5/1/2019

1

Challenges in Anticoagulation:

Expert Panel

Kori Leblanc

Jennifer Pickering

Bill Semchuk

Yana Shamiss

Claudia Bucci

PAST MEDICAL HISTORY

Hyperlipidemia

Hypertension

MI, 4 years ago, LVEF: 50%

CVA, 6 years ago, no deficits

Ex-smoker, quit 4 years ago

GERD

CURRENT TREATMENTS

Rivaroxaban 2.5 mg BID

EC ASA 81 mg

Ramipril 10 mg daily

Bisoprolol 2.5 mg daily

Pantoprazole 40mg daily

Rosuvastatin 20 mg at bedtime

RELEVANT FINDINGS

ECG: Atrial fibrillation

HR: 95 irregular

BP: 135/85

LDL: 2.0

LABSDATE: 1 week ago

CBC: WNL

Cr: 95 umol/L

CrCl: ~61 mL/min

Frank Age: 75 Weight: 77 kg

Presents to GP with complaints of fluttering in his

chest and periods of feeling tired and faint. ECG done

in clinic shows AFIB at a rate of 95bpm.

Med Work:

www.phri.ca

R

Rivaroxaban 2.5 mg bid

+ Aspirin 100 mg od

Aspirin 100 mg od

Rivaroxaban 5 mg bid

Expected mean follow up: 3-4 years

Run-in

(aspirin plus

rivaroxaban placebo)

Stable CAD or PAD

N = 27 395

Bosch J, et al. Can J Cardiol 2017; 33: 1027-1035.

COMPASS Design

• On February 6, 2017 the DSMB recommended discontinuation of rivaroxaban and aspirin arms for

efficacy (combination: Z= -4.59, 0.000004; rivaroxaban: Z= -2.44, P=0.01) Mean F/U = 23 months

PPI randomization:

Pantoprazole 40mg

od vs. placebo

Q. reduces the risk

of upper GI

complications?

www.phri.ca

COMPASS: Baseline Characteristics

R + A

N=9,152

Rivaroxaban

N=9,117

Aspirin

N=9,126

Age, yr* 68 68 68

Female 23% 22% 22%

Diabetes 38% 38% 38%

CAD 91% 90% 91%

PAD 27% 27% 27%

Previous MI 61.8% 62.0% 62.7%

Previous Stroke 3.8% 3.8% 3.7%

*Mean

Eikelboom J, et al. N Engl J Med 2017; 377: 1319-1330.

www.phri.ca

Cum

ula

tive H

azard

Rate

0.0

0.0

20.0

40.0

60.0

80.1

0

0 1 2 3

9152 7904 3912 658

9117 7825 3862 670

9126 7808 3860 669

No. at Risk

Rivaroxaban + Aspirin

Rivaroxaban

Aspirin

Rivaroxaban + Aspirin

Rivaroxaban

AspirinRivaroxaban + Aspirin vs. Aspirin HR: 0.76 (0.66-0.86) P=<0.0001

Rivaroxaban vs. Aspirin HR: 0.90 (0.79-1.03) P= 0.115

Cardiovascular Death / Stroke / Myocardial Infarction

Primary outcome: CV death, Stroke, MI

Eikelboom J, et al. N Engl J Med 2017; 377: 1319-1330.

P=0.12

R + A vs. A: HR 0.76; 95% CI: 0.66-0.86, p<0.0001

R vs. A: HR 0.90; 95% CI: 0.79-1.03, p=0.12Aspirin 5.4 %

Riva 2.5 mg + ASA 4.1%

Rivaroxaban 5mg 4.9%

www.phri.ca

Components of primary outcome

0

1

2

3

4

5

6

Overall CV Death Stroke MI

% E

vents

Riva + Aspirin

Aspirin

HR 0.78

95% CI, 0.64-0.96

HR 0.58

95% CI, 0.44-0.76

HR 0.86

95% CI, 0.70-1.05

HR 0.76

95% CI, 0.66-0.86

Eikelboom J, et al. N Engl J Med 2017; 377: 1319-1330.

