Krista M. Dale

Dronedarone: An Amiodarone Analog for the Treatment of Atrial Fibrillation and Atrial Flutter

Objective: To review the pharmacology, pharmacokinetics, clinical efficacy, and safety profile of dronedarone for the treatment of atrial fibrillation. Data Sources: A literature search was conducted using the search terms dronedarone, SR 33589, atrial fibrillation, and antiarrhythmic medication in MEDLINE (1966–February 2007), International Pharmaceutical Abstracts (1970–February 2007), and EMBASE (1990–February 2007). References from the identified trials and selected review articles were evaluated. Additional information, including abstracts and posters, was obtained from Sanofi-Aventis. Study Selection and Data Extraction: Published studies and meeting abstracts evaluating the effects of dronedarone in humans and animals were reviewed. Data Synthesis: Dronedarone is a novel antiarrhythmic medication to treat atrial fibrillation. Dronedarone has a multifaceted mechanism of action similar to that of amiodarone. Dronedarone works by blocking potassium, sodium, and calcium channels and exhibits antiadrenergic properties. The drug has been evaluated at doses of 400, 600, and 800 mg twice daily. It prolonged the time to atrial fibrillation recurrence to 60–158 days compared with 5–59 days with placebo and decreased heart rate during atrial fibrillation by 12–25 beats/min in clinical trials. Major adverse events include gastrointestinal side effects and risk of proarrhythmia. Dronedarone may increase the risk of mortality in patients with congestive heart failure. Conclusions: Dronedarone is a new antiarrhythmic agent for the treatment of atrial fibrillation. Further studies are needed to better define dronedarones safety profile and place in therapy.

Impact of gender on statin efficacy.

ABSTRACT Objective: To determine the impact of statin therapy on the combined endpoint of cardiovascular events in women and men separately. Research design and methods: A systematic literature search through May 2006 was conducted to identify randomized, controlled statin trials evaluating the gender specific incidence of cardiovascular events. Weighted averages were reported as relative risks (RRs) with 95% confidence intervals (CI) calculated via random-effects model. Main outcome measures: The primary outcome measured was a composite endpoint of all cardiovascular events. Secondary outcomes measured included death, myocardial infarction (MI), and stroke. Results: Fifteen trials were included in this meta-analysis. Cardiovascular events were reduced in men (RR 0.76 [95% CI 0.70, 0.81]) and women (RR 0.79 [95% CI 0.69, 0.90]). Reductions in mortality, MI, and stroke predominantly contributed to the reduction in cardiovascular events in men taking statins. Women did not have a reduction in mortality or stroke, suggesting that the reductions in cardiac events may have been predominantly due to reductions in need for revascularization and/or unstable angina. Conclusions: Statins reduced the risk of cardiovascular events in men and women, but women on statins may not have reductions in mortality and stroke like their male counterparts.

The relationship between statin use and atrial fibrillation

ABSTRACT Objective: To investigate the relationship between statin therapy and the development of new-onset, recurrent, and postoperative atrial fibrillation (AF). Research design and methods: A systematic literature search was conducted through September 2006. Included studies were either randomized, controlled trials or observational studies with adjusted analyses using multivariate regression or covariate matching, compared patients receiving or not receiving a statin, and reported data on the incidence of AF. Weighted averages were reported as odds ratios with 95% confidence intervals (CIs) using a random-effects model. Main outcome measures: The primary outcome measured was a combined endpoint of any AF type. Secondary outcomes included new-onset, recurrent, and postoperative AF. Results: Fourteen trials reporting the results of 15 unique analyses (n = 7402) were included. There was a 20% incidence rate for any AF with varying rates depending on AF type (new-onset [11%], recurrent [56%], recurrent after cardioversion [54%], postoperative [22%]). The use of a statin reduced the odds of developing any AF by 45% (odds ratio [OR] 0.55; 95% CI 0.43–0.70); Q statistic p = 0.001). Statins reduced the odds of developing new-onset AF by 32% (OR 0.68; 95% CI 0.51–0.90), recurrent AF by 57% (OR 0.43; 95% CI 0.24–0.79), recurrent AF after cardioversion by 42% (OR 0.58; 95% CI 0.32–1.05) and postoperative AF by 58% (OR 0.42; 95% CI 0.27–0.65). Limitations: We considered studies that were observational in nature or only available in abstract form. Publication bias could not be ruled out. Conclusions: Statin therapy was associated with a reduced odds of developing AF, thus providing evidence of the benefit of statins beyond the lipid-lowering activity.

