Samah & Manar1

Supervised by:

Dr. Seema Syed

King Faisal Specialist Hospital and Research Center

(2007-1428)

Presented by: Manar LashkarSamah Al-shehriPharm.D candidates

Samah & Manar2

In the long-term management of atrial fibrillation (AF), the strategy of rhythm control offers no long-term benefit

in cardiac outcomes beyond that of symptom relief, and may be harmful

Current antiarrhythmic agents used to maintain sinus rhythm have a multitude of adverse effects that can attenuate their value

Ablative therapy is not possible for a sizable percentage of AF patients, so the search for safer pharmacological agents

continues

This review focuses on non-antiarrhythmic agents

in preventing AF, the proposed mechanism of

effectiveness, and clinical trials that support their

use

Samah & Manar3(Cardiovasc Electrophysiol, Vol. 18, pp. 1222-1228, November 2007)

Samah & Manar4

This article reviews current

evidence of non-

antiarrhythmic agents for the AF prevention

and maintenance of sinus rhythm in

patients with atrial fibrillation

calcium channel blockers

antiinflammatory agents

angiotensin receptor blockers

beta-blockers

Angiotensin converting enzyme inhibitors

Samah & Manar5

Atrial Remodeling

RAASInflammation

Sympathatic Nervous System

Intracellular Calcium Overload

Oxidation

ACE-I, ARB

Vitamin C.

Beta blocker

Statin,steroid,

Fish Oil

Vitamin C,

CCBs

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.

Statins

Vitamin CStatin,steroid,

Fish Oil

Vitamin C,

.

Beta blocker

CCBs

ACE-I, ARB

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Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockade

ACE-I, ARB

Atrial Fibrillation

Increase ACE Upregulation of ATreceptors

ACE-I ARB

Reduce Atrial Fibrosis

Lower Left Atrial Pressure

Reduce Atrial Ectopy

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Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockade

ACE-I, ARB

Atrial Fibrillation

ACE-I ARB=?Upregulation of AT

receptorsIncrease ACE

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I)Drug vs Placebo1) Randomized Clinical Trials of ACE-I

ACE-I, ARB

TRACE = TRAndolapril Cardiac Evaluation

TRACE Trial:

1577 patients

Left ventricular dysfunction after myocardial infarctionSinus rhythm

Trandolapril Placebo

5.3%2.8% Developed AF

3 years

)P< 0.05(

SOLVD Trial:

Left ventricular dysfunction patients

Enalapril

2.9 years

5.4% 24%Developed AF

Similar findings were noted in the Val-HeFT trial

Placebo

SOLVD = The Studies of Left Ventricular Dysfunction Val-HeFT = Valsartan Heart Failure Trial

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ACE-I, ARB

I)Drug vs Placebo1) Randomized Clinical Trials of ARBs

CHARM Trial

Systolic and diastolic dysfunctionpatients

Candesartan Placebo

38 months

5.6% 6.7%Developed new onset AF

CHARM = Candesartan in Heart failure - Assessment of moRtality and Morbidity Trial

)P= 0.048(

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Ueng et al trial: Use of enalapril to facilitate sinus rhythm maintenance after external cardioversion of long-standing persistent atrial fibrillation. Results of a prospective and controlled study

ACE-I, ARB

II)Drug vs Drug1) Randomized Clinical Trials of ACE-I

Ueng trial

125 patients After cardioversion

Enalapril Amiodarone

4 weeksStay in sinus rhythm 61.3%84.3%

)P=0.002(

270 daysStay in sinus rhythm

74.3% 57.3%

)P=0.021(

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ACE-I, ARB

II) Drug vs Drug1) Randomized Clinical Trials of ARBs

LIFE: Losartan Intervention For Endpoint reduction in hypertension

LIFE Trial

8851 patientsHypertensionLeft ventricular hypertrophySinus rhythm

Losartan Atenolol

3.5% 5.3%

4.8 years

)P=0.001(

New onset AF

Madrid Trial

154 patients

AmiodaroneIrbesartan

Amiodarone

37% 15%

2 months

Recurrent AF

Cardioverted for

Persistent AF

)P=0.008(

Other trials found similar benefits with ACE-I

and ARBs

Madrid et al Trial: Use of irbesartan to maintain sinus rhythm in patients with long-

