Download Recent learnings in CV therapy with Angiotensin Receptor Blockers

Atrial Fibrillation
and Heart Failure
Bologna, February 2009
Upstream Therapy for AF
Prof. C. Moro, Madrid
AF Treatment
Cardioversion
Antiarrhythmic
Drugs
Antiagregation
Anticoagulation
Upstream
Therapy
Substrate
Ablation
AVN Ablation
AF Atrial Structural
Remodeling
– Cell stretch and reduced conexins.
– Atrial enlargement.
– Myocarditis.
– Patchy Fibrosis.
– Apoptotic death.
– Cellular Degeneration.
– Increased expression of MMP and
Collagen turnover.
Upstream Therapy in AF
– Angiotensin II Inhibitor Drugs
•ACEI`s
•ARB`s
–
–
–
–
Statins
PUFA
Steroids. Anti-Inflammatory Agents
Antioxidants
Experimental Data
• 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
Nakashima et al, 2000
Effect of
Candesartan/
Captopril
preventing
electrical
remodeling with
rapid atrial
pacing in the
animal model
Experimental AF. Electro/Anatomic Changes with Candesartan
Candesartan
Control
Kumagai K et al. JACC 2003
Electrophysiological Effect of Irbesartan
1. Irbesartan does not modify IKr or IKs:
Should not alter APD at VENTRICULAR level
2. Irbesartan blocks moderately IKur and Ito currents:
it should prolong APD at ATRIAL level
IKur: hKv1.5
Control
ITo: Kv4.3
Irbesartan
0.1 M
Irbesartan
0.1 M
200 ms
1 nA
0.5 nA
Control
50 ms
Moreno et al., J Pharmacol Exp Ther 2003;304:862
Maintenance of Sinus Rhythm
after Conversion from Persistent AF
% Event-free patients
1.0
0.9
0.8
0.7
Amiodarone + Irbesartan
Amiodarone
0.6
0.5
0.4
0.3
0.2
0.1
0.0
2-month lower recurrence rate of atrial
fibrillation
Longer time to first arrhythmia recurrence
Log Rank = 0.007
0
30 60 90 120 150 180 210 240 270 300 330 360 390
Follow-up (days)
Madrid AH, Moro C et al. Circulation 2002;106:331-6.
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 apoptosis
Madrid A , Moro C. Circulation 2002;106:331–6
Prevention of Atrial Fibrillation
Metaanalysis with ACEI’s ARB’s
Madrid AH, Moro C. PACE 2004
Irbesartan in Lone AF
Dose 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, myocarditislike 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
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/Am
lo+Amio
Sig Reduction
Yin
177
Losar+Amio/
Sig Reduction
Peri+Amio/Amio
Statins to prevent Atrial
Remodeling
• Anti-inflammatory Effect.
• Anti-oxidant Effect.
• Anti-fibrotic Effect
• Modulation of MMP.
• Interaction with Peroxisome receptor.
• Interaction with Endotelial Nitric
Oxide Synthase .
• Antiatherogenic properties.
Statins for AF
Statins for AF
Gillis AM Eur Heart J 2008 ;29:1873
Statins for Post Operative AF
Statins for Post operative 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 Reduction
Virani/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. Followup 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
Author/Year Publication
Patients
Follow up
Results
• Mozaffarian/04
4815
12 years
++
• Calo/05
160
days
++
• Frost/05
47949
5,7 years
--
• Brouwer/06
5284
6,4 years
--
Non AA Drugs with Antiarrhythmic efficacy for AF
Prevention
Drug
Mechanism
Main Effect
Approved
ACEI
Reduce Angio II
Reduce Fibrosis
HF
ARBs
AT1 Rec Ant
Reduce Fibrosis
HF
Spironolactone
Aldosterone
Antag.
Reduce fibrosis
HF
Pirfenidone
Unknown
Antifibrotic
Investigational
Statins
HMGCo-A R. I
Antinflammatory
Lipid Low
PUFA
Antioxidant
Antioxidant
Investigational
Conclusions I
•ACEI`s and ARB´s are
supplementary agents to fight
against AF in primary and
secondary prevention .
•Lone AF may also be treated with
them. (Not recognized yet in
Guidelines).
•The RR achieved with those drugs
is higher in patients with high
arrhythmogenic risk.
Conclusions II
•Steroids should not be used in
AF prevention due to its plural
and potent adverse effects.
•Statins are useful for primary
/secondary AF prevention.
•PUFA effects for AF prevention
show controversial results.