Classification (ACC/AHA/ESC 2006)

Transcription

1 ATRIAL FIBRILLATION

2 Atrial Fibrillation Atrial fibrillation is a common disorder which affects 0.4% of the general population. The risk increases sharply with age so that the lifetime prevalence of AF is 2% for people years old compared with greater than 6% for year olds.

3 Classification (ACC/AHA/ESC 2006) Paroxysmal (self-terminating): terminates spontaneously within 7 days, and usually within 24 hours. Persistent: fails to self-terminate within 7 days. May eventually terminate spontaneously, or can be terminated with cardioversion. Permanent: lasts for more than one year and cardioversion has either failed or has not been attempted. Lone: any of the above with absence of any structural heart disease. Usually applies to patients less than 60 years old.

4 Risk Factors In the Framingham heart study cohort, there were six clinical variables identified as independent risk factors for atrial fibrillation: Age Diabetes Hypertension Congestive heart failure Valvular heart disease (generally mitral valve disease) History of myocardial infarction

5 Causes APPLE CRATES Acute MI Pulmonary (pneumonia, lung disease) Pharmacologic Lone AF (atrial fibrillation with no structural cardiac or pulmonary disease) Electrolytes (magnesium and potassium) Cardiomyopathy Rheumatic heart disease (valvular diseases, particularly mitral) Addison s Thyrotoxicosis EtOH ( holiday heart ) Surgery

6 Evaluation History and physical examination: define symptoms, onset, frequency and duration. Electrocardiogram Chest X-ray Echocardiogram Assessment for hyperthyroidism: TSH, T4 Additional testing: exercise testing, cardiac cath, electrophysiology studies, etc.

7 Manifestations of AF Rapid and irregular ventricular response Exceedingly rapid response may cause CHF, hemodynamic instability, chest pain, syncope and ischemia. Loss of atrioventricular synchrony Results in lack of atrial contribution to ventricular filling with resultant decreased exercise tolerance, CHF or dyspnea. The decrease in stroke volume can be up to 20%. Formation of intracardiac thrombus Risk of systemic embolization Symptoms of AF can range from pulmonary edema to palpitations, but the most common presenting symptom is fatigue and other non-specific complaints. Episodes of AF may be asymptomatic.

8 Who should be hospitalized? Hospitalization is not required for all patients with new onset AF those with hemodynamic compromise or severely symptomatic arrhythmia.... those at high risk of embolism.... those in whom early cardioversion is considered.

9 Who should get ruled out for ACS? Patients with angina Evidence of ischemia or infarction on ECG Other patients do not need to be ruled out for MI since ischemic heart disease rarely presents as AF without other symptoms.

10 ECG in Atrial Fibrillation Typical ECG shows irregular R-R interval No P-waves A wide QRS complex which is irregularly irregular is suggestive of a bypass tract such as WPW. Such patients can reach heart rates of over 250 bpm. A resting rate of above 150 is suggestive of a hyperadrenergic state. eg thyrotoxicosis, fever or acute GI bleed A slow ventricular response in the absence of rate control drugs can be seen in young athletes or patients with conducting system disease.

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12 Irregularly Irregular Rhythm: Differential Diagnosis Atrial fibrillation Atrial flutter with variable AV block Multifocal atrial tachycardia or chaotic atrial rhythm Sinus tachycardia with variable AV or SA block Automatic atrial tachycardia with variable AV block Marked sinus arrhythmia

13 Echocardiography All patients with new onset AF should undergo echocardiography to evaluate for: Valvular heart disease Left and right atrial sizes, which are used as prognostic factors for maintenance of sinus rhythm LA thrombus (low sensitivity) LV size and function

14 Initial Laboratory Work-Up Thyroid Function Tests (TSH, T4) Should be checked in all patients Patients with subclinical hyperthyroidism are at three fold increase of AF. Electrolytes Specifically potassium and magnesium

15 Case Rate Vs. Rhythm Control What pharmacologic options are available for controlling this patient s heart rate?

16 Goal for patient s heart rate: Resting - <80 Exercise < 115 Drugs that can be used for rate control Digoxin Beta-blockers Calcium channel blockers (AV nodal blockers are contraindicated in Wolff- Parkinson White syndrome, because of the risk of enhanced conduction down the accessory pathway)