lasting persistent atrial fibrillation: A prospective and randomized study

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Meta-analysisincluded 11 randomized controlled trials of ACE

inhibitorsor ARBs for their efficacy in preventing AF

ACE-I, ARB

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ACE-I, ARB

Only patients with LV dysfunction had lower rates of AF with an ACE-I or an ARB

significant reductionin AF, with a 44% RRR in the onset of AF

Studies of patients with more significant LV dysfunction showed a larger RRR in AFIn the Captopril Prevention Project (CAPP) and the

Swedish Trial in Old Patients`with Hypertension-2 ,there was no reduction in new-onset AF in patients on ACE inhibitors versus beta-blockers, calcium channel blockers, or diuretics. Unlike the LIFE trial that enrolled patients with hypertension and LVH, these trials enrolled patients with hypertension alone.

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In ACTIVE-I, 9,000 patients with AF

with and without hypertension will be

randomized to irbesartan or placebo with a primary endpoint of the composite of stroke, MI, and vascular

deathA substudy of the trial will

evaluate the effect of irbesartan on recurrences

of paroxysmal AF

Substudies of ONTARGET and

TRANSCEND will examine the role of telmisartan alone,

telmisartan in combination with

ramipril, and telmisartan in ACE inhibitor

intolerant patients in preventing recurrences

of AF

ACTIVE: The Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events

ONTARGET: Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint TrialTRANSCEND: The Telmisartan Randomized AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease

ACE-I, ARB

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.

Statins

Fish oil

.

Beta blocker

CCBs

ACE-I, ARB

Anti-inflammatory

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Anti-inflammatory

Anti-inflammatory

There is emerging evidence that inflammation may play a role in the genesis and propagation of AF

higher levels of CRP in patients with AF

compared with patients in sinus

rhythm

Higher CRP levels may reflect a larger

AF burden

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Anti-inflammatory

131 patientsAtrial arrhythmia

71 patientsSinus rhythm

Median CRP= 0.3 mg/dL Median CRP= 0.15 mg/dL

Persistent AFCRP= 0.43 mg/dL

Paroxysmal AFCRP= 0.18 mg/dL

)P=0.001(

Chung et al Trial: C-reactive protein elevation in patients with atrial arrhythmias: Inflammatory mechanisms and persistence of atrial fibrillation

Anti-inflammatory

Chung et at trial

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Anti-inflammatory

12 patient with lone AF

Right atrial biopsies

8 Have myocarditis 4 none

Whether CRP itself can initiate the atrial remodeling that leads to AF or is just a marker for generalized inflammation is still not

clear

Frustaci et al Trial: Histological substrate of atrial biopsies in patients with lone atrial fibrillation

Anti-inflammatory

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Anti-inflammatoryfirst episode of

symptomatic and persistent AF

104 patients

5 months methylprednisolone taper

Placebo

1 Month

CRP levels Decreased by 80%

2 Years9.6% Recurrence of AF 50% Recurrence of AF

)P<0.001(

Dernellis et al Trial: Relationship between c-reactive protein concentrations during glucocorticoid therapy and recurrent atrial fibrillation

Anti-inflammatory

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Antioxidant

Vitamin C

Anti-inflammatory

scavenging reactive oxygen species attenuate calcium accumulation

that affect atrial myocytes

Anti-inflammatory

decrease serum CRP levels

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Vitamin C

Anti-inflammatory

Carnes et al Trial Korantzopoulos et al Trial

patients for CABG

43 patients received Vit. C

before and 5 days after CABG

placebo

16.3% developed Post operative AF

39.9% developed Post operative AF

)P= 0.048(

44 patients after cardioversion

Vit C Placebo

1 week

)P= 0.024(

4.5 % Developed AF

36.3 % Developed AF

These findings are of a preliminary nature, however;

larger trials are needed to draw any firm conclusions on

the role of vitamin C in preventing AF

Carnes et al Trial: Ascorbate attenuates atrial pacing-induced peroxynitrite formation and electrical remodeling and decreases the incidence of postoperative atrial fibrillation

Korantzopoulos et al Trial: Oral vitamin C administration reduces early recurrence rates after electrical cardioversion of persistent atrial fibrillation and attenuates associated inflammation

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.

