1. Management of Atrial FibrillationScience, Myths and Fashion What you need to know as a community practitioner Dr Duncan Hogg Consultant Cardiologist, Aberdeen Royal Infirmary.

2. Atrial FibrillationScience, Myths and Fashion By the end of this talk I hope you will: Have increased understanding of the epidemiology & pathophysiology of atrial fibrillation (AF) Recognise the clinical consequences of AF. Understand the different treatment options in AF Be aware of current & future developments.

3. Atrial Fibrillation: Epidemiology AF is the commonest cardiac dysrhythmia. Estimated to affect 5% of the population over 60 years & increasing to 10% over 75 years old. Likely to become more prevalent with an ageing population and their increased exposure to pre-disposing cardiovascular disease. Wolf et al. Secular trends in the prevalence of atrial fibrillation: The Framingham Study. Am Heart J 1996;131:790-795.

4. AF: Costs to the Health Care System 1985-1990, 35% of all arrhythmia hospitalizations had principal diagnosis of atrial fibrillation. Average hospital stay = 5 days. Other AF-related provision include: Outpatient reviews and day-case cardioversions Anti-arrhythmic drugs & INR monitoring AF-induced strokes. The significant cost to the healthcare system is clear. Geraets DR. Clin Pharm. 1993;12:721-735.

5. Cardiac risk factors for AF Independent risk factors for AF include- Male gender, hypertension, diabetes, LV systolic (& diastolic) dysfunction, any valvular disease. Hypertension now more responsible than any other. AF also associated with any structural abnormality e.g all forms cardiomyopathies, tumours (atrial myxoma), or acute insults e.g. pericarditis, post cardiac surgery, myocardial infarction. Kannel et al. Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates. Am J Cardiol 1998;82:2N-9N.

6. Non-cardiac risk factors for AF Non-cardiac causes of AF include: Pulmonary: Any acute or chronic lung disease e.g. COPD, pneumonia, pulmonary embolism Metabolic: Hyperthyroidism, electrolyte disorder Toxic: Alcohol, acute & chronic systemic illness. “Lone AF”. Those AF patients with absence of identifiable cardiovascular, or acute systemic insult or disease:

7. Electrophysiology of AF AF is caused by multiple circulating wavelets of excitation around the cardiac atria.

8. Electrophysiology of AF Atrial fibrillation is triggered into existence. Single initiator or the interaction of many e.g. supraventricularectopy, myocardial ischaemia, left atrial stretch due to pressure or volume load. Atrial myocardium electrically remodels increasing the stability of AF- ‘AF begets AF’. Later pathological remodelling (left atrium fibrosis) permanently affects the atrias’ electrical conductivity.

9. Electrophysiology of AF 2 broad overlapping electrophysiological groups Patients with normal hearts generally have a ‘trigger-predominant’ initiation. Patients with abnormal hearts generally have a ‘substrate-predominant’ initiation. Therapeutic potentials may differ between these two, particularly with respect to potential for AF ablation.

10. ‘3P’ classification of AF AF first detected Paroxysmal AF (Self-terminating) Persistent AF (Non self-terminating) Permanent AF Gallagher & Camm. Classification of atrial fibrillation. PACE 1997;20:1603-1605.

11. Clinical: Mortality of AF Relative risk of stroke & mortality in patients with AF cf in SR

12. Clinical: Mortality of AF Excess mortality in patients with AF is linked with severity of underlying heart disease eg CHF. AF can facilitate the induction of ventricular arrhythmias eg Wolf-Parkinson-White. Iatrogenic- anti-arrhythmic drugs (AADs) used for AF can be pro-arrhythmic and anticoagulants can cause fatal haemorrhagic events.

13. Clinical: Morbidity of AF Two aspects of patient morbidity in AF Thromboembolic risk and Cardiovascular symptoms

14. Thromboembolism in AF Atrial fibrillation can be a prothrombotic state. AF is associated with an increased risk of stroke or thromboembolism (TE) of 1-17% per annum, depending on co-existent risk factors e.g. age >65yrs, hypertension, diabetes, left ventricular dysfunction (LVD) or mitral valve disease. Exact causes of thrombus formation not clear.

15. AF thrombus formation in LAA

16. AF thrombus formation in LAA Virchows’ triad Loss of ordered atrial contraction produces turbulent blood flow within the cardiac atria. Fibrillating atria can activate the endothelium. The turbulent blood flow & endothelial activation of AF can produce platelet activation.