17 Should this patient be referred for cardioversion of her atrial fibrillation?

18 Potential benefits of keeping a patient in normal sinus rhythm Fewer symptoms Possibly decreased risk of stroke Discontinuation of anticoagulation Prevention of tachycardia induced cardiomyopathy

19 A comparison of rate control and rhythm control in patients with atrial fibrillation: The AFFIRM investigators. N Engl J Med 2002; 247: Non-blinded trial of 4060 patients randomized to rhythm vs. rate control. Inclusion criteria: -- Patients > 65 yrs. or who had other risk factors for stroke or death -- Atrial fibrillation was likely to be recurrent, cause illness of death and long-term therapy was warranted -- No contraindication to anticoagulation. Rhythm control strategy: -- Antiarrhythmic therapy chosen by treating physician (amiodarone and sotalol most commonly used) -- Electrical cardioversion could be used. -- Continuous anticoagulation was encouraged but could be stopped if sinus rhythm was maintained Rate control strategy: -- Choice of AV nodal blockers at the discretion of the treating physician. -- Continuous anticoagulation mandated. Primary outcome: Overall mortality Secondary outcome: Composite endpoint of death, disabling stroke, disabling anoxic encephalopathy, major bleeding and cardiac arrest.

20 Results (at 5 years) 35% of the rate control group was in sinus rhythm compared to 63% of the rhythm control group. No difference in overall mortality. No difference in composite endpoint. No difference in rate of ischemic stroke. Most ischemic strokes occurred in patients off anticoagulation Rhythm control group had higher rates of torsade de point, hospitalization and adverse drug effects.

21 Who should undergo cardioversion? Hemodynamic instability, unstable angina or CHF not responding to medical maneuvers Inability to maintain rate control with maximal AV blockade (although AV nodal ablation with pacemaker implantation is another management strategy for this) Wolff-Parkinson-White syndrome

22 After cardioversion, does the patient need to stay on anti-arrhythmic therapy? What are the major risks of anti-arrhythmics?

23 While 90% of patients convert to normal sinus rhythm with electrical cardioversion, only 25% remain in normal sinus rhythm at 1 year without antiarrhythmic therapy With anti-arrhythmic therapy, 40-70% remain in sinus rhythm at one year With most anti-arrhythmics, the major adverse effect is ventricular arrhythmia, especially torsades

24 One of the major risks of cardioversion of atrial fibrillation is an increased rate of embolism. If you decide to pursue cardioversion, what can you do to minimize the risk?

25 Even after sinus rhythm is restored, the atria may not resume normal contractility until several weeks afterwards, and a thrombus may form in the interim. The risk of thromboembolism is 5% in the first month after cardioversion Similar between pharmacologic and electrical cardioversion Highest in atrial fibrillation of >48 hour duration

26 Klein A, et al. For the Assessment of Cardioversion Using TEE (ACUTE) Investigators. Use of transesophageal echocardiography to guide cardioversion in patients with atrial fibrillation. N Engl J Med 2001; 344: Methods 1222 patients with atrial fibrillation referred for cardioversion randomized to conventional treatment vs. TEE-guided treatment Conventional treatment: Anticoagulation for 3 weeks prior and 4 weeks after DC cardioversion TEE-guided treatment: -- TEE performed -- No thrombus seen >>> DC cardioversion -- Thrombus seen >>> warfarin for 3 weeks, then repeat TEE and DC cardioversion if no thrombus seen -- Anticoagulation for 4 weeks after DC cardioversion

27 Results (at 8 weeks) Trial terminated early because of low rate of events Thrombi seen in 14% of patients in the TEE-guided group Compared to patients in the TEE-guided group, patients in the conventional treatment group had: -- Higher rate of hemorrhage, mostly minor (5.5% vs. 2.9%) -- Higher rate of spontaneous conversion (21% vs. 5%) -- Same rate of embolic events (<1% in both groups) -- Same rate of maintenance of normal sinus rhythm (about 50% in both groups) -- Nonsignificant trend towards lower rate of death (1% vs. 2.4%) Conclusion: TEE-guided cardioversion is a clinically effective alternative strategy to conventional therapy for patients in whom elective cardioversion is planned. Limitations High drop-out rate. Hemorrhage rate was higher than expected No discussion of whether TEE might have been responsible for increased number of deaths Study was underpowered, so increased rate of death in TEE group might have been real

