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Scuola di specializzazione in malattie cardiovascolari I farmaci antiaritmici: Esistono?

Scuola di specializzazione in malattie cardiovascolari I farmaci antiaritmici: Esistono? Ci servono? Sono efficaci Sono sicuri ?. Savelieva&Camm , Europace 2008. Dagres et al, Europace 2013. Il farmaco antiaritmico ideale: Efficacia: endpoint elettrofisiologici

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Scuola di specializzazione in malattie cardiovascolari I farmaci antiaritmici: Esistono?

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  1. Scuola di specializzazione in malattie cardiovascolari I farmaci antiaritmici: Esistono? Ci servono? Sono efficaci Sono sicuri ?

  2. Savelieva&Camm, Europace 2008

  3. Dagres et al, Europace 2013

  4. Il farmaco antiaritmico ideale: Efficacia: endpoint elettrofisiologici Ripristinare il ritmo sinusale Ridurre o abolire le recidive Ridurre la risposta VM in caso di recidiva Non avere un effetto inotropo negativo endpoint clinici: Ridurre i sintomi Ridurre la mortalità aritmica Ridurre la mortalità totale Ridurre i ricoveri ospedalieri Sicurezza: endpoint elettrofisiologici Non alterare la conduzione AV, QRS e QT Non indurre torsioni di punta Non indurre una conduzione AV 1:1. endpoint clinici: Non avere effetti pro-aritmici Non avere tossicità d’organo (tiroide, fegato..) Non aumentare la mortalità aritmica o totale

  5. Electrophysiological targets for anti-arrhythmiceffects Mechanisms of action of antiarrhythmic drugs Nattel et al, 2012

  6. Kober et al, Lancet 2000

  7. Pedersen et al, Circulation 2001

  8. Dronedarone pharmacology: key points • Dronedarone is a multichannel blocker AAD with all four Vaughan Williams class properties • Dronedarone exhibits multiple potentially beneficial properties beyond ion channel inhibition that may contribute to its unique clinical profile • Dronedarone has an electrophysiological profile characterized by a low proarrhythmic effect BP = blood pressure; LV = left ventricular; NO = nitric oxide. Adapted from: Doggrell SA, Hancox JC. Expert Opin Investig Drugs. 2004;13:415-26. Gautier P, et al. J Cardiovasc Pharmacol. 2003;41:191-202. Guiraudou P, et al. Eur J Pharmacol. 2004;496:119-27. Kathofer S, et al. Cardiovasc Drug Rev. 2005;23:217-30. Le Heuzey JY, et al. J Cardiovasc Electrophysiol. 2010;21:597-605. Wegener F, et al. J Cardiovasc Electrophysiol. 2006;17 Suppl 2:S17-20.

  9. HR = 0.76 (95% CI, 0.69–0.84) p < 0.001 24% reduction in relativerisk Placebo on top of standard therapy ATHENA: morbidity/mortality study in 4,628 patients with AF – Primary endpoint 50 40 30 The number needed to treat (NNT) to prevent one first CV hospitalization or death is 16. Cumulative incidence (%) 20 10 Dronedarone 400 mg b.i.d. on top of standard therapy 0 0 6 12 18 24 30 Patients at risk: Follow-up time (months) The enrolled AF population in the ATHENA study is broader than the indicated population for dronedarone. Hohnloser SH, et al. N Engl J Med. 2009;360:668-78. EMA Assessment Report for Multaq. Page 8. Available at: http://www.ema.europa.eu. Accessed August 2013. Any unplanned hospitalization (i.e., admission with an overnight stay in the hospital) was classified by the investigator as a hospitalization due to either CV or non-CV causes.

  10. Dronedarone: the mostextensivelystudiedantiarrhythmicdrugin AF Dronedarone is contraindicated in permanent AF and should not be used for rate control. The enrolled AF population in the ATHENA study is broader than the indicated population for dronedarone. a Planned patient enrolment. AF, atrial fibrillation; AFL, atrial flutter; CHF, congestive heart failure; LV, left ventricular; SR, sinus rhythm. 1. TouboulP, et al. Eur Heart J. 2003;24:1481-7. 2. Singh BN, et al. N Engl J Med. 2007;357:987-99. 3. Davy JM, et al. Am Heart J. 2008;156:527.e1-527.e9. 4. Le Heuzey JY, et al. J CardiovascElectrophysiol. 2010;21:597-605. 5. Køber L, et al. N Engl J Med. 2008;358:2678-87. 6. Hohnloser SH, et al. N Engl J Med. 2009;360:668-78. 7. Connolly SJ, et al. N Engl J Med 2011;365:2268-76.

