ATRIAL FIBRILLATION: FOCUSED UPDATE FOR THE PCP. Kevin Mikielski, DO, FACC LOMA 2016

Transcription

1 ATRIAL FIBRILLATION: FOCUSED UPDATE FOR THE PCP Kevin Mikielski, DO, FACC LOMA 2016

2 OBJECTIVES Recognize that defining atrial mechanism is extremely important on EKG Understand how CHADS-VASC score predicts thromboembolism risk Recognize that ASA is inferior to anticoagulation in patients with high risk CHADS-VASC score Recognize that NOACs should NOT be used in patients with mechanical valves Understand risks versus benefits when comparing Warfarin vs NOACs Know how long to hold anticoagulants prior to elective surgery

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4 ATRIAL FIBRILLATION

5 Definition and Background Supraventricular tachyarrhythmia with uncoordinated atrial activation and consequently ineffective atrial contraction EKG characteristics: 1) irregular R-R intervals 2) absence of distinct repeating P waves 3) irregular atrial activity

6 Atrial Fibrillation with Slow VR Just because the ventricular rate is slow, doesn t mean that it is NOT atrial fibrillation May be due to: AV nodal blocking agents Intrinsic conduction system disease/sss Complete heart block-vr will be regular Conduction system disease due to conditions such as sarcoidosis, amyloidosis, Lyme, etc.

7 VERY IMPORTANT!!! Must identify and report the underlying atrial mechanism/rhythm Failure to do so may result patient not receiving anticoagulation and will be at higher risk for stroke/thromboembolism Reporting only Ventricular Pacing is not sufficient

8 EPIDEMIOLOGY Most common cardiac arrhythmia Prevalence: 1.2 million; expected to increase to 2.6 million by 2030 Significantly increases with age By age 85, approximately 12.5% of people will have been diagnosed with atrial fibrillation

9 MAJOR RISK FACTORS FOR DEVELOPING A FIB Hypertension Most prevalent RF-accounts for over 16% of cases Markedly increases risk further if LVH present on EKG Age DM CHF Both HFREF and HFPEF Male gender Valvular disease Especially MR and MS Sleep apnea Obesity Tobacco use

10 All of above factors increase INFLAMMATION and activation of the Renin-Angiotension-Aldosterone system-all cause increased cardiac irritability.

11 Mechanisms of Atrial Fibrillation- Multiple Wavelets vs Foal Trigger

12 Atrial rate of bpm Ventricular rate of bpm Less than atrial rate because of decrimental/concealed conduction Protective to prevent ventricular fibrillation Patients would die if VR was bpm Would result in ventricular fibrillation Usually conduction occurs fat ratio of 4-2:1 VR may be slower if AV nodal conduction system disease present

13 CLASSIFICATION OF ATRIAL FIBRILLATION

14 SYMPTOMS Palpitations; rapid heart action Dyspnea Chest pain Especially if rapid ventricular rate results in subendocardial ischemia in setting of CHF/CAD/aortic stenosis Fatigue Edema ASYMPTOMATIC!!! Many patients will NOT have palpitations and may only have vague symptoms

15 TREATMENT GOALS Modify risk factors Both to prevent development and reduce recurrences/paroxysms Control ventricular rate Restore sinus rhythm if indicated Prevent stroke/thromboembolism

16 Most of the Risk Factors are Modifiable! LEGACY TRIAL: All patients had Paroxysmal or Persistent A fib and a BMI > or = to 27 Significant reductions in ablation/antiarrhythmic drug therapy and total AF burden in patients that lost weight and/or improved MET level

17 VENTRICULAR RATE CONTROL Old mantra was to keep VR less than 100 bpm All med classes below can be used acutely and chronically Medication classes include: Beta Blockers-Most effective Calcium Channel Blockers-Nondihydropyradine Class Dihydropyridines Amlodipine and Nifedipine have no significant effect on AV node Digoxin Less effective particularly with exertion but may need to use if BP low/borderline low or if systolic heart failure present (Verapamil and Diltiazem are negative inotropes) Narrow therapeutic window-don t rely on therapeutic range as shown in DIG TRIAL Antiarrhythmic drugs such as Amiodarone If all else fails, can refer to EP for AV node ablation with PPM