28 Management of AF Rate vs. Rhythm Control In general, rate control is preferred over rhythm control. Rhythm control should be considered in patients who cannot be rate controlled, or have persistent symptoms despite adequate rate control. In the stable patient with chronic AF and atrial enlargement, chemical or electrical cardioversion is unlikely to be successful. In such patients, control of ventricular response is the goal of therapy.

29 Rate vs. Rhythm Control Several major clinical trials (eg, AFFIRM and RACE) compared rhythm and rate control: Rate control is not inferior to rhythm control for prevention of death and morbidity from cardiovascular causes. Embolic events occur with equal frequency regardless of whether a rate control or rhythm control strategy is pursued, and occur most often after warfarin has been stopped or when the INR is subtherapeutic. Both studies showed an almost significant trend toward a lower incidence of the primary end point with rate control (hazard ratio 0.87 for mortality in AFFIRM and 0.73 for a composite end point in RACE). There was no difference in functional status or quality of life.

30 Rate vs. Rhythm Control (cont) Rate control is the preferred initial approach in most patients. There are three primary settings in which a rhythm control strategy using antiarrhythmic drugs to maintain sinus rhythm should be considered: Persistent symptoms, such as palpitations, dyspnea, lightheadedness, angina, presyncope, and heart failure despite adequate rate control An inability to attain adequate rate control Patient preference Consider cardioversion to sinus rhythm in most patients, particularly younger patients, with a first detected episode of AF in whom the arrhythmia is of recent onset and the risk for recurrence appears to be low. Maintenance antiarrhythmic drug therapy is not routinely used after cardioversion in patients with newly detected AF.

31 Rate Control An ideal rate is between when resting and beats per minute with moderate exercise. Cardiac glycosides: Digoxin decreases ventricular rate by increasing vagal activity of the AV node. Digoxin is less effective in patients with hyperadrenergic states or with exercise or stress. In patients given IV digoxin for rate control, the onset is usually delayed with an effect about 6 hours after injection. ß-blockers: Useful in patients with hypertension, angina or thyrotoxicosis. Effective for resting heart rate and controlling ventricular rate with exercise. Contraindicated in patients with active CHF, wheezing or hypotension. IV B-blockers have a rapid onset of action.

32 Rate Control (cont) Calcium channel blockers: Use cardiac selective CCBs (diltiazem and verapamil). Effective for resting heart rate and controlling ventricular rate with exercise. Both are rapid acting with a peak effect within 5 minutes. Can be used in patients with asthma/copd. Use with caution in patients with active CHF or hypotension. Amiodarone: Also effective for rate control. A suitable alternative agent when other measures are ineffective or contraindicated. Caution should be used in patients with wide complex AF due to the risk of WPW in such patients. Digoxin, ß-blockers and CCBs should be avoided in such patients. Procainamide or amiodarone can be used for rate control and cardioversion in these patients.

33 Rhythm Control (Cardioversion) Only 20-30% of patients who are successfully cardioverted maintain NSR for more than one year without chronic antiarrhythmic therapy. Maintenance of NSR is more likely to occur in patients with AF for less than one year, no enlargement of the left atrium (ie, 4.0 cm), and a reversible cause of AF such as hyperthyroidism, pericarditis, pulmonary embolism, or cardiac surgery. Patients with angina, hemodynamic instability, severe heart failure, or evidence of pre-excitation should be urgently electrically cardioverted. Patients with a known acute episode of atrial fibrillation lasting less than 48 hours are candidates for immediate cardioversion due to their low risk of embolic complications. Patients with AF for > 48 hours are at risk for embolization after cardioversion.

