Disclosures High Bleeding Risk Patient with AF Research support - - PDF document

12/3/17 1

MINTU TURAKHIA, MD MAS

Associate Professor Executive Director, Center for Digital Health Stanford University Director, Cardiac Electrophysiology VA Palo Alto Health Care System mintu@stanford.edu @leftbundle

Treatment of the Low Stroke Risk or High Bleeding Risk Patient with AF

§Research support §VA, NIH, AHA, Janssen, Medtronic, iRhythm, Cardiva, AstraZeneca, Boehringer Ingelheim §Advisor/Consultant §Abbott, Medtronic, Boehringer Ingelheim, Zipline Medical, Precision Health Economics, AliveCor, Armetheon, Akebia §Lecture honoraria §Medtronic, St Jude Medical

Disclosures

§54 year old male with Zio patch placed for syncope §Found to have 6 AT

• episodes. Longest is 7

minutes §PMH: HTN §Meds: ASA 81, no OAC, beta blocker, ACE

Clinical case 1

What would you do next?

• A. Keep ASA 81
• B. ASA + OAC
• C. OAC only

D.Increase ASA to 325

• E. LAA occlusion

§69 year old male with dual chamber pacemaker placed 8 years ago for syncope §Found to have 6 atrial high rate episodes. Longest is 1 hour §PMH: HTN §Meds: ASA 81, no OAC, beta blocker, ACE

Clinical case 2

What would you do next?

• A. Keep ASA 81
• B. ASA + OAC
• C. OAC only

D.Increase ASA to 325

• E. LAA occlusion

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§76 year old female with ILR placed 1 year ago for syncope comes for routine check §Found to have 6 AF

• episodes. Longest is 3 days

§PMH: HTN, diabetes, EF 45% §Meds: ASA 81, no OAC, beta blocker, ACE

Clinical case 3

What would you do next?

• A. Keep ASA 81
• B. ASA + OAC
• C. OAC only

D.Increase ASA to 325

• E. LAA occlusion

§70 year old female with chronic AF and small intracranial hemorrhage 90 days ago while on on warfarin (INR 2.7) + ASA. Minor speech and motor deficits §PMH: HTN, stroke 3 years ago, EF 50%, GFR 74 §Meds: beta blocker, ACE, no OAC

• r ASA

§ECG: AF, LVH, V-rate 70s

Clinical case 4

What would you do next?

• A. ASA only
• B. NOAC only
• C. ASA + NOAC

D.LAA occlusion

• E. Nothing

“When the gods wish to punish us, they answer our prayers.”

Go AS. JAMA. 2001 / Miyasaka Y. Circulation 2006 / Naccarelli GV. Am J Cardiol. 2009

§4% of the population over age 60; 10% over age 80

0.00 1.75 3.50 5.25 7.00

2009:

2.23M

1995:

1.8M Projections of AF Prevalence in the USA

2030:

5M-12M

2017:

(3-5M)

Prevalence of AF

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• 1. Clinical decision making is based on poor data
• 2. AF-stroke relationship is complex

§Causation vs. risk marker vs. coincident §Atrial rhythm vs. atrial substrate

• 3. Well-managed and well-selected anticoagulation is

generally low risk even after major bleeding

• 4. Don’t use aspirin as an attempted compromise

Take home points Stroke shortens lifespan the most

Peeters A, et al. Eur Heart J. 2002

Average Remaining Life Expectancy at Age 60 (Men) 4 8 12 16 20 Healthy History of AMI

• 9.2

years History of Cardiovascular Disease

• 7.4

years History of Stroke

• 12 years

Framingham Heart Study

Risk stratification for stroke

§1 point for §Congestive heart failure §Hypertension §Age ≥ 75 §Diabetes §2 points if prior Stroke or TIA §Not generalizable! §Bad data

§QI Medicare registry (age > 65) from 7 states in the South §1733 inpatients discharged with AF. Follow-up < 3 years §ICD9 codes, not chart review

First, there was CHADS2

Gage BF, JAMA 2001

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§Answer: not very

Validation: how good is CHADS2?

