stroke or systemic embolism. Patients with pacemakers were randomly assigned to receive or not to receive continuous atrial overdrive pacing. RESULTS By 3 months, subclinical atrial tachyarrhythmias detected by implanted devices had occurred in 261 patients (10.1%). Subclinical atrial tachyarrhythmias were associated with an increased risk of clinical atrial fibrillation (hazard ratio, 5.56; 95% confidence interval [CI], 3.78 to 8.17; P<0.001) and of ischemic stroke or systemic embolism (hazard ratio, 2.49; 95% CI, 1.28 to 4.85; P=0.007). Of 51 patients who had a primary outcome event, 11 had had subclinical atrial tachyarrhythmias detected by 3 months, and none had had clinical atrial fibrillation by 3 months. The population attributable risk of stroke or systemic embolism associated with subclinical atrial tachyarrhythmias was 13%. Subclinical atrial tachyarrhythmias remained predictive of the primary outcome after adjustment for predictors of stroke (hazard ratio, 2.50; 95% CI, 1.28 to 4.89; P=0.008). Continuous atrial overdrive pacing did not prevent atrial fibrillation. CONCLUSIONS Subclinical atrial tachyarrhythmias, without clinical atrial fibrillation, occurred frequently in patients with pacemakers and were associated with a significantly increased risk of ischemic stroke or systemic embolism. (Funded by St. Jude Medical; ASSERT ClinicalTrials.gov number, NCT00256152.).

Dronedarone for prevention of atrial fibrillation: A dose-ranging study

AIMS Dronedarone, a benzofurane derivative without iodine substituents, shares the electrophysiologic properties of amiodarone. This study was designed to determine the most appropriate dose of dronedarone for prevention of atrial fibrillation (AF) after cardioversion. METHODS AND RESULTS Patients with persistent AF were randomly allocated to 800, 1200, 1600 mg daily doses of dronedarone or placebo. The main analysis was conducted on 199/270 patients, who entered the maintenance phase following pharmacological cardioversion or, if unsuccessful, DC cardioversion. Within 6-month follow-up, the time to AF relapse increased on dronedarone 800 mg, with a median of 60 days vs 5.3 days in the placebo group (relative risk reduction 55% [95% CI, 28 to 72%] P=0.001). No significant effect was seen at higher doses. Spontaneous conversion to sinus rhythm on dronedarone occurred in 5.8 to 14.8% of patients (P=0.026). There were no proarrhythmic reactions. Drug-induced QT prolongation was only noticed in the 1600 mg group. Premature drug discontinuations affected 22.6% of subjects given 1600 mg dronedarone versus 3.9% on 800 mg and were mainly due to gastrointestinal side effects. No evidence of thyroid, ocular or pulmonary toxicity was found. CONCLUSION Dronedarone, at a 800 mg daily dose, appears to be effective and safe for the prevention of AF relapses after cardioversion. The absence of thyroid side effects and of proarrhythmia are important features of the drug. Further studies are needed to better delineate the antiarrhythmic profile of the drug.

Temporal Relationship Between Subclinical Atrial Fibrillation and Embolic Events

Background— Among patients with implantable pacemakers and defibrillators, subclinical atrial fibrillation (SCAF) is associated with an increased risk of stroke; however, there is limited understanding of their temporal relationship. Methods and Results— The Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the Atrial Fibrillation Reduction Atrial Pacing Trial (ASSERT) enrolled 2580 pacemaker and defibrillator patients aged ≥65 years with a history of hypertension but without a history of atrial fibrillation. Pacemakers and implantable cardioverter-defibrillators precisely logged the time and duration of all episodes of SCAF and recorded electrograms that were adjudicated by experts. We examined the temporal relationship between SCAF >6 minutes in duration and stroke or systemic embolism. Of 51 patients who experienced stroke or systemic embolism during follow-up, 26 (51%) had SCAF. In 18 patients (35%), SCAF was detected before stroke or systemic embolism. However, only 4 patients (8%) had SCAF detected within 30 days before stroke or systemic embolism, and only 1 of these 4 patients was experiencing SCAF at the time of the stroke. In the 14 patients with SCAF detected >30 days before stroke or systemic embolism, the most recent episode occurred at a median interval of 339 days (25th to 75th percentile, 211–619) earlier. Eight patients (16%) had SCAF detected only after their stroke, despite continuous monitoring for a median duration of 228 days (25th to 75th percentile, 202–719) before their event. Conclusions— Although SCAF is associated with an increased risk of stroke and embolism, very few patients had SCAF in the month before their event. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00256152.