34 Rhythm Control (cont) There are two potential treatment options for AF lasting > 48 hours: Anticoagulation for 3-4 weeks at a goal INR of , then subsequent cardioversion One study of anticoagulation (n=228) versus no anticoagulation (n=209) showed a decrease in the risk of embolism from 5.3% to 0.8%. TEE with immediate cardioversion TEE can be used to exclude atrial thrombi and determine which patients can undergo immediate cardioversion. All patients who undergo cardioversion should be placed on anticoagulation for at least four weeks afterwards. Patients are at risk for formation of thrombus even after cardioversion. Most embolic episodes occur within 10 days of cardioversion. Late embolic events are likely due to atrial stunning and delayed recovery of atrial contraction after cardioversion.

35 Options for Cardioversion Electrical Cardioversion Synchronized direct current (DC) cardioversion is frequently required to restore sinus rhythm. Overall success rate is 75-93% and is inversely related to both the duration of AF and the left atrial size. The use of concurrent antiarrythmic medications to decrease the risk of relapse into AF is controversial and dependent on risk-benefit. Patients who need immediate cardioversion and who are unstable need to undergo electrical cardioversion.

36 Pharmacologic Cardioversion Same risk of thromboembolic complications as electrical cardioversion. Multiple drugs are available: Amiodarone Modestly effective for recent onset AF. Acts less rapidly and effectively than others. Restoration of sinus rhythm may not occur for days or weeks. Side effects include bradycardia, hypotension, visual disturbances, nausea, thyroiditis and pulmonary fibrosis. Flecainide Effective for cardioversion of recent onset AF in placebo-controlled trials. Effective for maintenance of sinus rhythm. Response occurs rapidly, 1-3 hours after infusion. Side effects include arrythmias, including atrial flutter with RVR. Should be avoided in patients with organic heart disease. Ibutilide Effective for cardioversion within a few weeks after onset of AF. An effect may be expected within 1 hour after administration. There is a small but definite risk of torsade de pointes. Serum Mg and K should be measured before administration and monitored for at least 4 hours afterward.

37 Case A Fib (Stroke Prevention)

38 In patients with atrial fibrillation, without a history of thromboembolism, what is the overall risk of stroke?

39 The annual risk of stroke in the average patient with atrial fibrillation is 4-5%

40 In patients with atrial fibrillation without a history of thromboembolism, how effective is aspirin in preventing stroke?

41 Hart R, Pearce L, Aguilar M. Meta-analysis: Antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Int Med 2007; 146: Methods Meta-analysis of 29 randomized trials of antithrombotic therapy in over 28,000 patients with nonvalvular atrial fibrillation. Mean age of patients was 71 years Primary outcome: All stroke (ischemic + hemorrhagic), expressed as an annual risk

42 Results (Warfarin vs. placebo or no treatment) In patients with no history of thromboembolism, annual risk of stroke decreased from 4.6% to 1.9% in the warfarin group -- ARR = 2.7%, NNT = 37 In patients with a history of thromboembolism, annual risk of stroke decreased from 12.3% to 4.6% in the warfarin group -- ARR = 7.7%, NNT = 13 Annual rate of intracranial hemorrhage doubled in the warfarin group, but the numbers were extremely small (6 vs. 3 patients) Nonsignificant, absolute increase of 0.3% for major extracranial bleeding in the warfarin group Overall, all-cause mortality decreased in the warfarin group by 1.6% (NNT = 63)

43 Results (Aspirin vs. placebo or no treatment) In patients with no history of thromboembolism, annual risk of stroke decreased in the aspirin group: -- ARR = 0.8%, NNT = 125 In patients with a history of thromboembolism, annual risk of stroke decreased in the aspirin group: -- ARR = 2.5%, NNT = 40 Annual rate of intracranial hemorrhage doubled in the aspirin group, but the numbers were extremely small (8 vs. 4 patients) Nonsignificant, absolute increase of 0.2% for major extracranial bleeding in the aspirin group Nonsignificant, absolute decrease of 0.5% in mortality in the aspirin group

44 Results (Warfarin vs. antiplatelet therapy) In head-to-head trials, warfarin was superior to aspirin therapy: -- Primary prophylaxis: ARR = 0.7%, NNT = Secondary prophylaxis: ARR = 7%, NNT = 14 In head-to-head trials, warfarin was superior to other antiplatelet agents: -- Primary prophylaxis: ARR = 0.9%, NNT = (Authors unable to compute numbers for secondary prophylaxis) Absolute increase of 0.2% in intracranial hemorrhage in the warfarin group (NNH = 500)

