Direct Oral Anticoagulant Use in Valvular Atrial Fibrillation

Transcription

1 Direct Oral Anticoagulant Use in Valvular Atrial Fibrillation September 14, 2018 Nina Maguire, PharmD PGY1 Pharmacy Resident Seton Healthcare Family

2 ASCENSION TEXAS Direct Oral Anticoagulant (DOAC) Use in Atrial Fibrillation with Valvular Heart Disease Nina Maguire, PharmD PGY-1 Pharmacy Resident, DSMC-UT Disclosures No conflicts of interest to disclose September 14, Objectives 1. Understand the multiple definitions of valvular atrial fibrillation and the thromboembolic risk associated with valvular dysfunction. 2. Summarize the evidence for the use of DOACs in various valvular heart disease patient populations. 3. Apply DOAC study results to the clinical setting in anticoagulation decision making for patients with valvular atrial fibrillation. Meet the patient RR is a 67 year old male presenting to clinic with a new diagnosis of atrial fibrillation. Past medical history is significant for bioprosthetic mitral valve (placed 2013), hypertension, and gout. Patient also has a history of alcohol abuse and has a baseline INR of 1.3. Which of the following anticoagulants is the most appropriate therapy for RR? A. Warfarin B. Enoxaparin C. Apixaban D. Rivaroxaban 3 4 Background Atrial fibrillation Estimated up to 6.1 million people in the US have atrial fibrillation (AF) Number of patients with AF is expected to double over the next 25 years AF increases the risk for ischemic stroke fivefold 750,000 hospitalizations and 130,000 deaths per year 5 January CT, et al J Amer Col Card. 2016;64(21): Feinberg WM, et al Arch Intern Med. 1995;155(5): Agen Healthcare Research and Quality

3 Role of structural heart disease in AF AF commonly occurs in patients with structural heart disease - Heart failure, valvular heart disease, coronary artery disease Left atrial enlargement - Every 5 mm increase in left atrium diameter increases the risk of AF by 39% Pathophysiology and thromboembolic risk of valvular heart disease 7 Iwasaki Y et al. Circulation. 2011:124: Vaziri S, et al. Circulation. 1994:89(2): Valvular heart disease Regurgitation: - leaky that cause backflow of blood Stenosis: - narrowing of valve opening that causes restricted blood flow Mitral stenosis Incidence: - 29% of those with mitral stenosis have AF Thromboembolic risk: - Low blood flow increases risk of thrombi due to stasis - 15x more likely to have a stroke in mitral stenosis with AF 9 Laupacts A et al. Chest. 1995:108:352S-9S. 10 Diker E et al. Am J Card 1996:77(1):96-8. Mitral valve stenosis. Available at: mayoclinic.org Valve repair and replacement Factors to consider Thromboembolic (TE) Risk Mitral Valve Repair Bioprosthetic Valve Mechanical Valve Native valve remains Used to treat mitral regurgitation Small risk of TE with the highest risk occurring during the first year after surgery Last years Do not require lifelong anticoagulation Annual TE rates up to 0.7% with no anticoagulation Highest risk of TE first year after surgery Longest lasting type of valve replacement Require life long anticoagulation Annual TE rates up to 4% with no anticoagulation Mitral are 2x higher risk of TE than aortic Mechanism of mechanical valve thrombus Hemodynamics Slow blood flow Local blood flow turbulences Incomplete apposition Hemostatics Tissue injury Prosthesis malpositioning Surface factors Incomplete endothelialization Malpositioning Leaflet injury Cannegieter S et al. 1994;89: Heras, M et al. J Am Coll Cardiol 1995;24: Iung B et al. Eur Heart J 2003;24:1231;1243. Williams JB et al. Ann Thorac Surg 1980;30: Dangas G et al. J Am Coll Cardiol 2016;28:

4 Thromboembolic risk summary Risk Stratum Valvular dysfunction High Mechanical heart valve Mitral stenosis Low Bioprosthetic valve Mitral valve repair Other native valve disease (mitral regurgitation, etc) Defining valvular atrial fibrillation Diker E et al. Am J Card 1996:77(1): Cannegieter S et al. 1994;89: Williams JB et al. Ann Thorac Surg 1980;30: AF classifications and clinical tools Valvular AF guideline recommendations VKA = warfarin Non valvular atrial fibrillation (NVAF) CHA 2 DS 2 VASc score determines if anticoagulation is necessary Valvular atrial fibrillation No clinical tool to evaluate anticoagulation modalities Bleeding risk assessment HAS-BLED Guideline Definition Anticoagulation Recommendations AHA/ACC/HRS 2014 Atrial Fibrillation Guidelines ESC/EACTS 2016 Atrial Fibrillation Guidelines European Heart Rhythm Association 2018 DOAC use in AF Guidelines Rheumatic mitral stenosis, mechanical or bioprosthetic heart valve, or mitral valve repair Moderate to severe mitral stenosis or mechanical heart Mechanical prosthetic or moderate to severe mitral stenosis. Biological or valve repair are in a grey area. Mitral stenosis: VKA Mechanical valve: VKA Bioprosthetic valve: DOAC use has not been studied Mitral stenosis: VKA Mechanical valve: VKA Bioprosthetic valve: gap in evidence Moderate to severe mitral stenosis: VKA Mechanical valve: VKA Bioprosthetic valve: DOACS appropriate (except for 1 st 3 months post-op) Native valvular disease: DOACs appropriate 15 Molteni M, et al. Europace. 2014:16: Kirchhof P et al. Europace 2014:16: Kirchhof P et al. Euro Heart Journ 2016;37: January C et al. J Americ Col Cardiol 2014;64:1-72. Steffel J et al. Euro Heart Jounr 2018;39: Valvular AF guideline recommendations VKA = warfarin Why valvular atrial fibrillation is a misnomer Guideline Definition Anticoagulation Recommendations AHA/ACC/HRS 2014 AF Guidelines ESC/EACTS 2016 AF Guidelines European Heart Rhythm Association 2018 DOAC use in AF Guidelines Rheumatic mitral stenosis, mechanical or bioprosthetic heart valve, or mitral valve repair Moderate to severe mitral stenosis or mechanical heart Mechanical prosthetic or moderate to severe mitral stenosis. Biological or valve repair are in a grey area. Mitral stenosis: VKA Mechanical valve: VKA Bioprosthetic valve: DOAC use has not been studied Mitral stenosis: VKA Mechanical valve: VKA Bioprosthetic valve: gap in evidence Moderate to severe mitral stenosis: VKA Mechanical valve: VKA Bioprosthetic valve: DOACS appropriate (except for 1 st 3 months post-op) Native valvular disease: DOACs appropriate Lack of internal homogeneity in valvular atrial fibrillation - Pathogenesis of thromboembolism - Thromboembolic risk - Treatment needs 17 Kirchhof P et al. Euro Heart Journ 2016;37: January C et al. J Americ Col Cardiol 2014;64:1-72. Steffel J et al. Euro Heart Jounr 2018;39: De Caterina R, et al. Eur Heart Journ. 2014:35:

5 Thromboembolic risk summary Risk Stratum Valvular dysfunction High Mechanical heart valve Mitral stenosis Low Bioprosthetic valve DOAC trials in valvular atrial fibrillation Mitral valve repair Other native valve disease (mitral regurgitation, etc) Mechanical and rheumatic mitral valve atrial fibrillation (MARM-AF) Diker E et al. Am J Card 1996:77(1): Cannegieter S et al. 1994;89: Williams JB et al. Ann Thorac Surg 1980;30: DOAC review DOAC use in valvular atrial fibrillation FDA Indication: non-valvular atrial fibrillation Factor Xa Inhibition: rivaroxaban, edoxaban, apixaban Direct Thrombin Inhibitor: dabigatran Mitral stenosis Mechanical Bioprosthetic Mitral valve repairs/native valve dysfunction Rivaroxaban Apixaban Edoxaban Dabigatran 21 Anticoagulation therapy: new opportunities, new challenges. Available at: cardiologyreport.com 22 ROCKET-AF Study: - Multicenter, double blind, double dummy event driven trial Population - Significant valvular disease (SVD), n = 1,992 Mitral valve repair, native valve disease (other than mitral stenosis) - No significant valvular disease, n = 12,179 Primary endpoints: - Efficacy: Composite of stroke and systemic embolism - Safety: Major or non major clinically relevant bleeding or intracranial hemorrhage Efficacy outcomes as a function of the absence or presence of significant valvular disease SVD events/100 patient years (total events) No SVD events/100 patient years (total SVD vs. no SVD events) n = 1992 n = HR (95% CI) P-value Stroke or SE 2.23 (88) 2.09 (487) 1.07 ( ) 0.58 Stroke 1.92 (76) 1.96 (458) 0.98 ( ) 0.89 Systemic embolism 0.32 (13) 0.14 (34) 2.02 ( ) All cause death 5.54 (212) 4.39 (1002) 1.09 ( ) 0.29 SE = systemic embolism 23 Breithardt G et al. Eur Heart Journ 2014;35: Breithardt G et al. Eur Heart Journ 2014;35:

6 Safety outcomes as a function of the absence or presence of significant valvular disease Efficacy of rivaroxaban vs warfarin in patients with and without significant valvular disease SVD events/100 patient years (total events) No SVD HR (95% CI) P-value events/100 patient SVD vs. no SVD years (total events) n = 1999 n = Major or NMCR (493) (2431) 1.14 ( ) bleeding Major bleeding 5.11 (156) 3.27 (625) 1.32 ( ) Intracranial 0.80 (25) 0.59 (114) 1.35 ( ) 0.18 hemorrhage NMCR = non-major clinically relevant Stroke or SE All cause death SVD, n = 1992 No SVD, n =12179 Rivaroxaban Warfarin Rivaroxaban Rivaroxaban Warfarin Rivaroxaban P-value for events/100 pt events/100 pt vs. warfarin events/100 pt events/100 pt vs. warfarin HR interaction years years HR (95% CI) years (total years (95% CI) of SVD and (total events) (total events) events) (total events) treatment 2.01 (38) 2.43 (50) (231) 2.22 (256) ( ) ( ) 5.48 (100) 5.60 (112) (482) 4.60 (520) ( ) ( ) 25 Breithardt G et al. Eur Heart Journ 2014;35: Breithardt G et al. Eur Heart Journ 2014;35: Safety of rivaroxaban vs warfarin in patients with and without significant valvular disease Major or NMCR bleeding Rivaroxaban events/100 pt years (total events) SVD, n = 1999 No SVD, n =12179 Warfarin events/100 pt years (total events) Rivaroxaban vs. warfarin HR (95% CI) Rivaroxaban events/100 pt years (total events) Warfarin events/100 pt years (total events) Rivaroxaban vs. warfarin HR (95% CI) P-value for interaction of SVD and treatment (253) (240) (1222) (1209) ( ) ( ) Major bleeding 6.14 (88) 4.20 (68) 1.56 ( ) 3.22 (307) 3.33 (318) 0.98 ( ) Clinical application No significant difference in rates of stroke and systemic embolism in warfarin or rivaroxaban group in either SVD or no SVD Higher bleeding rates seen in rivaroxaban use in significant valvular heart disease than warfarin Rivaroxaban can be used in native valve disease with the exception of mitral stenosis Intracranial hemorrhage 0.88 (13) 0.73 (12) 1.27 ( ) 0.43 (42) 0.74 (72) 0.59 ( ) Breithardt G et al. Eur Heart Journ 2014;35: DOAC use in valvular atrial fibrillation ARISTOTLE Mitral stenosis Mechanical Bioprosthetic Mitral valve repairs/native valve dysfunction Rivaroxaban Apixaban Edoxaban Dabigatran Study: - Multicenter, randomized, double blind, double dummy trial Population: - Valvular heart disease (VHD), n = 4,808 Native valve diseases, bioprosthetic - No valvular heart disease, n = 13,389 Primary endpoints - Efficacy: Rates of stroke or systemic embolism - Safety: Major bleeding Avezum A et al. Circulation AHA 2015;