18 RACE II TRIAL Compared strict (<80 bpm at rest) vs lenient (<110 bpm at rest) VR control in patients with PERMANENT a fib. Primary outcome was composite of death from cardiovascular causes, hospitalization for CHF, and stroke, systemic embolism, bleeding, and lifethreatening arrhythmic events. No significant difference in adverse events and symptoms between groups CONCLUSION: In patients with permanent atrial fibrillation, lenient rate control is as effective as strict rate control and is easier to achieve. If patient is doing well clinically, do not be obsessed with strict VR control. Exceptions include symptomatic patients and if HFREF is presentcontrolling VR may prevent further deterioration of LV systolic function.

19 RHYTHM CONTROL OPTIONS Electrical cardioversion Need to document therapeutic INR/anticoagulation for 3-4 weeks before procedure and then at least 3-4 weeks afterward If INR has been subtherapeutic or if patient not on AC for 3-4 weeks, will need TEE to document absence of left atrial appendage thrombus My practice: Would not electively cardiovert while only on antiplatelet therapy Antiarrhythmic drugs Most commonly used are: Amiodarone: Most effective but multiple organ system-related side effects Dronedarone (Multaq): Cannot use if recent CHF exacerbation or permanent a fib Sotalol: Not indicated for conversion but used to maintain sinus rhythm Dofetilide (Tikosyn): Usually only prescribed by EP Very important that electrolytes atnd QT interval be closely monitored, especially with Sotalol and Dofetilide-risk of Torsades de Pointes

20 Case Study 77 yo white female with pulmonary fibrosis/copd, diastolic CHF, and paroxysmal atrial fibrillation Placed on Tikosyn for symptomatic a fib Doing well for 6 months but developed URI and placed on antibiotics; decreased PO intake and then diarrhea 2 syncopal episodes Called office and told to go to ER (lives 120 miles away) Labs: K-3.0. and Mag-1.3

21 In ER QT-740 msec!!!

22 Then... Near Syncope but spontaneously converted to sinus rhythm

23 Antiarrhythmic Drugs: Take Home Points They have a place in the treatment armamentarium But, need to be extremely diligent with regards to electrolytes, bradycardia (may prolong QT), drug interactions Ask yourself... Does my patient really need to be on this medication? Refer or defer question to cardiology is unsure.

24 AFFIRM TRIAL RATE VS RHYTHM CONTROL No survival benefit by maintaining sinus rhythm More hospitalizations with antiarrhythmic drug therapy Postulated to be secondary to medication-related side effects TAKE HOME POINTS: Reserve rhythm control for symptomatic patients or those with compelling indications to maintain sinus rhythm. Often times side effects from antiarrhythmic drugs are worsen that symptoms from a fib

25 ANATOMY OF PULMONARY VEINS VERY COMPLEX!!! -Atrial myocardium encircles the ostia of pulmonary veins -Foci for initiation of atrial fibrillation -Provides targets for pulmonary vein isolation/ablation

26 PULMONARY VEIN ISOLATION-RADIOFREQUENCY ABLATION TREATMENT OPTION FOR ATRIAL FIB Completely encircle pulmonary veins with intracardiac catheter Isolation of pulmonary veins Best utilized in patients who are refractory to medical therapy Should not be considered a cure Do not refer for the sole purpose of not using anticoagulation Not indicated when patient says Do the procedure so I don t have to take Coumadin. Patient should remain on anticoagulation after procedure Rely on cardiologist to decide about continuing anticoagulation