45 Aspirin decreases the annual risk of stroke by about 20%. This is the relative risk reduction (RRR). If the annual rate of stroke is about 5% in patients on no treatment, what is the annual rate of stroke in patients on aspirin? (Answer: about 4%) How many patients do they need to treat with aspirin to prevent one stroke? To answer this question, you have to perform two calculations: The absolute risk reduction (ARR) is 5% minus 4%, or 1%. The number needed to treat (NNT) is the inverse of the ARR, or 1/0.01 = 100. In other words, you would need to treat about 100 patients with aspirin to prevent one stroke. Given the low cost of aspirin and the low side-effect profile, most physicians would agree that aspirin is better than no treatment at all in most patients with atrial fibrillation.

46 Warfarin decreases the annual risk of stroke by about 60%. If the annual rate of stroke is about 5% in untreated, what is the annual rate of stroke in patients on warfarin? (Answer: about 2%) How many patients do they need to treat with warfarin to prevent one stroke? The ARR is 5% minus 2%, or 3%. The NNT would be 1/0.03 = 33. Clearly, warfarin is superior to aspirin in stroke prevention, but the monitoring is more cumbersome and costly. The decision to treat a patient with warfarin (or any medication) should also depend upon the side effect profile. Small increase in the rate of major extracranial bleeding (a non-statistically significant absolute risk increase of 0.3% compared to no treatment) Extremely small increase in the rate of intracranial hemorrhage (a non-statistically significant absolute risk increase of 0.2% compared to no treatment) These numbers are actually similar to those seen in patients on aspirin. Note that warfarin has also been shown to decrease mortality in these patients, with an ARR = 1.6% and an NNT = 63.1

47 Is there a way to estimate this patient s individual risk for stroke more precisely, to help decide whether he should be on aspirin or warfarin?

48 Gage B, et al. Validation of clinical classification schemes for predicting stroke: Results from the National Registry of Atrial Fibrillation. JAMA 2001; 285: Observational cohort study using the National Registry of Atrial Fibrillation (NRAF) data set, which consisted of patient records gathered by quality improvement/peer review organizations in 7 states Purpose of study was to devise a stroke risk score in Medicare patients with atrial fibrillation, not on anticoagulation Investigators combined risk factors for stroke identified in the Atrial Fibrillation Investigators (AFI) and the Stroke Prevention and Atrial Fibrillation (SPAF) trials to produce a new risk scoring system, CHADS2: C Congestive heart failure (recent admission) 1 point H History of hypertension 1 point A Age > 75 yrs. 1 point D Diabetes mellitus 1 point S Prior stroke or transient ischemic attack 2 points

49 Chart review performed on Medicare patients with a primary or secondary diagnosis of atrial fibrillation. Charts excluded from analysis if: -- Age < 65 or > 95 yrs. -- Atrial fibrillation was acute (e.g., perioperative) -- Rheumatic heart disease was present -- Patient died during the index hospitalization -- Patient was discharged with a prescription for warfarin Study outcome was subsequent hospitalization for ischemic stroke, as determined by Medicare claims

50 Results Patients in the NRAF data set were older and had more comorbidities than patients in the AFI and SPAF trials Overall 4.4% per year readmission rate for an ischemic event CHADS2 score predicted the risk of stroke: CHADS2 score Stroke Rate (per year)* 0 1.9% 1 2.8% 2 4.0% 3 5.9% 4 8.5% % % *Adjusted stroke rate, not on aspirin Investigators also found that aspirin led to a 20% relative risk reduction in ischemic stroke

51 Strengths & Limitations This study gives a helpful real-world view of stroke risk in non-trial participants with atrial fibrillation CHADS2 score may have underestimated the true risk of stroke: -- Patients who had ischemic events without being hospitalized would not have been counted -- Some of the patients may have been started on warfarin after hospital discharge Alternatively, the CHADS2 score may overestimate the risk of stroke, since this was a presumably sicker cohort of hospitalized patients, whose physicians chose not to start on anticoagulation. CHADS2 score may not be applicable to younger, healthier patients, who may have a lower risk of stroke overall. True risk of a CHADS2 score of 5 or 6 unknown, as there were very few patients in these groups Does not directly answer the question of whether elderly patients with multiple comorbidities should be started on warfarin, as these patients are more likely to have hemorrhagic complications Unclear if the CHADS2 score should be recalculated in patients as their risk factors change (e.g., as they recover from their CHF)