Statins

Fish oil

.

Beta blocker

CCBs

ACE-I, ARB

Fish oil

Anti-inflammatory

.

Statins

Non-Antiarrhythmic Drugs in Atrial Fibrillation

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altering serum levels of polyunsaturated fatty acids that have been shown to exert a stabilizing effect on cardiac membranes

HMG-CoA-Reductase Inhibitors

Antiarrhythmic

.

Statins

Statins have been shown in several clinical trials to reduce serum levels of CRP

AntiischemicAnti-

inflammatoryAntioxidant

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HMG-CoA-Reductase Inhibitors Siu et al Trial (Retrospective)

persistent lone AFafter DC cardioversion44 months

significant decrease in the risk of recurrence

62 patients

Young-Xu et al Trial (Observational)

449 patientscoronary artery disease

at high risk for AF

Statin users Non statin users

AF occurance

15%9% )P=0.01(

The ability of the statins to lower the rates of AF was independent of the cholesterol lowering effect, suggesting an alternative mechanism

Statin users

Siu et al Trial: Prevention of atrial fibrillation recurrence by statin therapy in patients with lone atrial fibrillation after successful cardioversionYoung-Xu et al Trial: Usefulness of statin drugs in protecting against atrial fibrillation in patients with coronary artery disease

.

Statins

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HMG-CoA-Reductase InhibitorsARMYDA3 Trial

ARMYDA-3 = Atorvastatin for Reduction of MYocardial Dysrhythmia After cardiac surgery

200 patients without a prior history of AF scheduled to undergo CABG

Seven daysatorvastatin 40 mg/day

Placebo

30 dayspostoperative AF occurrence

57%35%)P=0.003(

This study suggests a preventative effect on post-op AF and warrant a larger prospective trial

.

Statins

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Anti- inflammatory

CCBs

.

Statins

Fish oil

.

Beta blocker

ACE-I, ARB

Fish oil

Non-Antiarrhythmic Drugs in Atrial Fibrillation

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membrane stabilization

Reduce ventricular

arrhythmias

Fish oil

Fish Oil

treat inflammatory diseases such as rheumatoid arthritis and Crohn's disease

lower plasma levels of CRP and the inflammatory marker TNF-alpha

Treat lipid disorders Anti-inflammatory effect

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Fish OilMozaffarian et al

consumption of broiled and baked fish

4,815 patients over age 65

Calo et al

160 patients

starting five days before CABG and continued throughout their hospital stay

2 g/day of fish oils

Placebo

PostoperativeAF occurrence

33%15.2%

)P=0.013(

Intake of one to four times a week

intake of five or greater times a week

28% 31%

)P=0.005( )P=0.008(

No intake

consumption of broiled and baked fish

correlated with elevated plasma levels of

omega 3 fatty acids

Lowered AF incidence

Results of fish oil in AF have been mixed

Mozaffarian et al = Fish intake and risk of incident atrial fibrillation

Fish oil

Calo et al = N-3 fatty acids for the prevention of atrial fibrillation after coronary artery bypass surgery

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Fish Oil

A study by Brouwer et al. of 5,184 patients free of AF, greater amounts of fish intake as measured through a dietary questionnaire were not associated with lower rates of incident AF

A similar study by Frost et al. that evaluated food consumption by use of a semiquantitative questionnaire in 47,949 subjects found no reduction in rates of AF with increased fish consumption

However

Brouwer et al = Intake of very long-chain n-3 fatty acids from fish and incidence of atrial fibrillation.

Frost et al = N-3 Fatty acids consumed from fish and risk of atrial fibrillation or flutter: The Danish Diet, Cancer, and Health Study

Fish oil

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CCBs.

Statins

Anti- inflammatory

.