Moxifloxacin and Torsade de Pointes

Objective: To report a case of torsade de pointes in a patient receiving moxifloxacin. Case Summary: An 87-year-old woman was admitted to the hospital for pneumonia, and antibiotic therapy with intravenous moxifloxacin 400 mg/day was initiated. The patient was noted to have significant QTc interval prolongation 2 hours after administration of moxifloxacin and developed torsade de pointes 8–10 hours after moxifloxacin administration. She was converted back to normal sinus rhythm after a precordial thump. Moxifloxacin was discontinued, and the womans QTc interval subsequently returned to baseline. Discussion: Torsade de pointes is a life-threatening arrhythmia that has previously been associated with the use of fluoroquinolones. Minimal information is available regarding the risk of torsade de pointes with moxifloxacin. According to the Naranjo probability scale, the episode in this case was probably related to administration of intravenous moxifloxacin. Conclusions: In patients with underlying risk factors for a prolonged QT interval, the use of moxifloxacin can lengthen the interval further and ultimately trigger episodes of torsade de pointes. Moxifloxacin administration in these patients therefore should be administered and monitored judiciously.

Effect of Magnesium L-Lactate on Blood Pressure in Patients with an Implantable Cardioverter Defibrillator

Background: Previous studies have evaluated the impact of oral magnesium on blood pressure; however, they used magnesium salts with low bioavailability, had methodological issues, and showed differing results. Objective: To evaluate the long-term blood pressure–lowering ability of oral magnesium L-lactate versus placebo in patients with implanted cardioverter defibrillators (ICDs). Methods: In this double-blind, 24-week trial, 50 patients with ICDs were randomized to receive magnesium L-lactate (6 tablets daily, supplying a total of 504 mg of elemental magnesium daily) or matching placebo for at least 12 weeks. Baseline intracellular and serum magnesium concentrations were determined. The primary efficacy endpoint was the mean sitting systolic blood pressure at 24 weeks. Results: In 50 patients who completed at least 12 weeks of follow-up, 86% of patients, regardless of randomization, had a baseline intracellular magnesium deficiency, but no patients had a serum magnesium deficiency. At 12 weeks, magnesium L-lactate significantly reduced systolic blood pressure compared with placebo (117.7 ± 11.8 vs 126.3 ± 16.7 mm Hg, respectively; p = 0.04). In the 45 patients who continued in the study through the 24-week time period, the systolic blood pressure reduction was maintained, but statistical significance was lost (118.1 ± 14.1 vs 125.5 ± 17.2 mm Hg, respectively; p = 0.13). Magnesium L-lactate did not impact diastolic blood pressure at either time period (p ≥ 0.75 for both). Patients with a documented history of hypertension at baseline showed similar qualitative results to the primary analysis. Conclusions: A large number of subjects with ICDs have an intracellular magnesium deficiency not captured through serum magnesium determination. The use of magnesium L-lactate in patients with an ICD results in significant improvement in systolic blood pressure at 12 weeks, which may be maintained through 24 weeks.

Impact of amiodarone on the ability of anterior fat pad retention to prevent postcoronary arterial bypass grafting atrial fibrillation incidence: a substudy of the AFIST III (Atrial Fibrillation Suppression Trial III)

Background: In the AFIST III (Atrial Fibrillation Suppressions Trial III), anterior fat pad (AFP) retention did not decrease the incidence of postoperative atrial fibrillation (POAF), but prophylaxis with amiodarone did. In order to examine the inter-relationship between amiodarone with AFP retention on POAF, we performed a planned subgroup analysis of AFIST III. Methods: Coronary artery bypass graft (CABG) patients were randomized to AFP maintenance or removal with prophylactic amiodarone used via the discretion of the caregiver. Patients were categorized into four groups: AFP retention alone, AFP retention plus amiodarone, AFP removal alone and AFP removal plus amiodarone. Multivariate logistic regression was used to calculate adjusted odds ratios with 95% confidence intervals for development of POAF. Results: Amiodarone was used in 28% of the 178 patients (mean age = 66 ± 10, 80% male, 5% previous atrial fibrillation) undergoing CABG surgery. The overall POAF occurrence rate, regardless of subgroup designation was 35.4%. On multivariate logistic regression, amiodarone plus AFP retention was associated with an 81% reduction in the odds of the patient developing POAF (p = 0.015). Amiodarone prophylaxis without AFP retention was associated with a 68% reduction (p = 0.040). Conclusion: Amiodarone prophylaxis with or without AFP retention is an independent negative predictor of POAF. Combining amiodarone with AFP retention may provide a synergistic effect in the prevention of POAF. Further studies are needed to validate the results of this study.