52 What about the combination of aspirin and clopidogrel? How does it compare to aspirin alone or warfarin?

53 The ACTIVE-W trial, which compared aspirin plus clopidogrel to warfarin, was terminated early because warfarin was shown to be superior. Key findings were: Aspirin + clopidogrel reduced the risk of stroke by 28% compared to aspirin alone, with an ARR = 0.9% and an NNT = 111. Aspirin + clopidogrel associated with a higher rate of major bleeding, with an ARI = 0.7% and an NNH = 142. Reduction in stroke was similar in magnitude to the increase in major bleeding. Calculate this patient s benefit if he were placed on aspirin + clopidogrel instead of aspirin alone: Annual baseline risk = 3%* RRR = about 30% ARR = 0.9% NNT = 111

54 Case 2 What is this patient s annual risk for stroke?

55 Patients in atrial fibrillation who have had a stroke or TIA have a substantially higher rate of recurrent stroke of about 12% per year Her CHADS2 score is 5, so her annual risk of stroke is 12-13%

56 Would you add clopidogrel to this patient s aspirin, or would you switch her to warfarin?

57 Effect of clopidogrel added to aspirin in patients with atrial fibrillation. The ACTIVE Investigators. N Engl J Med 2009; 360: Methods Randomized, double-blind, placebo-controlled trial of aspirin ( mg) alone vs. aspirin plus clopidogrel in atrial fibrillation Enrolled patients considered to be unsuitable for vitamin-k antagonist therapy Patients had to have at least 1 of the following risk factors: -- Age > 75 yrs. -- Hypertension -- Previous stroke, TIA or systemic embolism -- Left ventricular ejection fraction < 45% -- Peripheral vascular disease -- Age 55 to 74 yrs and diabetes or coronary artery disease Excluded patients at risk for bleeding (e.g., thrombocytopenia, recent ulcer, etc.) Primary outcome was any major vascular event (stroke, systemic embolism, myocardial infarction or vascular death) Most important secondary outcome was stroke (ischemic + hemorrhagic)

58 Results 7554 patients enrolled and followed for a median of 3.6 years. -- Mean CHADS2 score was Reasons for enrollment were physician s judgment that warfarin was inappropriate (50%), patient had a specific risk for bleeding (24%) or patient preferred not to be

59 Primary Outcome ASA ASA + Clopid ARR/ARI NNT/NNH 7.6% 6.8% 0.8% 125 Stroke 3.3% 2.4% 0.9% 111 Major Bleeding 1.3% 2.0% 0.7% 142 Hemorrhagic CVA 0.17% 0.23% NS NS Overall, aspirin + clopidogrel reduced the risk of stroke by 28% compared to aspirin alone.

60 Is warfarin safe in the very elderly?

61 Clopidogrel plus aspirin versus oral anticoagulation in atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of vascular events (ACTIVE W): a randomized controlled trial. Lancet 2006; 367: Methods Randomized patients with atrial fibrillation and at least one risk factor for stroke to clopidogrel + aspirin versus anticoagulation with a vitamin K antagonist (target INR ) Primary composite endpoint: stroke, non-cns systemic embolism, myocardial infarction or vascular death.

62 Results Trial terminated early after patients enrolled, because of clear superiority of oral anticoagulation group. Median CHADS2 score was 2. Annual risk of primary endpoint decreased from 5.6% in clopidogrel + ASA to 3.9% in oral anticoagulation group -- ARR = 1.7%, NNT = 59 Annual risk of stroke decreased from 2.4% in clopidogrel + ASA to 1.4%.in oral anticoagulation group -- ARR = 1%, NNT = 100