5/1/2019

2

www.phri.ca

Subgroup Analysis: with or without previous Stroke

Primary Outcome

CV death/Stroke

or MI

R + A

N=9,152

Aspirin

N=9,126

Rivaroxaban + aspirin

vs. aspirin

Annual Rate

(%)

Annual

Rate

(%)

HR

(95% CI)p

No previous

stroke2.1 2.8

0.77

(0.67-0.88)<0.0002

Previous stroke 3.7 6.50.57

(0.34-0.96)0.04

Sharma, M. Circulation 2019;139(9):1134-1145

p value for

interaction:

0.27

www.phri.ca

Major Bleeding

Outcome

R + A

N=9,152

Aspirin

N=9,126

Rivaroxaban + aspirin

vs. aspirin

(%) (%)

HR

(95% CI)p

Major Bleed288

(3.1%)

170

(1.9%)

1.70

(1.40-2.05)<0.0001

Non-Critical210

(2.3%)

112

(1.2%)

1.88

(1.49-2.36)<0.0001

Critical87

(1.0%)

64

(0.7)

1.35

(0.98-1.87)0.07

Eikelboom J, et al. N Engl J Med 2017; 377: 1319-1330.

PAST MEDICAL HISTORY

Hyperlipidemia

Hypertension

MI, 4 years ago, LVEF: 50%

CVA, 6 years ago, no deficits

Ex-smoker, quit 4 years ago

GERD

CURRENT TREATMENTS

Rivaroxaban 2.5 mg BID

EC ASA 81 mg

Ramipril 10 mg daily

Bisoprolol 2.5 mg daily

Pantoprazole 40mg daily

Rosuvastatin 20 mg at bedtime

RELEVANT FINDINGS

ECG: Atrial fibrillation

HR: 95 irregular

BP: 135/85

LDL: 2.0

LABSDATE: 1 week ago

CBC: WNL

Cr: 95 umol/L

CrCl: ~61 mL/min

Frank Age: 75 Weight: 77 kg

Presents to GP with complaints of fluttering in his

chest and periods of feeling tired and faint. ECG done

in clinic shows AFIB at a rate of 95bpm.

Med Work:

ASA/OAC in Stable Vascular Disease:

What do we know?

• ASA decreases the risk of mortality and CV

events in CAD patients

• Warfarin is also effective in decreasing CV

events and mortality in CAD patients1,2,3

Similar effect on mortality

Superior prevention of MI and stroke vs ASA

More bleeding

• Adding ASA to OAC increases major bleeding

1 Hurlen M, NEJM 2002;347(13)

2 van Es RF, Lancet 2002;360

3 Anand S, JAMA 1999;282

11

Increased Bleeding Risk with

OAC + Antiplatelet Combination

Therapy

Bleeding risk increases 30-60% with OAC + antiplatelet

combination therapy1-4

NOAC ParameterMB NOAC + ASA vs. NOAC

alone (HR 95% Cl)

Apixaban1 ASA at baseline 1.31 (1.14-1.52)

Dabigatran2 ASA at baseline 1.60 (1.41-1.81)

Edoxaban3 ASA at baseline 1.46 (1.27–1.67)

Rivaroxaban4 ASA at baseline 1.42 (1.23-1.64)

1. Hylek et al. J Am Coll Cardio. 2014;63:2141-7; 2. Dans et al. Circulation. 2013;127:634-40; 3. Xu et al. J Am Heart Assoc. 2016;5(2); 4. Goodman et al. J Am Coll Cardiol. 2014;63:891-900.

Do we need the ASA too?

ACTIVE Writing Group Lancet 2006;367:1903-12

Stroke, Non-CNS Systemic Embolus, MI, or Vascular Death

Target INR 2-3

N=3371

75 mg + 75-100 mg/day

N=3335

Major Bleed 2.42%/yr vs. 2.21%/yr; p=0.53

Minor Bleed 13.58%/yr vs. 11.45%/yr; p=0.0009

Total Bleeds 15.40%/yr vs. 13.21%/yr; p=0.001

Intracranial bleeds (including subdural hematoma) 21 vs. 11; p=0.08

Myocardial Infarction:

