Atrial Fibrillation: Changing Indications and New Medications - PowerPoint PPT Presentation

Atrial Fibrillation: Changing Indications and New Medications Jessica Evert MD UCSF Department of Family and Community Medicine Special Thanks and Recognition: Edward Kersh, MD, FACC Chief of Cardiology, St. Luke ’ s Hospital, SF Clinical Professor of Medicine, UCSF Sutter Pacific Medical Foundation

Terminology: No longer paroxysmal /chronic  Lone (no heart disease)  Paroxysmal (lasts less than 7 days; self terminating)  Persistent (more than 7 day; requires intervention to terminate)  Long-standing persistent (last more than 12 months)  Permanent (pt or physician decide not to seek restoration/maintenance of NSR)  NVAF (non-valvular AFib)

WHY? AF Increases Stroke Risk by Nearly 500% Risk ratio = 4.8 P < 0.001 Wolf et al. Stroke. 1991;22:983-988.

The annual risk of Stroke with AFIb is 8% on average. 8% of 5,000,000 = 400,000 strokes per year.

Incidence of AF Increases with Age 15% of octogenarians will have A fib Fuster, V. et al. J Am Coll Cardiol 2011;57:e101-e198

Risk of Stroke in AF Increases with Age 8% Stroke rates in relation to age in untreated control groups of randomized trials Fuster, V. et al. J Am Coll Cardiol 2011;57:e101-e198

Severe Disability Is Increased in Patients With Stroke Due to AF 3x incidence of being bedridden with AFib Lin et al. Stroke . 1996;27:1760-1764.

WHY? Oral Anticoagulation Reduces Stroke in AF (8% to 3%) Warfarin Compared With Placebo The aggregate RRR for all stroke was 62% (95% CI, 48%–72%) AFASAK (n=671) SPAF (n=421) BAATAF (n=420) CAFA (n=378) SPINAF (n=571) EAFT (n=439) All 6 Trials (n=2900) 100% 50% 0 -50% -100% Warfarin Better Warfarin Worse RRR=relative risk reduction Adapted from Hart. Ann Intern Med . 1999;131:492; with permission.

WARFARIN 3% SPAF, Circulation 1991

History of Anticoagulation (70 years of warfarin) 1933 - a farmer shows up at the U. of Wisconsin School of Agriculture with a milk can full • of blood which would not coagulate. In his truck, he had also brought a dead heifer and some spoiled clover hay. He wanted to know what had killed his cow. 1939 – Dr. Paul Link isolates dicumerol • 1941 - Patented by WARF • 1950 – Marketed as rat poison • 1951 – unsuccessful overdose treated with Vitamin K • 1954 – FDA approves use in humans • 1983 – INR introduced • 1991 – Framingham demonstrates role of Afib in Stroke • 1991 – Generic warfarin (FDA requires absorption to be within 80–125%) • 1999 – Risk reduction with anticoagulants demonstrated • 2005 – Sportif Trial - ximelagratan • 2011 – New agents introduced •

WHO? Rate control and anticoagulate everyone initally

Who? : Clinical predictors of stroke in AFIB  Prior TIA or CVA  Prosthetic Valve  RHD  Hypertension  LV dysfunction/CHF  Age > 75  Cardiomyopathies (restrictive or hypertrophic)  Diabetes  CAD  Thyrotoxicosis

Who? : Echo Predictors of Stroke in Afib • LV Dysfunction • Mitral Valve Disease, Annular Calcium • LA Enlargement • Spontaneous Echo Contrast (Smoke) • LAA emptying velocity • LA thrombus • Absence of mitral regurgitation

Thrombus Forms in the Left Atrium (rarely seen on TTE)

LAA Clot

LAA Clot by TEE in appendage

Classes of Recommendations I IIa IIb III Intervention is useful and effective Evidence conflicts/opinions differ but lean toward efficacy Evidence conflicts/opinions differ but lean against efficacy Intervention is not useful/effective and may be harmful Braunwald E, et al. 2002. http://www.acc.org/clinical/guidelines/unstable/unstable.pdf.

Applying Classification of Recommendations Class I Class IIa Class IIb Class III Benefit >>> R >>> Risk Benefit >> R Risk sk Benefit ≥ Risk Risk ≥ Benefit Addit itio ional s studies ies w wit ith Addit itio ional s studies ies w wit ith No addit itio ional s studies ies broad objectives n s needed; focuse sed objectives n s needed needed Additional r registry data IT IS REASONABLE to would be be he helpful Procedure/Treatment Procedure/ Treatment perform should NOT be SHOULD be procedure/administer Procedure/Treatment performed/administered performed/ SINCE IT IS NOT treatment MAY BE CONSIDERED administered HELPFUL AND MAY BE HARMFUL should is reasonable may/might be considered is not recommended is recommended can be useful/effective/ may/might be reasonable is not indicated is indicated beneficial usefulness/effectiveness is should not is useful/effective/ is probably recommended or unknown /unclear/uncertain is not indicated beneficial or not well established useful/effective/beneficial may be harmful

Weighing the Evidence Weight of evidence grades: = Data from many large, randomized trials = Data from fewer, smaller randomized trials, careful analyses of nonrandomized studies, observational registries = Expert consensus Braunwald E, et al. 2002. http://www.acc.org/clinical/guidelines/unstable/unstable.pdf.

