James A. Reiffel

Efficacy and Safety of Prescription Omega-3 Fatty Acids for the Prevention of Recurrent Symptomatic Atrial Fibrillation: A Randomized Controlled Trial

CONTEXT Atrial fibrillation (AF) is common, yet there remains an unmet medical need for additional treatment options. Current pharmacological treatments have limited efficacy and significant adverse events. Limited data from small trials suggest omega-3 polyunsaturated fatty acids may provide a safe, effective treatment option for AF patients. OBJECTIVE To evaluate the safety and efficacy of prescription omega-3 fatty acids (prescription omega-3) for the prevention of recurrent symptomatic AF. DESIGN, SETTING, AND PARTICIPANTS Prospective, randomized, double-blind, placebo-controlled, parallel-group multicenter trial involving 663 US outpatient participants with confirmed symptomatic paroxysmal (n = 542) or persistent (n = 121) AF, with no substantial structural heart disease, and in normal sinus rhythm at baseline were recruited from November 2006 to July 2009 (final follow-up was January 2010). INTERVENTIONS Prescription omega-3 (8 g/d) or placebo for the first 7 days; prescription omega-3 (4 g/d) or placebo thereafter through week 24. MAIN OUTCOME MEASURES The primary end point was symptomatic recurrence of AF (first recurrence) in participants with paroxysmal AF. Secondary analyses included first recurrence in the persistent stratum and both strata combined. Participants were followed up for 6 months. RESULTS At 24 weeks, in the paroxysmal AF stratum, 129 of 269 participants (48%) in the placebo group and 135 of 258 participants (52%) in the prescription group had a recurrent symptomatic AF or flutter event. In the persistent AF stratum, 18 participants (33%) in the placebo group and 32 (50%) in the prescription group had documented symptomatic AF or flutter events. There was no difference between treatment groups for recurrence of symptomatic AF in the paroxysmal stratum (hazard ratio [HR], 1.15; 95% confidence interval [CI], 0.90-1.46; P = .26), in the persistent stratum (HR, 1.64; 95% CI, 0.92-2.92; P = .09), and both strata combined (HR, 1.22; 95% CI, 0.98-1.52; P = .08). Other, secondary end points were supportive of the primary result. A total of 5% of those receiving placebo and 4% of those receiving prescription omega-3 discontinued due to adverse events. Eicosapentaenoic and docosahexaenoic acid blood levels were significantly higher in the prescription group than in the placebo group at weeks 4 and 24. CONCLUSION Among participants with paroxysmal AF, 24-week treatment with prescription omega-3 compared with placebo did not reduce recurrent AF over 6 months. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00402363.

Autonomic nervous system influences on QT interval in normal subjects

OBJECTIVES We sought to determine whether the relationship between heart rate (HR) and QT interval (QT) differs as HR increases in response to exercise, atropine and isoproterenol. BACKGROUND Autonomic nervous system influences on repolarization are poorly understood and may complicate the interpretation of QT measurements. METHODS Twenty-five normal subjects sequentially underwent graded-intensity bicycle exercise, atropine injection and isoproterenol infusion. Serial 12-lead electrocardiograms were recorded at steady state during each condition and analyzed using interactive computer software. The HR-QT data were modeled linearly and the slopes (quantifying QT adaptation to HR) as well as the QT intervals at 100 beats/min for each intervention were compared by repeated-measures analysis of variance. RESULTS As HR increased, QT was longer for isoproterenol in comparison to exercise or atropine, which were similar. The HR-QT slope (ms/beats/min) was less steep for isoproterenol (-0.83 +/- 0.53) than for atropine (-1.45 +/- 0.21) or exercise (-1.37 +/- 0.23) (p < 0.0001). In comparison to men, women had more negative HR-QT slopes during all interventions. At 100 beats/min, the QT was 364 ms during isoproterenol, which was significantly longer than that during exercise (330 ms) or atropine (339 ms) (p < 0.0001). Isoproterenol produced a dose-dependent increase in U-wave amplitude that was not observed during exercise or atropine. CONCLUSIONS In comparison to exercise and atropine, isoproterenol is associated with much less QT shortening for a given increase in HR and, therefore, greater absolute QT intervals. Our findings demonstrate that autonomic conditions directly affect the ventricular myocardium of healthy subjects, causing differences in QT that are independent of HR.