0.86%/yr vs. 0.55%/yr

RR 1.58 (0.94-2.67);p=0.09

28% CAD

4% PAD

5/1/2019

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2018 CCS AF Guidelines

Dosing

1. Eliquis® Product Monograph.2. Pradaxa® Product Monograph.

3. Xarelto® Product Monograph.4. Lixiana® Product Monograph

AgentRecommended

dose

Dose

adjustmentCriteria for dose adjustment

Apixaban1 5 mg BID 2.5 mg BID

• CrCl >25mL/min, with 2 of the following:• ≥80 years old• ≤60 kg• ≥133 µmol/L

Dabigatran2 150 mg BID 110 mg BID

• 75-79y years old with one or more risk factors for bleeding

• 80y or older

• CrCl 30-50mL/min (consider 110mg bid)

Edoxaban4 60 mg DAILY 30 mg DAILY

• CrCl 30–50mL/min

• Weight 60kg or less

• PG-P inhibitor EXCEPT verapamil and amiodarone

Rivaroxaban3 20 mg DAILY 15 mg DAILY • CrCl 15*–49mL/min

What if Frank weighed 112 or 122 kg?

• Estimated that by 2019 (now), more than 55% of the Canadian population

Will by overweight or obese. (Twells L et al. CMAJ Open 2014;2(1):E18.

Weight Based Dosing of NOACs

Go To Sources….

• CCPN SPAF Tool - X

• Thrombosis Canada: DOACs in Obese Patients – Guide

“data on the clinical efficacy and safety of DOACs in obese patients are limited. NO randomized controlled trials have examined the safety and efficacy of DOACs only in obese patients. Overall, <20% of patients in DOAC trials weighted >90-100kg…”

“if DOACs are to be used in patients with a BMI>40 or >120 kg, this should be as a last resort (ie. When vitamin K antagonists cannot be used) and patients should be informed of the limitations of the available information and potential risk of underdosing”

• 2018 European Practical Guide1: “because of limited data in extreme obesity, the use of VKA in patients with

a BMI> 40 kg/m2 or weight > 120 kg should be considered… in rare cases when a NOAC is needed in such circumstances, specific measurements of drug trough levels should be considered… under the guidance of a hematologist…”

Steffel J et al. The 2018 European Heart Rhythm Association Practical Guide

on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation

European Heart Journal 2018;39:1330-1393

ARISTOTLE Subgroup analysis: Efficacy and Safety

Outcomes Stratified by Weight Categories for Apixaban vs

Warfarin Use - Weight > 120 kg (n=982)

*Rates per 100 patient-years.

CI, confidence interval; CRNM, clinically relevant non-major; GI, gastrointestinal.

Hohnloser et al. Efficacy and safety of apixaban versus warfarin in patients with atrial fibrillation and

extremes in body weight: Insights from the ARISTOTLE trial. Circ 2019

(10.1161/CirculationAHA.118.037955)

Weight > 120 kgApixaban

Rate (n)*

Warfarin

Rate (n)*

Hazard Ratio (95% CI)

Apixaban vs Warfarin

Efficacy Endpoints

Stroke or systemic embolism 0.44 (4) 1.13 (11) 0.387 (0.123 to 1.215)

Stroke 0.44 (4) 1.03 (10) 0.426 (0.134 to 1.357)

Ischemic or uncertain stroke 0.44 (4) 0.61 (6) 0.711 (0.201 to 2.521)

Hemorrhagic stroke 0.00 (0) 0.41 (4) -

All cause death 3.00 (28) 2.52 (25) 1.190 (0.694 to 2.042)

Myocardial infarction 0.33 (3) 0.41 (4) 0.806 (0.180 to 3.600)

Safety Endpoints

Major bleeding 1.55 (13) 2.08 (19) 0.742 (0.366 to 1.502)

Major or CRNM bleeding 2.77 (23) 4.83 (43) 0.575 (0.347 to 0.954)

Intracranial bleeding 0.00 (0) 0.43 (4) -

GI bleeding 0.47 (4) 0.33 (3) 1.436 (0.321 to 6.416)

Any bleeding16.44

(119)25.13 (176) 0.670 (0.531 to 0.846)

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 6.5

Favor Apixaban Favor Warfarin

Comparative Effectiveness and Safety of Rivaroxaban and

Warfarin among Morbidly Obese Patients with AF:

Propensity Matched Cohort

Rivaroxaban

(n=3563)

Warfarin

(n=3563)

OR

(95% CI)