27 RADIOFREQUENCY VS ANTIARRHYTHMIC DRUG THERAPY Efficacy of therapies: RFA-70% Antiarrhythmics-19% However, guidelines still recommend failure of one antiarrhythmic drug prior to referral for ablation

28 PULMONARY VEIN ISOLATION- CRYOABLATION Uses deep freeze catheter to ablate within ostium of pulmonary veins Similar efficacy to radiofrequency ablation

29 STOP AF TRIAL CRYOABLATION VS AAD THERAPY Patients needed to have failed one AAD drug prior to randomization Cryoablation superior to antiarrhythmic drug therapy for preventing atrial fibrillation occurrence

30 COMPLICATIONS OF ABLATION Pulmonary vein stenosis 1% Present with dyspnea, hemoptysis, and chest pain 1-6 months after procedure Left atrial-esophageal fistula 0.1%-improved with better temperature-monitoring probes Alerts EP to heating up of esophagus during RFA procedure Odynophagia, fever/systemically ill, stroke Occurs within 1 month of procedure Very high mortality Phrenic nerve injury More common with cryoablation Pericardial tamponade

31 THE MOST FEARED COMPLICATION OF ATRIAL FIBRILLATION!!!!!

32 PREVENTION OF STOKE/THROMBOEMBOLISM Main goal/target in treatment of atrial fibrillation Need to evaluate stroke vs bleeding risk on individual basis CHADS2-VASC risk stratification score has become gold standard in assessing stroke risk Remember: Antiplatelet and anticoagulants are not the same Antiplatelet agents such as Aspirin and Clopidogrel reduce platelet aggregation and are not blood thinners Anticoagulants inhibit action/synthesis of clotting factors and are classified as blood thinners Stroke/thromboembolism in atrial fibrillation is due to thrombus formation not platelet aggregates Different from ACS

33 ANTIPLATELET THERAPY FOR STROKE AND SYSTEMIC EMBOLISM REDUCTION Antiplatelet agents do not thin the blood Ultimately reduce platelet aggregation INR and PTT should be normal when on these agents unless another process/medication is present

34 ASPIRIN VS PLACEBO FOR STROKE PREVENTION Only SPAF-1 showed benefit; all other trials neutral Aspirin alone of marginal benefit for reducing stroke based on Meta Analysis-results driven by SPAF-1 Not effective for those >75 and much less effective for secondary prevention; does not protect from severe stroke

35 Clopidogrel and Aspirin vs Aspirin Alone Active A Trial

36 ACTIVE A Results Significant reduction in primary composite endpoint (stroke, myocardial infarction, non central nervous system systemic embolism, or death from vascular causes) with Clopidogrel and Aspirin vs Aspirin alone Significant reduction in stroke with Clopidogrel and Aspirin vs Aspirin alone Higher bleeding risk with combination therapy CONCLUSION: Benefit of combination therapy offset by significantly higher bleeding risk; therefore, not recommended in AHA/ACC guidelines

37 ANTICOAGULATION FOR STROKE AND SYSTEMIC EMBOLISM REDUCTION Tested against placebo, ASA and other antithrombotic agents

38 WARARIN/VITAMIN K ANTAGONISTS Inhibit production of clotting factors II, VII, IX, and X Levels of protein C and S also decline Ultimately reduce thrombin levels Use PT or INR (more common) to monitor therapeutic levels Usually target INR of

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40 WARFARIN VS PLACEBO FOR STROKE PREVENTION Warfarin superior to Placebo for stroke reduction Warfarin associated with significantly higher bleeding risk

41 WARFARIN VS ASPIRIN FOR STROKE PREVENTION -Warfarin superior to Aspirin for stroke reduction -However, Warfarin associated with significantly higher risk of bleeding

42 WARFARIN VS COMBINATION OF CLOPIDOGREL AND ASPIRIN FOR STROKE PREVENTION-ACTIVE W TRIAL Warfarin superior to combination of Clopidorel and Aspirin for reducing primary composite endpoint of stroke, systemic embolism, MI and vascular death Warfarin superior to combination of Clopidogrel and Aspirin for stroke reduction