63 Would you consider prescribing dabigatran in this patient?

64 Dabigatran is an oral direct thrombin inhibitor Review the methods and results of the RE-LY trial, which compared two doses of dabigatran to warfarin in patients with atrial fibrillation.4 Key findings of this trial were: Dabigatran (110 mg) and warfarin had a similar rate of stroke or systemic embolism, while dabigatran (150 mg) had a slightly lower rate. Dabigatran (150 mg) and warfarin had a similar rate of major bleeding, while dabigatran (110 mg) had a slightly lower rate. Warfarin had the highest rate of intracranial hemorrhage There was no statistically significant difference in mortality. Based on these results, ask your learners whether they would prescribe dabigatran instead of warfarin. Given the similarities in outcomes, with the added benefit of not requiring INR checks, dabigatran appears to be a reasonable first-line agent for stroke prevention. The patient still needs to be educated about and monitored for bleeding. In addition, liver function testing may be warranted, given that another direct thrombin inhibitor, ximelagatran, was associated with acute liver failure (although the RE-LY trial did not find any increased risk of hepatic complications in the dabigatran arms).

65 If you decide to start this patient on warfarin, do you need to anticoagulate with IV unfractionated or low-molecular-weight heparin while waiting for the patient s INR to become therapeutic? How soon after a cerebrovascular accident or transient ischemic attack should anticoagulation be started?

66 None of the major studies of anticoagulation in atrial fibrillation overlapped heparin and warfarin. In patients who have had an acute cardioembolic stroke, immediate full-dose anticoagulation with unfractionated heparin or low-molecular-weight heparin is not beneficial. Moreover, it increases the risk of hemorrhagic conversion of the CVA. The optimal timing for initiation of anticoagulation is not well established, but a reasonable answer would be to start warfarin upon hospital discharge, since it takes a few days for the INR to become therapeutic.

67 Warfarin Therapy The goal INR is Higher levels of anticoagulation tend to increase the risk of intracerebral bleeding with a minimal incremental decrease in stroke risk. The annual CNS hemorrhage rate is 1.3% with warfarin in most studies, which is not significantly different from the risk with aspirin or placebo. In older patients, the risk of CNS hemorrhage increases. However, the risk of embolic stroke also increases. Overall the risk-benefit ratio favors anticoagulation. Contraindications to anticoagulation include recent hemorrhage, frequent falls, poor compliance and severe hypertension. Lower intensity anticoagulation with an INR < 1.5 along with aspirin does not provide any benefit over aspirin.

68 Aspirin Therapy The role of aspirin in the prevention of stroke remains controversial. In one trial, a daily dose of 325 mg reduced the annual rate of stroke by 42% as compared to placebo. However, in two other trials a statistically insignificant reduction was seen. A meta-analysis of 5 randomized trials showed a stroke reduction of 19%. Aspirin should be used only in patients at low risk of embolism since the benefit of warfarin use in such patients is small.

69 CHADS 2 Although a number of risk stratification models are available for patients with chronic non-valvular AF, CHADS2 score is currently the best validated and most clinically useful. CHADS2 score of 0: Low risk for ischemic stroke or peripheral embolization. 0.5 % per year risk of stroke in the absence of warfarin. Can be managed with aspirin. CHADS2 score of 3: High risk 5.3 to 6.9 % per year Should be treated with warfarin (in the absence of contraindications). CHADS2 score of 1 or 2: Intermediate risk (1.5 to 2.5 percent per year) The choice between warfarin therapy and aspirin will depend upon many factors, including patient preference.

70 Other Therapies Available Radiofrequency catheter ablation of the AV junction with ventricular pacing. Ventricular pacing with maximal beta blockers if needed. Direct surgical intervention such as a maze procedure. Implantable atrial defibrillators.

71 Snow V, et al. Management of newly detected atrial fibrillation: A clinical practice guideline from the American Academy of Family Physicians and the American College of Physicians. Ann Int Med 2003; 139: Section 1: Rate control vs. rhythm control Four randomized, controlled trials have failed to show a benefit of rhythm control (with cardioversion and antiarrhythmics) over rate control and chronic anticoagulation. Higher rates of hospitalizations seen in rhythm control groups, with a trend towards higher mortality. Recommendation: Rate control with chronic anticoagulation is the recommended strategy for the majority of patients with atrial fibrillation.

72 Section 2: Anticoagulation Recommendation: Patients with atrial fibrillation should receive chronic anticoagulation with adjusted-dose warfarin, unless they are at low risk of stroke or have a specific contraindication to the use of warfarin.

