RENIN-ANGIOTENSIN-
ALDOSTERONE-SYSTEM
INHIBITORS: TREATMENT
AND PREVENTION OF
ATRIAL FIBRILLATION
Adam Wood, Pharm.D. Candidate

trial Fibrillation (AF) is a source of signifi-

cant morbidity and mortality. It is estimated
that 2.2 million Americans experience par-
oxysmal or persistent AF. This number is expected to
rise with the increasing age of the population and
success of treating cardiovascular disease. AF can
lead to deep vein thrombosis, worsening heart fail-
ure, stroke, and reductions in quality of life.1
The current treatment options available to pa-
tients with AF have been unsuccessful in finding a
satisfactory balance between safety and efficacy.
Current antiarrhythmic drugs like amiodarone are
effective in maintaining sinus rhythm for patients
with AF, but are associated with serious adverse
events. Ablative therapy can restore sinus rhythm,
but is an invasive procedure that puts patients at risk
for procedural stroke and pulmonary vein stenosis.1
In addition to the limitations of current therapies,
there are relatively few modalities for preventing AF
in the first place.
The unbalanced benefit to risk ratio in AF has
lead to the idea of upstream therapy. Upstream ther-
apy deals with altering physiologic mechanisms that
produce an arrhythmogenic substrate with the hopes
of preventing AF from developing. Upstream thera-
pies are designed to prevent further damage to the
heart, limiting relapses in patients with established

AF. Currently, upstream therapy is focused on alter-
ing known factors in the pathogenesis of AF includ-
ing neurohormonal activation, tissue inflammation,
oxidative stress, and electrical remodeling.2
Specifically, agents that act by inhibiting the
Renin-Angiotensin-Aldosterone-System (RAAS) are
being examined as upstream therapy. Many large,
randomized, controlled trials have shown a seren-
dipitous benefit of preventing both AF relapses and
the incidence of new-onset AF with the use of RAAS
inhibitors (RAASI's). The objective of this article is
to review the clinical evidence of RAASI's in the
setting of AF and to discuss the potential utility of
these agents in AF therapy.

MECHANISM OF RAAS INHIBITION IN AF

The mechanism of AF prevention through the use
of RAASI's is a direct function of modulating the
effects of angiotensin II (Ang II) on the heart. By
inhibiting the effect of Ang II, RAASI's can prevent
the electrical and structural remodeling that is char-
acteristic of AF.3
The most frequently encountered changes that
occur in AF patients include atrial muscle loss and

INSIDE THIS ISSUE:
RAAS INHIBITORS: TREATMENT AND
PREVENTION OF ATRIAL FIBRILLATION

,l ^ ^ ^ -^^ ^ ^ -r ,

mm

PharmaNote

VOLUME 24, ISSUE 12 SEPTEMBER 2009
i -i

Volume 24, Issue 12 1 September 2009

PharmaNote

atrial fibrosis. While these changes can be geneti-
cally predisposed, they can also be a consequence of
disease states that induce atrial dilation. Disease
states often associated with atrial dilation include
valvular heart disease, hypertension, chronic heart
failure (CHF), and coronary artery disease (CAD).1
Following atrial stretching, several molecular
pathways are activated, including the RAAS. Activa-
tion of this system up-regulates the production of
Ang II and transforming growth factor-betal (TGF-
betal), which in turn leads to increased levels of con-
nective tissue growth factor (CTGF).1 Patients with
persistent AF have a 3-fold increase in ACE levels.4
These changes in signaling molecules lead to produc-
tion of fibrous cardiac tissue that can serve as ar-
rhythmogenic substrates. Additionally, myocardial
dilation can lead to electrical remodeling that pro-
longs conduction time and causes conduction abnor-
malities within cardiac muscle.
Ang II can cause atrial dilation indirectly via its
vasoconstrictive actions. As a potent vasoconstrictor,
Ang II can increase afterload and cardiac wall pres-
sure. This increased stress on the walls of the heart
leads to dilation and the development of arrhythmic
substrates.3 The RAAS can also influence the devel-
opment of AF through electrical remodeling. Ang II
is responsible for shortening the refractory period of
the atria and increasing intracellular calcium levels.
The increase in intracellular calcium along with a
decrease in potassium efflux may cause a decreased
refractoriness that leads to arrhythmias.3 In an animal
model, Ang II was shown to significantly decrease
the atrial refractory period during rapid atrial pacing,
which was reversed with candesartan and captopril.5
The induction of the RAAS is associated with
many arrhythmia producing changes in the atria. The
RAAS system tends to be up-regulated in many
chronic, cardiovascular disease states including hy-
pertension, CHF, and CAD. Therefore, the goal of
upstream therapy with RAASI's is to mitigate the
RAAS's arrhythmogenic influence on the heart in
order to preserve atrial function and either prevent
relapse of AF or prevent the initial development of
AF in at-risk patients.