43 ACTIVE W: MAJOR BLEEDING No significant difference in major bleeding between Warfarin and combination of Aspirin and Clopidogrel

44 Odds Ratio Therapeutic Range for Warfarin INR Values at Stroke or ICH Stroke Intracranial Hemorrhage INR Need to be in Sweet Spot to reduce stroke while not significantly increasing bleeding Fuster et al. J Am Coll Cardiol. 2001;38:

45 Warfarin excellent when INR therapeutic but not so good when INR sub- or supratherapeutic

46 So, here come the New Kids on the Block... The NOACs.

47 DABIGATRAN (PRADAXA) Approved by FDA in 2010 Direct thrombin inhibitor Half-life of hours BID dosing No need to monitor INR No common significant drug interactions Patients can eat veggies

48 RELY TRIAL- DABIGATRAN VS WARFARIN DESIGN Randomized trial designed to compare two fixed doses of dabigatran (150 mg BID and 110 mg BID), each administered in a blinded manner, with open-label use of warfarin in patients who had atrial fibrillation and were at increased risk for stroke. Patients were eligible if they had atrial fibrillation documented on electrocardiography performed at screening or within 6 months beforehand and at least one of the following: previous stroke or TIA, LVEF less than 40%, New York Heart Association class II or higher heart-failure symptoms within 6 months before screening, and an age of at least 75 years or an age of 65 to 74 years plus diabetes mellitus, hypertension, or coronary artery disease. Key exclusion criteria included: presence of a severe heart-valve disorder (i.e., prosthetic valve or hemodynamically relevant valve disease), stroke within 14 days or severe stroke within 6 months before screening, a condition that increased the risk of hemorrhage, a creatinine clearance less than 30 ml per minute, and active liver disease.

49 RELY TRIAL OUTCOMES-EFFICACY Stroke or systemic embolism occurred in 182 patients receiving 110 mg of dabigatran (1.53% per year), 134 patients receiving 150 mg of dabigatran (1.11% per year), and 199 patients receiving warfarin (1.69% per year). The 150-mg dose of dabigatran was SUPERIOR to warfarin. The 110-mg dose was noninferior to warfarin. CONCLUSION: 150 mg dose better than Warfarin in reducing stroke or systemic embolism.

50 RELY TRIAL OUTCOMES-SAFETY The rate of major bleeding was 3.36% per year in the warfarin group, as compared with 2.71% per year in the group that received 110 mg of dabigatran and 3.11% per year in the group that received 150 mg of dabigatran. Rates of life-threatening bleeding, intracranial bleeding, and major or minor bleeding were higher with warfarin than with either the 110-mg dose and 150-mg of dabigatran. There was a significantly higher rate of major gastrointestinal bleeding with dabigatran at the 150-mg dose than with warfarin. CONCLUSION: 150 mg dose safer than Warfarin with regards to bleeding, and in particular, life-threatening and intracranial bleeding; trade-off is higher GI bleed rate with Dabigatran.

51 DABIGATRAN WHAT TO TELL PATIENTS Don t know what to say if the patient qualifies for 75 mg per day because this dose was not tested; 110 mg dose not available Dabigatran better than Warfarin at preventing stroke and systemic embolism Dabigatran safer than Warfarin with regards to bleeding with the exception of GI bleeding (this rarely kills people) Can always give blood but cannot give back the brain! Remember to check the CrCl: Use 150 mg BID if CrCl more than 30 ml/min Use 75 mg BID if CrCl between ml/min Don t use if CrCl less than 15 ml/min

52 RIVAROXABAN (XARELTO) Approved by FDA in 2011 Factor Xa inhibitor Half-life of 6-12 hours; longer in elderly But Factor Xa levels do not return to normal for 24 hours so drug can be used qday QDAY dosing No need to monitor INR No common significant drug interactions Patients can eat veggies

