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Medical Management Atrial Fibrillation

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1 Medical Management Atrial Fibrillation
Stuart Beldner, MD, FHRS Assistant Professor NSLIJ Hofstra School of Med

2 Disclosures None

3 A-Fib “There’s no reason to panic. While it is true that one of the crew members is ill, slightly ….”

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5 ECG Recognition Absence of discrete P waves Chaotic atrial activity
During A Fib, the atrial rate is 400 bpm or more. The atria quiver instead of contract. P waves and T waves are not visible during A Fib. Instead, wavy deflections replace the entire isoelectric line between QRS complexes, which occur irregularly because of the inherent delay in the AV node. The ventricular rate can range from bpm. Absence of discrete P waves Chaotic atrial activity Ventricular rate irregularity

6 Mechanisms of AF. AF indicates atrial fibrillation; Ca++, ionized calcium; and RAAS, renin-angiotensin-aldosterone system. Mechanisms of AF. AF indicates atrial fibrillation; Ca++, ionized calcium; and RAAS, renin-angiotensin-aldosterone system. January C T et al. Circulation. 2014;130:e199-e267 Copyright © American Heart Association, Inc. All rights reserved.

7 2014 AF guidelines classification of AF
Term Definition Paroxysmal AF •AF that terminates spontaneously or with intervention within 7 d of onset. •Episodes may recur with variable frequency. Persistent AF •Continuous AF that is sustained >7 d. Longstanding persistent AF •Continuous AF >12 mo in duration. Permanent AF •The term “permanent AF” is used when the patient and clinician make a joint decision to stop further attempts to restore and/or maintain sinus rhythm. •Acceptance of AF represents a therapeutic attitude on the part of the patient and clinician rather than an inherent pathophysiological attribute of AF. •Acceptance of AF may change as symptoms, efficacy of therapeutic interventions, and patient and clinician preferences evolve. Nonvalvular AF •AF in the absence of rheumatic mitral stenosis, a mechanical or bioprosthetic heart valve, or mitral valve repair.

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10 65 year old man presents to his doctor’s office for his routine physical and is found to be in atrial fibrillation. 1. rate control and anticoagulation 2. electrical cardioversion 3. electrical cardioversion plus antiarrhythmic therapy 4. ablation

11 Rate versus Rhythm Trials HR (Rate vs Rhythm Control)
Year n Primary End Point HR (Rate vs Rhythm Control) P PIAF3 2000 252 Improvement AF symptoms 1.10 0.31 AFFIRM1 2002 4060 Overall mortality 0.87 0.08 RACE2 522 Composite 0.73 0.11 STAF4 2003 200 1.09 0.99 HOT CAFE5 2004 205 1.98 >0.71 AF-CHF6 2008 1376 Cardiovascular mortality 0.94 0.59 PABA-CHF15 81 Multiple <0.001 AF-CHF and PABA-CHF Trials enrolled only patients with congestive heart failure. PABA-CHF compared rate control via AV nodal ablation with biventricular pacing versus rhythm control via AF ablation (±antiarrhythmic medication). All other trials compared predominantly pharmacological rate control with pharmacological rhythm control. Composite primary outcomes are as follows: RACE (death from cardiovascular causes, heart failure, thromboembolic complications, bleeding, pacemaker implantation, severe adverse drug effects), STAF (death, cardiopulmonary resuscitation, cerebrovascular event, and systemic embolism), HOT CAFÉ (all-cause mortality, thromboembolic events, major bleeding), PABA-CHF (Minnesota Living with Heart Failure Questionnaire score, left ventricular ejection fraction at 6 months, 6-minute walk distance—note that all 3 individual components of the composite end point in PABA-CHF favored AF ablation over AV nodal ablation with biventricular pacing with P<0.001). HR indicates hazard ratio for primary end point, comparing rate versus rhythm control strategies.