  11. Dronedarone’s clinical programme (1/2) *Standard therapy may have included rate control agents (beta-blockers, and/or Ca-antagonist and/or digoxin) and/or anti-thrombotic therapy (Vit. K antagonists and/or aspirin and other antiplatelet therapy) and/or other CV agents such as ACEIs/ARBs and statins • Adapted from: • Touboul P, et al. Eur Heart J. 2003;24:1481-7. • Singh BN, et al. N Engl J Med. 2007;357:987-99. • Davy et al. Am Heart J. 2008;156:527.e1-527.e9.

  12. Dronedarone’s clinical programme (2/2) *Standard therapy may have included rate control agents (beta-blockers, and/or Ca-antagonist and/or digoxin) and/or anti-thrombotic therapy (Vit. K antagonists and/or aspirin and other antiplatelet therapy) and/or other CV agents such as ACEIs/ARBs and statins Adapted from: Hohnloser SH, et al. N Engl J Med 2009;360:668-78. Le Heuzey JY et al. J CardiovascElectrophysiol. 2010;21(6):597-605.  Køber L, et al. N Engl J Med. 2008;358:2678-87. Connolly SJ et al. N Engl J Med 2011; 365:2268-2276

  13. Recentclinicalstudies G. Naccarelli et al Switching Patients with Atrial Fibrillation from Amiodarone to Dronedarone: Results of the ARTEMIS AF Studies available at http://www.abstractsonline.com/plan/ViewAbstract.aspx?mID=2974&sKey=35a86d48-af09-4459-bc4e-9c6a57d7207e&cKey=6879180e-9105-4139-8e22-151e5fe9c35e&mKey={14145D5B-F96B-4354-8237-8F0937744BA4} accessed on 04/03/13 Michael D Ezekowitz et al. A Placebo-Controlled, Double-Blind, Randomized, Multicenter Study to Assess the Effects of Dronedarone on Atrial Fibrillation Burden in Subjects with Permanent Pacemakers (HESTIA) available at http://www.abstractsonline.com/plan/ViewAbstract.aspx?mID=2974&sKey=35a86d48-af09-4459-bc4e-9c6a57d7207e&cKey=8ee7947f-fb4f-4a62-ac7d-5dcbf3f3688f&mKey=%7B14145D5B-F96B-4354-8237-8F0937744BA4%7D accessed on 04/03/13

  14. Dronedarone demonstrates consistent rhythm control efficacy across studies and AF populations *Dronedarone is indicated after successful cardioversion. **The enrolled AF population in the ATHENA study is broader than the indicated population for dronedarone. • Adapted from: • Touboul P, et al. Eur Heart J. 2003;24:1481-7. • Singh BN, et al. N Engl J Med. 2007;357:987-99. # Median duration ## Mean duration • Hohnloser SH et al. N Engl J Med 2009;360:668-78. • Page et al. Am J Cardiol. 2011;107 (7):1019-1022 • Le Heuzey JY et al. J CardiovascElectrophysiol. 2010;21(6):597-605. 

  15. Inclusion and exclusion criteria • Originally the protocol had allowed patients <70 years of age with additional risk factors into the study • The protocol was subsequently amended to include only patients≥70 years of age The enrolled AF population in the ATHENA study is broader than the indicated population for dronedarone Adapted from Hohnloser SH, et al. J Cardiovasc Electrophysiol 2008;19:69-73.

  16. Baseline patient characteristics The enrolled AF population in the ATHENA study is broader than the indicated population for dronedarone Adapted from Hohnloser SH, et al. J Cardiovasc Electrophysiol 2008;19:69-73.

  17. Concomitant medications Rate Control Agents Anti-thrombotics The enrolled AF population in the ATHENA study is broader than the indicated population for dronedarone Adapted from Hohnloser SH, et al. J Cardiovasc Electrophysiol 2008;19:69-73.

