1. Samah & Manar1 Supervised by: Dr. Seema Syed King Faisal Specialist Hospital and Research Center (2007-1428) Presented by: Manar Lashkar Samah Al-shehri Pharm.D candidates

2. 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

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

4. 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

5. Samah & Manar5 Atrial Remodeling RAAS Inflammation Sympathatic Nervous System Intracellular Calcium Overload Oxidation ACE-I, ARB Vitamin C. Beta blocker Statin,steroid, Fish Oil Vitamin C, CCBs

6. Samah & Manar6. Statins Vitamin C Statin,steroid, Fish Oil Vitamin C,. Beta blocker CCBs ACE-I, ARB

7. Samah & Manar7 Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockade ACE-I, ARB Atrial Fibrillation Increase ACE Upregulation of AT receptors ACE-IARB Reduce Atrial Fibrosis Lower Left Atrial Pressure Reduce Atrial Ectopy

8. Samah & Manar8 Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockade ACE-I, ARB Atrial Fibrillation ACE-I ARB = ? Upregulation of AT receptors Increase ACE

9. Samah & Manar9 I)Drug vs Placebo 1) Randomized Clinical Trials of ACE-I ACE-I, ARB TRACE = TRAndolapril Cardiac Evaluation TRACE Trial: 1577 patients Left ventricular dysfunction after myocardial infarction Sinus rhythm TrandolaprilPlacebo 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

10. Samah & Manar10 ACE-I, ARB I)Drug vs Placebo 1) Randomized Clinical Trials of ARBs CHARM Trial Systolic and diastolic dysfunction patients 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)

11. Samah & Manar11 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 Drug 1) Randomized Clinical Trials of ACE-I Ueng trial 125 patients After cardioversion EnalaprilAmiodarone 4 weeks Stay in sinus rhythm 61.3%84.3% (P=0.002) 270 days Stay in sinus rhythm 74.3% 57.3% (P=0.021)

12. Samah & Manar12 ACE-I, ARB II) Drug vs Drug 1) Randomized Clinical Trials of ARBs LIFE: Losartan Intervention For Endpoint reduction in hypertension LIFE Trial 8851 patients Hypertension Left ventricular hypertrophy Sinus rhythm Losartan Atenolol 3.5%5.3% 4.8 years (P=0.001) New onset AF Madrid Trial 154 patients Amiodarone Irbesartan 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

13. Samah & Manar13 Meta-analysis included 11 randomized controlled trials of ACE inhibitors or ARBs for their efficacy in preventing AF ACE-I, ARB

14. Samah & Manar14 ACE-I, ARB Only patients with LV dysfunction had lower rates of AF with an ACE-I or an ARB significant reduction in AF, with a 44% RRR in the onset of AF Studies of patients with more significant LV dysfunction showed a larger RRR in AF In 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.

15. Samah & Manar15 ACTIVE-I 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 death A substudy of the trial will evaluate the effect of irbesartan on recurrences of paroxysmal AF ONTARGET TRANSCEND 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 Trial TRANSCEND: The Telmisartan Randomized AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease ACE-I, ARB

16. Samah & Manar16. Statins Fish oil. Beta blocker CCBs ACE-I, ARB Anti- inflammatory

17. Samah & Manar17 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

18. Samah & Manar18 Anti-inflammatory 131 patients Atrial arrhythmia 71 patients Sinus rhythm Median CRP= 0.3 mg/dL Median CRP= 0.15 mg/dL Persistent AF CRP= 0.43 mg/dL Paroxysmal AF CRP= 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

19. Samah & Manar19 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

20. Samah & Manar20 Anti-inflammatory first episode of symptomatic and persistent AF 104 patients 5 months methylprednisolone taper Placebo 1 Month CRP levels Decreased by 80% 2 Years 9.6% 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

21. Samah & Manar21 Antioxidant Vitamin C Anti- inflammatory scavenging reactive oxygen species attenuate calcium accumulation that affect atrial myocytes Anti-inflammatory decrease serum CRP levels

22. Samah & Manar22 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

23. Samah & Manar23. Statins Fish oil. Beta blocker CCBs ACE-I, ARB Fish oil Anti- inflammatory. Statins Non-Antiarrhythmic Drugs in Atrial Fibrillation

24. Samah & Manar24 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 Antiischemic Anti- inflammatory Antioxidant

25. Samah & Manar25 HMG-CoA-Reductase Inhibitors Siu et al Trial (Retrospective) persistent lone AF after DC cardioversion 44 months significant decrease in the risk of recurrence 62 patients Young-Xu et al Trial (Observational) 449 patients coronary artery disease at high risk for AF Statin usersNon 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 cardioversion Young-Xu et al Trial: Usefulness of statin drugs in protecting against atrial fibrillation in patients with coronary artery disease. Statins

26. Samah & Manar26 HMG-CoA-Reductase Inhibitors ARMYDA3 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 days atorvastatin 40 mg/day Placebo 30 days postoperative AF occurrence 57% 35% (P=0.003) This study suggests a preventative effect on post-op AF and warrant a larger prospective trial. Statins

27. Samah & Manar27 Anti- inflammatory CCBs. Statins Fish oil. Beta blocker ACE-I, ARB Fish oil Non-Antiarrhythmic Drugs in Atrial Fibrillation

28. Samah & Manar28 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

29. Samah & Manar29 Fish Oil Mozaffarian 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 Postoperative AF 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

30. Samah & Manar30 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

31. Samah & Manar31 CCBs. Statins Anti- inflammatory. Beta blocker ACE-I, ARB Fish oil CCBs Non-Antiarrhythmic Drugs in Atrial Fibrillation

32. Samah & Manar32 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

33. Samah & Manar33 Calcium channel blockers (CCB) VEPARAF Trial 363 patients prior cardioversion Amiodarone Verapamil Flecanide Verapamil 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

34. Samah & Manar34 Calcium channel blockers (CCB) PAFAC Trial Sotalol QunidineVerapamilPlacebo 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

35. Samah & Manar35 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

36. Samah & Manar36. Statins Anti- inflammatory ACE-I, ARB Fish oil CCBs. Beta blocker Non-Antiarrhythmic Drugs in Atrial Fibrillation

37. Samah & Manar37 Beta-blockers Although 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 stimulationPericardial inflammation Attenuated by beta-blocker. Beta blocker

38. Samah & Manar38. Beta blocker Ability to prevent AF 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

39. Samah & Manar39. 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

40. Samah & Manar40 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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47. Samah & Manar47 Studies Studies discussed briefly and simply: Type and the number of patients Type of the study Conclusion Probability BUT Sometime the author didn’t write the P value and patients number or wrote incomplete information

48. Samah & Manar48. Statins Fish oil. Beta blocker CCBs ACE-I, ARB Anti- inflammatory

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