6 th ACC-SHA Joint Meeting Jeddah, Saudi Arabia

Transcription

1 6 th ACC-SHA Joint Meeting Jeddah, Saudi Arabia October 31 st - November 1 st, 2015 NOACS vs. Coumadin in Atrial Fibrillation: Is It Worth to Switch? Raed Sweidan, MD, FACC Consultant and Head of Cardiac Electrophysiology King Fahd Armed Forces Hospital Jeddah, Saudi Arabia

2 AF: Prevalence and Incidence Prevalence: 0.95% in the general population Male patients > Female patients (1.1% vs. 0.8%) Age dependent: 0.1% less than 55 years old, 9% over 80 years old Lone AF: Less than 12% of all AF cases Incidence: 0.1% per year in people < 40 years old 2.0% per year in men > 80 years old 10% is the 3-y incidence in HF patients

3 AF: Prognosis and Consequences Mortality : Patients with AF have double that mortality of patients in NSR Ischemic stroke: 2% - 10% per year (NRAF) 1.5% (age years old) 23.5% (age years old) In rheumatic AF risk is 5 times greater than NRAF Strokes due to AF are associated with an increased risk of death 30-day mortality rate of 25% 1-year mortality rate of ~50% Risk of death from AF stroke increases approximately 2-fold versus non-af stroke AF-related stroke is associated with increased severity and disability Hospitalizations for AF have recently increased 2- to 3-fold in the US

4 Anticoagulation for Atrial Fibrillation The NOAC are recommended for non-valvular heart disease to reduce the risk of thromboembolism. They are not recommended in valvular atrial fibrillation What is valvular atrial fibrillation? In the AHA/ACC/HRS guidelines: Mitral stenosis Mechanical or bio-prosthetic valves Mitral valve repair In the ESC guidelines: Mitral stenosis Mechanical or bio-prosthetic valves

5 Risk Stratification in Nonvalvular AF CHADS₂ vs. CHA₂DS₂VASc Definition and score for CHADS2 CHADS2 Stroke risk stratification with CHADS2 Score Adjusted stroke rate (% per year) CHF HTN Age 75 years DM CVA/TIA/TE Maximum score Definition and score for CHA2DS2-VASc CHA2DS2-VASc Stroke risk stratification with CHA2DS2-VASc Score Adjusted stroke rate (% per year) CHF HTN Age DM CVA/TIA/TE Vascular disease Age years Female sex Maximum score

6 Challenges with Warfarin therapy Warfarin reduces the risk of thromboembolism by 65% but: Narrow therapeutic range Lag in effect Requirement for frequent blood monitoring Interaction with many drugs and foods Compliance and difficulty in staying at target levels (TTR) Studies have shown that half of eligible patient were on warfarin, and only half of those were in therapeutic range. Fang MC, et al. Ann Intern Med 2004; 141:745

7 NOACs: Direct Thrombin and Factor Xa Inhibitors Simplified dosing regimen No monitoring or blood tests Limited food and drug interactions The RCT showed them to be: Non inferior to warfarin in efficacy Safer than warfarin: Less fatal bleeding and ICH

8 Patient Characteristics in the NOAC trials ARISTOTEL RE-LY ROCKET-AF ENGAGE-AF Age (Median) Men (%) Paroxysmal AF (%) Prior TIA/CVA/SE (%) Heart failure (%) Diabetes (%) Mean CHADS2 (%) or 1 (%) (%) (%) VKA-naïve (%) Mean TTR (%)

9 NOACs vs. Warfarin Ischemic strokes in NOACs vs. Warfarin trials Bleeding in NOACs vs. Warfarin trials Giugliano RP, et. al. NEJM. 2013; 369:

10 Warfarin vs. NOACs Meta Analysis of The Four Major NOACs Trials ICH vs. GI bleeding

11 GI Bleeding: NOACs vs. Warfarin NOACs (%) Warfarin (%) HR (95% CI) P Dabigatran 150mg (RE-LY) Dabigatran 110mg (RE-LY) Rivaroxaban (ROCKET AF) Apixaban ARISTOTLE) Endoxaban 60mg ENGAGE AF-TIMI48) Endoxaban 30mg ENGAGE AF-TIMI48) (1.19-1,89) < ( ) NA NA ( ) ( ( ) < 0.001

