Prof. C. Moro, Madrid

Non antiarrhythmic drugs for AF

AF Treatment

Substrate Modifyers

Drugs

Antiagregation

Anticoagulation

Rate Control ?

Substrate Ablation AVN

Ablation

Rhythm Control ?

Therapy Objectives for AF•Symptomatic Improvement•Quality of life Improvement•Thromboembolism

Prevention•Remodelling Prevention•Heart Failure Prevention •Mortality Reduction

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

Upstream Therapy in AF – Renin Angiotensin Inhibitors Drugs

•ACE`s•ARB`s

– Statins– Steroids– PUFA

• 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

Nakashima et al . 2000

Effect of Candesartan/ Captopril preventing electrical remodeling with rapid atrial pacing in the animal model

Genetic Determinants of AF Genetic Determinants of AF Potasium and Sodium ChannelsPotasium and Sodium Channels

Candesartan

Kumagai K et al. JACC 2003

Experimental AF. Electro/Anatomic Changes with Candesartan

Control

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

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.

ACEI`s or ARB`s for IHD Prevention

•Plaque Stabilization• Improvement of Endothelial Dysfunction• Improvement of Fibrinolysis• Modulation of Arterial Vasoconstriction • Blood Pressure Reduction

ACEI´s and ARB´s Antiproliferative Effects

•Reduction of Vascular Hypertrophy.

•Reduction of Ventricular Hypertrophy.

•Reduce Extracellular Proliferation. –Reduction of Fibrosis.

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

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

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

Madrid AH, Moro C. PACE 2004

Prevention of Atrial Fibrillation Metaanalysis with ACEI’s ARB’s

Irbesartan in Lone AFDose Response : 150-300 mg

Madrid AH, Moro C. JRAAS 2004; 5 :114-120

RAS Inhibitors in Lone AF

RAS Inhibitors in Lone AF

RAS Inhibitors in Lone AF

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

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%

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

APD

EEF

SR

AF

SR

AF

ACTION POTENTIAL

ANATOMICAL

Fybrosis

Hypertrophy

Inflammation

Reduced AERP

Loss of AERP adaptation to rate

Inflammation and AF

Statins for AF

Statins for AF

Statins for AF

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

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

Steroids for AF Prevention

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

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.