53 ROCKET AF- RIVAROXABAN VS WARFARIN DESIGN Randomized trial designed to compare fixed-dose rivaroxaban (20 mg daily or 15 mg daily in patients with a CrCl of 30 to 49 ml per minute) with adjusteddose warfarin (target international normalized ratio [INR], 2.0 to 3.0) in patients with atrial fibrillation and at moderate-to-high risk for stroke. Elevated risk was indicated by a history of stroke, transient ischemic attack, or systemic embolism or at least two of the following risk factors: CHF or LVEF of 35% or less, hypertension, an age of 75 years or more, or the presence of diabetes mellitus (i.e., a CHADS 2 score of 2 or more, on a scale ranging from 1 to 6, with higher scores indicating a greater risk of stroke). Key exclusion criteria included: hemodynamically significant mitral valve stenosis and prosthetic heart valve (annuloplasty with or without prosthetic ring, commissurotomy and/or valvuloplasty were permitted), a creatinine clearance less than 30 ml/min, and active liver disease.

54 ROCKET AF TRIAL OUTCOMES-EFFICACY Stroke or systemic embolism occurred in 188 patients in the rivaroxaban group (1.7% per year) and in 241 patients in the warfarin group (2.2% per year). Rivaroxaban is NONINFERIOR but not SUPERIOR to Warfarin CONCLUSION: Rivaroxaban is equivalent to Warfarin in reducing stroke and systemic embolism.

55 ROCKET AF OUTCOMES-SAFETY Major and clinically relevant nonmajor bleeding occurred in 1475 patients in the rivaroxaban group and in 1449 patients in the warfarin group (14.9% and 14.5% per year, respectively). Events occurred at similar incidence. Rates of intracranial hemorrhage were significantly lower in the rivaroxaban group than in the warfarin group. Major bleeding from a gastrointestinal site was more common in the rivaroxaban group, with 224 bleeding events (3.2%), as compared with 154 events in the warfarin group (2.2%). CONCLUSION: Rivaroxaban is similar to Warfarin with regards to total major and nonmajor bleeding events. However, Rivaroxaban resulted in less intracranial bleeding but with a higher GI bleeding incidence.

56 RIVAROXABAN OH NO!

57 Legal Ramifications! Document that you discussed bleeding risks with patient I tell my patients that the drug s most common side effect is bleeding-duh! But, the bleeding incidence is not higher compared to the GOLD STANDARD, which is Warfarin Case Study: My partner s patient with atrial fib stopped Xarelto after seeing TV ads and had a major stroke with hemiparesis Did not call to discuss issue/concerns Who should be responsible??? You should not be held accountable if you document as above, adjust dose based on CrCl, and not use drug in off-label indication.

58 XARELTO WHAT TO TELL PATIENTS Xarelto equivalent to Warfarin at preventing stroke and systemic embolism Xarelto equivalent to Warfarin with regards to bleeding events; less ICH but higher GI bleeding incidence Remember to check the CrCl: Use 20 mg qday if CrCl more than 50 ml/min Use 15 mg qday if CrCl between ml/min Don t use if CrCl less than 15 ml/min

59 APIXABAN (ELIQUIS) Approved by FDA in 2012 Factor Xa inhibitor Half-life 9-14 hours BID dosing No need to monitor INR No common significant drug interactions Patients can eat veggies

60 AVERROES TRIAL- APIXOBAN VS ASPIRIN DESIGN Patients were eligible if they were 50 years of age or older and had atrial fibrillation documented in the 6 months before enrollment or by 12-lead electrocardiography on the day of screening. Patients also had to have at least one of the following risk factors for stroke: prior stroke or transient ischemic attack, an age of 75 years or older, HTN (receiving treatment), diabetes, CHF (New York Heart Association class 2 or higher at the time of enrollment), an LVEF of 35% or less, or documented PAD. In addition, patients could not be receiving vitamin K antagonist therapy, either because it had already been demonstrated to be unsuitable for them or because it was expected to be unsuitable. The reasons that vitamin K antagonist therapy was unsuitable for the patient had to be documented on the study case-report forms. Patients were deemed to be Warfarin-ineligible!?!? Patients were randomly assigned to receive apixaban (5 mg twice daily or 2.5 mg BID if 2.5 mg twice daily if two of the following criteria were met: an age of 80 years or older, body weight of 60 kg or less, or serum creatinine level of > 1.5 mg/dl).