  18. Dronedarone significantly decreased riskof unplanned CV hospitalisation or death from any cause by 24% The enrolled AF population in the ATHENA study is broader than the indicated population for dronedarone Any unplanned hospitalisation (i.e., admission with an overnight stay in the hospital) was classified by the investigator as a hospitalisation due to either CV or non-CV causes Adapted from: Hohnloser SH, et al. N Engl J Med 2009;360:668-78. EMA Assessment Report for Multaq. Page 8. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/001043/WC500121610.pdf accessed 04/03/13

  19. Dronedarone reduced unplanned CV hospitalisation or all-cause death across important subgroups The enrolled AF population in the ATHENA study is broader than the indicated population for dronedarone Adapted from Hohnloser SH, et al. N Engl J Med 2009;360:668-78.

  20. 16% reduction in relativerisk Placebo on top of standard therapy DR 400mg bid on top of standard therapy Dronedarone non-significantly reduced risk of all-cause death by 16% Secondary endpoint 10 8 HR=0.84 NS (p=0.18) 6 Cumulative Incidence (%) 4 The number needed to treat (NNT) to prevent one death from any cause is 105 2 Months 0 0 6 12 18 24 30 Patients at risk: The enrolled AF population in the ATHENA study is broader than the indicated population for dronedarone Mean follow-up 21 ±5 months. Adapted from Hohnloser SH, et al. N Engl J Med 2009;360:668-78.

  21. 7.5 5.0 2.5 29% reduction in relativerisk Placebo on top of standard therapy DR 400mg bid on top of standard therapy 0 Dronedarone significantly decreasedrisk of CV death by 29% Secondary endpoint HR=0.71 p=0.03 Cumulative Incidence (%) The number needed to treat (NNT) to prevent one CV death is 80 Months 0 6 12 18 24 30 Patients at risk: The enrolled AF population in the ATHENA study is broader than the indicated population for dronedarone Mean follow-up 21 ±5 months. Adapted from Hohnloser SH, et al. N Engl J Med 2009;360:668-78.

  22. Dronedarone effect on mortality Secondary endpoints Dronedarone significantly decreased risk ofCV death by 29% and arrhythmic death by 45% The enrolled AF population in the ATHENA study is broader than the indicated population for dronedarone Adapted from Hohnloser SH, et al. N Engl J Med 2009;360:668-78.

  23. Dronedarone significantly reduced the risk of CV-related mortality in AF patients Secondary endpoints Reduction in the relative risk of death (Dronedarone vs. placebo*) All-cause mortality CV-related mortality** Cardiac arrhythmic death** Reduction in relative risk of mortality with dronedarone treatment vs. placebo (%) -16% p=0.18 p<0.001 p<0.001 -29% p=0.03 -45% p=0.01 p<0.001 * Dronedarone and placebo treatments were additional to standard therapy ** CV and arrhythmic deaths were secondary endpoints The enrolled AF population in the ATHENA study is broader than the indicated population for dronedarone Adapted from Hohnloser SH, et al. N Engl J Med 2009; 360: 668–78

  24. Dronedarone significantly reduced combined stroke mortality endpoints The enrolled AF population in the ATHENA study is broader than the indicated population for dronedarone ACS=Acute Coronary Syndrome. Adapted from Connolly et al. Circulation. 2009;120:1174-1180.

  25. 32% reduction in relativerisk Placebo on top of standard therapy DR 400mg bid on top of standard therapy Dronedarone significantly reduced the risk of stroke, acute coronary syndrome or CV death 15 HR=0.68 10 p<0.001 Cumulative Incidence (%) 5 Months 0 0 6 12 18 24 30 Patients at risk: The enrolled AF population in the ATHENA study is broader than the indicated population for dronedarone Adapted from Connolly et al; Circulation. 2009;120:1174-1180

  26. Meta-analysis shows that amiodarone isnot associated with an improvement inall-cause hospitalisation in AF Total events: 168 amiodarone, 126 control Test for heterogeneity: 2=38.76, df=4, p<.00001, I2=89.7% Test for overall effect: z=0.29, p=.77 0.1 0.2 0.5 1 2 5 10 Favors amiodarone Favors control Adapted from Doyle JFD, et al. Mayo Clin Proc. 2009;84(3):234-242 Doyle J, et al; Mayo Clin Proc 2009; 84(3):234-42.