Beta blocker

ACE-I, ARB

Fish oil

CCBs

Non-Antiarrhythmic Drugs in Atrial Fibrillation

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Calcium channel blockers are used in AF to control heart rate. There are mixed data that calcium channel blockers may prevent AF by attenuating electrical remodeling

Calcium channel blockers (CCB)

In theory,calcium influx during episodes of AF may be partly responsible for the atrial electrical remodeling that

makes AF persistent. Consequently, reducing calcium influx could prevent episodes of AF

CCBs

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Calcium channel blockers (CCB)VEPARAF Trial

363 patients prior cardioversion

Amiodarone AmiodaroneVerapamil

Flecanide FlecanideVerapamil

Verapamil reduced AF recurrences when added to amiodarone or flecainide from 35% to 20%

3 months

)P=0.004(

VEPARAF = VErapamil Plus Antiarrhythmic drugs Reduce Atrial Fibrillation recurrences after an electrical cardioversion

CCBs

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Calcium channel blockers (CCB)PAFAC Trial

Sotalol Qunidine Verapamil Placebo

848 patients after cardioversion

67% 65% 83%65%

Recurrence rate after 1 year

PAFAC = Prevention of Atrial Fibrillation After Cardioversion

)P < 0.05(

The findings were similar in (SOPAT), which evaluated the

same agents as PAFAC in patients with paroxysmal AF

SOPAT = Suppression Of Paroxysmal Atrial Tachyarrhythmias

CCBs

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Calcium channel blockers (CCB)

Calcium channel blockers are not effective for the prevention of postoperative AF. Four randomized trials with a total of 541 patients evaluated verapamil for the prevention of postoperative AF, compared with control therapy. None of the trials showed a benefit of verapamil therapy

A randomized trial using diltiazem showed no benefit in preventing postoperative AF, compared with placebo. Much of the success seen with calcium channel blockers in conjunction with electrical cardioversion for AF came when the calcium channel blockers were used in conjunction with other antiarrhythmics

CCBs

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.

Statins

Anti- inflammatory

ACE-I, ARB

Fish oil

CCBs

.

Beta blocker

Non-Antiarrhythmic Drugs in Atrial Fibrillation

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Beta-blockersAlthough the use of beta-blockers for rate control in AF

is well known, their efficacy in prevention of AF is less clear

Beta-blockers are useful in postoperative AF; they have been given a class I recommendation in the 2006 ACC/AHA/ESC Guidelines

postoperative AF

Excessive adrenergic stimulation Pericardial inflammationAttenuated

by beta-blocker

.

Beta blocker

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.

Beta blocker

Ability to preventAF outside of the postoperative arena is questionable

Kuhlkamp et al Trial

394 patients with persistent AF after cardioversion

metoprolol CR/XL placebo

The primary end point was the cumulative number of patients relapsing into AF or flutter during a period of six months follow-up

Kuhlkamp et al Trial: Use of metoprolol CR/XL to maintain sinus rhythm after conversion from persistent atrial fibrillation: A randomized, double-blind, placebo-controlled study

65% 50.6%)P=0.002(

The median time to relapse

7.5 day 13 day

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.

Beta blocker

Given the lack of convincing evidence that beta-blockers have a clinically significant benefit in maintenance of sinus rhythm, they are not considered primary therapy at this time

Beta-blockers

However,beta-blockers may still offer benefit in subgroups of patients who have hypertension or hyperadrenergic states, and their utility in

those patients should be further explored

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The findings of the LIFE study suggest inhibition of the RAAS for primary prevention of AF in patients with hypertension may be

preferred therapy, compared with beta-blockers. This advantage may also extend to secondary prevention

Beta-blocker therapy should be confined to prevention of postoperative AF. Their use as routine initial therapy for the

treatment of hypertension is being redefined

Summary

The role of other agents such as HMG-CoA reductase inhibitors and fish oils should be limited to their primary indications pending conclusive studies

.

Beta blocker

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Studies

Studies discussed briefly and simply: • Type and the number of patients• Type of the study • Conclusion• Probability

BUTSometime the author didn’t write the P value and patients number or wrote incomplete information

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.

Statins

Fish oil

.

Beta blocker

CCBs

ACE-I, ARB

Anti-inflammatory

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