SUPPORT FOR RAAS INHIBITION IN AF

Much of the evidence supporting RAAS inhibi-
tion in AF is derived from post hoc analyses of large,
randomized, controlled trials. Since using these

agents as upstream therapy is a relatively new con-
cept, there are few trials prospectively designed to
study this effect. Until more large scale trials are
published, it is difficult to define a true cause and
effect relationship with these agents in AF. There is
also the question of whether the benefits seen in the
post hoc analyses are due to preventing damage and
remodeling of the atria or if RAAS inhibition has a
direct antiarrhythmic effect on the heart.

PREVENTION OF NEW-ONSET AF

One of the first trials to look at the use of angio-
tensin converting enzyme inhibitors (ACEI) in the
prevention of AF was the Trandolapril Cardiac
Evaluation (TRACE) study.6 In this study, trandola-
pril was compared to placebo in patients who had a
myocardial infarction (MI) with a left ventricular
ejection fraction (LVEF) < 36%. The primary end-
point was ECG confirmed development of AF. Dur-
ing the 2-4 year follow-up period, patients receiving
trandolapril had a significantly reduced risk of devel-
oping AF (RR of 0.45; 95% CI 0.26-0.76; p < 0.01).
When controlling for baseline characteristics be-
tween groups, CHF, left ventricular function, male
sex, use of digitalis, age, and systolic blood pressure
were all significantly related to the development of
AF. This study was one of the first large, randomized
controlled trials to suggest that ACEI's may have a
significant impact on the incidence of AF in patients
with left ventricular impairment.6
In a retrospective analysis of the Studies of Left
Ventricular Dysfunction (SOLVD) trials, ACEI use
was associated with a lower incidence of AF.8 This
study examined patients with a reduced LVEF (<
35%) that were randomized to placebo or enalapril 5-
20 mg/day. Treatment with enalapril was associated
with an absolute risk reduction in the incidence of
AF by 18.6% (5.4% of patients in the enalapril group
vs. 24% in the placebo treated group; p < 0.0001).
Even after excluding patients with a history of su-
praventricular arrhythmias, enalapril demonstrated a
close association with a decreased incidence of AF
vs. placebo (4.5% vs. 23%, respectively; p < 0.0001).
The investigators felt that the risk reduction observed
in SOLVD was greater than the TRACE study since
SOLVD data came from patients with established
myocardial dysfunction. In the TRACE study, pa-
tients were studied immediately after an MI when
atrial remodeling may not yet have occurred. The

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PharmaNote

Table 1. RAAS inhibition for primary prevention of AF.

LIFE14
(2005)

CAPPP12
(1999)

STOP-213
(1999)

HOPE17 (2007)

DESIGN

POPULATION

STUDY
TRACE6 (1999)

SOLVD7 (2003)

SOLVD8 (2004)

Val-HeFT9
(2005)
CHARM10
(2006)
VALUE15
(2008)

L'Allier et al.16
(2004)

Post hoc analysis

Post hoc analysis

Post hoc analysis

Post hoc analysis

Prescpecified sec-
ondary endpoint
Prespecified secon-
dary analysis

Retrospective, lon-
gitudinal cohort
study

Prespecified secon-
dary analysis

Prespecified secon-
dary endpoint

Prespecified secon-
dary endpoint

Post hoc analysis

AMI and reduced LV func-
tion
Asymptomatic to overt
CHF with LVEF < 35%
Asymptomatic to overt
CHF with LVEF < 35%

CHF and LVEF 40%

CHF and reduced or pre-
served LVEF
Aged > 50 y and HTN with
at least one CV risk factor

Aged > 18 y with HTN (At
baseline: AF=2.4%;
CHF=3.7%)

Aged 55-80 y with HTN,
LVH and no AF

Aged 25-66 y with HTN (At
baseline: < 1% with AF or
CHF)
Aged 70-84 y with HTN (At
baseline: AF=4.7%;
CHF=1.9%)

Aged > 55 y, high CV risk,
and preserved LVEF

ACEI = angiotensin converting enzyme inhibitor; AF = atrial fibrillation; AMI = acute myocardial infarction; BB = beta blocker; CHF = chronic heart failure; Cl = confi-
dence interval; CV = cardiovascular; HR = hazard ratio; HTN = hypertension; LV = left ventricular; LVEF = left ventricular ejection fraction; NSR = normal sinus
rhythm: RR = relative risk; SR = sinus rhythm.