Response to programmed ventricular stimulation: Sensitivity, specificity and relation to heart disease☆

This prospective study of 100 patients evaluated the sensitivity and specificity of the repetitive ventricular response and ventricular tachycardia induced by programmed electrical stimulation for identifying patients with spontaneous ventricular tachyarrhythmias. The influence of underlying heart disease on such sensitivity and specificity was also evaluated. The repetitive ventricular response was sensitive (92 percent) for detecting patients with prior spontaneous ventricular tachyarrhythmias, but lacked specificity (57 percent); the rate of false positive responses was 43 percent. Inducible ventricular tachycardia was less sensitive (65 percent) but more specific (98 percent); the rate of false positive responses was only 3 percent. Among the 100 patients, 71 had heart disease, 29 did not. The presence of underlying heart disease had no significant effect on the sensitivity and specificity of repetitive ventricular responses or ventricular tachycardia induced by programmed stimulation; it did not increase the rate of false positive responses. It is concluded that (1) ventricular tachycardia induced with programmed ventricular stimulation is an excellent basis for guiding the management of clinically significant ventricular tachyarrhythmias, regardless of underlying heart disease; and (2) the repetitive ventricular response is not useful for this purpose because of its high rate of false positive responses among patients with or without significant heart disease.

Personalized management of atrial fibrillation: Proceedings from the fourth Atrial Fibrillation competence NETwork/European Heart Rhythm Association consensus conference.

The management of atrial fibrillation (AF) has seen marked changes in past years, with the introduction of new oral anticoagulants, new antiarrhythmic drugs, and the emergence of catheter ablation as a common intervention for rhythm control. Furthermore, new technologies enhance our ability to detect AF. Most clinical management decisions in AF patients can be based on validated parameters that encompass type of presentation, clinical factors, electrocardiogram analysis, and cardiac imaging. Despite these advances, patients with AF are still at increased risk for death, stroke, heart failure, and hospitalizations. During the fourth Atrial Fibrillation competence NETwork/European Heart Rhythm Association (AFNET/EHRA) consensus conference, we identified the following opportunities to personalize management of AF in a better manner with a view to improve outcomes by integrating atrial morphology and damage, brain imaging, information on genetic predisposition, systemic or local inflammation, and markers for cardiac strain. Each of these promising avenues requires validation in the context of existing risk factors in patients. More importantly, a new taxonomy of AF may be needed based on the pathophysiological type of AF to allow personalized management of AF to come to full fruition. Continued translational research efforts are needed to personalize management of this prevalent disease in a better manner. All the efforts are expected to improve the management of patients with AF based on personalized therapy.

Importance of beta blockade in the therapy of serious ventricular arrhythmias

Beta blockers have traditionally been considered relatively poor antiarrhythmic agents for patients with ventricular arrhythmias. This view is based on the observations that beta blockers are less effective in suppressing spontaneous ventricular ectopy or inducible ventricular arrhythmias than are the class I and class III agents. However, there are convincing data that beta blockers can have a clinically important antiarrhythmic effect and prevent arrhythmic and sudden death. Beta blockers have multiple potential effects that can contribute to a therapeutic antiarrhythmic action, including an antiadrenergic/vagomimetic effect, a decrease in ventricular fibrillation threshold, and prevention of a catecholamine reversal of concomitant class I/III antiarrhythmic drug effects. Postinfarction trials, recent congestive heart failure studies, and observations in patients who are at risk for sustained ventricular arrhythmias all suggest a potent antiarrhythmic effect of beta blockade.

Beta-blocker use and survival in patients with ventricular fibrillation or symptomatic ventricular tachycardia: the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial.

OBJECTIVES To evaluate whether use of beta-adrenergic blocking agents, alone or in combination with specific antiarrhythmic therapy, is associated with improved survival in persons with ventricular fibrillation (VF) or symptomatic ventricular tachycardia (VT). BACKGROUND The ability of beta-blockers to alter the mortality of patients with VF or VT receiving contemporary medical management is not well defined. METHODS Survival of 1,016 randomized and 2,101 eligible, nonrandomized patients with VF or symptomatic VT followed in the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial through December 31, 1996 was assessed using Cox proportional hazards analysis. RESULTS The 817 (28%) patients discharged from hospital receiving beta-blockers had less ventricular dysfunction, fewer symptoms of heart failure and a different pattern of medication use compared with patients not receiving beta-blockers. Before adjustment for important prognostic variables, beta-blockade was not significantly associated with survival in randomized or in eligible, nonrandomized patients treated with specific antiarrhythmic therapy. After adjustment, beta-blockade remained unrelated to survival in randomized or in eligible, nonrandomized patients treated with amiodarone alone (n = 1142; adjusted relative risk [RR] = 0.96; 95% confidence interval [CI] 0.64-1.45; p = 0.85) or a defibrillator alone (n = 1347; adjusted RR = 0.88; 95% CI 0.55 to 1.40; p = 0.58). In contrast, beta-blockade was independently associated with improved survival in eligible, nonrandomized patients who were not treated with specific antiarrhythmic therapy (n = 412; adjusted RR = 0.47; 95% CI 0.25 to 0.88; p = 0.018). CONCLUSIONS Beta-blocker use was independently associated with improved survival in patients with VF or symptomatic VT who were not treated with specific antiarrhythmic therapy, but a protective effect was not prominent in patients already receiving amiodarone or a defibrillator.

