Ijc102307(nabha)

335 views

Published on

Dronedarone for Maintenance of

Published in: Health & Medicine
  • Be the first to comment

  • Be the first to like this

Ijc102307(nabha)

  1. 1. Dronedarone for Maintenance of Sinus Rhythm in Atrial Fibrillation or Flutter Singh, B, MD; Connolly, S, MD; Crijns, H, MD; Roy, D, MD; Kowey, P, MD; Capucci, A., MD; Radzig, D., MD; Aliot, E, MD for the Euridis and Adonis Investigators. NEJM, September 6, 2007 Linda Nabha, MD October 23, 2007
  2. 2. Atrial Fibrillation <ul><li>Most common arrythmia </li></ul><ul><ul><li>~2.2million Americans </li></ul></ul><ul><li>Characterized by the absence </li></ul><ul><li>of coordinated atrial systole </li></ul><ul><li>Symptoms include palpitations, </li></ul><ul><li>dyspnea, fatigue, dizziness </li></ul><ul><li>associated with a 2-fold higher </li></ul><ul><li>risk of death, which may be </li></ul><ul><li>due to thromboembolic stroke </li></ul>
  3. 3. Treatment Strategies for AF <ul><li>Rhythm control </li></ul><ul><ul><li>reversion to NSR </li></ul></ul><ul><ul><li>maintenance of NSR </li></ul></ul><ul><li>Rate Control – administration of meds to control ventricular rate </li></ul><ul><li>Choosing Rhythm vs. Rate Control </li></ul><ul><li>Prevention of Embolization </li></ul>
  4. 4. Amiodarone <ul><li>Most effective drug for maintenance of sinus rhythm </li></ul><ul><li>Side effects: </li></ul><ul><ul><li>Pulmonary toxicity </li></ul></ul><ul><ul><li>Thyroid Dysfunction </li></ul></ul><ul><ul><li>Hepatotoxicity </li></ul></ul><ul><ul><li>Ocular Changes </li></ul></ul><ul><ul><li>Bradycardia </li></ul></ul>
  5. 5. Dronedarone <ul><li>Noniodinated </li></ul><ul><li>benzofuran derivative </li></ul><ul><li>Electrophysiologic </li></ul><ul><li>effects similar to amiodarone and also has antiadrenergic properties </li></ul><ul><li>Half life 1-2 days </li></ul><ul><li>ANDROMEDA trial was discontinued early due to an increased incidence of death in the patients assigned to dronedarone </li></ul>
  6. 6. Study Hypothesis <ul><li>Is Dronedarone effective in maintaining sinus rhythm in atrial fibrillation? </li></ul><ul><li>Does Dronedarone decrease the risk of side effects associated with Amiodarone? </li></ul>
  7. 7. Selection of Subjects <ul><li>>21 yo age </li></ul><ul><li>Males and Females </li></ul><ul><li>> 1 episode of AF in </li></ul><ul><li>preceding 3 months </li></ul><ul><li>Sinus rhythm at least 1 hour before randomization </li></ul><ul><ul><li>Pt previously on amiodarone permitted </li></ul></ul>
  8. 8. Exclusion Criteria <ul><li>permanent AF ( > 12 months) </li></ul><ul><li>Torsades de Pointes </li></ul><ul><li>Bradycardia <50 bpm </li></ul><ul><li>PR interval > 0.28ms on EKG </li></ul><ul><li>2 nd degree AV block </li></ul><ul><li>Taking class I or III antiarrhythmic agents </li></ul><ul><li>NYHA class III or IV CHF </li></ul><ul><li>Serum Cr > 1.7mg/dL </li></ul><ul><li>Severe electrolyte abnormality </li></ul><ul><li>Clinically significant hepatic pulmonary endocrine disease </li></ul>
  9. 9. Study Design <ul><li>2 identical multicenter, double-blind, parallel group trials </li></ul><ul><ul><li>European, non-European </li></ul></ul><ul><li>Randomly assigned to Dronedarone or placebo in 2:1 ratio </li></ul><ul><li>Sponsored by </li></ul>
  10. 10. Baseline Evaluation, Randomization, Therapy <ul><li>Pt evaluation: History, ROS, CV exam, 12 lead EKG, CXR, lab tests, 2D Echo </li></ul><ul><li>Eligible pt assigned in 2:1 ratio to receive 400mg of oral dronedarone BID or placebo for one year </li></ul><ul><li>In combined trials </li></ul><ul><ul><li>n= 348 received placebo </li></ul></ul><ul><ul><li>n= 828 received dronedarone </li></ul></ul>
  11. 11. Follow up <ul><li>ROS, VS, EKG performed </li></ul><ul><ul><li>Days 7, 14, 21 </li></ul></ul><ul><ul><li>Months 2, 4, 6, 9,12 </li></ul></ul><ul><li>Blood tests: BMP, LFTs, Thyroid </li></ul><ul><ul><li>Day 21 </li></ul></ul><ul><ul><li>Months 4, 9, 12 </li></ul></ul><ul><li>Transtelephonic EKG monitoring </li></ul><ul><ul><li>days 2,3, 5 </li></ul></ul><ul><ul><li>Months 3,5,7,10 </li></ul></ul><ul><ul><li>Symptomatic </li></ul></ul><ul><li>CXR performed in case of pulmonary symptoms only </li></ul>