61 AVERROES TRIAL OUTCOMES-EFFICACY Stroke or systemic embolism occurred in 51 patients assigned to apixaban and 113 (3.7% per year) assigned to aspirin. Trial terminated early. CONCLUSION: Apixaban is SUPERIOR to Aspirin in reducing stroke and systemic embolism. Tells us what we already knew!!!- Systemic anticoagulation is superior to antiplatelet therapy in reducing stroke and systemic embolism.

62 AVERROES TRIAL OUTCOMES-SAFETY There were 44 major bleeding events (1.4% per year) among patients taking apixaban and 39 (1.2% per year) among those taking aspirin. No significant difference in intracranial bleeding with Apixaban compared to Aspirin. CONCLUSION: Apixaban did not increase bleeding (incuding ICH) compared to Aspirin.

63 ARTISTOTLE TRIAL- APIXABAN VS WARFARIN DESIGN Randomized trial designed to compare fixed-dose Apixaban (5 mg BID or 2.5 mg BID in patients with two or more of the following: age >80, weight < 60 kg, and creatinine >1.5 mg/dl) with adjusted-dose warfarin (target international normalized ratio [INR], 2.0 to 3.0) in patients with atrial fibrillation and at least one additional risk factor for stroke. Eligible patients had atrial fibrillation or flutter at enrollment or two or more episodes of atrial fibrillation or flutter, as documented by electrocardiography, at least 2 weeks apart in the 12 months before enrollment. In addition, at least one of the following risk factors for stroke was required: an age of at least 75 years; previous stroke, transient ischemic attack, or systemic embolism; symptomatic heart failure within the previous 3 months or LVEF < 40%; diabetes; or HTN requiring treatment. Key exclusion criteria included: moderate or severe mitral stenosis, conditions other than atrial fibrillation that required anticoagulation (e.g., a prosthetic heart valve), and severe renal insufficiency (serum creatinine level of >2.5 mg per deciliter [221 μmol per liter] or calculated creatinine clearance of <25 ml per minute).

64 ARISTOTLE TRIAL OUTCOMES-EFFICACY Stroke or systemic embolism occurred in 212 patients in the apixaban group (1.27% per year) as compared with 265 patients in the warfarin group (1.60% per year). Apixaban superior to Warfarin in reducing stroke/systemic embolism. The rate of death from any cause was also significantly lower in the apixaban group than in the warfarin group Largely attributable to reduction in ICH CONCLUSION: Apixaban superior to Warfarin in reducing stroke and systemic embolism as well as death.

65 ARISTOTLE TRIAL OUTCOMES-SAFETY Major bleeding occurred in 327 patients in the apixaban group (2.13% per year), as compared with 462 patients in the warfarin group. The rate of intracranial hemorrhage was 0.33% per year in the apixaban group and 0.80% per year in the warfarin group. The rate of any bleeding was 18.1% per year in the apixaban group and 25.8% per year in the warfarin group. GI bleeding rate was similar between groups. CONCLUSION: Apixaban safer compared to Warfarin.