7 Efficacy of apixaban vs warfarin in patients with and without significant valvular disease Safety of apixaban vs warfarin in patients with and without significant valvular disease VHD, n = 4788 No VHD, n =13350 Apixaban Warfarin events/100 events/100 pt years pt years (total (total events) events) VHD, n = 4808 No VHD, n = Apixaban vs. warfarin HR (95% CI) Apixaban Warfarin events/100 events/100 pt years pt years (total (total events) events) Apixaban vs. warfarin HR (95% CI) P- value Stroke or SE 1.46 (64) 2.08 (89) 0.70 ( ) 1.20 (148) 1.43 (176) 0.84 ( ) Major bleeding Apixaban Warfarin Apixaban vs. Apixaban Warfarin Apixaban vs. P-value events/100 pt events/100 pt warfarin HR events/100 pt events/100 pt warfarin HR years years (95% CI) years years (95% CI) (total events) (total events) (total events) (total events) 2.49 (99) 3.14 (119) 0.79 ( ) 2.01 (228) 3.07 (343) 0.65 ( ) Stroke 1.37 (60) 2.03 (87) 0.67 ( ) 1.12 (139) 1.33 (163) 0.85 ( ) Death from 4.95 (222) 4.88 (215) 1.01 ( ) 3.02 (381) 3.61 (454) 0.84 ( ) any cause Intracranial bleeding Major or CRNM bleeding 0.25 (10) 0.88 (34) 0.28 ( ) 0.37 (42) 0.78 (88) 0.47 ( ) (191) 6.36 (235) 0.77 ( ) 3.78 (422) 5.89 (642) 0.64 ( ) Breithardt G et al. Eur Heart Journ 2014;35: Breithardt G et al. Eur Heart Journ 2014;35: Aortic vs mitral valve heart disease Bioprosthetic valve subgroup analysis Apixaban rate %/year Warfarin rate %/year Hazard Ratio Apixaban number Warfarin number P -value (no. of events) (no. of events) (95% CI) (rates per 100 (rates per 100 patient Mitral VHD n = 1801 n = 1777 patient years) years) Stroke or SE 1.32 (43) 1.89 (61) 0.70 ( ) Major bleeding 2.12 (63) 2.94 (84) 0.72 ( ) Aortic VHD n = 604 n = 546 Stroke or SE 1.57 (17) 2.88 (27) 0.55 ( ) Major bleeding 2.98 (29) 4.21 (34) 0.72 ( ) n = 41 n = 41 Stroke or SE 2 (2.9) 0 (0) - Major bleeding 4 (7.9) 3 (5.2) 0.61 All cause death 5 (6.9) 5 (7.1) 0.88 Cardiovascular 1 (1.4) 2 (2.8) 0.51 death 33 Breithardt G et al. Eur Heart Journ 2014;35: Pokorney SD et al. Circulation 2015;132;abstract Clinical application Similar benefits of apixaban over warfarin were seen in patients with and without valvular heart disease DOAC use in valvular atrial fibrillation Rivaroxaban Apixaban Edoxaban Dabigatran Mitral stenosis Apixaban is appropriate to use in native valvular disease (excluding mitral stenosis) and bioprosthetic Mechanical Bioprosthetic Mitral valve repairs/native valve dysfunction

8 ENGAGE-AF Study: - Randomized, double blind, double dummy trial Population: - Bioprosthetic, n = Native, n = 20,914 Primary endpoints: - Efficacy: Stroke or systemic embolic events - Safety: Major bleeding Regimens: - LDER = low dose edoxaban regimen, 30 mg daily - HDER = high dose edoxaban regimen, 60 mg daily Clinical outcomes in patients with bioprosthetic by randomized treatment group 37 Carnicelli, A et al. Circulation 2017;135: Carnicelli, A et al. Circulation 2017;135: Clinical application DOAC use in valvular atrial fibrillation Edoxaban is appropriate to use in patients with atrial fibrillation and bioprosthetic Rivaroxaban Apixaban Edoxaban Dabigatran Mitral stenosis Mechanical Bioprosthetic Mitral valve repairs/native valve dysfunction 39 Carnicelli, A et al. Circulation 2017;135: RE-ALIGN Study: - Prospective, randomized, phase 2 open label trial with blinded end point adjudication Population: - n = Population A: patients who had undergone mechanical aortic or mitral valve replacement within the past 7 days - Population B: patients who had undergone mechanical aortic or mitral valve replacement at least 3 months earlier Outcomes: - Primary endpoint was the trough plasma concentration of dabigatran - Additional efficacy and safety outcomes included stroke, systemic embolism, transient ischemic attack, valve thrombosis, bleeding, venous thromboembolism, myocardial infarction, and death Efficacy of dabigatran vs warfarin in mechanical heart Population A Dabigatran (n=133), % Warfarin (n=66), % Dabigatran (n=35), % Population B Warfarin (n=18), % Hazard Ratio (95% CI) P-value Death ( ) 0.2 Stroke NA NA Death, stroke, TIA, SE, or myocardial infarction TIA = transient ischemic attack ( ) Eikelboom, A et al. New Eng J Med 2013;369: Eikelboom, A et al. New Eng J Med 2013;369:

9 Safety of dabigatran vs warfarin in mechanical heart Any bleeding Major bleeding Major bleeding with pericardial location Dabigatran (n=133), % Population A Warfarin (n=66), % Dabigatran (n=35), % Population B Warfarin (n=18), % Hazard Ratio (95% CI) P-value ( ) ( ) ( ) 0.48 Clinical application Increased rates of thromboembolic and bleeding complications when compared to warfarin Target dabigatran levels are unknown in this patient population Dabigatran should not be used in patients with mechanical heart 43 Eikelboom, A et al. New Eng J Med 2013;369: Eikelboom, A et al. New Eng J Med 2013;369: DOAC use in valvular atrial fibrillation Rivaroxaban Apixaban Edoxaban Dabigatran Mitral stenosis Clinical Question Why were there such poor outcomes with dabigatran use in mechanical heart? Mechanical Bioprosthetic Mitral valve repairs/native valve dysfunction Meet the patient RR is a 67 year old male presenting to clinic with a new diagnosis of atrial fibrillation. Past medical history is significant for bioprosthetic mitral valve (placed 2013), hypertension, and gout. Patient also has a history of alcohol abuse and has a baseline INR of 1.3. Which of the following anticoagulants is the most appropriate therapy for RR? A. Warfarin B. Enoxaparin C. Apixaban D. Rivaroxaban Eikelboom, A et al. New Eng J Med 2013;369: Action of anticoagulants in the coagulation cascade. Available at radcliffecardiology.com 48 8