12 Should We Truly Believe that AF and NSR are really equal?
Trials such as AFFIRM and RACE, did NOT prove that rate-controlled and anticoagulated AF is as good as NSR. They show that a rhythm control strategy using an ITT analysis, suggests equivalence in at least some populations. These trials do NOT disprove that sinus rhythm would be better than AF in regard to QOL if one were to actually attain and maintain it with a safe and effective therapy. AFFIRM and RACE did not prove that rate control in anticoagulated afib is as good as sinus rhythm. They showed that a rhythm-control strategy, using intention-to-treat analysis, suggests equivalence in this type of population, and these were all high-risk patients, but AFFIRM cannot be extrapolated to the overwhelming majority of afib patients that did not meet the entrance criteria to this trial. They do not disprove that sinus rhythm would be better, both in terms of survival and quality of life, if we were to actually attain and maintain it with a safe and effective therapy.

13 AFFIRM: Prevalence of Sinus Rhythm at Follow-up
Patients in Sinus Rhythm, % For example, in the rate-control arm, in yellow, and in the rhythm-control arm, in blue, there were patients in sinus rhythm. Many of the people in AFFIRM had PAF [paroxysmal atrial fibrillation], and although they were assigned to rate control, a lot of them, as you can see, were in sinus rhythm at many or most of the visits. And the ones assigned to rhythm control, only some of them were in sinus rhythm at the time of their visits. Many of them failed their rhythm control. The primary analysis was not done by outcome against rhythm; it was done by outcome against the strategy, the assignment to a rhythm- or rate-control approach. And that will become important in a few moments. Time The AFFIRM Investigators. NEJM: 2002; 347:

14 Atrial Fibrillation Complications
5 fold increase in risk for stroke* AF strokes are usually more severe than nonAF strokes 3 fold risk of heart failure ** 2 fold risk of dementia*** and mortality * *Kannel et al. Am J of Coll. 1998 **Wang et al. Circu. 2003 *** Ott et al. Stroke 1997.

15 Atrial Fibrillation: Follow-up Investigation of Rhythm Management
Time dependant, on treatment, Multivariate Analysis of Survival HR (99%) 1.06 (1.05 – 1.08) 1.56 (1.20 – 2.04) 1.57 (1.18 – 2.09) 1.56 (1.17 – 2.07) 1.78 (1.25 – 2.53) 1.70 (1.24 – 2.33) 0.74 (0.55 – 0.98) 1.36 (1.03 – 1.80) 0.50 (0.37 – 0.69) 1.42 (1.09 – 1.86) 0.53 (0.39 – 0.72) 1.49 (1.11 – 2.01) Factor Age (per year) CAD CHF Diabetes Smoking Stroke/TIA Normal LVEF Mitral Regurg Warfarin Digoxin Sinus Rhythm AA drug From the AFFIRM database. This data demonstrates that there are things that are independently “bad” and independently “good”. Being in sinus rhythm is good, but using an antiarrhythmic drug to achieve sinus is bad. 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 Better Worse

16 Effects on Maintaining Sinus Rhythm on QOL and Exercise Capacity: SAFE-T Investigators
SF-36 Change in One Year In addition, if we look at other recent trials whose primary analyses featured issues, such as quality of life, here I picked some of the analyses from the SAFE-T trial -- quality of life consistently better, exercise parameters consistently better in sinus rhythm. So even if there's no mortality difference, there's a benefit. There's a reason to treat patients for sinus rhythm. HR Peak Singh BN, et al, NEJM 2005; 352:

17 Antiarrhythmic Drugs for AF
Class I: Class IC: propafenone (also very weak β-blocker), flecainide (no β-blockade effects) Sustained-release propafenone (Rythmol SR) and flecainide are bid; Propafenone appears to be less proarrhythmic Class IA: disopyramide, quinidine, procainamide No longer included in the ACC/AHA/ESC algorithm Disopyramide may be useful in vagally induced AF Class III: Sotalol (class III plus β-blocker) Dofetilide (pure class III) Amiodarone (class III plus class I, II, IV); highly overused Dronedarone (similar to amiodarone with different pharmacokinetics and markedly reduced organ toxic potential) The currently evaluated antiarrhythmic agents for the conversion of AF to normal sinus rhythm include Vaughn Williams class IA (disopyramide, procainamide, quinidine), class IC (flecainide, propafenone), and class III (amiodarone, dofetilide, sotalol, ibutilide) antiarrhythmics.1 Disopyramide may be useful in vagally induced AF.1 Dronedarone is similar to amiodarone but has different pharmacokinetics and markedly reduced organ toxic potential.2 Fuster V, Rydén LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006;114:e257-e354. Zimetbaum PJ. Dronedarone for atrial fibrillation—an odyssey. N Engl J Med. 2009;360(18): 17