  12. 12. Study End Points <ul><li>Primary End Point </li></ul><ul><ul><li>Time from randomization to the first documented recurrence of AF </li></ul></ul><ul><li>Secondary End Points </li></ul><ul><ul><li>Symtoms * related to AF during EKG recording or TTP monitoring </li></ul></ul><ul><ul><li>Mean Ventricular rate during first occurrence of AF </li></ul></ul>
  13. 13. Statistical Analysis <ul><li>Sample size based upon efficacy trials of antiarrhythmic drugs for tx of AF </li></ul><ul><li>Primary analysis performed according to a modified intention-to-treat principle </li></ul><ul><li>Two-sided Fisher’s exact test used for qualitative measures. </li></ul>
  14. 14. Enrollment and Outcomes
  15. 15. Enrollment and Outcomes
  16. 16. Baseline Characteristics European Placebo Dronedarone Non-European Placebo Dronedarone Combined Placebo Dronedarone Age (yr) 61.3 62.3 63 64.6 62.2 63.5 Sex (%F) 30.3 30.7 32.7 29.7 31.5 30.2 Structural HD 33.3 36.3 45.6 48.5 39.7 42.4 LVEF % 59.83 + 9.37 59.6 + 10 57.1 + 12.2 57.9 + 11.2 58.5 + 11 58.6 + 1.8 Recent cardio-version* % 37.3 37.2 22.1 21.6 29.6 29.3
  17. 17. Results <ul><li>Median times from randomization to documented recurrence of AF in combined trials: </li></ul><ul><ul><li>53 days with placebo </li></ul></ul><ul><ul><li>116 days with Dronedarone </li></ul></ul><ul><li>At 12 mo. AF recurred in </li></ul><ul><ul><li>75% pt in placebo grp </li></ul></ul><ul><ul><li>64% pt in Dronedarone grp </li></ul></ul><ul><li> (p<0.001, HR=0.75) </li></ul>
  18. 18. Results
  19. 19. Results <ul><li>In combined trials: </li></ul><ul><ul><li>1st symptomatic AF occurred in </li></ul></ul><ul><ul><ul><li>46% for placebo grp </li></ul></ul></ul><ul><ul><ul><li>38% for dronedarone grp </li></ul></ul></ul><ul><ul><li>VR at first recurrence of AF occurred in </li></ul></ul><ul><ul><ul><li>placebo at 117.1 + 30.4 bpm </li></ul></ul></ul><ul><ul><ul><li>dronedarone 103.4 + 26 bpm </li></ul></ul></ul><ul><ul><li>30.9% of placebo and 22.8% of dronedarone resulted in hospitalization or death </li></ul></ul>
  20. 20. Results
  21. 21. Adverse Events VARIABLE DRONEDARONE N=828 PLACEBO N=409 P value Stroke 4 (0.5) 3 (0.7) 0.69 Cough Dyspnea 19 (2.3) 7(1.7) 0.67 Hyperthyroidism Hypothyroidism 67/801 (8.4) 44/801 (5.5 56/396 (14.1) 14/396 (3.5) 0.002 0.15 Abnormal LFTs 100/822 (12.2) 55/404(13.6) 0.52 Elev of Serum Creatinine 20 (2.4) 1 (0.2) 0.004 Bradycardia Heart Failure 22 (2.7) 20 (2.4) 8 (2.2) 4 (1.0) 0.56 0.12
  22. 22. Limitations <ul><li>No direct comparison of Amiodarone to Dronedarone </li></ul><ul><li>Follow up EKGs were infrequent </li></ul><ul><li>Short duration of trial may not have exposed possible adverse events. </li></ul><ul><ul><li>Pulmonary toxicity </li></ul></ul>
  23. 23. Discussion <ul><li>Dronedarone </li></ul><ul><ul><li>reduced the incidence of </li></ul></ul><ul><ul><li>first occurrence of AF </li></ul></ul><ul><ul><li>decreased the VR during 1st </li></ul></ul><ul><ul><li>occurrence of arrhythmia </li></ul></ul><ul><ul><li>reduced rate of hosp. or death </li></ul></ul><ul><ul><li>compared to placebo </li></ul></ul><ul><ul><li>may increase the risk of mortality in patients with CHF </li></ul></ul><ul><ul><li>significantly worsened kidney function </li></ul></ul><ul><li>Low rate of adverse events </li></ul><ul><li>Comparative trials with amiodarone would be needed to show dronedarone had a better adverse effect profile </li></ul>
  24. 24. Applications to Clinical Practice <ul><li>The application of Dronedarone may be useful in low risk patients </li></ul><ul><ul><li>NYHA Class I and II </li></ul></ul><ul><li>Amiodarone remains the drug of choice for maintenance of NSR despite its multiple, toxic adverse effects. </li></ul>
  25. 25. QUESTIONS?

×