prof. c. moro, madrid
DESCRIPTION
Non antiarrhythmic drugs for AF. Prof. C. Moro, Madrid. AF Treatment. Therapy Objectives for AF. Symptomatic Improvement Quality of life Improvement Thromboembolism Prevention Remodelling Prevention Heart Failure Prevention Mortality Reduction. Therapy Options in AF . - PowerPoint PPT PresentationTRANSCRIPT
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Prof. C. Moro, Madrid
Non antiarrhythmic drugs for AF
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AF Treatment
Substrate Modifyers
Drugs
Antiagregation
Anticoagulation
Rate Control ?
Substrate Ablation AVN
Ablation
Rhythm Control ?
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Therapy Objectives for AF•Symptomatic Improvement•Quality of life Improvement•Thromboembolism
Prevention•Remodelling Prevention•Heart Failure Prevention •Mortality Reduction
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Therapy Options in AF – Type and Duration of AF– Type y Severity of Symptoms– Associated Cardiac Diseases– Age– Systemic Associated Diseases– Long or Short Term Follow up– Pharmacologic or Non
Pharmacologic
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Upstream Therapy in AF – Renin Angiotensin Inhibitors Drugs
•ACE`s•ARB`s
– Statins– Steroids– PUFA
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• Blockade of Ang II prevents electrical remodeling induced by rapid atrial pacing. Nakashima, 2000.
• ACE–dependent Ekr1/Ekr2 responsible of atrial fibrosis. Goette, 2000
• Candesartan prevents development of structural remodeling in the atria. Kumagai, 2003
Experimental DataExperimental Data
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Nakashima et al . 2000
Effect of Candesartan/ Captopril preventing electrical remodeling with rapid atrial pacing in the animal model
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Genetic Determinants of AF Genetic Determinants of AF Potasium and Sodium ChannelsPotasium and Sodium Channels
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Candesartan
Kumagai K et al. JACC 2003
Experimental AF. Electro/Anatomic Changes with Candesartan
Control
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ACEI´s and ARB´s Hemodynamic Effects
• Decrease Peripheral Vascular Resistance
• Improve Cardiac Distensibility• Reduce Arterial Pressure in
Hypertension• In HF patients
– Venous and Arterial Dilatation– Reduce Preload and Afterload– Reduce PWP and Pulmonary Congestion– Increase Cardiac Output
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ACEI´s and ARB´s Neurohormonal Effects
•Decrease Angiotensin II.•Decrease Aldosterone. •Increase in Renin and Angiotensin I.
•Reduce Epinephrine and Norepinephrine.
•ACEI´s increase Bradikinin.
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ACEI`s or ARB`s for IHD Prevention
•Plaque Stabilization• Improvement of Endothelial Dysfunction• Improvement of Fibrinolysis• Modulation of Arterial Vasoconstriction • Blood Pressure Reduction
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ACEI´s and ARB´s Antiproliferative Effects
•Reduction of Vascular Hypertrophy.
•Reduction of Ventricular Hypertrophy.
•Reduce Extracellular Proliferation. –Reduction of Fibrosis.
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Atrial Remodeling: Mechanisms of Efficacy for ARB´s• Hemodynamic effect:
– Decreased atrial stretch– Lowering end-diastolic left ventricular pressure
• Prevention of electrical remodeling:– Direct action on ionic currents at the atrial level– Modifying the sympathetic tone
• Preventing structural remodeling– Reduction of atrial fibrosis
• Reduction of atrial dilatation and apoptosisMadrid A , Moro C. Circulation 2002;106:331–6
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Electrophysiological Effect of Irbesartan
1. Irbesartán does not modify IKr or IKs:Should not alter APD at VENTRICULAR level
2. Irbesartán blocks moderately IKur and Ito currents: it should prolong APD at ATRIAL level
200 ms
0.5
nA
Control
Irbesartan0.1 M
50 ms
1 nA
Control
Irbesartan0.1M
IKur: hKv1.5 ITo: Kv4.3
Moreno et al., J Pharmacol Exp Ther 2003;304:862
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Maintenance of Sinus Rhythm after Conversion from Persistent AF
Amiodarone + Irbesartan
Amiodarone
1.00.90.80.70.60.50.40.30.20.10.0
0 30 60 90 120 150 180 210 240 270 300 330 360 390
Follow-up (days)
2-month lower recurrence rate of atrial fibrillation
Longer time to first arrhythmia recurrence
Log Rank = 0.007
Madrid AH, Moro C et al. Circulation 2002;106:331-6.