18 Dronedarone Clinical Trials
Study Design Dronedarone Effects ERATO Dronedarone vs placebo Significant decrease in ventricular rates (24-hr Holter and maximal exercise) DAFNE Efficacy vs placebo in time to first AF recurrence with 400 mg bid dose EURIDIS and ADONIS Dronedarone vs placebo in 1237 patients with AF/AFL Significant and consistent reduction in first recurrence of AF/AFL; comparable safety vs placebo ANDROMEDA 627 patients with severe HF Excess mortality risk vs placebo (n=25 vs n=12; HR, 2.13; P=.03); trial stopped early DIONYSOS Dronedarone vs amiodarone in 504 patients with persistent AF Mixed observations ATHENA PALLAS 4628 high-risk AF patients Dronedarone vs placebo in 3236 patient with permanent AF Efficacy against AF Reduction in CV mortality and hospitalization Reduction in additional end points a 2.29-fold increase in the coprimary end point of stroke, MI, embolism, or cardiovascular death events, compared to placebo, and led to a halt in a planned 10,800-patient international randomized trial The safety and efficacy of dronedarone have been studied in a number of clinical trials. The ERATO trial demonstrated the rate-reduction effects of dronedarone.1 The dose-finding trial DAFNE demonstrated 400 mg bid as the only dose to consider.2 Two successful pivotal trials against placebo in AF (EURIDIS and ADONIS) showed dronedarone’s efficacy and safety in maintaining sinus rhythm in patients with nonpermanent AF or atrial flutter and no clinically significant structural heart disease or heart failure.3 The ANDROMEDA trial then examined mortality and morbidity among patients with a depressed left ventricular ejection fraction (≤35%) and decompensated heart failure.4 The study was terminated by the data and safety monitoring committee after 7 months because of a doubling of the death rate in the dronedarone group—excess mortality that was predominantly attributed to cardiovascular (CV) causes, most notably congestive heart failure. In part because of the requirements of the European Medicines Agency, the DIONYSOS trial was conducted comparing dronedarone with amiodarone.5 This efficacy study involved 504 patients and had a follow-up period of only 6 months, at which point dronedarone was less effective for the maintenance of sinus rhythm but was associated with significantly fewer adverse effects and less premature discontinuation of drug treatment. Results of the ATHENA trial, which included 4628 patients with nonpermanent AF or flutter, showed a significant reduction in the rate of a composite end point of death from CV causes and hospitalization due to CV events.6 Davy JM, Herold M, Hoglund C, et al; ERATO Study Investigators. Dronedarone for the control of ventricular rate in permanent atrial fibrillation: the Efficacy and safety of dRonedArone for the cOntrol of ventricular rate during atrial fibrillation (ERATO) study. Am Heart J. 2008;156(3):527:e1-527.e9. Touboul P, Brugada J, Capucci A, Crijns HJ, Edvardsson N, Hohnloser SH. Dronedarone for prevention of atrial fibrillation: a dose-ranging study. Eur Heart J. 2003;24(16): Singh BN, Connolly SJ, Crijns HJ, et al; EURIDIS and ADONIS Investigators. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl Med. 2007;357(10): Køber L, Torp-Pedersen C, McMurray JJ, et al; Dronedarone Study Group. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med. 2008;358(25): Zimetbaum PJ. Dronedarone for atrial fibrillation—an odyssey. N Engl J Med. 2009;360(18): Hohnloser SH, Crijns HJ, van Eickels M, et al; ATHENA Investigators. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med. 2009;360(7): 18