Effectiveness of loading oral flecainide for converting recent-onset atrial fibrillation to sinus rhythm in patients without organic heart disease or with only systemic hypertension

Sixty-two patients with recent-onset (less than or equal to 1 week) atrial fibrillation (New York Heart Association functional class 1 and 2) were randomized in a single-blind study to 1 of the following treatment groups: (1) flecainide (300 mg) as a single oral loading dose; or (2) amiodarone (5 mg/kg) as an intravenous bolus, followed by 1.8 g/day; or (3) placebo for the first 8 hours. Twenty-four-hour Holter recording was performed, and conversion to sinus rhythm at 3, 8, 12 and 24 hours was considered as the criterion of efficacy. Conversion to sinus rhythm was achieved within 8 hours (placebo-controlled period) in 20 of 22 patients (91%) treated with flecainide, 7 of 19 (37%) treated with amiodarone (p less than 0.001 vs flecainide), and 10 of 21 (48%) treated with placebo (p less than 0.01 vs flecainide). Resumption of sinus rhythm within 24 hours occurred in 21 of 22 patients (95%) with flecainide and in 17 of 19 (89%) with amiodarone (p = not significant). Mean conversion times were shorter for flecainide (190 +/- 147 minutes) than for amiodarone (705 +/- 418; p less than 0.001). No major side effects occurred. At Holter monitoring, a pause of 9.3 seconds was observed in 1 asymptomatic patient treated with flecainide. Phases of atrial flutter with a ventricular rate less than or equal to 150 beats/min were detected before sinus conversion in 1 patient receiving placebo and in 2 receiving flecainide.(ABSTRACT TRUNCATED AT 250 WORDS)

A Randomized Active-Controlled Study Comparing the Efficacy and Safety of Vernakalant to Amiodarone in Recent-Onset Atrial Fibrillation

OBJECTIVES This randomized double-blind study compared the efficacy and safety of intravenous vernakalant and amiodarone for the acute conversion of recent-onset atrial fibrillation (AF). BACKGROUND Intravenous vernakalant has effectively converted recent-onset AF and was well tolerated in placebo-controlled studies. METHODS A total of 254 adult patients with AF (3 to 48 h duration) eligible for cardioversion were enrolled in the study. Patients received either a 10-min infusion of vernakalant (3 mg/kg) followed by a 15-min observation period and a second 10-min infusion (2 mg/kg) if still in AF, plus a sham amiodarone infusion, or a 60-min infusion of amiodarone (5 mg/kg) followed by a maintenance infusion (50 mg) over an additional 60 min, plus a sham vernakalant infusion. RESULTS Conversion from AF to sinus rhythm within the first 90 min (primary end point) was achieved in 60 of 116 (51.7%) vernakalant patients compared with 6 of 116 (5.2%) amiodarone patients (p < 0.0001). Vernakalant resulted in rapid conversion (median time of 11 min in responders) and was associated with a higher rate of symptom relief compared with amiodarone (53.4% of vernakalant patients reported no AF symptoms at 90 min compared with 32.8% of amiodarone patients; p = 0.0012). Serious adverse events or events leading to discontinuation of study drug were uncommon. There were no cases of torsades de pointes, ventricular fibrillation, or polymorphic or sustained ventricular tachycardia. CONCLUSIONS Vernakalant demonstrated efficacy superior to amiodarone for acute conversion of recent-onset AF. Both vernakalant and amiodarone were safe and well tolerated in this study. (A Phase III Superiority Study of Vernakalant vs Amiodarone in Subjects With Recent Onset Atrial Fibrillation [AVRO]; NCT00668759).

