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 EAFT

(n=571) (n=439)

All 6 Trials (n=2900) 100%

50%

Warfarin Better RRR=relative risk reduction Adapted from Hart. Ann Intern Med. 1999;131:492; with permission.

0

-50%

-100%

Warfarin Worse

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 >>> Risk

Benefit >> Risk Additional studies with focused objectives needed

Benefit ≥ Risk Additional studies with broad objectives needed; Additional registry data would be helpful

Risk ≥ Benefit No additional studies needed

Procedure/ Treatment SHOULD be performed/ administered

should is recommended is indicated is useful/effective/ beneficial

IT IS REASONABLE to perform procedure/administer treatment

is reasonable can be useful/effective/ beneficial is probably recommended or indicated

Procedure/Treatment MAY BE CONSIDERED

may/might be considered may/might be reasonable usefulness/effectiveness is unknown /unclear/uncertain or not well established

Procedure/Treatment should NOT be performed/administered SINCE IT IS NOT HELPFUL AND MAY BE HARMFUL is not recommended is not indicated should not is not 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) Rivaroxaban (Xarelto) Apixaban (Eliquis) Edoxaban (Savaysa, Lixiana)

Do not use in ESRD; reduce dose in mod/sev CKD

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

 Dominated by RBC’s  Low Pressure systems (veins, LA)  Rx anti-thrombin agents  Stasis (DVT, AFib)

White thrombus

 Dominated by platelets  High-pressure systems (arteries, bypass)  Rx antiplatlet agents (ASA, Plavix)  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 Drug

Trial

Dose

TTR %

(chads2)

Stroke Reduction %

ICH %/yr

RR Mortality (p value)

Major Bleed

Dabig DTI

RELY (2.1)

150 bid

64

35%

0.10 .88 (0.051)

7%

Rivaro Xa

Rocket AF (3.5)

20 qd

55

21%

0.50 .92 (0.15)

6%

Apixa Xa

Aristotle (2.1)

5 bid

62

24%

0.24 .89 (0.047)

31%

Edoxa Xa

Engage AF

60 qd

68

13%

0.50 .86 (.003)

20%

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

Dosing the NOACs Dabigatran (Pradaxa) CrCl>30 = 150 mg BID When CrCl < 15 or ESRD, Warfarin is CrCl 15-30 = 75mg BID recommended med Rivaroxaban (Xarelto) CrCl > 50 = 20 mg Qday Crcl 15-50 = 15 mg Qday Aphixaban (Eliquis) –liver metabolized, only one you can use in ESRD 5mg BID 2.5 mg BID (if has 2 or more of following: age > 80, weight > 60 kg, Cr > 1.5 mg/dL) Endoxaban (Savaysa, Lixiana) CrCl > 95 = don’t use CrCl 51-95 = 60mg Qday CrCl 15-50 = 30 mg Qday

Appendectomy • Surgical • Interventional

Maisel W. N Engl J Med 2009;360:2601-2603

When and for how long ? • Anticoagulate and rate control everyone initially • Decide on cardioversion, ablation, or rate control • 4 weeks after cardioversion, decide on the need for long term anticoagulation based on CHADS2-VASc Score

AFFIRM: Rhythm-Control vs Rate-Control

5300 patients >65 0r < 65 + 1 risk factor with current or recent Afib (225 centers 1995-99)

The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM). N Engl J Med 2002;347:1825-1833

AFFIRM: On treatment Post-Hoc Analysis Variable

Sinus Rhythm

Warfarin

Digoxin

AAD

RR

0.54 (.42-.70) P