§c-statistic = 0.56-0.62 §(0.50 = pure chance) §Substantial misclassification §Untreated “low risk” patients who get strokes §Treated “high risk” patients who bleed

(Fang M, JACC 2006)

Then came CHA2DS2-VASc…

(Lip GY, Chest 2010)

§CHADS2 score gets reclassified upward §Age, CAD, female §Few stroke events in derivation §European Heart Survey §1,577 of 5,333 untreated AF patients 2003-2004 §1-year follow up

Weaknesses of CHA2DS2-VASc

(Lip GY, Chest 2010)

§Score is calibrated for for high sensitivity §Contemporary therapy has tilted in favor

• f having a low treatment threshold

§Low bleeding risk with NOACs §Warfarin: less ICH, major bleeding now Why did guidelines go with CHA2DS2-VASc?

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Summary of NOAC trials

RE-LY (Dabigatran) ROCKET-AF (Rivaroxaban) ARISTOTLE (Apixaban) ENGAGE AF TIMI 48 (Edoxaban) Efficacy % Warfarin vs. OAC

(CVA or SE)

1.69 vs. 1.11

p<.001

NNT = 167

*150 mg shown

2.42 vs. 2.12 p=.12

(2.2 vs 1.7 on treatment)

1.60 vs. 1.27 p <

.001

NNT = 303 1.80 vs. 1.57 p=.08

(1.5 vs. 1.18 on treatment) *High-dose (60 mg)

Major Bleeding % 3.57 vs. 3.32

p=0.31

3.45 vs. 3.6 p=0.58 3.09 vs. 2.13

p<.001

3.43 vs. 2.75 p<.001

ICH%

0.74 vs. 0.30

p< .001

0.74 vs. 0.49

p=.019

0.47 vs. 0.24 p<

.001

0.85 vs. 0.39 p< .001 All-cause mortality %/yr 4.13 vs. 3.64

p = 0.051

NNT = 204 4.91 vs. 4.52 p=NS 3.94 vs 3.52

p = 0.05

NNT = 238 4.35 vs. 3.99 p=0.08 NNT = 277 Conclusion vs. warfarin

Superior efficacy, similar bleeding, less ICH Non-inferior on efficacy and safety measures Superior efficacy, less major bleeding and ICH, lower mortality Non-inferior on efficacy; less bleeding

AHA ACC HRS ESC

Low stroke risk is the greatest area of uncertainty

2 4 6 8 10 12 14 16 18 20 1 2 3 4 5 6 7 8 9

Annual Risk of Stroke (%)

CHADS2 CHA2DS2-VASc

Lip GY, Am J Med. 2010 Camm AJ, Eur Heart J. 2010 Friberg L, JACC, 2015

§Derivation: ROCKET-AF (rivaroxaban) §Validation: Kaiser §Adding a binary predictor of GFR < 60 to CHADS2 score substantially improves discrimination and reclassification

§c-statistic 0.74

§AHA/ACC/HRS 2014 guidelines did not endorse R2CHADS2

R2CHADS2: Yet another risk score

(Piccini J, Circulation 2012)

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§Risk factors §Age 67 §Female §Carotid disease §GFR < 60

Answer choices:

• 1. Very low (< .5%)
• 2. Low (~1-2%)
• 3. Medium (~3-6%)
• 4. High (~8-18%)

Q: What is this patient’s annual risk of stroke?

• CHADS2: 0 (low)
• CHA2DS2-VASc: 3 (med)
• R2CHADS2: 2 (med)

§AF defined by treatment, not disease §Hospitalization with AF; cardiology care §ICD9 codes, not AF burden §Transient or lone AF not well represented §Diagnosis creep §Device-detected AF, ambulatory ECG, episodic detection with wearables §Result: external miscalibration and overtreatment

Limitations of stroke risk scores

§In non-AF patients, CHADS2 and other scores predict… §Left atrial dysfunction, LAA thrombus §Ischemic stroke §AF

Vascular risk factors also predict AF

Welles C / Turakhia M, JACC 2011 Welles C / Turakhia M, Am Heart J 2013 Wong J / Turakhia M, Am Heart J 2014 Melgaard L, JAMA 2015

§Cardioembolic §Atheroembolic §Small vessel

Mechanisms of stroke in AF are diverse

§CHA2DS2-VASc increase risk of all types §More AF in all types

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LA dysfunction AF Stroke LA dysfunction AF Stroke AF Stroke LA dysfunction

Rethinking the conceptual framework

Other vascular risk factors Stroke LA dysfunction AF

How much AF is too much?