Dynamic Electrophysiological Behavior of Human Atria During Paroxysmal Atrial Fibrillation

BACKGROUND The aims of our study were to investigate the meaning of local atrial activation and its behavior during paroxysmal atrial fibrillation and to study the effect of overdrive pacing on local atrial activity. METHODS AND RESULTS Twenty-five patients with lone paroxysmal atrial fibrillation underwent electrophysiological study. Functional and effective atrial refractoriness was determined. Mean and fifth percentile values of 100 consecutive atrial fibrillation intervals (FF) were evaluated at three atrial sites either at arrhythmia onset or at self-termination (or at minute 5). A high-voltage burst pacing was performed after 6 minutes of stable atrial fibrillation in 10 patients. Mean FF intervals were evaluated 5 seconds before and after atrial pacing. Forty-nine atrial fibrillation episodes were induced: 39 self-terminating within 5 minutes and 10 long-lasting. A significant correlation was found between mean FF and atrial functional refractory period (r = .73, P < .001) and between fifth percentile FF and atrial effective refractory period (r = .57, P < .005). Atrial fibrillation self-termination was associated with significant mean FF prolongation, whereas long-lasting fibrillation behaved the opposite. In 10 patients, burst pacing resulted in significant shortening of the mean FF at the stimulation site; no changes were observed in the two distant recording sites. CONCLUSIONS The analysis of the FF intervals demonstrates a strict correlation with atrial functional refractoriness. The self-termination of atrial fibrillation is related to a prolongation of the functional refractoriness (mean FF), whereas a shortening of both functional and effective refractoriness (fifth percentile) is associated with atrial fibrillation persistence. The provoked shortening of the mean FF at the stimulation site is consistent with the presence of a gap of excitability during atrial fibrillation in the human atria.

Improving Stroke Risk Stratification Using the CHADS2 and CHA2DS2-VASc Risk Scores in Patients With Paroxysmal Atrial Fibrillation by Continuous Arrhythmia Burden Monitoring

Background and Purpose— In patients with atrial fibrillation (AF), stroke risk stratification schema do not consider AF parameters. The aim of the study is to assess the impact of combining risk factors with continuous AF burden monitoring. Methods— In this retrospective study 568 patients implanted with a DDDR-P pacemaker (AT-500; Medtronic) and a history of AF were continuously monitored for 1 year. Results— During follow-up, 14 patients (2.5%) had a thromboembolic event. Patients were divided into 3 groups: AF burden ⩽5 minutes per day (AF-free; n=223 [39%]), AF burden >5 minutes but <24 hours per day (AF-5 minutes; n=179 [32%]), and AF burden ≥24 hours (AF-24 hours; n=166 [29%]). Patients were also classified according to CHADS2 and CHA2DS2-VASc risk scores. The discrimination ability of each risk score was evaluated performing a logistic regression analysis and calculating the corresponding C-statistic. The addition of AF burden improved C-statistics: for CHADS2 from 0.653 (P=0.051) to 0.713 (P=0.007); for CHA2DS2-VASc, from 0.898 (P<0.0001) to 0.910 (P<0.0001). Conclusions— The CHA2DS2-VASc score had a high sensitivity to predict thromboembolism. Implementation of device data on AF presence/duration/burden has the potential to contribute to improved clinical risk stratification and should be tested prospectively.

Oral Propafenone To Convert Recent-Onset Atrial Fibrillation in Patients with and without Underlying Heart Disease: A Randomized, Controlled Trial