ACC/AHA Guidelines 2014: Determine the Risk

ACC/AHA Guidelines 2014: Determine the Risk 0 = no anticoagulation 1= options Oral Anticoagulation for score >/= 2 Hypertropic Cardiomyopathy= Ignore Score (and anticoagulate )

What to do with 1? • No Anticoagulation • Oral Anticoagulation • Aspirin (IIb)

What? • Parenteral Agents – heparin, enoxaparin, Arixtra • Antiplatelet Agents • Aspirin • clopidigrel • Vitamin K antagonists- Coumadin • Direct Thrombin Inhibitors • Dabigatran • Factor XA inhibitors • Apixaban • Rivaroxaban • Appendectomy

Newer Oral AntiCoagulants (NOACs) • Dabigatran (Pradaxa) Do not use in ESRD; reduce dose in mod/sev CKD • Rivaroxaban (Xarelto) • Apixaban (Eliquis) • Edoxaban (Savaysa, Lixiana) Contraindicated in patients with mechanical heart values or hemodynamically significant mitral stenosis

The problem with warfarin: The Therapeutic Window Stroke vs intracranial bleeding in relation to intensity of anticoagulation Therapeutic window Fuster, V. et al. J Am Coll Cardiol 2011;57:e101-e198

Connolly SJ et al. Circ. 2008,118:2029-2037

Emergency Hospitalizations for Adverse Drug Events in Older U.S. Adults Budnitz DS et al. N Engl J Med 2011;365:2002-2012.

What About Aspirin? Fuster, V. et al. J Am Coll Cardiol 2011;57:e101-e198

Aspirin – half as effective SPAF, Circulation 1991

ASA + PLAVIX – less stroke, more bleeding n = 7554 pts unsuitable for warfarin Stroke, MI, Embolism, death Risk of stroke decreased 28% The ACTIVE Investigators. N Engl J Med 2009;360:2066-2078

Red vs White Thrombus Red Thrombus White thrombus  Dominated by platelets  Dominated by RBC ’ s  Low Pressure systems (veins,  High-pressure systems (arteries, LA) bypass)  Rx anti-thrombin agents  Rx antiplatlet agents (ASA, Plavix)  Stasis (DVT, AFib)  Plaque Rupture (ACS)

New Agents • Direct Thrombin Inhibitor – Dabigatran • Factor Xa Inhibitor – Rivaroxiban – Apixaban – Edoxaban

RELY - RESULTS 35% reduction in stroke and emboli with D 150 Connolly SJ et al. N Engl J Med 2009;361:1139-1151

Rivaroxiban: Rocket AF Trial 21% reduction in stroke and emboli Patel MR et al. N Engl J Med 2011. DOI: 10.1056/NEJMoa1009638

Rocket AF - Primary End Point of Stroke or Systemic Embolism. Patel MR et al. N Engl J Med 2011. DOI: 10.1056/NEJMoa1009638

ARISTOTLE – Apixaban vs Warfarin n = 18000 24% reduction in stroke and emboli 31% reduction in major bleeding Granger CB et al. N Engl J Med 2011. DOI: 1056

Aristotle – Apixaban vs Warfarin n=18000 Granger CB et al. N Engl J Med 2011. DOI: 1056

Edoxaban: Engage AF – Timi48 13% stroke reduction 20% bleeding reduction Giugliano RP et al. N Engl J Med 2013;369:2093-2104

COMPARISON Dose TTR Stroke ICH RR Major Drug Trial Reduction Mortality Bleed % %/yr (chads2) % (p value) RELY Dabig 150 64 35% 0.10 .88 7% (2.1) bid DTI (0.051) Rivaro Rocket 20 qd 55 21% 0.50 .92 6% AF Xa (0.15) (3.5) Aristotle Apixa 5 bid 62 24% 0.24 .89 31% (2.1) Xa (0.047) Engage Edoxa 60 qd 68 13% 0.50 .86 20% AF Xa (.003)

Efficacy (stroke) vs Side Effect (bleeding)

Treating Bleeding • Wait – short half life compared to warfarin • Maintain renal perfusion – PRBC – Fluids – Diuretic (?) • Drive Thrombin production – FFP (?) – Vitamin K (?) – Prothrombin Complex Concentrates • Dialysis • Antibody – Praxbind • Dummy factor Xa – in development

DTI and Xa Summary Points • Onset of action in 2 hours • No need to bridge with heparin (shorter LOS) • Less time off therapy • No dose titration/no INR ’ s • Superior or non-inferior to warfarin • Fewer drug interactions • Less ICH