SOLVD data also showed that treatment of patients
with reduced LVEF had a lower rate of hospitaliza-
tions due to AF when treated with enalapril than with
placebo.8
The reduced incidence of new-onset AF is also
seen in patients treated with angiotensin II receptor
blockers (ARB's). In the Valsartan Heart Failure
(Val-HeFT) trial, the occurrence of AF was exam-
ined in patients with CHF who were in normal sinus
rhythm at study entry. The valsartan group had a sig-
nificantly decreased occurrence of AF vs. placebo

(5.12% vs. 7.95% p = 0.0001)9. Unfortunately, this
study did not differentiate between patients with or
without a past history of AF so it is unknown if val-
sartan is associated with a prevention of AF relapse
or prevention of new-onset AF. The Candesartan in
Heart Failure: Assessment of Reduction in Mortality
and Morbidity (CHARM) study included a planned
secondary analysis designed to observe the develop-
ment of newly diagnosed AF. Across the arms of the
CHARM study (preserved ejection fraction of >
40%, and low ejection fraction), candesartan was as-

Phrm~oe oum 2, sue12I etebe 20

PharmaNote

TREATMENT
. Trandolapril (n=790)
. placebo (n=787)
. Enalapril (n=186)
. placebo (n=188)
. Enalapril (n=3396)
. placebo (n=3401)

. Valsartan (n=2205)
. placebo (n=2190)
. Candesartan (n=3191)
. placebo (n=3188)
. Valsartan (n=7649)
. amlodipine (n=7596)

. ACEI (n=5463)
. CCB (n=5463)

MAIN FINDINGS
New-onset AF: trandolapril 5.3%
vs. placebo 2.8% (p<0.05)
New-onset AF: enalapril 5.4%
vs. placebo 24% (p<0.0001)
RR of hospitalization due to AF
in enalapril group (patients
without AF at study entry): 0.64
(95% Cl: 0.46-0.88; p=0.004)

AF occurrences: valsartan 5.12%
vs. placebo 7.95% (p<0.0001)
New-onset AF: candesartan
5.55% vs. 6.74% (p=0.048)
New-onset AF: valsartan 3.7%
vs. amlodipine 4.3% (HR 0.843;
95% Cl: 0.713-0.997)
HR for new-onset AF: ACEI 0.85
(95% Cl: 0.62-0.89) Incidence
ratio of AF related hospitaliza-
tions with ACEI 0.74 (95% Cl:
0.62-0.89)

New-onset AF: losartan 3.5% vs.
atenolol 5.3%: RR 0.67 (95% Cl:
0.55-0.83); p<0.001
New-onset AF: captopril 2.1%
vs. control 2.5% (NS)

New-onset AF: No significant
difference between groups

New-onset AF: Ramipril 2.0% vs.
placebo 2.2% (NS)

. Losartan (n=4298)
. atenolol (n=4182)

. Captopril (n=5492)
. diuretic, BB, or both
(n=5493)
. ACE inhibitors
(n=2205)
. CCB (n=2196)
. diuretic, BB, or both
(n=2213)

. Ramipril (n=4645)
. placebo (n=4652)

Volume 24, Issue 12 i September 2009

sociated with a significant decrease in the occurrence
of newly diagnosed AF (OR of 0.81; 95% CI 0.66-
0.99) vs. placebo. This effect was maintained in the
subset of data from the two low ejection fraction
studies (OR of 0.78; 95% CI 0.61-0.99). Interest-
ingly, candesartan did not reduce new-onset AF in
those patients with a preserved ejection fraction.10
This finding was later confirmed in the Irbesartan in
Heart Failure with Preserved Ejection Fraction (I-
PRESERVE) Study."1
These studies suggest a significant association
between a reduced incidence of AF and the use of
RAASI's in patients with CHF or decreased ejection
fraction. Since RAASI's are associated with im-
proved morbidity and mortality in patients with
CHF, post-MI, and reduced LVEF, this data adds
another reason for clinicians to evaluate their patients
as potential RAASI candidates.
Several studies have evaluated RAASI's in the
prevention of new-onset AF in patients without CHF
or other structural heart disease. In the Captopril Pre-
vention Project (CAPPP) and Swedish Trial in Old
Patients with Hypertension-2 (STOP-2) studies, pa-
tients with hypertension were treated with ACEI's or
placebo. The difference in the incidence of AF be-
tween groups failed to achieve significance.12'13
In contrast, the Losartan for End Point Reduction
(LIFE) study was a randomized, controlled trial that
compared patients with hypertension and no history
of AF to losartan or atenolol.14 Those subjects in the
losartan treatment arm were significantly less likely
to develop new-onset AF than patients taking at-
enolol (RR of 0.67; 95% CI 0.55-0.83; p < 0.001).
Patients treated with losartan were also significantly
less likely to experience stroke (HR of 0.49; 95% CI
0.29-0.86; p = 0.01) and the overall composite end-
point (HR of 0.60; 95% CI 0.38-0.94; p = 0.03).14
The available evidence seems to support the use of
RAASI's in patients with hypertension to help pre-
vent the occurrence of AF (Table 1).