The optimal way to convert recent-onset atrial fibrillation to sinus rhythm is a subject of much debate. The effectiveness of intravenous propafenone has been shown [1-3], but the full antiarrhythmic effect of this regimen depends not only on the parent compound but on its 5-hydroxylated metabolite [4, 5]. This dependence provides a strong rationale for the use of oral loading regimens [3]. Results of previous controlled studies have shown that oral loading of propafenone is highly effective in converting recent-onset atrial fibrillation to sinus rhythm [6, 7]. Safety is a major concern with antiarrhythmic therapy. One of the primary proarrhythmic risks of propafenone and flecainide is the transformation of atrial fibrillation to flutter with 1:1 atrioventricular conduction and hemodynamic impairment [8-10]. We sought to determine whether the effectiveness and safety of propafenone differ in patients who have structural heart disease and patients who do not. Methods From June 1990 to June 1994, consecutive patients with recent-onset atrial fibrillation ( 7 days) who presented to one of three centers were considered for enrollment. Onset of arrhythmia was documented by electrocardiography or by an abrupt onset of palpitations with subsequent evidence of atrial fibrillation on electrocardiography. Patients were excluded for any of the following reasons: age greater than 80 years, heart failure greater than NYHA (New York Heart Association) class II, mean ventricular rate during atrial fibrillation less than 70 beats/min, recent myocardial infarction (within <6 months), unstable angina pectoris, previous or current electrocardiographic evidence ventricular preexcitation or complete bundle-branch block, previous electrocardiographic evidence of second- or third-degree atrioventricular block or bifascicular block, the sick sinus syndrome, hypokalemia (potassium level <3.5 mEq/L), renal or hepatic failure with severe hypoxia (Pao 2 < 55 mm Hg), severe metabolic disturbances, or known thyroid dysfunction. Patients who were receiving long-term digoxin therapy or antiarrhythmic drugs or had received such treatments within 8 hours before study entry were also excluded. Patients who had atrial fibrillation that lasted 72 hours or longer were enrolled only if they were receiving long-term warfarin therapy for anticoagulation. Patients provided informed consent. Eligible patients had a 24-hour Holter monitor applied; after 1 to 2 hours of observation to assess the stability of atrial fibrillation, they were randomly assigned by center in a single-blind manner to receive propafenone (300 mg in two tablets as a single oral dose) or placebo. All patients received intravenous saline throughout the study period. The electrocardiogram was monitored by telemetry, blood pressure was measured every 2 hours, and 12-lead electrocardiography was done every hour for the first 4 hours and then every 2 hours for the next 4 hours. When patients converted to sinus rhythm, 12-lead electrocardiography was done immediately. Conversion was defined as a stable sinus rhythm that lasted for at least 1 hour. Eight hours after the study drug was administered, physicians could continue treatment with the study drug or switch to a different therapeutic option. Holter monitor tapes were analyzed by two blinded observers using computer scanning systems (Marquette 8000, Milwaukee, Wisconsin, and Del Mar Avionics, Irvine, California) to determine the time of conversion to sinus rhythm and whether an abnormal rhythm was present. Within 24 hours after enrollment, echocardiography was done for each patient and left atrial diameter was measured in the left parasternal long-axis view. On the basis of clinical history and the results of physical examination, echocardiography, and chest radiography, patients were classified as having structural heart disease (defined as the presence of cardiac abnormalities other than atrial fibrillation), hypertension without structural heart disease (defined as previously recognized systemic hypertension according to the criteria of the World Health Organization), or neither. Continuous outcomes and baseline characteristics of the patients were compared by using the chi-square statistic and t-test as appropriate. The rates of conversion to sinus rhythm were assessed at 3 and 8 hours. Odds ratios and corresponding CIs were calculated according to the methods of Gardner and Altman [11]. We did logistic regression analysis to describe how the interaction of treatment with the presence or absence of heart disease and hypertension affected the probability of conversion to sinus rhythm. Analyses were done using SPS software, version 6.1.3 (SPS, Inc., Chicago, Illinois). Results Patients During the study period, 407 patients presented to the three centers and were screened for eligibility. Two hundred forty-three patients were eligible, and 240 gave consent. A total of 164 patients were excluded for one or more of the following