Safety of Bisphosphonates in the Treatment of Osteoporosis

In this review 4 experts consider the major safety concerns relating to bisphosphonate therapy for osteoporosis. Specific topics covered are skeletal safety (particularly with respect to atypical fractures and delayed healing), gastrointestinal intolerance, hypocalcemia, acute-phase (i.e., postdose) reactions, chronic musculoskeletal pain, renal safety, and cardiovascular safety (specifically, atrial fibrillation).

The human sinus node electrogram: a transvenous catheter technique and a comparison of directly measured and indirectly estimated sinoatrial conduction time in adults.

To improve methods for evaluating human sinus node function (SNF), we developed a transvenous electrode catheter technique for direct recording of sinus node electrograms in adults. Sinus node electrograms (SNE) characterized by low-frequency, anatomically localized pre-P-wave potentials were obtained in 19 of 23 patients. The SNE configuration was similar to that previously found for endocardial SNE recordings in in vitro atrial preparations, in open-chest dogs and during human open heart surgery. In 16 patients with normal SNF, directly recorded sinoatrial conduction times (SACTs) were 46-116 msec. In three patients with sick sinus syndrome, SACT was 110-126 msec. In 15 of the 19 patients, SACT was estimated by the atrial premature stimulus technique and was compared with the directly measured SACT. When atrial premature depolarizations produced no sinus node depression, the mean difference between the direct and estimated SACT was 1.8 ± 5.6 msec.

The Effect of Quinidine and Other Oral Antiarrhythmic Drugs on Serum Digoxin: A Prospective Study

We compared the effects of quinidine and three alternate antiarrhythmic drugs on serum digoxin concentration in 63 patients before and during administration of quinidine, procainamide, disopyramide, or mexiletine. Quinidine increased digoxin concentration by at least 0.5 nmol/L in 21 of 22 patients: Mean serum digoxin rose from 1.2 nmol/L to 2.4 nmol/L (P less than 0.001). Procainamide, disopyramide, or mexiletine increased serum digoxin by 0.5 nmol/L in one of 41 patients. Anorexia, nausea, and vomiting develop soon after starting quinidine therapy in 10 of the 22 patients who received quinidine but in only five of the 41 patients who received procainamide, disopyramide, or mexiletine (P less than 0.01). Quinidine prolonged the PR intervals from 160 +/- 14 ms to 183 +/- 26 ms, but procainamide, disopyramide, and mexiletine did not change the PR interval (P less than 0.005). In digitalized patients, quinidine increases serum digoxin concentration, increases digoxins effect on atrioventricular conduction, and produces more adverse gastrointestinal effects than procainamide, disopyramide, or mexiletine.

The HARMONY Trial: Combined Ranolazine and Dronedarone in the Management of Paroxysmal Atrial Fibrillation: Mechanistic and Therapeutic Synergism

Background—Atrial fibrillation (AF) requires arrhythmogenic changes in atrial ion channels/receptors and usually altered atrial structure. AF is commonly treated with antiarrhythmic drugs; the most effective block many ion channels/receptors. Modest efficacy, intolerance, and safety concerns limit current antiarrhythmic drugs. We hypothesized that combining agents with multiple anti-AF mechanisms at reduced individual drug doses might produce synergistic efficacy plus better tolerance/safety. Methods and Results—HARMONY tested midrange ranolazine (750 mg BID) combined with 2 reduced dronedarone doses (150 mg BID and 225 mg BID; chosen to reduce dronedarone’s negative inotropic effect—see text below) over 12 weeks in 134 patients with paroxysmal AF and implanted pacemakers where AF burden (AFB) could be continuously assessed. Patients were randomized double-blind to placebo, ranolazine alone (750 mg BID), dronedarone alone (225 mg BID), or one of the combinations. Neither placebo nor either drugs alone significantly reduced AFB. Conversely, ranolazine 750 mg BID/dronedarone 225 mg BID reduced AFB by 59% versus placebo (P=0.008), whereas ranolazine 750 mg BID/dronedarone 150 mg BID reduced AFB by 43% (P=0.072). Both combinations were well tolerated. Conclusions—HARMONY showed synergistic AFB reduction by moderate dose ranolazine plus reduced dose dronedarone, with good tolerance/safety, in the population enrolled. Clinical Trial Registration—ClinicalTrials.gov; Unique identifier: NCT01522651.