§AF subtype clinically classified, not based on ECG monitoring

Vanassche T, Eur Heart J, 2015 (Healey JS, NEJM 2012)

ASSERT Study

12/3/17 8 Short AT/AF and stroke (ASSERT)

§Subclinical atrial tachyarrhythmias (AT) (> 6 minutes) in 10% by 3 months AT associated w/clinical AF (HR 5.6) §AT associated w/ischemic stroke/SE (HR 2.5) §But, population attributable risk low: 13% Healey JS, NEJM 2012

Atrial tachycardia

§Among 51 patients with stroke/SE §Only 1 had AT/AF at time of stroke §25 (49%) had no AT/AF §Only 4 (8%) had AT/AF > 6 min in prior 30 days §Median time to AF was 339 days prior §8 had AT/AF only after stroke

ASSERT

(Brambatti M, Circulation 2014) Freedman B, Circulation, 2017

§Pooled analysis §10,000 patients with PPM, ICD, CRT

SOS-AF

Boriani G et al. Eur Heart J, 2014

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Threshold did not matter (30 sec to 6 hours) – risk pattern was the same

Is there transient risk?

Turakhia M, et al. Circ EP, 2015

Contribution to prediction (attributable risk) is low

Enrollment Successful Reveal ICM insertion Monthly device transmission In-office follow-up visits every 6 months for a minimum of 18 and maximum of 30 months Baseline

REVEAL AF

DESIGN:

• Prospective, single-arm, open-label, multi-

center, post-market study

• Enrollment November 2012 – June 2015

INCLUSION CRITERIA:

• CHADS2 score of ≥ 3 or CHADS2 = 2 and at

least 1 of the following:

• CAD, CKD, Sleep apnea, COPD

Primary outcome

• Incidence of adjudicated AF ≥6 minutes at 18

months

Reiffel J, et al. Am Heart J 2014;167:22-27.

Incidence Rate, % Number of Months Post-Insertion Data presented by James A. Reiffel, MD. HRS Chicago May 5, 2017.

RE REVEAL AF: In Incid idence of AF AF Last stin ing ≥ 6 Min inutes

• Median time to

detection: 123

• [IQR 41-330] days.
• Detection rate at:

– 18 months (primary endpoint): 29.3%. – 30 days: 6.2%. – 30 months: 40.0%.

• AF may have gone

undetected in over ¾

• f patients had

monitoring been limited to 30 days

Trial pipeline

Gorenek B, et al (EHRA Consensus Document), Europace, 2017

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Clinical recommendations Clinical recommendations

Gorenek B, et al (EHRA Consensus Document), Europace, 2017

OAC treatment by site for AF ≥ 1 hour (PPM, ICD)

§12,000 VA patients with Carelink data + EHR + labs §1,967 with AF ≥ 1 hour and > 75% remote monitoring coverage §≥6 minutes: 292/2431 (12%) §> 6 hours: 279/1455 (19%) §> 24 hours: 232/914 (25%)

Perino AC / Turakhia MP, in review

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§Low risk (CHA2DS2-VASc) §Risk is related to longer periods of AT/AF, is transient, and is low overall §High risk (CHA2DS2-VASc ≥ 3-4) §Risk is related to substrate and extracardiac risk §Brief AT/AF is a marker of high-risk substrate

Rethinking the clinical framework

§My own treatment thresholds: §> 1 hour in CHA2DS2-VASc ≥ 4 or prior stroke §> 6 hours in everyone else

§Remember: Guidelines suggest higher thresholds (> 5.5 hours) but provide latitude down to 5 minutes

My own treatment thresholds Bleeding and anticoagulation

Patient factors affecting bleeding risk §Age §Prior major bleeding §Anemia §Kidney disease §Antiplatelet agents, NSAIDS §Hypertension (SBP > 160) §Prior stroke §High alcohol use §Moderate to severe liver disease §High INRs or low TTR

What about bleeding risk?