reasons: age greater than 80 years (n = 10), heart failure greater than NYHA class II (n = 33), recent myocardial infarction (n = 20), bundle-branch block (n = 24), the sick sinus syndrome (n = 6), severe hypoxia (n = 13), thyroid dysfunction (n = 12), and previous antiarrhythmic treatment (n = 63). Two hundred forty patients were randomly assigned to receive propafenone (n = 119) or placebo (n = 121). The two groups were similar with regard to age, sex, cause of atrial fibrillation, NYHA class, left atrial dimension (measured by echocardiography), structural heart disease, and hypertension (Table 1). The duration of atrial fibrillation before randomization ranged from 2.5 to 120 hours and did not differ significantly between the treatment groups. Table 1. Patient Characteristics Conversion to Sinus Rhythm and Presence of Heart Disease The probability of conversion to sinus rhythm was greater after propafenone than after placebo at 3 and 8 hours (P < 0.001) (Figure 1). Corresponding odds ratios were 3.8 (95% CI, 2.1 to 6.8) at 3 hours and 5.4 (CI, 3.0 to 9.4) at 8 hours. Figure 1. Conversion to sinus rhythm within 8 hours in patients receiving propafenone or placebo. At 8 hours, the probability of conversion to sinus rhythm was significantly higher in the propafenone group than in the placebo group for patients who had heart disease (odds ratio, 21.7 [CI, 5.9 to 80.1]; P < 0.001), patients who had hypertension (odds ratio, 6.4 [CI, 2.3 to 17.6]; P < 0.001), and patients who did not have structural heart disease (odds ratio, 2.8 [CI, 1.2 to 6.7]; P = 0.02). Conversion rates at 8 hours for patients receiving propafenone were similar among the three heart disease subgroups, but conversion rates for patients receiving placebo differed significantly (56% for patients without structural heart disease, 27% for patients with hypertension, and 17% patients with structural heart disease [P = 0.009 by logistic regression model]). At 3 hours, the probability of conversion to sinus rhythm was higher in the propafenone group than in the placebo group for patients who did not have heart disease (48% for propafenone compared with 26% for placebo; odds ratio, 2.6 [CI, 1.2 to 6.0]; P = 0.02), patients who had hypertension (41% for propafenone compared with 16% for placebo; odds ratio, 3.5 [CI, 1.2 to 10.5]; P = 0.02), and patients who had structural heart disease (47% for propafenone compared with 7% for placebo; odds ratio, 12.3 [CI, 2.5 to 60.5]; P < 0.001). By logistic regression analysis, no significant correlation between heart disease and treatment was seen at 3 hours (P = 0.2). Mean time SD for conversion to sinus rhythm within 8 hours was 181 118 minutes for propafenone and 181 112 minutes for placebo (P > 0.2). Adverse Effects Sustained atrial flutter or tachycardia (lasting 1 min) occurred in eight patients (7%) receiving propafenone and seven patients (6%) receiving placebo (P > 0.2), regardless of heart disease status. Among these patients, atrioventricular conduction was 2:1 in two patients receiving propafenone (heart rate, 115 to 140 beats/min) and three patients receiving placebo (heart rate, 120 to 150 beats/min), 3:1 in six patients receiving propafenone (heart rate, 60 to 95 beats/min) and three patients receiving placebo (heart rate, 60 to 100 beats/min), and 1:1 in one patient receiving placebo (heart rate, 240 beats/min). This patient developed atrial flutter and collapsed. Pauses in ventricular rate lasting longer than 2 seconds were seen in one patient (1%) receiving propafenone and three patients (2%) receiving placebo (P > 0.2). Among patients receiving propafenone, nine (8%) had the following adverse effects: QRS complexes of the electrocardiogram greater than 120 ms (n = 3), hypotension (n = 2), slight hypotension and bradycardia at conversion (n = 3), and phases of junctional rhythm after conversion (n = 1). No ventricular proarrhythmic effects occurred. Discussion Oral loading of propafenone was effective for conversion to sinus rhythm in our study, as it has been in smaller studies [3, 6, 7, 12, 13]. The recent findings of Wijffels and colleagues [14] in a model of chronic atrial fibrillation in animals indicate that electrophysiologic remodeling occurs within a few hours of persistent atrial fibrillation and results primarily from changes in atrial refractoriness that enhance the persistence of atrial fibrillation. This observation provides a strong rationale for prompt conversion to sinus rhythm. Therefore, oral loading of propafenone (which has an effectiveness similar to that of intravenous propafenone [3]) offers many advantages over such regimens as oral quinidine and intravenous amiodarone, which require titration of dose or a longer period of time to achieve an effect [6, 13, 15]. In controlled trials, propafenone was shown to be more effective and to take effect more quickly than amiodarone [13] or digoxin plus quinidine [6]. Intravenous amiodarone was no more effective than placebo and