19 ATHENA: Summary Results show dronedarone significantly prolongs the time to AF recurrence compared with placebo No significant difference was found between placebo and dronedarone in all-cause mortality Dronedarone reduced CV mortality, CV hospitalizations, ACS, arrhythmic deaths, and stroke Adverse events occurring significantly more frequently with dronedarone than with placebo included bradycardia, QT-interval prolongation, diarrhea, nausea, rash, and an increase in the serum creatinine level Total discontinuation rates for dronedarone and placebo were identical, no pulmonary or thyroid toxicity was evident, and there were no TDP/VF deaths in the “high-risk” AF population in dronedarone-treated patients ATHENA is the largest trial for AF to date. Results show dronedarone significantly prolongs the time to AF recurrence compared with placebo. No significant difference was found between placebo and dronedarone in all-cause mortality. However, dronedarone reduced CV mortality, CV hospitalizations, ACS, arrhythmic deaths, and stroke. Adverse events occurring significantly more frequently with dronedarone than with placebo included bradycardia, QT-interval prolongation, diarrhea, nausea, rash, and an increase in the serum creatinine level. However, total discontinuation rates for dronedarone and placebo were identical, no pulmonary or thyroid toxicity was evident, and there were no torsades de pointes/ventricular fibrillation deaths in the “high-risk” AF population in dronedarone-treated patients. Hohnloser SH, et al. N Engl J Med. 2009;360(7): Hohnloser SH, Crijns HJ, van Eickels M, et al; ATHENA Investigators. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med. 2009;360(7): 19

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21 Efficacy of Antiarrhythmic Drug Therapy for A Fib
Gold Standard for Judging Ablative Therapy AFFIRM TRIAL – Rhythm Control Arm Overestimate AF control with drug (No Sxs) Increased Mortality? (The prevalence of sinus rhythm in the rhythm-control group at follow-up was 82.4 percent, 73.3 percent, and 62.6 percent at one, three, and five years, respectively.) 100 80 20 40 % Patients Free of Symptomatic AF 2 4 6 8 10 12 Months 60 AFFIRM Atrial Flutter # RATE VS RHYTHM CONTROL Amiodarone* Sotalol** Propafenone** This slide shows the outcome associated with antiarrhythmic drug therapy used in the treatment of atrial fibrillation. The % of patients free of symptomatic AF over time associated with amiodarone, sotalol and propafenone used as primary therapy is shown by the broken colored lines. Also shown as the white solid line is an estimate of the % of patients free from A fib with a history of failing two antiarrhythmic drugs adapted from the work of Crijins and colleagues., I believe I have defined the approximate risk of A fib recurrence with pharmacologic therapy in our target population by drawing the solid yellow line equidistant between those failing two drugs and those failing primary therapy. I believe this audience would agree that I am being generous by indicating that in this patient population,a recurrence rate of at least 60% should be anticipated.by six months. Hx of Two Failed Drugs*** * Roy et al NEJM, 2000 **Antman et al, JACC 1990 ***Crijns et al, AJC 1991 #Natale et al JACC 2001

22 New Pharmacologic Rhythm Control Agents
Ranalozine (Ranexa) Has a greater effect on the late sodium current (late > peak) which should make it more effective in ischemic patients. Vernakalat Ikur Blocker

23 Ranexa (ranolazine) Approved for the treatment of chronic stable angina An atrially effective compound, substantially inhibiting peak Na+ current mainly in the atria and has been shown to decrease the incidence of atrial fibrillation in an in vitro model. MERLIN TIMI 361 (Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes) 6,560 patients with prior chronic angina A neutral effect on overall mortality Suggested (P= 0.08) a 26% reduction in new onset atrial fibrillation. The incidence of significant arrhythmias was screened with holter monitoring 75 (2.3%) 55 (1.7%) P= 0.08 May have a role in postop AF. JACC 2009;53:1510-6

24 Synergistic Effect of the Combination of Ranolazine and Dronedarone to Suppress AF
Synergistic Effect of Ranolazine and Dronedarone to Depress Vmax in PVSynergistic effect of the combination of ranolazine and dronedarone on maximal rate of rise of the action potential upstroke (Vmax) after an abrupt change in rate in pulmonary vein (PV) sleeve preparations. (A) Vmax traces recorded after a change in cycle length (CL) from 5,000 to 300 ms. (B) Graph displaying composite data of Vmax changes after acceleration of pacing rate from a CL of 5,000 to 300 ms (n = 4 to 8). *p < 0.05 versus control. †p < 0.05 versus ranolazine or dronedarone alone. **p < 0.05, change in Vmax induced by combination ranolazine plus dronedarone (from washout) versus the sum of changes caused by ranolazine and dronedarone independently (both from washout). Burashnikov A et al. JACC 2010