73 Section 3: Efficacy of different agents for rate control Verapamil and diltiazem are more effective than digoxin or placebo in reducing ventricular rate both at rest and during exercise. Atenolol and metoprolol also reduce resting and exercise heart rates. Studies comparing digoxin with placebo have been inconsistent, particularly during exercise. Recommendation: The following drugs are recommended for their demonstrated efficacy in rate control during exercise and while at rest: atenolol, metoprolol, diltiazem and verapamil. Digoxin is only effective for rate control at rest and therefore should only be used as a second-line agent for rate control in atrial fibrillation.

74 Section 4: Acute conversion Immediate efficacy of DC cardioversion is 90% Risk of thromboembolic events similar between DC cardioversion and pharmacologic cardioversion No increased efficacy with most antiarrhythmic therapy initiated before DC cardioversion Strong efficacy for acute conversion of atrial fibrillation with ibutilide, fleicanide, dofetilide, propafenone and amiodarone. Risk of ventricular arrhythmias lowest with amiodarone and procainamide, moderate for fleicanide, proprafenone, and sotalol and high for ibutilide, quinidine and dofetilide No head-to-head studies comparing anti-arrhythmics to each other.

75 Section 5: The role of echocardiography in the acute conversion of atrial fibrillation. Overall, TEE-guided cardioversion with a shorter duration of anticoagulation is equivalent to a conventional, longer course of preand postcardioversion anticoagulation. An inverse relationship exists between left atrial size and success of cardioversion, but there is no recommended threshold above which cardioversion should not be attempted. Recommendation: Both transesophageal echocardiography with short-term prior anticoagulation followed by acute cardioversion (in the absence of intracardiac thrombus) with postcardioversion anticoagulation versus delayed cardioversion with pre- and postanticoagulation are appropriate management strategies

76 Section 6: Maintenance Therapy Strong evidence for the efficacy of amiodarone, disopyramide, propafenone and sotalol in maintaining sinus rhythm Moderate evidence for the efficacy of flecainide, quinidine and azimilide Lowest rates of ventricular arrhythmias seen with amiodarone and disopyramide High rates of noncardiac side effects seen with amiodarone (especially pulmonary toxicity and thyroid disease) Recommendation: Most patients converted to sinus rhythm from atrial fibrillation should not be placed on rhythm maintenance therapy since the risks outweigh the benefits. In a selected group of patients whose quality of life is compromised by atrial fibrillation, the recommended pharmacologic agents for rhythm maintenance are amiodarone, disopyramide, propafenone and sotalol. The choice of agent predominantly depends on specific risk of side effects based on patient characteristics.

77 Anticoagulation for Chronic AF Thromboembolism is a well-known risk. The stroke rate in patients with AF is on average 6 times higher than the rates in patients without AF and accounts for 25% of death in AF population. Cardioembolic strokes are on average more disabling than noncardioembolic strokes.

78 Valvular AF The presence of valvular heart disease (usually mitral stenosis or regurgitation from rheumatic heart disease) along with atrial fibrillation. These patients are at particularly high risk for thromboembolism. In a study of 754 patients with rheumatic valvular heart disease: 22.3% of the 219 patients with AF developed thromboembolic events as compared to 3.8% of the patients in sinus rhythm. Risk of stroke of 5.2% per patient year for patients with rheumatic heart disease and AF.

79 Lone AF Lone AF usually refers to atrial fibrillation that occurs in patients without clinical heart disease, and age < In a report from the Mayo Clinic on 97 patients who met these criteria: The incidence rate for stroke was 0.35 events for 100 patients-years. Thus, the risk of thromboembolism is low and warfarin will not benefit these patients.

80 Non-Valvular AF Most patients with AF fall into this category. In the late 80s and early 90s, there were six studies that compared anticoagulation with warfarin versus placebo: 5 of the 6 studies found that warfarin significantly decreased the risk of stroke compared with placebo or no therapy. The average risk reduction ranged from 58% to 86%. The benefit appeared to extend to men and women and to patients older than 75. The 6th study showed a risk reduction of 37% but was not statistically significant.