  27. 30 32% reductionin relativerisk 20 10 Placebo on top of standard therapy DR 400mg bid on top of standard therapy 0 6 12 18 24 30 0 Dronedarone significantly prolonged time to first electrical cardioversion Paroxysmal/persistent AF patients HR=0.684 p<0.001 Cumulative Incidence (%) Months The enrolled AF population in the ATHENA study is broader than the indicated population for dronedarone Adapted from Page et al. Am J Cardiol. 2011;107 (7):1019-1022.

  28. AF recurrence and MTC analysisWhen directly randomised comparisons are not available, indirect analyses can be performed to compare results from different trials Antiarrhythmic Efficacy AAD vs. placebo* AAD vs. Dronedarone** Dronedarone (n=1,131) 0.53 (0.40, 0.72, p=0.0002) 0.68 (0.46–1.00) Propafenone (n=1,228) 0.36 (0.28, 0.48, p<0.0001) 0.41 (0.29–0.57) Amiodarone (n=978) 0.22 (0.16, 0.29, p<0.0001) 0.75 (0.52–1.08) Sotalol (n=1,404) 0.40 (0.31, 0.52, p<0.0001) 0.57 (0.33–0.99) Flecainide (n=305) 0.31 (0.19, 0.49, p<0.0001) 0.1 0.2 0.5 1 2 5 10 ** Odds ratios are reporting amiodarone vs. dronedarone; sotalol vs. dronedarone; flecainide vs. dronedarone; and propafenone vs. dronedarone * Odds ratio lower than 1 describes a lower rate of atrial fibrillation recurrence for the active treatment Adapted from Freemantle et al. Europace. 2011;13(3):329-45.

  29. 0.2 0.5 1 2 5 10 100 Dronedarone may be associated with fewer serious adverse events compared to other AADs Dronedarone n=3,657 0.95 (0.73 to 1.24) p=0.699 amiodarone 427 2.41 (0.96 to 6.06) p=0.060 sotalol n=1,113 1.28 (0.71 to 2.31) p=0.338 flecainide n=231 2.02 (0.29 to13.81) p=0.450 propafenone n=550 1.56 (0.49 to 4.98) p=0.429 Compared with placebo Adapted from Freemantle et al. Europace. 2011;13(3):329-45.

  30. Where can dronedarone be used alongthe course of AF? Consider dronedarone discontinuation and reintroduction after successful CV or spontaneous return to SR Dronedarone initiation possible in indicated patients that are in sinus rhythm Dronedarone not initiated or discontinued = cardioversion (electrical or pharmacological) Adapted from Kirchhof P, et al. Europace. 2007;9(11):1006-1023.

  31. PALLAS PALLAS study design • Multicentre, randomized, double-blind, placebo-controlled Randomization Dronedarone:placebo = 1:1 Discontinued July 2011 Dronedarone 400 mg BID Dronedarone 400 mg b.i.d 10,800 patients with permanent AF and risk factors for major vascular events Planned study end After the enrolment of 3,236 patients, the study was stopped for safety reasons Placebo Placebo Screening period • Patients were seen on Day 7 and 30, at 4 months, and every 4 months thereafter Two co-primary outcomes: Stroke, myocardial infarction, systemic embolism or cardiovascular death Unplanned cardiovascular hospitalization or death Dronedarone is contraindicated in permanent AF patients. Connolly SJ, et al. N Engl J Med. 2011; 365:2268-76.

  32. 1.0 0.04 0.8 0.03 0.02 0.6 0.01 0.4 0 0 1 3 6 0.2 0 0 1 3 6 PALLAS: first co-primary outcome (stroke, MI, SEE, CV death) Dronedarone Median follow-up 3.5 months HR 2.29 (1.34–3.94) p = 0.002 Cumulative hazard Placebo Months Patients at risk Connolly SJ, et al. N Engl J Med. 2011; 365:2268-76. MI, myocardial infarction; SEE, systemic embolic event.