25 HARMONY A Phase 2, Proof of Concept, Randomized, Placebo- Controlled, Parallel Group Study to Evaluate the Effect of Ranolazine and Dronedarone When Given Alone and in Combination on Atrial Fibrillation Burden in Subjects With Paroxysmal Atrial Fibrillation Primary endpoint The effect of ranolazine and of low dose dronedarone when given alone and in combination at different dose levels on atrial fibrillation burden (AFB) over 12 weeks of treatment the combination of ranolazine (Ranexa, Gilead Sciences) and dronedarone (Multaq, Sanofi) appeared to lower the burden of atrial fibrillation (AF) by >70% over three months in 45% to 60% of patients with the paroxysmal form of the arrhythmia Caution as this is a small study. Kowey et al. Presented at HRS 2014 25

26 A 59-year-old woman is referred to you for management of permanent atrial fibrillation that she has had for three years. The referring physician reports that recently performed echocardiography revealed normal findings. The patient's current medications are dabigatran and metoprolol, 50 mg daily. During your initial evaluation, the patient says she feels well and has no symptoms. A 12-lead electrocardiogram shows a resting heart rate of 100 beats per minute (bpm). (A) Continue the current drug regimen and schedule follow-up evaluation (B) Increase metoprolol dosage and obtain a 24-hour ambulatory electrocardiographic recording; adjust metoprolol dosage to achieve a heart rate of less than 70 bpm during rest and less than 120 bpm during moderate exercise (C) Increase metoprolol dosage and obtain a 24-hour ambulatory electrocardiographic recording; adjust metoprolol dosage to achieve a heart rate of less than 80 bpm during rest and less than 110 bpm during moderate exercise (D) Increase metoprolol dosage and obtain a 24-hour ambulatory electrocardiographic recording; adjust metoprolol dosage to achieve a heart rate of less than 80 bpm during rest and less than 130 bpm during moderate exercise

27 Rate control 2006 guidelines for AF recommended AFFIRM RACE
target heart rates of 60 to 80 bpm at rest and 90 to 115 bpm during moderate exercise AFFIRM no higher than 80 bpm at rest and no higher than 110 bpm during a 6-minute walk test, and an average heart rate no higher than 100 bpm over 18+ hours of Holter monitoring with no rates >100% of maximal age-predicted heart rate, as well RACE Resting heart rate < 100 bpm Although strict rate control was not beneficial in these retrospective analyses, an analysis of both RACE and AFFIRM did suggest a benefit to moderate rate control, because patients with resting heart rates >100 bpm were more likely to reach a composite end point of mortality, cardiovascular hospitalization, or myocardial infarction in comparison with patients with resting rates ≤100 bpm.

28 RACE II * For noninferiority Lenient control (n = 311) Strict control
Trial design: Patients with permanent AF were randomized to lenient (resting heart rate [HR] <110 bpm) or strict rate control (resting HR <80 bpm). Patient follow-up was 3 years. Results (p = 0.001)* (p = NS) Primary outcome was similar in lenient and strict control arms (12.9% vs. 14.9%) Stroke ↓ with lenient control (1.6% vs. 3.9%, p < 0.05) CHF (3.8% vs. 4.1%), CV death, PPM implantation (0.8% vs. 1.4%) were similar 30 30 20 20 14.9 % % 12.9 Conclusions Lenient rate control easier to achieve than strict control, and noninferior for clinical outcomes Most patients had lower CHADS2 score. Safety and efficacy in patients with higher CHADS2 score will need to be explored Needs to be tested in patients with significant LV dysfunction 10 Achieved resting heart rates in the study were 93±9 bpm in the lenient rate control group and 76±12 bpm in the strict rate control group (P<0.001). Based on RACE II, and subanalyses of RACE and AFFIRM, as well, the consensus guidelines for rate control were changed in the 2011 update. Specifically, strict rate control as defined in RACE II was given a class III (no benefit) rating in comparison with lenient rate control for patients with persistent AF, acceptable symptoms, and LVEF >40%. These data do NOT apply to patients with HF. In general target resting heart rates in the range of 60 to 70 bpm for patients with AF and CHF, with attention paid to avoiding excessively slow heart rates during rest/sleep and avoiding extremely high rates (above the maximal age-predicted heart rate) during exertion. 10 3.9 2.9 Primary endpoint CV mortality * For noninferiority Lenient control (n = 311) Strict control (n = 303) Van Gelder IC, et al. N Engl J Med 2010;Mar 15:[Epub]

