Dronedarone for Maintenance of Sinus Rhythm in Atrial Fibrillation or Flutter Singh, B, MD; Connolly, S, MD; Crijns, H, MD...
Atrial Fibrillation <ul><li>Most common arrythmia </li></ul><ul><ul><li>~2.2million Americans </li></ul></ul><ul><li>Chara...
Treatment Strategies for AF  <ul><li>Rhythm control  </li></ul><ul><ul><li>reversion to NSR  </li></ul></ul><ul><ul><li>ma...
Amiodarone <ul><li>Most effective drug for maintenance of sinus rhythm  </li></ul><ul><li>Side effects: </li></ul><ul><ul>...
Dronedarone <ul><li>Noniodinated  </li></ul><ul><li>benzofuran derivative  </li></ul><ul><li>Electrophysiologic  </li></ul...
Study Hypothesis <ul><li>Is Dronedarone effective in maintaining sinus rhythm in atrial fibrillation? </li></ul><ul><li>Do...
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>...
Exclusion Criteria <ul><li>permanent AF ( > 12 months) </li></ul><ul><li>Torsades de Pointes </li></ul><ul><li>Bradycardia...
Study Design <ul><li>2 identical multicenter, double-blind, parallel group trials </li></ul><ul><ul><li>European, non-Euro...
Baseline Evaluation, Randomization, Therapy <ul><li>Pt evaluation:  History, ROS, CV exam, 12 lead EKG, CXR, lab tests, 2D...
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...
Study End Points <ul><li>Primary End Point </li></ul><ul><ul><li>Time from randomization to the first documented recurrenc...
Statistical Analysis <ul><li>Sample size based upon efficacy trials of antiarrhythmic drugs for tx of AF </li></ul><ul><li...
Enrollment and Outcomes
Enrollment and Outcomes
Baseline Characteristics European Placebo  Dronedarone Non-European Placebo  Dronedarone Combined Placebo  Dronedarone Age...
Results <ul><li>Median times from randomization to documented recurrence of AF in combined trials: </li></ul><ul><ul><li>5...
Results
Results <ul><li>In combined trials: </li></ul><ul><ul><li>1st symptomatic AF occurred in </li></ul></ul><ul><ul><ul><li>46...
Results
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) ...
Limitations <ul><li>No direct comparison of Amiodarone to Dronedarone </li></ul><ul><li>Follow up EKGs were infrequent  </...
Discussion <ul><li>Dronedarone </li></ul><ul><ul><li>reduced the incidence of  </li></ul></ul><ul><ul><li>first occurrence...
Applications to Clinical Practice <ul><li>The application of Dronedarone may be useful in low risk patients </li></ul><ul>...
QUESTIONS?
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Ijc102307(Nabha)

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  • Approximately 2.5 million Americans, or close to 1% of the total population, currently have atrial fibrillation lack of coordinated atrial contraction leads to unusual fluid flow states through the atrium that are permissive for formation of thrombus that is then at risk to embolize
  • There are two standard approaches to converting AF to sinus rhythm: synchronized external DC cardioversion and pharmacologic cardioversion. Anticoagulation should be achieved with adjusted-dose warfarin unless the patient is considered at low embolic risk or has a contraindication.
  • Amiodarone has multiple effects on myocardial depolarization and repolarization that make it an extremely effective antiarrhythmic drug. pulmonary toxicity usually occurs several months to as late as several years after the initiation Thyroid dysfunction (including both hypothyroidism and hyperthyroidism
  • The iodine moiety has been thought involved in amiodarone &apos;s pulmonary toxicity, hepatitis, thyroid side effects, and eye disturbances. Thus, dronedarone may have fewer of the long-term complications associated with amiodarone. In the ANDROMEDA trial, pt were high risk pt with severe CHF and ventricular dysfunction
  • Interesting to note here, sinus rhythm was achieved in these participants in multiple ways: Including cardioversion up to one hour prior to randomization and Previous treatment of with amiodaone was permitted and pt who had received the drug could be enrolled immediately after its discontinuation.
  • Class I includes:Digoxin, quinidine Class III includes
  • The hypothesis for determining the number of pt needed for the study was based on efficacy trials comparing amiodarone to placebo and the presumption that 60% of pt in the placebo group would have a recurrence of an arrythmia and those in the dronedarone group would a a decreased in this rate of at least 25%
  • Each trial would have a power of 90% to detect a between group difference .
  • This was defined as an episode lasting for at least 10 minutes and confirmed by 2 consecutive recordings taken 10 min apart on a 12 lead EKG or transtelephonic monitoring. Symptoms included dyspnea, chest pain, fatigue, dizziness
  • With all randomized patients who received at least one dose of a study drug included
  • Recent cardioversion included within last 5 days of randomization
  • This information is seen in chart form: On the verticle axis is the variables Horizontally are the trials. Median Days to recurrence Recurrence rate at 12 months
  • Again on verticle axis are the variables On the horizontal axis is the trials
  • This is a modified chart of the adverse side effects and lab values. Singh et al excluded pt who inconsistent changes in measeures of thyroid function. Pt with no abnormalityh and with at least one missing measurement of liver function were exluded
  • 1. Since the study didn’t directly compare the drugs there is no certainty that dronedarone is as efficacious as amiodarone or that the adverse events is lower. 2. The majority of AF in general fibrillation may be symptomatic. It is likely they were not able to detect all or the first episode of Afib in a patient Since the primary endpoint was to detect the occurrence of the endpoint. 3. One of the major side effects of amio is the pulmonary toxicity which occurs years into taking amio. Most patients did not have CXR done during the study unless pt had pulmonary symptoms.
  • 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?

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