Influencing sudden cardiac death by pharmacotherapy Polypharmacy - arrhythmic risks in patients with heart failure Professor Dan Atar Head, Dept. of Cardiology Oslo University Hospital Ullevål Norway 27.8.2012 - ESC Munich
Declaration of conflict of interest Dan Atar has received speakers honoraria and advisory board fees from: Sanofi-Aventis Merck / MSD
Introduction Pasients with HF present a variety of therapeutic challenges One of these challenges is the treatment of arrhythmias Patients with HF have a high incidence of SV and V arrhythmias Over 40 % of deaths in HF are sudden, i.e., presumably caused by an acute arrhythmia
MERIT-HF NYHA Class and Cause of Death Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure NYHA II NYHA III NYHA IV Arrhythmic death 64% other 24% CHF 12% Arrhythmic death 59% other 15% CHF 26% other 11% Arrhythmic death CHF 56% 33% MERIT-HF Study Group. Lancet 1999;353:2001-7
Influencing sudden cardiac death by pharmacotherapy FOCUS: Few classes of drugs, if any, confer pro-arrhythmia as much as antiarrhythmic drugs do
Singh Vaughan Williams classification of antiarrhythmic agents Class I: Interfere with sodium (Na + ) channel Class II: Beta blockers Class III: affect potassium (K + ) efflux Class IV: Calcium channel blockers Class V: other mechanisms, e.g., Digitalis
Prelude: Antiarrhythmic Drugs in General The unbearable difficulty of being an antiarrhythmic drug :
Patients without event (%) CAST Trial 1991 Encainide and flecainide increase mortality after MI 100 95 90 85 0 91 182 273 364 455 Time after randomization (days) Class I: Dismissed in SHD p = 0.001 Placebo (n = 743) Encainide or flecainide (n = 755) Echt DS. N Engl J Med. 1991;324:781-788.
Antiarrhythmic Drugs in CHF Class I Class III
GESICA NYHA Class II advanced, III and IV
EMIAT & CAMIAT EMIAT Entry criteria 5 21 days post-mi Ejection fraction 40% Primary endpoint Total mortality Secondary endpoints Cardiac mortality Arrhythmic death Arrhythmic death and resuscitated cardiac arrest CAMIAT Entry criteria 6 45 days post-mi 10 VPDs/hr one run of VT Primary endpoint Arrhythmic death and resuscitated cardiac arrest Secondary endpoints Cardiac mortality Total mortality Primary analysis Intention to treat Secondary analysis Efficacy (3 month cut-off) Primary analysis Efficacy (3 month cut-off) Secondary analysis Intention to treat
EMIAT All cause mortality Survival 1.00 Intent to treat analysis 0.95 0.90 0.85 Placebo Amiodarone 102 103 0.80 0.75 3 6 12 24 Months A743 708 698 663 272 P743 702 693 658 250
SWORD Class III
ANDROMEDA Multichannel, mainly class III
ATHENA trial design Prospective double-blind trial to assess the efficacy of dronedarone in preventing cardiovascular hospitalization or death from any cause in AF and AFL patients with additional risk factors* AF and AFL patients with additional risk factors* R Dronedarone 400 mg b.i.d. (n = 2,301) Double-blind Placebo (n = 2,327) 12 30 months All patients treated with standard of care treatment. * Age 75 years or 75 years with hypertension, diabetes, prior stroke/tia, LAD > 50 mm, or LVEF 0.40 AFL = atrial flutter; TIA = transient ischaemic attack. Hohnloser S, et al. N Engl J Med. 2009;360:668-78.
Baseline Patient Characteristics Placebo n=2327 Dronedarone n=2301 All patients n=4628 Age (mean ±SD, years) 71.7 ±9.0 71.6 ±8.9 72 ±9.0 <65yr 442 (19.0%) 431 (18.7%) 873 (18.9%) 65 to 75yr 907 (39.0%) 923 (40.1%) 1830 (39.5%) 75yr 978 (42.0%) 947 (41.2%) 1925 (41.6%) Female gender 1038 (44.6%) 1131 (49.2%) 2169 (46.9%) AF/AFL at baseline 586 (25.2%) 569 (24.7%) 1155 (25.0%) Structural heart disease 1402 (60.9%) 1330 (58.3%) 2732 (59.6%) Hypertension 1996 (85.8%) 1999 (86.9%) 3995 (86.3%) Coronary heart disease 737 (31.7%) 668 (29.0%) 1405 (30.4%) Valvular heart disease 380 (16.3%) 379 (16.5%) 759 (16.4%) Non-ischemic cardiomyopathy 131 (5.6%) 123 (5.3%) 254 (5.5%) History of CHF NYHA II/III 515 (22.1%) 464 (20.2%) 979 (21.2%) LVEF <0.45 285/2281 (12.5%) 255/2263 (11.3%) 540/4544 (11.9%) LVEF <0.35 87/2281 (3.8%) 92/2263 (4.1%) 179/4544 (3.9%) Lone atrial fibrillation 139 (6.0%) 140 (6.1%) 279 (6.0%) Pacemaker 243 (10.4%) 214 (9.3%) 457 (9.9%) Hohnloser SH, et al. J Cardiovasc Electrophysiol 2008;19:69-73.
Cumulative incidence (%) Primary Outcome: Cardiovascular hospitalization or death 50 40 30 Hazard ratio = 0.76 p < 0.001 Placebo on top of standard therapy Dronedarone 400 mg b.i.d. on top of standard therapy 24% reduction in relative risk 20 Mean follow-up 21 ± 5 months 10 Patients at risk Placebo 2,327 1,858 1,625 1,072 385 3 Dronedarone 400 mg b.i.d. 0 0 6 12 18 24 30 Follow-up time, months 2,301 1,963 1,776 1,177 403 2 Hohnloser S, et al. N Engl J Med. 2009;360:668-78.