17. Stroke prevention in AF Aspirin & warfarin have been studied in AF thromboembolic prophylaxis. Warfarin has strongest evidence for both primary & secondary prevention. The SPAF (stroke prophylaxis in AF) investigators suggested prescription of warfarin to those at high thromboembolic risk.

18. Stroke prevention in AF From meta-analysis of thrombo-prophylaxis trials the overall benefit of treatment was- Warfarin (INR 1.8-2.6) reduces risk of AF thrombo-embolic event by 66%. Aspirin (75-300mg) reduces risk of AF thrombo-embolic events by 25%. (Clopidogrel alone, probably equivalent to aspirin)

19. Thrombo-embolic risk stratification CHADS2 score is a simple way to estimate stroke risk: 0: low risk 1-2: moderate risk >2 : high-risk

20. Thrombo-embolic risk stratification CHA2DS2 VASc score is a newer, still simple but more complete way to estimate risk:

21. Thrombo-embolic risk stratification Newly devised HAS-BLED score predictive tool for bleeding AF patients on warfarin

22. Thrombo-embolic risk stratification Balancing the risks and benefits of warfarin: No warfarinif: HAS-BLED > CHADS2 or HAS-BLED >2 in CHADS2 0/1 HAS-BLED >3 in CHADS2 2 Using this algorithm would reduce >10% of major bleeds

23. AF cardiovascular morbidity At least 40% of patients are asymptomatic at initial detection of AF. Most patient symptoms are at the onset of AF and/ or related to exertion. Symptoms are predominately caused by the elevated resting heart rate and rapid increase associated with exertion.

24. Ventricular rate control in AF AADs for ventricular rate (VR) control should aim to address VR at rest and on exertion. ß-blockers, calcium channel blockers if no concern of left ventricular dysfunction (LVD). If LVD, digoxin or amiodarone can be 1st line. NB. digoxin does not control VR on exertion. Choice of rate or rhythm control management.

25. Rhythm control of AF Remains no evidence that restoration of SR is beneficial in reducing patient mortality or morbidity. The PIAF study assessed rhythm or rate control effects on patient symptoms or QoL. No difference in QoL assessment despite statistically better 5 min walking test in rhythm control group. Rhythm or rate control in AF- Pharmacological Intervention in Atrial Fibrillation: a randomised trial. Lancet 2000;356:1789-94.

26. Rhythm control of AF The AFFIRM study found no benefit in overall mortality, thromboembolic events, 6-minute walk or QoL in rhythm control patients. Decision on rhythm or rate control is guided by patient symptoms & clinic parameters for success in maintaining SR for example: Longevity of AF, LA size, LVD & MVD. The AFFIRM investigators. NEJM 2002;347:1825-33.

27. Rhythm control options for AF Pharmacological conversion is most often effective for recent onset AF i.e. <48 hrs. Many small studies for acute onset AF, but in a randomised comparison flecainide > propafenone > amiodarone (~90%) (~ 70%) (~ 60%) Amiodarone best (10-15%) for persistent AF

28. Rhythm control options in AF

29. Electrical cardioversion (DC-CV) DC-CV has a high initial success rate but high probability of future relapse to AF. AADs differ in SR post DC-CV maintainenance Van Gelder et al., Arch Intern Med 1996;156:2585–92.

30. Maintaining SR post DC-CV In CTAF study amiodarone > sotalol/propafenone Debated whether sotalol has extra benefit over regular ß-blockers; potential pro-arrhythmic by QT prolongation. Class I AAD (flecainide, propafenone) reduce relapse and often used in combination with ß-blockers. Calcium channel blockers have modest benefit alone. Canadian trial of atrial fibrillation (CTAF). NEJM 2000;342:913-20.

31. Electrical cardioversion in AF Without warfarin DC-CV associated with a significant risk of thrombo-embolic events, most in 2-10 days; significantly reduced risk with warfarin, but even with therapeutic INR about 1 in 200/250. Elevation of thrombotic markers post DC-CV, probably due to ‘atrial stunning’. phenomenon of atrialasystole in SR post DC-CV. Optimal duration of warfarin post DC-CV still unclear.