29 62 year old female has symptomatic paroxysmal atrial fibrillation
62 year old female has symptomatic paroxysmal atrial fibrillation. History is negative for hypertension, heart failure, diabetes mellitus, vascular disease, or prior stroke. You reccomend: Nothing ASA ASA + Plavix NOAC or Vit K antagonist NOAC + ASA

30 Patients Adjusted Stroke Risk CHADS2 Score
CHADS2 Score stroke risk patients with nonvalvular AF not treated with Anticoagulation According to CHADS index CHADS2 Risk Criteria Score Prior stroke or TIA Age > 75 Hypertension Diabetes Mellitus Heart Failure 2 1 Patients Adjusted Stroke Risk CHADS2 Score Opinion is divided about A/C for those at intermediate risk (stroke rate of 3 – 5%/year). Some advocate the routine use of A/C while others favor selective anticoagulation in patients depending on bleeding risk. Using this system the risk of stroke is expected to increase by a factor of 1.5 for each 1 point increase in score. 120 468 528 337 65 5 1.9 (1.2 – 3.0) 2.8 ( ) 4.0 (3.1 – 5.1) 8.5 ( ) 12.5 ( ) 18.2 ( 1 2 3 4 5

31 Refining Risk Stratification in AF
CHA 2 DS 2 -VASc Risk Factor Score C ongestive heart failure/LV dysfunction 1 H ypertension A ge > 75 y D iabetes mellitus S troke/TIA/TE V ascular disease A ge y S ex category (ie female gender) 1 V ascular disease (prior myocardial infarction, peripheral artery disease, or aortic plaque)

32 Summary of Recommendations for Risk-Based Antithrombotic Therapy.
January C T et al. Circulation. 2014;130:e199-e267 Copyright © American Heart Association, Inc. All rights reserved.

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34 Cardioversion on Dabigatran
Re-LY 18,113 patients randomized to dabigatran 110, 150, or warfarin 1983 cardioversions in 1270 patients Antecedent TEE (% thrombus) Continuous therapy for > 3 weeks pre DCCV Stroke/systemic embolism D110 25.5 (1.8%) 76.4 0.8 D150 24.1 (1.2%) 79.2 0.3 Warfarin 13.3 (1.1%) 85.5 0.6 Nagarakanti et al. Circ 2011

35 Cardioversion on Rivaroxaban
Rivaroxaban vs. vitamin K antagonists for cardioversion in atrial fibrillation  1504 patients (2:1 randomisation rivaroxaban Vs warfarin TEE guided DCCV versus 3 weeks of oral AC at the discretion of the treating physician For early cardioversion rivaroxaban was started at least 4 hours prior to cardioversion. composite of stroke, transient ischaemic attack, peripheral embolism, myocardial infarction, and cardiovascular 5 (two strokes) of 978 patients (0.51%) in the rivaroxaban group 5 (two strokes) of 492 patients (1.02%) in the VKA group [risk ratio 0.50; 95% confidence interval (CI) 0.15–1.73]. Major bleeding 6 patients (0.6%) in the rivaroxaban group 4 patients (0.8%) in the VKA group (risk ratio 0.76; 95% CI 0.21– 2.67 Cappato et al. European Heart Journal. 2014

36 Cardioversion on Apixaban
In ARISTOTLE 743 cardioversions in 540 patients and thromboembolic complications similar to warfarin