These factors also affect risk

• f stroke

}

Gage BF, et al. Am Heart J. 2006 Fang MC, et al. J Am Coll Cardiol. 2011 Pisters R, et al. Chest. 2010 Piccini JP, et al. Circulation. 2013

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§~ 12,000 ICD/PPMs §256 major bleeds §17 ICH §Most bleeds during AF-free periods

Major bleeding and rhythm discordance

Askari M / Turakhia MP, ISC 2017 §Risk scores in Case 1 patient §HAS-BLED = 2 (age, NSAIDs) §ATRIA = 1 (history of hypertension) §Scores are complex and have limitations §Derived from historical warfarin users; not well validated with NOACs §Designed to predict “major bleeding”, not necessarily intracranial or fatal bleeding §ACC/AHA guidelines do not endorse formal use of bleeding scores; ESC recommends HAS-BLED §Benefit of OAC persists even at increased bleeding risk §For decision making, stratify first based on stroke risk, then think about bleeding §Patient preferences and shared-decision making

Bleeding risk with anticoagulation

HAS-BLED score

Friberg L, et al. Circulation, 2012

§Observational data suggests that well-managed OAC is safe after major bleeding §NOAC >> warfarin §Need to address other risk factors §Stop antiplatelet therapy §BP control §Evaluate competing risks §Make decision together with patient

Take-home points

§Multiple trials found that prognosis (survival) after a major bleed on dabigatran is better than warfarin (even in absence of reversal agent) §NOAC trials had the results that they did without reversal agents §For warfarin, evidence to support Vitamin K is weak §Vit K and FFP in blinded clinical trials but no difference in the fatal bleeds §However, reversal agents may provide practical management

• ptions during emergency situations or in patients requiring urgent

surgery Should absence of a reversal agent temper utilization of NOACs?

Majeed A et al, Circulation

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*Recommendation based only on limited non-clinical data; no experience in volunteers or patients rFVIIa = recombinant activated clotting Factor VIIa; PCC = prothrombin complex concentrates (non-activated or activated) van Ryn J et al. Thromb Haemost 2010;103:1116–27

Managing bleeding complications

Mild bleeding Moderate-to-severe bleeding Life-threatening bleeding Delay next dose local measures discontinue treatment as appropriate

• Symptomatic treatment
• Mechanical compression
• Surgical intervention
• Fluid replacement and

haemodynamic support

• Blood product transfusion
• Reversal agent
• Oral charcoal application*

( ingested <2 hrs before)

• Consideration of rFVlla
• r PCC*
• Charcoal filtration*

Patient with bleeding on NOAC therapy

§3- or 4-factor prothrombin complex concentrate §FEIBA (50 IU/kg) §rFVIIa (90 μg/kg) §Effect on NOACs is partial and delayed

Nonspecific Reversal Agents

Marlu R, et al. Thromb Haemost 2012;108:217.

NOAC Reversal Agents

Anticoagulant Class Idarucizumab Andexanet alfa PER977 Dabigatran IIa inhibitor

✓

O

✓

Apixaban Xa inhibitor O

✓ ✓

Rivaroxaban Xa inhibitor O

✓ ✓

Edoxaban Xa inhibitor O

✓ ✓

Unfractionated heparin Heparin O O

✓

LMWH Heparin O O

✓

Fondaparinux AT-III Xa inhibitor O ?

✓

Warfarin VKA O O O Modified after Crowther M, Crowther MA. Arterioscler Thromb Vasc Biol 2015.

Pollack CV Jr, et al. N Engl J Med 2015

REVERSE trial (dabigatran)

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Watchman 4-year data

(Reddy V, JAMA 2014)

§Conceptual framework of AF-stroke relationship has changed, but clinical trials and guidelines lag this new understanding §Stroke prevention in low-risk AF patients is a challenge §We are stuck with CHA2DS2-VASC for now §Reasonable to avoid OAC in low-risk patients with minimum amounts of paroxysmal AF, but no trials

§Elderly, heart failure, prior stroke: should not stop OAC

§OAC after major bleeding is reasonable in high-risk patients

Summary

§Center for Digital Health

§Bob Harrington , Euan Ashley, Lauren Cheung §Steve Torchia, Avani Gupta, Janet Kalesnikoff, Justin Norden

§Stanford Center for Clinical Research

§Ken Mahaffey, Amol Rajmane, Sharmin Nasrullah §Maja Holy, Shea Smith, Sharanya Ramasubramanian, Vandana Sundaram, Victoria Ding

§VA Research Group

§Jun Fan, Mariam Askari

§ Graduate Students

§Lichy Han, Aditya Ullal, Claire Than

§ Residents, Fellows, and Early Career

§Andrew Chang, Fahd Yunus, Andrew Cluckey, George Leef, Alex Perino, Christoph Olivier, Celina Yong, Krishna Pundi

The Team

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Thank you !

mintu@stanford.edu @leftbundle