Primary Outcome: Consistency Across Important Clinical Subgroups Age (years) <75 75 Gender Male Female Presence of AF/AFL Yes No Structural Heart Disease Yes No Congestive Heart Failure Yes No LVEF (%) <35 35-45 45 ACE/ARB Yes No Beta Blocking Agents Yes No N 2703 1925 2459 2169 1155 3473 2732 1853 1365 3263 179 361 4004 3216 1412 3269 1359 HR [95% CI] 0.76 [0.67;0.87] 0.75 [0.65;0.87] 0.74 [0.64;0.85] 0.77 [0.67;0.89] 0.74 [0.61;0.91] 0.76 [0.68;0.85] 0.76 [0.67;0.85] 0.77 [0.65;0.92] 0.75 [0.64;0.88] 0.76 [0.68;0.86] 0.68 [0.44;1.03] 0.66 [ 0.47;0.92] 0.78 [0.70;0.86] 0.74 [0.66;0.83] 0.79 [0.66;0.95] 0.78 [0.69;0.87] 0.71 [0.58;0.86] P-value 0.93 0.65 0.85 0.85 0.83 0.55 0.59 0.41 0.1 1 10 Dronedarone better Placebo better Hohnloser SH et al. ATHENA Investigators. N Engl J Med. 2009 Feb 12;360(7):668-78.
Inclusion criteria PALLAS Patient Inclusion / Exclusion Permanent AF Atrial fibrillation or flutter, present for at least 6 months Age 65 years Major Risk factor (at least one) History of either coronary artery or peripheral arterial disease History of stroke or TIA Heart failure hospitalization in past year, or LVEF 40% Age 75 years, with both hypertension and diabetes mellitus Major exclusion criteria Severe heart failure symptoms (NYHA class IV) or recent unstable NYHA class III Bradycardia < 50 bpm or QTc interval > 500 ms without pacemaker Implantable cardioverter-defibrillator
PALLAS Design Eligible Patients R Dronedarone 400 mg BID N=5400 Placebo N=5400 Two Co-Primary Outcomes 1. Stroke, myocardial infarction, systemic embolism or cardiovascular death 2. Unplanned cardiovascular hospitalization or death Planned study enrolment of 10,800 patients Prematurely stopped by DSMB; 1619 + 1617 pts.
Baseline Characteristics Dronedarone N=1619 Placebo N=1617 Age years mean (SD) 75.0 (5.9) 75.0 (5.9) Duration of permanent AF > 2 years 1119 (69.1%) 1124 (69.5%) Coronary artery disease 661 (40.8%) 666 (41.2%) Peripheral arterial disease 187 (11.6%) 213 (13.2%) Prior Stroke or TIA 436 (26.9%) 458 (28.3%) History of heart failure 1139 (70.4% ) 1117 (69.1%) Left ventricular ejection fraction 40% 345 (21.3%) 335 (20.7%) Baseline use of a Beta-blocker 1201 (74%) 1201 (74%) Baseline use of Vitamin K antagonist 1359 (84%) 1363 (84%)
Components of the Primary Outcomes Dronedarone N=1619 Placebo N=1617 HR 95% CI, p-value Death 25 13 1.94 [0.99-3.79 ] p=0.049 Cardiovascular Death 21 10 2.11 [1.00-4.49], p=0.046 Arrhythmic Death 13 4 3.26 [1.06-10.0], p=0.03 Stroke 23 10 2.32 [1.11-4.88], p=0.02 Myocardial Infarction 3 2 1.54 [0.26-9.21], p=0.63 Unplanned CV Hospitalization 113 59 1.97 [1.44-2.70], p<0.001 Heart Failure Hospitalization 43 24 1.81 [1.10-2.99], p=0.02
Antiarrhythmic Drugs for Cardioversion
Pharmacologic cardioversion: Chart from ESC 2012 A-Fib guideline Multichannel Camm J et al
Vernakalant: Incidence of Hypotension and Ventricular Arrhythmia During the First 2 Hours 1 Hypotension Placebo (%) Vernakalant (%) All patients Patients with CHF -Serious/discontinuation Patients without CHF 5.1 4.7 0 5.2 7.6 16.1 2.9 5.7 Ventricular arrhythmia Patients with CHF a Patients without CHF 1.6 3.6 7.3 3.2 CHF = congestive heart failure a These arrythmias typically presented as asymptomatic, monomorphic, non-sustained (average 3-4 beats) ventricular tachycardias. 1. EU Summary of Product Characteristics, BRINAVESS, MSD, 2010.
What do the guidelines say?
www.escardio.org
ESC 2012 HF guideline McMurray J et al
ESC 2012 HF guideline McMurray J et al
Camm J et al
ESC 2012 A-Fib guideline Camm J et al
Conclusions: Treatment of HF Patients: Role of Antiarrhythmic Drugs? No evidence exists to support the use of any antiarrhythmic drug in this population, most studies point to a harmful effect The only drug that does not exert harm is amiodarone Hence, in an absolute need of antiarrhythmic drug, amiodarone is the only choice The new antiarrhythmic drug dronedarone ok in mild HF, but not in advanced HF The new antiarrhythmic converting agent vernakalant ok in mild HF, but not in advanced HF 39
Condensed Conclusion: Treatment of Patients with Advanced HF: Role of Antiarrhythmic Drugs?: No No Recommendation 40
Thank you for your attention 41