  33. The ARTEMIS AF Loading and Long-term studies evaluated switching paroxysmal or persistent AF patients from amiodarone to dronedarone Adapted from: G. Naccarelli et al Switching Patients with Atrial Fibrillation from Amiodarone to Dronedarone: Results of the ARTEMIS AF Studies; AHA 2012 abstract

  34. Choice of antiarrhythmic drug according to underlying pathology

  35. Kumar & Zimetbaum, CCR 2013

  36. Kumar & Zimetbaum, CCR 2013

  37. Lombardi et al, EHJ 2006

  38. Vernakalant: A new AAD for rapid conversion of atrial fibrillation • Vernakalant blocks important potassium currents that affect repolarization at all phases of the atrial action potential (Ito, IKur, IKACh, IKr) • Modest inhibition of IKr at therapeutic plasma concentrations • Vernakalant, at clinically relevant doses, does not inhibit IKs and IK1, which are important for ventricular repolarization • Vernakalant blocks sodium channels in a frequency- and voltage-dependent manner • Sodium channel blockade in the fibrillating atria is greater than in the ventricles, because the atria in atrial fibrillation are rapidly activating and partially depolarized • Vernakalant blocks the late component of sodium current. • This blockade attenuates the prolonging effect of IKr inhibition on the cardiac action potential Fedida D. Expert OpinInvestig Drugs 2007;16:519-532; Fedida D et al. J CardiovascElectrophysiol. 2005;16:1227-1238.

  39. ACT Studies (Phase III)Treatment Schedule and Follow-up Continuous Holter Monitoring Continuous Heart Rhythm Monitoring Discharge (≥8 hours) Randomization Follow-up Visit† Telephone Follow-Up Screening Primary EndpointEfficacy Period 90 min Time 2 h 25 min 35 min 24 h 7 d 0 30 d 10 min 1st Infusion: Vernakalant (3 mg/kg) or Placebo 2nd Infusion: (if patient in AF or AFL) Vernakalant (2 mg/kg) or Placebo Electrical cardioversion and other treatments permitted † In ACT II, a follow-up visit occurred at discharge from facility or up to 14 days post-discharge. AF: Atrial fibrillation AFL: Atrial flutter Kowey PR, et al. Circ Arrhythmia Electrophysiol 2009;2:652-9

  40. ACT Studies (Phase III)Primary Efficacy Endpoint • Proportion of patients in the short-duration AF (3 hours to 7 days*) group who had conversion to sinus rhythm for at least 1 minute within 90 minutes of drug initiation (overall AF group in ACT II*) 51.7% 51.2% 50.9% 47.0% Percent conversion of AF to sinus rhythm (%) p<0.001 compared to placebo in ACT I, ACT II, and ACT III 14.0% 4.0% 3.6% * *ACT II enrolled patients with AF duration 3-72 hours.Roy D et al. Circulation. 2008;117:1518-25; Kowey PR et al. Circ Arrhythmia Electrophysiol 2009;2:652-9. AF: Atrial fibrillation

  41. % conversion to sinus rhythm Time (minutes) ACT Studies (Phase III)Other Findings • In those patients who converted to sinus rhythm: • Conversion was successful with the first dose in ~75% • 97.2% of patients remained in sinus rhythm at 24 hours (pooled analysis of ACT I and ACT III studies) • The median time to conversion to sinus rhythm with vernakalant was 11 minutes (pooled analysis of ACT I and ACT III studies) • Vernakalant was not successful in terminating primary atrial flutter* *Secondary atrial flutter was often amenable to treatment with second infusion of vernakalant.

  42. AVRO Primary Efficacy Endpoint:Conversion From AF to SR within 90 Minutes Full Analysis Set P<0.0001 (CMH Test) Percent (%) of Patients Conversion from AF to SR within 90 Minutes CSR AVRO 1/15/10

  43. Vernakalant (N=116) 0.6 Amiodarone (N=116) Proportion of Patients with 0.4 P<0.0001 (Log-rank test) Conversion to SR 0.2 0.0 0 5 10 15 20 25 35 50 70 90 Time (Minutes) AVRO Secondary Endpoint:Time to Conversion from AF to SR Full Analysis Set Median time to conversion in vernkalant responders was 11 minutes CSR AVRO 1/15/10

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