66 APIXABAN WHAT TO TELL PATIENTS Apixaban better than Warfarin and Aspirin at preventing stroke and systemic embolism Apixaban prevents death better than Warfarin Largely due to reduction in intracranial hemorrhage Apixaban better than Warfarin with regards to bleeding Apixaban does not increase bleeding more than Aspirin Remember to reduce the dose from 5 mg BID to 2.5 mg BID if 2 or more of the following are present: Age 80 or over Weight 60 kg or less Creatinine 1.5 mg/dl or more May be able to use in patients with end stage renal disease based on extrapolated data but ACC/AHA guidelines still favor Warfarin in this setting

67 EDOXABAN (SAVAYSA) Approved by FDA in 2015 Factor Xa inhibitor Half-life of hours QDAY dosing No need to monitor INR No common significant drug interactions Patients can eat veggies

68 ENGAGE AF-TIMI 48 TRIAL- EDOXABAN VS WARFARIN DESIGN Randomized, double-blind, trial comparing two once-daily regimens of edoxaban (60 mg and 30 mg) with warfarin in 21,105 patients with moderate-to-high-risk atrial fibrillation. Eligible patients were 21 years of age or older and had atrial fibrillation documented by means of an EKG within the 12 months preceding randomization, a score of 2 or higher on the CHADS2 risk assessment, and anticoagulation therapy planned for the duration of the trial. Key exclusion criteria were an estimated CrCl of less than 30 ml/min, moderate-tosevere mitral stenosis and other indications for anticoagulation therapy (including mechanical valves).

69 ENGAGE TRIAL OUTCOMES-EFFICACY Stroke or systemic embolic occurred in 232 patients in the warfarin group (representing a rate of 1.50% per year), as compared with 182 patients in the high-dose edoxaban group (rate of 1.18% per year) and 253 patients in the low-dose edoxaban group (rate of 1.61% per year). Both doses of Edoxaban resulted in lower incidence of cardiovascular death compared to Warfarin. CONCLUSION: Both doses of Edoxaban are equivalent to Warfarin in reducing stroke and systemic embolism. Both doses reduce cardiovascular death more than Warfarin.

70 ENGAGE TRIAL OUTCOMES-SAFETY The annualized rate of major bleeding events was 3.43% with warfarin, as compared with 2.75% with high-dose edoxaban and 1.61% with low-dose edoxaban Both doses of Edoxaban were associated with lower intracranial hemorrhage compared to Warfarin High-dose Edoxaban increased GI bleeding compared to Warfarin and low-dose Edoxaban resulted in lower GI bleeding compared to Warfarin CONCLUSION: Both doses of Edoxaban are safer than Warfarin with regards to major bleeding and intracranial hemorrhage. High-dose Edoxaban had a higher GI bleeding rate while low-dose had a lower GI bleeding rate compared to Warfarin.

71 EDOXABAN WHAT TO TELL PATIENTS Both doses of Edoxaban are similar to Warfarin at reducing stroke and systemic embolism. Both doses of Edoxaban are better than Warfarin at reducing cardiovascular death. Both doses of Edoxaban are safer than Warfarin with regards to major bleeding and intracranial hemorrhage. Low-dose Edoxaban is safer than Warfarin with regards to GI bleeding Warfarin is safer than high-dose Edoxaban with regards to GI bleeding Remember to adjust dose: 60 mg daily for CrCl ml/min 30 mg daily for CrCl ml/min Not recommended if CrCl<15 or >95 ml/min Usually CrCl results as >60 ml/min on BMP results. May complicate use of drug because high-dose was less effective in patients with high CrCl (postulated to be secondary to higher drug clearance and subsequent lower concentration).

72 SUMMARY-NOACS vs WARFARIN Dabigatran 110 Dagibatran 150 Rivaroxaban 15 Rivaroxaban 20 Apixaban 2.5 Apixaban 5 Edoxaban 30 Edoxaban 60 CHADS Stroke and systemic embolism EQUAL BETTER EQUAL EQUAL BETTER BETTER EQUAL EQUAL Major bleeding BETTER EQUAL EQUAL EQUAL BETTER BETTER BETTER EQUAL Intracranial hemorrhage BETTER BETTER BETTER BETTER BETTER BETTER BETTER BETTER GI Bleeding EQUAL WORSE WORSE WORSE EQUAL EQUAL BETTER WORSE

73 BALANCING ACT BETWEEN STROKE RISK AND BLEEDING RISK

74 CHADS2-VASC SCORE: STRATIFICATION OF STROKE RISK Need to calculate for every patient because the score should determine your therapy for stroke/systemic embolism reduction.