12 How good are the NOACs? The RCT showed the NOACs to be at least as effective as warfarin in reducing strokes/te, and definitely safer. (Less ICH and fatal bleeding) How about real live experience? Post market release registries Does one size fits all? Can we afford not to monitor? How can we assess compliance? Discontinuation rate is not low. What about old people and CKD patients? Drug interactions: They do exist. Reversal agents: Antidotes Cost

13 US Medicare Data: Warfarin vs Dabigatran Real life data mirrored RCT results

14 GARFIELD-AF Registry Prospective, 35 countries Newly diagnosed nonvalvular AF At least one risk factor for stroke 5 Sequential cohorts Data from the first two cohorts: Kakkar AK, et. PloS One. 2013;8:e63479

15 Prospective Over patients 35 countries Newly diagnosed AF At least one risk factor for strike 5 Sequential cohorts Anticoagulant use is increasing but not optimal The Use of NOAC is increasing while warfarin use in decreasing GARFIELD-AF Registry Mean TTR for patients receiving warfarin is only 55.8% Lord Ajay K. Kakkar, MD, PhD

16 Only two thirds are kept in adequate INR control PREFER-AF Registry ( ) Prospective, Western and central Europe Increasing rate of anticoagulation up to 80-85% Still low use for NOACs

17 Dosing of the NOACs One size does not fit all All NOACs have two dose regimen Main adjustment is done based on kidney function Do we need monitoring levels? After a stroke or after a bleed: Was the patient taking the drug, did it fail to prevent the stroke, was the level to high.. Pitfalls of interpretation: Not taking into account kidney and liver functions and timing of last dose taken. Remember: Fixed dosing was used in the trials and there was no level monitoring. The efficacy was safety were proven, and the real life experience with registries mirrored that.

18 NOACs: Target, Half life, Metabolism and Excretion Dabigatran Rivaroxaban Apixaban Edoxaban Target IIa Xa Xa Xa Half-life (h) Transporters P-glycoprotein P-gp/BCRP P-glycoprotein P-glycoprotein Renal elimination (%) 80% 35% 27% 50% Cytochrome P450 metabolism (%) None 66% 15% <4%

19 NOAC Dosing Adjustments for Nonvalvular AF Patients with Renal Disease* Dabigatran Rivaroxaban Apixaban Edoxaban CrCL is ml/min: Reduce dose to 75mg twice daily CrCL is < 15 ml/min: Do not use it CrCl is 15-30ml/min: Reduce dose to 15 mg daily Reduce dose to 2.5 mg twice daily if patient has 2 or more of: Age 80 years Weight 60 kg Creatinine 1,5 mg/dl CrCL is 15-50mg/dl: Reduce to 30 mg daily CrCL is: >50 to 95mg/dl: Use 60mg daily >95ml/min: Do not use due to increased risk for stroke compared to warfarin * US FDA recommendations

20 Discontinuation of NOACs pre-procedure Low bleeding risk procedures: 24 hours before procedure (2-3 half-lives). Resume 24 hours after procedure High bleeding risk procedures: 48 hours before procedure (4-5 half-lives). Resume hours after procedure. For Dabigatran: If CrCl 50 ml/min: 1-2 days before procedure If CrCl < 50 ml/min: 3-5 days prior to procedure In case of life threatening bleeding in a patient on NOAC: Supportive measures Activated prothrombin complex concentrates (apcc), activated recumbent factor VII (rfviia). In case of dabigatran: Dialysis can be considered There is a risk for rebound thrombosis