37 Primary Endpoint – stroke or systemic embolism
INR D150 VKA (RELY) Rivaroxaban VKA (ROCKET AF) Apixaban VKA (ARISTOLE) Quartlie 1 1.10% 1.7% (HR= 0.61) 1.5 2 (HR= 0.48) 1.72 2.36 (HR= 0.73) 2 2.2% (HR- 0.48) 2.6 (HR= 0.61) 1.61 1.72 (HR=0.94) 3 1.4% (HR= 0.76) 2.6 (HR= 0.66) 0.86 1.35 (HR= 0.64) 4 1.30% 1.4% (HR= 0.88) 1.2 2.3 (HR= 0.58) 0.91 1.04 (HR= 0.88) Major bleeding INR D150 VKA (RELY) Rivaroxaban* VKA (ROCKET AF)* Apixaban VKA (ARISTOLE) Quartlie 1 2.40% 3.3% (HR= 0.74) 11.3 14.12 (HR= 0.80) 1.44 2.89 (HR= 0.5) 2 3.20% 3.9% (HR= 0.84) 11.72 12.21 (HR= 0.81) 1.97 3.07 (HR= 0.64) 3 3.60% 3.2% (HR= 1.12) 15.1 14.88 (HR= 1.03) 2.61 3.06 (HR= 0.85) 4 3% (HR= 1.08) 20.61 16.72 (HR= 1.25) 2.48 3.31 (HR=0.75) Quartiles for Dab  < 56.9, 56.9 – 65.4, 65.4 – 72.4, > 72.4% Riva  < 50.71, – 58.44, – 65.66, – 100% Apix 24.3 – 60.5, 60.6 – 66.3, 66.4 – 71.1, 71.2 – 83.2% * Event rate (100 pt years)

38 Home monitoring of AC There is evidence from meta-analyses of RCTs that home monitoring of VKA therapy reduces thromboembolic events by 42% compared with usual monitoring. THIS IS SIMILAR TO THE 33% relative risk reduction with dabigatran 150 mg Bid!!!

39 ASA + Coumadin Dose adjusted VKA therapy + ASA is not recommended in stable coronary artery disease SPORTIF Associated with a nearly 2 fold increase in bleeding with NO significant reduction in stroke or MI. RE-LY Major bleeding was twice as high in patients on aspirin AND either dabigatran or wafarin

40 Triple threat (ASA + Plavix + VKA vs ASA+Plavix)
No increase in death Nonfatal stroke CHADS2= 0 2 fewer strokes/1000 CHADS2= 1 6 fewer strokes/1000 CHADS2= 2 11 fewer strokes/1000 CHADS2= 3 – 6 24 fewer strokes/1000 Nonfatal MI 21 fewer/1000 Nonfatal Major Extracranial Bleed 26 more bleeds/1000 (RR= 2.37) Recommendation: For patients with AF at high risk for stroke (CHADS2 ≥ 2) during the first month post bare metal stent or the first 3 – 6 months post drug elluting stent, we suggest triple therapy rather than dual antiplatelet therapy. After this initial period of triple therapy, we suggest a VKA plus a single antiplatelet drug rather than VKA alone. At 12 months post stent, antithrombotic therapy is suggested as for patients with AF and stable CAD. CHEST February 2012

41 Primary Endpoint: Total number of TIMI bleeding events
WOEST Primary Endpoint: Total number of TIMI bleeding events Days Cumulative incidence of bleeding 30 60 90 120 180 270 365 0 % 10 % 20 % 30 % 40 % 50 % 284 210 194 186 181 173 159 140 n at risk: 279 253 244 241 236 226 208 Triple therapy group Double therapy group 44.9% 19.5% p<0.001 HR= %CI[ ] |

42 Secondary Endpoint (Death, MI,TVR, Stroke, ST)
WOEST Secondary Endpoint (Death, MI,TVR, Stroke, ST) Days Cumulative incidence 30 60 90 120 180 270 365 0 % 5 % 10 % 15 % 20 % 284 272 266 261 252 242 223 n at risk: 279 276 273 263 258 234 Triple therapy group Double therapy group 17.7% 11.3% p=0.025 HR= %CI[ ]

43 PIONEER AF The primary purpose of this study is to evaluate the safety for 2 different rivaroxaban treatment strategies and one Vitamin K Antagonist (VKA) treatment strategy utilizing various combinations of dual antiplatelet therapy (DAPT) or low-dose aspirin (ASA) or clopidogrel (or prasugrel or ticagrelor).

44 Thank you


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