PREVENTION OF AF RELAPSE

Another potential use for RAASI's is the preven-
tion of AF relapse. Since patients with AF are more
likely to have some degree of atrial remodeling and
structural heart damage, RAASI's may remove some
of the burden from the RAAS and help prevent fur-
ther remodeling.
In 2002, Madrid et al. evaluated patients with re-
current, persistent AF who were either treated with
amiodarone or amiodarone in combination with irbe-
sartan.18 They demonstrated that patients on irbesar-
tan and amiodarone had a 2 month probability of
maintaining sinus rhythm after successful cardiover-
sion of 84.79% compared to the 63.16% probability
with amiodarone alone (p = 0.008). Even after con-
trolling for various patients factors including history
of diabetes, irbesartan demonstrated an 81% reduc-
tion in the risk of relapsing into AF vs. amiodarone
alone (RR of 0.19; 95% CI 0.04-0.86; p = 0.031).18
A subanalysis of the Atrial Fibrillation Follow-up
Investigation of Rhythm Management (AFFIRM)
trial investigated whether treatment with RAASI's
prevented AF relapses in patients in the rhythm con-
trol arm of the trial.19 Patients exposed to RAASI's
were significantly more likely to have hypertension,
history of CHF, CAD, diabetes, and reduced LVEF
(defined as less than < 40%). Initially, no significant
difference in AF relapse between the groups was
found (HR of 0.91; 95% CI 0.77-1.09; p = 0.31).
However, when patients with a history of CHF or
those with moderate to severe left ventricular dys-
function were compared separately, RAASI use was
associated with a significantly reduced risk of AF
recurrence (HR of 0.63; p = 0.02 for CHF and HR of
0.48; p = 0.04 for left ventricular dysfunction).19
Yin et al. prospectively compared paroxysmal AF
recurrence rates in patients taking amiodarone, amio-
darone plus losartan, or amiodarone plus perindo-
pril.20 All patients had preserved LVEF and after co-

Table 2. Changes in echocardiographic findings.21
RAMIPRIL BASELINE PLACEBO BASELINE RAMIPRIL FOLLOW-UP PLACEBO FOLLOW-UP
Left Atrium SI (cm) 4.1 0.3 4.3 0.4 4.0 0.3 4.5 0.4*
Left Atrium ML (cm) 3.4 0.4 3.6 0.3 3.3 0.3 4.2 0.5*+
Left Atrium area (cm2) 14.0 2.1 14.9 2.1 13.2 2.0 16.8 1.9*+
LVEF(%) 66 7 65 7 67 6 63 7
LVEDV (mL) 44 5 47 5 43 5 46 7
LVEDV = left ventricular end-diastolic volume; LVEF = left ventricular ejection fraction; ML = mediolateral atrial diameter; SI = superoinferior atrial diameter.
* = p < 0.05 vs. respective ramipril.
t = p < 0.05 vs. respective baseline.
mVm sS b