P value

Follow up time

(months), mean (SD)

10.27 (2.89) 10.56 (2.70) -0.29 (-0.42,

-0.16)

<0.0001

Composite risk of

ischemic stroke/

systemic embolism,

n(%)

Time to first composite

event (days), mean

(SD)

52 (1.5%)

111.87 (107.01)

59 (1.7%)

125.90

(105.65)

0.88 (0.60,

1.28)

0.90

(0.62.1.30)

0.5028

0.5690

Risk of major

bleeding, n (%)

Time to first major

bleeding event (days),

mean (SD)

77 (2.2)

127.99 (97.22)

96 (2.7)

147.56

(110.65)

0.80 (0.59,

1.08)

0.82 (0.61,

1.10)

0.1447

0.1878

Peterson E et al. Comparative effectiveness, safety and costs of rivaroxaban and Warfarin among

morbidly obese patients with atrial fibrillation. Am Heart J 2019; doi.10.1016/j.ahj.2019.02.001

5/1/2019

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Bill’s Clinical Approach:

Pt >120

kg

NoYes

VKAPatient not

able or

refusesNOAC >

VKA

Weight

Clot vs Bleed Risk

Renal Function

Age

Drug Interactions

Informed

Patient

Choice

Current Volumes at SRHC

• ICDs: 407

• Electrophysiological Studies 811 (combined for

EP studies, complex and SVT ablations)

Highest combined volume in the province

• Ablations 342 (SVT and flutter 80-100)

• Ablation with Advanced Mapping 400 (300 AF

and 100 VT approximate breakdown)

• PPM 1002

Why Catheter Ablation

• Catheter ablation can improve the quality of life in AF patients

CCC guidelines recognize it as a first line modality for highly

symptomatic patients; for the majority of patients a trial of

antiarrhythmic medications is still first line

Positive preliminary data in patients in HF

• Reduction in all-cause mortality (8.1% vs 15.9%; RR, 0.52; 95% CI,

0.35-0.76; P < 0.01)

• Reduction in HF hospitalization (17.7% vs 31.3%; RR, 0.57; 95%

CI, 0.45-0.72; P < 0.01) and improvement in ejection fraction,

compared with medical therapy

• Small data set under 300 patients larger trial on going, currently a

second line modality for symptomatic patients

• Canadian Journal of Cardiology 34 (2018) 1371e1392

• Marrouche NF, Brachmann J, Andresen D, et al. Catheter ablation for atrial fibrillation with heart failure. N Engl J Med 2018;378:417-27

• Di Biase et al. Ablation versus amiodarone for treatment of persistent atrial fibrillation in patients with congestive heart failure and an implanted

device: results from the AATAC multicenter randomized trial. Circulation 2016;133:1637-44..

• Packer et al. Catheter Ablation versus Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial: study rationale and design. Am Heart J

2018;199:192-9.

Periprocedural Anticoagulation

• North American and ESC guidelines 3 weeks of systemic therapeutic anticoagulation prior to

ablation procedure

• TEE maybe used to exclude the presence of LA thrombus allowing for the procedure to be per-formed within a shorter timeframe OR confirming the absence of left atrial clot inpatients taking DOAC therapy as adherence can-not be readily verified

• ACT above 300 periprocedurally

• Anticoagulation 2-3 months post procedure with continuation based on CHA2DS2VASC score not procedure success

Canadian Journal of Cardiology 34 (2018) 1371e1392 HRS/EHRA/ ECAS/APHRS/SOLAECE expert consensus

statement on catheter and surgical ablation of atrial fibrillation. Heart Rhythm 2017a;14:e275-e444..

To Bridge or NOT to Bridge • AHA/ACC/ Heart Rhythm Society and ESC guidance

documents recommended continuation of OAC instead

of bridging since 2014.

• AF ablations are classified as low bleeding risk

• What about uninterrupted DOACs vs uninterrupted

VKA?

Di Biase 2014

Doherty JU, Gluckman TJ, Hucker WJ, et al. 2017 ACC expert consensus decision pathway for periprocedural management of anticoagulation in

patients with nonvalvular atrial fibrillation. J Am Coll Cardiol 2017;69:871-98.