21 NOACs Antidotes in Clinical Trials Idarucizumab (Praxbind) Antidote for direct thrombin inhibitors Fully humanized antibody fragment Praxbind Received US FDA approval earlier this month Andexanet Antidote for factor Xa inhibitors Recombinant protein, targets and sequesters direct and indirect factor Xa with high specificity Aripazine Antidote for factor Xa inhibitors, direct thrombin inhibitors, LWMH, and fondaparinus Synthetic small molecule. Reversal through direct binding to the anticoagulant

22 NOACs: Drug interactions Heidbuchel H, et al. Europace, August 31, 2015

23 Recommendations for Risk-Based Antithrombotic Therapy AHA/ACC/HRS Practice Guidelines 2014 Antithrombotic therapy based on shared decision making, discussion of risks of stroke and bleeding, and patients preferences. I C Selection of antithrombotic therapy based on risk of thromboembolism I B CHA2DS2-VASc score recommended to assess stroke risk I B Warfarin recommended for prosthetic heart valves and target INR intensity based on type and location of prosthesis With prior stroke, TIA, or CHA2DS2-VASc score 2, oral anticoagulants recommended options include: I B Warfarin I A Dabigatran,rivaroxaban, or apixaban I B

24 Recommendations for Risk-Based Antithrombotic Therapy AHA/ACC/HRS Practice Guidelines 2014 Bridging therapy with UFH or LWMH recommended with mechanical heart valves if warfarin is interrupted. (Bridging therapy should balance risks of stroke and bleeding) For patients without mechanical heart valves, bridging therapy decisions should balance stroke and bleeding risks against duration of time patient will not be anticoagulated Evaluate renal function before initiation of direct thrombin or factor Xa inhibitors, and reevaluate when clinically indicated and at least annually I I I C C B For atrial flutter, antithrombotic therapy is recommended as for AF I C With nonvalvularaf and CHA2DS2-VASc score of 0, it is reasonable to omit antithrombotic therapy IIa B With CHA2DS2-VASc score 2 and end stage CKD (CrCL < 15mL/min) or on hemodialysis, it is reasonable to prescribe warfarin for oral anticoagulation With nonvalvularaf and CHA2DS2-VASc score of 1, no antithrombotic therapy or treatment with oral anticoagulant or aspirin may be considered IIa IIb B C

25 Recommendations for Risk-Based Antithrombotic Therapy AHA/ACC/HRS Practice Guidelines 2014 With moderate to severe CKD and CHA2DS2-VASc score 2, reduced dose of direct thrombin or factor Xa inhibitors may be considered IIb C After coronary revascularization in patients with CHA2DS2-VASc score 2, it is reasonable to use clopidogrel concurrently with oral anticoagulants but omit aspirin IIb B Direct thrombin dabigatran and factor Xa inhibitor rivaroxaban are not recommended in patients with AF and end stage CKD or on dialysis because of lake of evidence III No benefit C Direct thrombin inhibitor dabigatran should not be used with a mechanical heart valve III Harm B

26 Stroke Prevention in Nonvalvular Atrial Fibrillation ESC Guidelines 2012 Camm AJ, et al. Eur Heart J. 2012; 33:

27 CONCLUSIONS (1) Ongoing registries have supported the RCT results showing that the NOACs are as effective as warfarin and are safer in patient with Nonvalvular AF and increased risk for thromboembolism. (Main effect in reducing hemorrhagic strokes and ICH) The adherence to stroke prevention guidelines in nonvalvular AF, although not optimal, is improving. The majority of patients receiving warfarin are candidates for the NOACs. Given the drawbacks of warfarin therapy more patients are being started or switched to the NOACs. Advanced renal disease is the most important limitation for the use of the NOACs. (Renal function monitoring, dose reduction, or avoidance depending on the severity of renal disease)

28 CONCLUSIONS (2) There is no head to head compression between the different NOACs. The choice will depend on your patient s unique characteristics and preferences, availability, and cost.) Warfarin is not dead.. The only pharmacological option with severe kidney disease (CrCl 15ml/min) Patients preference: If there is good long term control with warfarin (TTR over 70%) Cost, reimbursement, and regulatory issues.. Valvular atrial fibrillation. (NOACs are contraindicated)

29 Thank You