32. Current & near future new options in AF management Holy grail of ‘cleaner amiodarone’ is now very close to reality with Dronedarone, after many false starts. An oral direct thrombin inhibitor (DTIs) ie ‘warfarin without monitoring’ is (again) almost ready for use having been assessed versus warfarin. Percutaneous occlusion of the left atrial appendage. Electrophysiological cure increasingly possible in a selected number of AF patients.

33. ‘Cleaner amiodarone’, the holy grail?! Dronedarone (Multaq, Sanofi-Aventis) appears to lack many of the extra-cardiac side-affects of amiodarone. It seems effective in reducing paroxysms of AF and maintaining SR post cardioversion c.f. placebo. Concerns remain in significant heart failure and/or LVD of ventricular pro-arrhythmias (prolongs QT interval). Many potential drug interactions (CYP3A4 drugs) with potential for induction of torsades de pointes. Cost.............

34. No more INRs in AF patients? First oral DTI Ximelagatran (Exanta,AstraZeneca), which was non-inferior to dose-adjusted warfarin in prevention of all strokes and systemic embolic events in non-valvular AF patients. The combined rate of major and minor bleedings was significantly lower for ximelagatran c.f warfarin. Concerns of transient LFT derangement lead to it not reaching the market for its AF indication.

35. No more INRs in AF patients? Dagibatran (Pradaxa, Boehringer Ingelheim), has received FDA approval for AF thrombo-prophylaxis RE-LY study was randomised, open-label study non-inferiority study assessing two doses 110mg & 150mg. 110mg had similar rate of stroke cf warfarin with significantly reduced major bleeding. 150mg had reduced risk of stroke cf warfarin with similar risk of major bleeding. Less ICH c.f. warfarin. No liver toxicity; GI upset main s-a.

36. No more INRs in AF patients? Dagibatran currently costs ......... Other oral DTIs in various stages of development: apixaban (Bristol-Myers Squibb/Pfizer), rivaroxaban (Xarelto, Bayer/Johnson & Johnson); doxaban (Daiichi-Sankyo); and, betrixaban (Portola Pharmaceuticals/Merck). This congested field may well bring the cost down.

37. High stroke risk but high bleeding risk - stop thrombus forming in appendage Sievert et al Circulation 2002;105:1887-1889

38. Percutaneous closure of appendage Left atrial angiogram: after trans-septal puncture and LAA cannulation, contrast injection outlines LAA from which an ostial diameter can be measured; contrast injection via a lumen through the implant reveals hang up of dye behind the sealing surface, indicating proper position and occlusion; after device release, contrast injection in the LA establishes complete seal.

39. Ablation: a cure for AF? Haissaguerre M.et al. Spontaneous initiation of AF by ectopic beats originating in the pulmonary veins. N Engl J Med 1998; 339: 659-666

40. Ablation: a cure for AF?

41. Ablation: a cure for AF? CS, coronary sinus; LUPV, left upper pulmonary vein; RUPV, right upper pulmonary vein; RA isthmus line, right atrial isthmus line. CT angiogram of the posterior aspect of the left atrium. Red lines indicate lines of electrical conduction block .

43. Ablation: a cure for AF? Substrate evolution leads to a change in ablation technique AF type: Paroxysmal Persistent Permanent Role of pulmonary veins: Role of muscle & scar: Ablation: PVI Substrate & hybrid

44. Summary of AF management Prevalence, hospitalisation and healthcare costs for AF are increasing. Thrombo-embolic risk stratification by CHADS2 score for all patients: not everybody needs warfarin. Rate control can be achieved with many drugs: but aim to control resting and exertional heart rate. Sinus is worth pursuing in many patients with AF, those that are symptomatic and likely to maintain SR.

45. Summary of AF management AADs are essential to reduce the risk of relapse to AF post DC-CV: ß-blockers & amiodarone. Dronedarone is a possible replacement for amiodarone Oral thrombin inhibitors “warfarin without the monitoring” are on the verge of replacing warfarin, but at what cost is not currently certain. AF catheter ablation can cure selected AF patients particularly paroxsymal, accepting procedural risks.

46. Atrial FibrillationScience, Myths and Fashion Hopefully now you will: Have increased understanding of the epidemiology & pathophysiology of atrial fibrillation (AF) Recognise the clinical consequences of AF. Understand the different treatment options in AF. Be aware of future developments including ablation.

47. Management of Atrial FibrillationScience, Myths and Fashion What you need to know as a community practitioner Dr Duncan Hogg Consultant Cardiologist, Aberdeen Royal Infirmary.