% E
vent
-free
pat
ient
s
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Madrid AH, Moro C. PACE 2004
Prevention of Atrial Fibrillation Metaanalysis with ACEI’s ARB’s
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Irbesartan in Lone AFDose Response : 150-300 mg
Madrid AH, Moro C. JRAAS 2004; 5 :114-120
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RAS Inhibitors in Lone AF
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RAS Inhibitors in Lone AF
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RAS Inhibitors in Lone AF
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Ramipril in Lone AF• Preventing histological remodeling
such as Inflammation, myocarditis-like changes,Fibrosis and atrial dilatation.
• Preventing electrical remodeling induced by Angiotensin II.
• Reducing atrial stretch and intraatrial pressure.
• Reduction of sympathetic tone. • Reduction of blood pressure.
Belluzi et al JACC 2009;53:24
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Randomized clinical trials of RAS I in AF Primary Prevention
Trial Pat N Drug Results
CAPP2 10985 Captopril/St No Diff
STOP-2 6628 Enal-Lisi/St No Diff
LIFE 8851 Losart/Ateno 3,5 vs 5,3%
HOPE 8335 Ramip/Plac No Diff
VALUE 13760 Vals/Amlod 3,7 vs 4,3%
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Randomized clinical trials of RAS I in AF Secondary Prevention
Author/year Pat N Drug Results
Van den Bergh
18 Lisinopril/Plac Sig reduction
Madrid 154 Irb+Amio/Amio Sig Reduction
Ueng 145 Ena+Amio/Amio Sig Reduction
Tveit 137 Cande/Plac Sig reduction
Fogari 222 Losar+Amio/Amlo+Amio
Sig Reduction
Yin 177 Losar+Amio/ Peri+Amio/Amio
Sig Reduction
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APD
EEF
SR
AF
SR
AF
ACTION POTENTIAL
ANATOMICAL
Fybrosis
Hypertrophy
Inflammation
Reduced AERP
Loss of AERP adaptation to rate
Inflammation and AF
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Statins for AF
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Statins for AF
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Statins for AF
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Review of randomized clinical trials of Statins to prevent Post Thoracic Surgery AF
Author/year Design n Findings
Auer/04 Prospective 253 Sig reduction
Amar/05 Prospective 131 Sig Reduction
Marin/06 Prospective 234 Sig Reduction
Patty/06 Double blind 200 Sig Reduction
Chello/06 Doble blind 40 Sig reduction
Ozaydin/07 Prospective 362 Sig ReductionVirani/08 Retrospective 4044 No Diff
Letsburapa/08 Prospective 555 Sig Reduction
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Steroids for AF Prevention• Double blind study with 104 patients• Persistent AF. After Cardioversion. High
PCR levels. • Profafenone + 16mg-4 mg
Methylprednisolone vs Placebo. Follow-up mean 23 months.
• Recurrent AF was reduced from 50-9,6%• Permanent AF was reduced from 29-2%.• Significant reduction also of PCR levels.
•Dernellis et al Eur H J 2004; 25:1100-07
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Steroids for AF Prevention
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Clinical Trials with PUFA
• Mozaffarian/04 4815 12 years ++• Calo/05 160 days ++• Frost/05 47949 5,7 years --• Brouwer/06 5284 6,4 years --
Author/Year Publication Patients Follow up Results
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Conclusions
• ACE`s and ARB´s are equipotent tools to fight against AF in primary and secondary prevention .
• Lone AF may also be treated with them. (Not recognized yet in Guidelines).
• The RR for AF prevention with those drugs is higher in patients with high arryhthmogenic risk.
• Steroids should not be used in AF prevention due to its plural and potent adverse effects.
• Statins are useful to prevent post surgical AF.• PUFA effects for AF prevention show controversial
results.