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PharmaNote

Table 3. RAAS inhibition for prevention of AF relapse.
REFERENCE DESIGN POPULATION TREATMENT MAIN FINDINGS
Madrid et al.18 R, OL History of persistent Irbesartan + amiodarone (n=79) AF recurrence: Irbesartan + amio-
(2002) AF > 7 days amiodarone (n=75) darone 15.2% vs. 36.8 % amiodar-
one (p=0.008)
Ueng et al.23 R, OL Chronic AF > 3 Enalapril + amiodarone (n=70) Patients remaining in SR: enalapril +
(2003) months amiodarone (n=75) amiodarone 74.3% vs. amiodarone
57.3%; p=0.021
Madrid et al.24 R, OL Normotensive with Irbesartan 300mg + amiodarone Time to recurrence of AF: both irbe-
(2004) persistent AF > 7 (n=30) sartan groups were significantly
days irbesartan 150mg + amiodarone more likely to stay in SR
(n=30)
amiodarone (n=30)
Yin et al.20 R, OL Lone paroxysmal AF Losartan + amiodarone Relapse of AF: losartan + amiodar-
(2006) perindopril + amiodarone one 19% vs. perindopril + amiodar-
Amiodarone one 24% vs. amiodarone 41% (both
groups were significant against
amiodarone monotherapy)
Belluzzi et al.21 R, DB Normotensive with Ramipril (n=31) AF relapse: ramipril 3 patients vs.
(2009) single episode of AF placebo (n=31) placebo 10 patients (p<0.03)
without structural
heart abnormalities
GISSI-AF22 R, DB NSR with a history of Valsartan (n=722) AF relapse: valsartan 51.4% vs. pla-
(2009) AF and > 1 CV dis- placebo (n=720) cebo 52.1% (NS)
ease risk factor
AFFIRM19 Retro- NSR in the rhythm ACEI or ARB (n=421) AF recurrence: patients with history
(2004) spective control arm of AF- control (n=732) of CHF or LV dysfunction had signifi-
analysis FIRM cantly lower AF recurrence with
ACEI or ARB than without
R= randomized; OL= open-label; DB = double-blind; ACEI = angiotensin converting enzyme inhibitor; AF= atrial fibrillation; AMI = acute myocardial infarction; BB
= beta blocker; CHF = chronic heart failure; Cl = confidence interval; CV = cardiovascular; HR = hazard ratio; HTN = hypertension; LV = left ventricular; LVEF = left
ventricular ejection fraction; NSR = normal sinus rhythm; RR = relative risk; SR = sinus rhythm.

variate adjustment, amiodarone alone was associated
with a significantly higher probability of relapse into
AF than those patients treated with amiodarone plus
losartan or perindopril (p = 0.02). There was no sig-
nificant difference between losartan and perindopril
(p = 0.47).20
A question that remains is whether RAASI's
have a direct antiarrhythmic effect or if they simply
reduce the atrial remodeling that increases a patient's
risk for AF recurrence. In 2009, Belluzzi et al. stud-
ied normotensive patients with no structural heart
abnormalities (based on echocardiogram) with rami-
pril 5 mg daily.21 Included patients had one episode
of lone AF that was cardioverted with propafenone.
Patients were randomized to ramipril 5 mg daily or
placebo. After a 3 year follow up period, patients
taking ramipril had significantly fewer relapses of
AF than placebo (3 cases vs. 10 cases, respectively; p
< 0.03). In addition, patients treated with ramipril

had no significant increases in left atrial size,
whereas the opposite was true in those treated with
placebo (p < 0.05) (Table 2). This suggests that
RAASI's may prevent relapses of AF in normoten-
sive patients, and by preventing atrial enlargement,
may prevent proarrhythmic substrates from form-
ing.21
In April, 2009, the results of the Gruppo Italiano
per lo Studio della Sopravvivenza nell'Infarto Mio-
cardico Atrial Fibrillation (GISSI-AF) trial were
published.22 This large scale randomized, controlled
trial enrolled 1,442 patients with a history of AF and
underlying cardiovascular disease, diabetes, or left
atrial enlargement. In this study, valsartan was com-
pared to placebo in the prevention of AF relapse. Af-
ter a mean follow-up of 1 year, no significant differ-
ences were observed in AF relapse between groups
(51.4% in the valsartan group and 52.1% in the pla-
cebo group; p = 0.73).22 One limitation of this study

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PharmaNote

is the relatively short follow-up; other studies have
observed patients for up to 3 years. This may be im-
portant given the uncertainty surrounding the length
of time necessary to realize RAASI-associated pre-
vention of AF relapse (Table 3).

SUMMARY

The rationale for RAASI therapy in the treatment
and prevention of AF is thought to be due to a miti-
gation of the RAAS's effect on the heart. By inhibit-
ing the RAAS, which is often up-regulated in pa-
tients with established heart disease, RAASI's pre-
vent the formation and further development of ar-
rhythmogenic substrates. Studies show conflicting
data regarding RASSI's ability to prevent new-onset
and relapse of existing AF. Overall, it appears that
patients with a history of structural heart disease with
lower LVEF achieve the greatest benefit whether
they have established AF or not. While further inves-
tigation through prospective, large scale trials is
needed, clinicians can feel confident in knowing that
patients who were already candidates for RAASI
therapy may derive an additional benefit from these
medications.

REFERENCES

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The PharmaNote is Published by:
The Department of Pharmacy
Services, UF Family Practice Medical
Group, Departments of Community
Health and Family Medicine and
Pharmacotherapy and Translational

John G. Gums Editor
PharmD, FCCP

R. Whit Curry, MD Associate Editor

Steven M. Smith Assistant Editor
PharmD

PhraoeVlme2,Ise1 ISpebr20

Volume 24, Issue 12 1 September 2009

PharmaNote