Periprocedural anticoagulation

• Lack of RCT data comparing interrupted vs bridged warfarin dosing

• Cohort studies supporting the use of uninterrupted warfarin – standard of care prior to NOACs

• Short half-life of NOACs ideally suited to a short interruption prior to the procedure with the greatest reported risk of life threatening bleeding historically related to transseptal puncture and non-reversible nature of the NOACs

• No data comparing interrupted vs non-interrupted NOACs

• Data comparing uninterrupted NOACs with uninterrupted warfarin

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VKA vs NOACs

• Meta-analysis of studies where neither NOAC,

nor VKA were interrupted for even 1 dose and

relevant outcomes were reported.

• In patients treated with rivaroxaban, patients

received last dose the night before the

procedure

• 80% of the dabigatran-treated patients received

their last dose < 8h prior to the procedure and

41% received it within 4h of the procedure

Cardoso et al. Heart Rhythm 2018;15:107–115

The incidence of ischemic stroke or TIA was low (NOAC, 0.08%; VKA, 0.16%)

and not significantly different between groups

(OR 0.66; 95% CI 0.19–2.30; P 5 .51; I 2 5 0%)

Three studies evaluated the incidence of silent cerebral embolic events

MRI and reported a similar incidence between NOACs (8%) and VKAs

(9.6%) (OR 0.86; 95% CI 0.42–1.76; P 5 .68; I 2 5 0%)

Only 1 death was reported in all studies.

Major bleeding was significantly lower in the uninterrupted NOAC group (20/2120

[0.9% VS VKA group (40/2024 [2.0%]) (OR 0.50; 95% CI 0.30–0.84; P , .01

Tamponade was not significantly different between groups (OR 0.86; 95% CI 0.47–

1.58; P 5 .63; I 2 5 0%)

Risks of AF ablation in the studies used in the Meta-

analysis and in the Real World

Acute Complication Agent Real world1, % Meta-analysis2, %

Stroke or TIA NOAC 0.08

warfarin 0.31 0.16

Cardiac tamponade 2.5% 1%

Vascular access

complications

2.7% 2.9%

2 patients in the meta-analysis required heart surgery and 9 patients required

vascular surgery

10 patients (out of 4156) in the real world cohort died acutely or within 30 days

of the procedure

1Shah, RUJ Am Coll Cardiol 2012;59:143–92Cardoso et al. Heart Rhythm 2018;15:107–115

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Combination Antithrombotic Therapy in AF + PCI

• Bleeding rates are significantly increased with triple antithrombotic therapy

• Various combinations of DOAC + single antiplatelet therapy (ie. clopidogrel) have been evaluated

• There has been a consistently lower risk of bleeding and similar efficacy with the dual therapy approach compared to the triple therapy approach.

• REDUAL PCI (dabigatran)

• PIONEER AF (rivaroxaban)

• AUGUSTUS (apixaban)

Balancing Bleeding vs. Thrombotic Risk

Bleeding Risk2

Need for OAC + DAPT

Advanced age (>75 years)

Frailty

Anemia with hemoglobin <110 g/dL

Chronic renal failure (CrCl <40 mL/min)

Low body weight (<60 kg)

Hospitalization for bleeding in past year

Prior stroke/intracranial bleed

Regular need for NSAIDs

Thrombotic RiskStroke Risk: age > 65 & CHADS65 score

Coronary Risk: ↑ with ACS

↓ with elective PCI

↑ with high-risk features

2Mehta et al. Can J Cardiol 2018

CHADS2: score based on history of congestive heart failure, hypertension, age

≥75, diabetes mellitus, stroke or TIA; ACS: acute coronary syndrome

*CrCl 30-49 ml/min: 10 mg OD; #first dose 72-96 hours after sheath removal; ‡clopidogrel (75 mg daily)

(alternative use of prasugrel or ticagrelor allowed, but capped at 15%); §ASA (75-100 mg daily) plus clopidogrel (75 mg daily)

(alternative use of prasugrel or ticagrelor allowed, but capped at 15%); ¶first dose 12-72 hours after sheath removal