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76 CHA2DS2-VASc SCORE 0 - No anti-thrombotic therapy 1 - No therapy, ASA, or oral anticoagulation 2 or more - oral anticoagulation The median practice rate for oral anticoagulant prescription for CHA 2 DS 2 - VAS C score 2 patient cohort is only 63.3%. So, up to 2/5 HIGH-RISK patients that SHOULD be receiving anticoagulation are receiving either antiplatelet agents or nothing Sometimes patients refuse anticoagulation or have an absolute contraindication but these situations are uncommon Usually it is the PROVIDER S decision to not anticoagulate rather than the patient s Recommend that you refer for a second opinion if you are uncomfortable with anticoagulating a particular patient Can always give blood but can t give back the brain!!

77 BLEEDING RISK Both CHADS2-VASC and HAS-BLED scores predict risk of bleeding Higher scores=higher bleeding risk Need to consider patient benefit vs risk when prescribing anticoagulation Inform patient of their individual risk Once again, recommend erring on side of protecting the brain!!

78 LEFT ATRIAL OCCLUSION DEVICE WATCHMAN device Positioned to occlude the left atrial appendage so that thrombus cannot exit the appendage and enter the left atrium Left atrial appendage will thrombose Effective method to reduce stroke risk in patients that are NOT candidates for anticoagulation Cannot refer patients just because they don t want to take Coumadin Several devices and surgical procedures have been and are currently being tested

79 COMMON QUESTIONS REGARDING NOACs What if my patient bleeds? What is nonvalvular atrial fibrillation? What do I do if my patient is having surgery?

80 NOACS AND REVERSAL AGENTS Only Dabigatran has a reversal agent Praxbind (idarucizumab) approved October 2015 Achieves complete reversal by 4 hours for 90% of patients The average wholesale price for a 5 g dose of Praxbind is $3500 Better make sure patient really needs it or you will be answering to the CEO/CFO Reversal agent (andexanet alfa) for Factor Xa inhibitors is in development Remember, it will also take several hours to reverse Warfarin If a patient has an ICH, the outcome will likely be catastrophic regardless of whether a reversal agent is available People rarely die from a GI bleed or severe epistaxis Just hold the NOAC because the ½ lives are short and provide supportive care Does not affect my decision regarding use of NOAC-remember bleeding safety of agents compared to Warfarin

81 NOACS and NONVALVULAR ATRIAL FIBRILLATION Based on AHA/ACC guidelines, currently refers to atrial fibrillation that occurs in the absence of: Mitral stenosis Mechanical valve replacement Bioprosthetic valve replacement Valve repair Therefore, should NOT use NOACs in these settings Warfarin recommended

82 RE-ALIGN TRIAL DABIGATRAN VS WARFARIN IN SETTING OF MECHANICAL VALVE 252 patients with mechanical AVR and/or MVR Warfarin vs Dabigatran mg BID Trial terminated early due to significantly higher incidence of thromboembolism and bleeding with Dabigatran AVOID NOACS IN PATIENTS WITH MECHANICAL HEART VALVES!!!

83 NOACS and SURGERY Unlike Warfarin, do not need to hold NOACs for 5-7 before procedure Much shorter ½ life than Warfarin Hold NOACS 1-2 days before most surgical procedures Exception: Hold for up to 5 days if epidural injection is planned Do not need to bridge with Lovenox/IV Heparin in most circumstances If any questions, please have conversation with surgeon Sometimes challenging because the surgeon does not want a bleeding complication and you don t want the patient to have a stroke

84 THANK YOU!