10 Meet the patient RR is a 67 year old male presenting to clinic with a new diagnosis of atrial fibrillation. Past medical history is significant for bioprosthetic mitral valve (placed 2013), hypertension, and gout. Patient also has a history of alcohol abuse and has a baseline INR of 1.3. Which of the following anticoagulants is the most appropriate therapy for RR? A. Warfarin B. Enoxaparin C. Apixaban D. Rivaroxaban 49 What s in the pipeline? Rivaroxaban for VHD and AF trial - Non-inferiority study of rivaroxaban vs warfarin in bioprosthetic mitral for major clinical event outcomes Rivaroxaban vs warfarin in patients with metallic prosthesis - Treatment study of rivaroxaban vs warfarin in mechanical heart Anti-thrombotic strategy after trans-aortic valve implantation - Superiority study of apixaban vs standard of care (warfarin or dual antiplatelet therapy) post TAVI in preventing cardiovascular events Investigation of rheumatic AF using VKA - Superiority study of rivaroxaban vs aspirin in rheumatic heart disease patients unable to take warfarin 50 TAVI = trans aortic valve implantation DOAC use in valvular atrial fibrillation Conclusions Mitral stenosis Mechanical Bioprosthetic Mitral valve repairs/native valve dysfunction Rivaroxaban Apixaban Edoxaban Dabigatran The term valvular atrial fibrillation should be removed from medical jargon - MARM-AF is an appropriate alternative definition DOACs are appropriate to use in native valve disease (excluding mitral stenosis) and in bioprosthetic DOAC use is inappropriate in mechanical heart Acknowledgements Evaluator - Bethany Kalich, PharmD, BCPS-AQ Cardiology Questions? Preceptors - Evan Peterson, PharmD, BCPS - Molly Curran, PharmD, BCPS, BCCCP

11 ASCENSION TEXAS DOAC Use in Atrial Fibrillation with Valvular Heart Disease Nina Maguire, PharmD September 14,

12 Appendices Appendix A: CHA2DS2VASc Score Appendix B: CHA2DS2VASc Risk of Stroke Appendix C: HAS-BLED Score Appendix D: HAS-BLED Risk of Bleed Appendix E: Abbreviations

13 Appendix A: CHA2DS2VASc Score CHA2DS2VASc Risk Score Congestive heart failure/left ventricular dysfunction Hypertension 1 Aged 75 years 2 Diabetes mellitus 1 Stroke/Transient Ischemic Attack/Thromboembolism Vascular disease (prior myocardial infarction, peripheral artery disease, or aortic plaque) Aged years 1 Sex category (female) 1 Lane, D et al. Circulation 2012;126:

14 Appendix B: CHA2DS2VASc Stroke Risk Score CHA2DS2VASc Adjusted Stroke Rate (%/year) Lane, D et al. Circulation 2012;126:

15 Appendix C: HAS-BLED Score HAS-BLED risk Score Hypertension (systolic blood pressure >160 mmhg) Abnormal renal/liver function 1 1 point each Stroke 1 Bleeding tendency or pre-disposition Age > 65 years 1 1 Drugs (concomitant aspirin or NSAIDs) or alcohol 1 point each Lane, D et al. Circulation 2012;126:

16 Appendix D: HAS-BLED Bleeding Risk Score HAS-BLED Risk of Major Bleeding/Year (%) >5 Undetermined Lane, D et al. Circulation 2012;126:

17 Appendix E: Abbreviations DOAC: direct oral anticoagulant AF: atrial fibrillation TE: thromboembolic NVAF: non-valvular atrial fibrillation VKA: warfarin MARM-AF: mechanical and rheumatic mitral valve atrial fibrillation SVD: significant valvular disease SE: systemic embolism NMCR: non-major clinically relevant VHD: valvular heart disease HDER: high dose edoxaban regimen LDER: low dose edoxaban regimen TIA: transient ischemic attack TAVI: transcatheter aortic valve implantation