A controlled study on oral propafenone versus digoxin plus quinidine in converting recent onset atrial fibrillation to sinus rhythm

UNLABELLED Eighty-seven patients with recent onset atrial fibrillation (< or = 8 days) without clinical signs of heart failure were randomly allocated to one of the following treatments: (i) oral propafenone (600 mg as a loading dose followed after 8 h by 300 mg t.i.d.); (ii) intravenous digoxin as acute scheme (up to 1.125 mg/24 h) followed after 6 h by hydroquinidine chlorhydrate (total dose, 1350 mg); or (iii) placebo. The patients were submitted to Holter monitoring for 48 h. RESULTS propafenone achieved higher successful conversion rates at 6, 12 and 24 h compared either with placebo (62% vs. 17%, 83% vs. 34%; 86% vs. 55%; P < 0.01, respectively) or with digoxin at 6 h (62% vs. 38%; P < 0.05) and digoxin plus quinidine at 12 h (83% vs. 48%; P < 0.05). At 48 h, a placebo conversion rate of 76% was observed with consequent lack of any significant difference with the active treatments. Mean conversion times within 48 h were 267 +/- 238 min for propafenone, 648 +/- 631 min for digoxin plus quinidine (P < 0.01 vs. propafenone) and 893 +/- 622 min for placebo (P < 0.001 vs. propafenone). Propafenone and digoxin plasma levels were within the therapeutic range. Asymptomatic phases of atrial flutter with > or = 2:1 atrio-ventricular conduction ratio were observed during Holter monitoring, before conversion to sinus rhythm, in four patients treated with propafenone, in one patient taking digoxin plus quinidine and in four patients with placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Reduced Peripheral Skeletal Muscle Mass and Abnormal Reflex Physiology in Chronic Heart Failure

Background— The muscle hypothesis implicates abnormalities in peripheral muscle as a source for the stimulus to the symptoms and reflex abnormalities seen in chronic heart failure (CHF). We investigated the relationship between skeletal muscle mass (with dual-energy x-ray absorptiometry) and activation of the ergoreflex (a peripheral reflex originating in skeletal muscle sensitive to products of muscle work) in CHF patients and whether this rapport is affected by the progression of the syndrome. Methods and Results— We assessed 107 consecutive CHF patients (mean age, 61.9±10.9 years; 95% male; 25 cachectics) and 24 age-matched normal subjects (mean age, 59.0±11.1 years; 91% male). Compared with normal subjects, patients had a higher ergoreflex (in ventilation, 6.2±.6.1 versus 0.6±0.6 L/min; P<0.0001) and a reduction in muscle mass (51.9±10.0 versus 60.3±8.8 kg; P<0.001). The ergoreflex was particularly overactive in cachectics (P<0.05), accompanied by marked muscle mass depletion (P<0.0005). In CHF, ergoreceptor hyperresponsiveness in both the arm and leg correlated with reduced muscle mass, abnormal indexes of exercise tolerance (peak &OV0312;o2, &OV0312;e/&OV0312;co2 slope), ejection fraction, and NYHA functional class (P<0.0001). In the cachectic population, the ventilatory response from ergoreflex to arm exercise was strongly inversely correlated with arm (r=−0.65), leg (r=−0.64), and total (r=−0.61) lean tissues (P<0.001 for all). Multivariate analysis showed that these relationships were independent of NYHA class, peak &OV0312;o2, and &OV0312;e/&OV0312;co2 slope. Conclusions— Depleted peripheral muscle mass is associated with ergoreflex overactivity and exercise limitation in CHF, particularly in cachectic patients. The systemic activation of the muscle reflex system in CHF may reflect progression and deterioration of the clinical syndrome.