1. Janssen Scientific Affairs, LLC. 2016. https://clinicaltrials.gov/ct2/show/NCT01830543 [accessed 10 Oct 2016];

2. Gibson CM et al, Am Heart J 2015;169:472-478e5; 3. Gibson CM et al, New Engl J Med 2016; doi: 10.1056/NEJMoa1611594

PIONEER AF-PCI

Design: An open-label, randomized, controlled phase IIIb safety study

Rivaroxaban 15 mg OD*# plus single antiplatelet‡

End of treatment

(12 months)

Rivaroxaban 2.5 mg BID#

plus DAPT§

VKA (INR 2.0–3.0)¶

plus DAPT§

Rivaroxaban 15 mg OD*

plus low-dose ASA

VKA plus low-dose ASA

N=2,124

1:1:1

Population:

patients with

paroxysmal,

persistent or

permanent

NVAF

undergoing

PCI (with stent

placement)

R1 mo: 16%

6 mos: 35%

12 mos: 49%

1 mo: 16%

6 mos: 35%

12 mos: 49%

Decision

for DAPT

duration:

1, 6 or 12

months

DAPT duration

(1 or 6 months)

12 mos:

100%

RRandomization

≤120 hours

post-PCI*

2,725

patients with

NVAF

undergoing

PCI with

stenting

Key excl.

CrCl<30

ml/min

Dabigatran 150 mg BID + P2Y12 inhibitor x 6-12 months3

Dabigatran 110 mg BID + P2Y12 inhibitor x 6-12 months2,3

Warfarin (INR 2.0–3.0) + P2Y12 inhibitor + ASA1 x 6-12 months1

Mean duration of

anticoagulant therapy

~12 months

Follow-up:

~14 months

REDUAL - Dabigatran vs. Triple Therapy With Warfarin

in AF Patients That Undergo a PCI With Stenting

Open-label

Primary Endpoint - Safety: Major or Clinically Relevant Non-major Bleeding

Secondary Endpoint - Efficacy: Composite of Death, MI, Stroke/SE or Unplanned revascularization

Cannon et al Clin Cardiol 2016;39:555-64 and N Engl J Med 2017;377:1513-24

*≤72 hrs preferred; study drug administered 6 hrs after sheath removal

In the initial protocol, a sample size of 8,520 patients had been planned to allow for a co-primary end-point comparison of

thromboembolic event rates in each dual-therapy group vs. triple-therapy group; however, enrollment of this number of patients in a

timely fashion was determined to be infeasible

~51% with ACS

Clopidogrel 88%

Ticagrelor 12%

TTR 64%

1ASA should be discontinued at 1 month (BMS) or 3 months (DES ~83%)2P2Y12 inhibitor can be discontinued or switched to ASA≤100 mg/day from month 123Pts ≥80 yrs outside of U.S. randomized to dabigatran 110 mg BID or warfarin

Piccini NEJM 2017

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VKA(INR 2 to 3)

Apixaban 5 mg BIDApixaban 2.5 mg BID in

selected patients

Primary outcome: ISTH major/CRNM bleeding

Secondary outcome(s): death/hospitalization,

death/ischemic events

Randomize

N = 4600

patients

AUGUSTUS

Aspirin for all on the

day of ACS or PCI

Aspirin versus placebo

after randomization

Open

Label

Aspirin Placebo Aspirin Placebo

AUGUSTUS

ISTH major or CRNM bleeding

All patients were concomitantly receiving P2Y12 therapy

Aspirin vs Placebo

Lopes RD, Heizer G, Aronson R, et al. N Engl J Med. 2019;doi: 10.1056/NEJMoa1817083

Apixaban:

10.5%

Apixaban vs VKA

VKA:

14.7%

Apixaban:

10.5%

14.7%

10.5%

16.1%

9.0%

Where Are We Now?

• Significant reduction in bleeding with dual therapy DOAC-containing regimens

There is a growing shift towards using DOACs + SAPT

• No apparent downside but some limitations…

• Underpowered for stroke and ischemic events

• Included very few patients at high embolic or ischemic risk ie. very high risk of stroke, less than < 50% had ACS

• Heterogeneity amongst trials

• Questions going forward ….

Patients with high ischemic burden (i.e. ACS) may still require triple therapy

Which combination of antithrombotics do you choose?

Back to the case ….

The menu of DOAC options:dabigatran 150 mg or 110 mg bidrivaroxaban15 mg od (10 mg od)apixaban 5 mg bid (2.5 mg bid)