which cyanotic patient needs anticoagulation? -...

Which Cyanotic Patient Needs

Anticoagulation?

Erwin Oechslin, MD, FRCPC, FESC

Director, Adult Congenital Heart Disease Program

The Bitove Family Professor of ACHD

Professor of Medicine, U of T

Peter Munk Cardiac Centre / Toronto General Hospital

Toronto, ON, Canada

1 1

Conflicts of Interest

None

Objectives

• To appreciate the risks of thrombotic and bleeding

complications

• To understand the complex mechanisms of

ischemic / thrombotic complications

• To determine the risks / benefit of anticoagulation in

pts

Outline – Which Cyanotic Pts Needs

Anticoagulation?

• Prevalence of thrombotic / bleeding complications?

• Survival benefit on anticoagulants?

• Which patients benefit from anticoagulation?

• Summary

Who Routinely Anticoagulates

Patients with CCHD?

35 y/o Man:

CCHD, Eisenmenger Physiology

Aneurysmal

PA

Laminated

Thrombus

Calcium *

*

Prevalence of Thrombus Formation in

PAs – Eisenmenger Syndrome

Year Institution N Thrombus Percent

1998 (Daliento, EHJ 1998)

London

Torino

Padua

188 25 13%

1999 (Niwa, JACC 1999)

UCLA 77 20 26%

2003 (Perloff, AJC 2003)

UCLA 31 (none on

anticoagulants)

31 (mild in 22

mod – massive in 9

100% (71%

29%)

2003 (Silversides, JACC 2003)

Toronto 34 (15% on anticoagulants)

7 21%

2007 (Broberg, JACC 2007)

London,

Brompton

55 (55% on Warfarin)

(15% on ASA)

11 20%

24% combined

Risk Factors for Thrombus Formation

Variable Thrombus

(n=11)

No

Thrombus

P

Age (yrs) 46.2 17.1 36.5 12 0.032

NYHA 3/4 64% 32% ns

Female Gender 55% 70% ns

Hemoptysis 73% 43% 0.08

Oxygen Saturation (%) 81 6 81 8 ns

Hemoglobin (g/dl) 18.8 3.6 19.9 2.7 ns

Platelet count (1,000/L) 162 67 144 52 ns

Brompton (n = 55)

Variable Thrombus

(n=7)

No

Thrombus

P

Age (yrs) 43 9 41 11 ns

NYHA 3/4 43% 26% ns

Female Gender 86% 37% 0.04

History of bleeding 57% 30% ns

Oxygen Saturation (%) 72 9 85 6 0.01

Hemoglobin (g/dl) 19.6 2.3 18.6 2.9 ns

Platelet count (1,000/L) 137 56 163 64 ns

Silversides C et al, JACC 2003 Broberg C et al, JACC 2007

Toronto (n = 34)

Risk Factors for Thrombus Formation

Variable Thrombus

(n=11)

No

Thrombus

P

MPA diameter (cm) 4.8 1.4 3.8 0.9 0.007

Calcified PA 73% 23% 0.002

RV ejection fraction (%) 41 15 53 13 0.017

LV ejection fraction (%) 48 12 60 9 0.002

BNP (pmol/L) 24 [43] 10 [15] 0.034

Brompton (n = 55)

Variable Thrombus

(n=7)

No

Thrombus

P

MPA diameter (cm) 4.7 1.5 4.3 0.9 ns

Calcified PA 71% 19% 0.01

RV dysfunction 71% 56% ns

LV ejection fraction N/A N/A

BNP (pmol/L) N/A N/A

Toronto (n = 34)

Silversides C et al, JACC 2003 Broberg C et al, JACC 2007

Mechanism of Thrombus Formation

• Embolic????

• Hypercoagulability?

• Related to MPA

diameter and flow

• Atherosclerosis

(vascular injury, Ca2+)

Ca++

Prevalence of Pulmonary Thrombosis in

Pts with CCHD

• Cross-sectional, descriptive, multicentre study

• Patient population: n=98

– Eisenmenger syndrome: 69 pts (70%)

Jensen AS, et al.

Heart 2015; 101:1540-6

Prevalence of Pulmonary Thrombosis

• MDCT – 20% (n= 15/76)

– Location: proximal and peripheral PAs

– Mural / occlusive thrombi; mural calcification of the PAs – 34%

– Aneurysmal dilatation of the PAs – 21%

• V/Q SPECT / CT of the lungs – 29% (n=19/66)

• OVERALL PREVALENCE:

– Either MDCT or V/Q SPECT/CT – 31% (24/78)

– Both imaging modality – 33% (21/64)

Jensen AS, et al.

Heart 2015; 101:1540-6

Risk Factor for Thromboembolic Complication

Jensen AS, et al.

Heart 2015; 101:1540-6

Cerebral Infarction Are Common

Prevalence of Cerebral Thrombosis

Jensen AS, et al.

Heart 2015; 101:1540-6

• Cerebral infarction: 47%

– 53% (18/34) had more

than one infarction

• Under-reporting:

– 22% stroke by clinical

history

• Open Questions:

– Embolic?

– Ischemic?

Risk Factor for Thromboembolic Complication

Jensen AS, et al.

Heart 2015; 101:1540-6

Cerebral Infarction / PA Thrombosis

NO Association:

• Secondary Erythrocytosis / Iron Status

• Hemostatic Abnormalities (Plt count, TEG)

Coagulation Abnormalities are Common

and Complex in CCHD

• Platelets

– Low Platelet Count

– Dysfunction

• Coagulation Pathway

– Intrinsic / Extrinsic Pathway

• Vascular Factors

– Endothelium dysfunction!

Forearm Blood Flow Response to

Acetylcholine

* p<0.05 vs baseline, †p<0.05 between groups

0

10

20

30

40

50

BL Ach1 Ach2 Ach3 Ach4 Ach5

FB

F (

ml/m

in/1

00

ml F

AV

)

Controls

CCHD

*†

***

*†

*†

*†Interaction

Controls vs CCHD p<0.0001

Controls

p<0.0001

CCHD p=0.01

Oechslin E, et al. Circulation 2005; 112:1106-1112

Severe

Endothelial Dysfunction!

Should We Routinely Anticoagulate

Patients With CCHD?

• Hard End-points

– Improved survival

– Decreased prevalence of thromboembolic complications

without increased risk of bleeding

• Risk - Benefit Assessment

Bleeding

Prevention of

Thrombus Formation Bleeding Prevention of

Thrombus Formation

Landmark Paper on ES: Paul Wood

Courtesy of Prof. Jane Somerville, London

Prevalence of Hemoptysis

Year Institution N Hemoptysis Percent

1958 (Wood, BMJ 5099)

London,

Brompton

127 42 33%

1998 (Daliento, EHJ 1998)

Torino

Padua

London

188 38 20%

1999 (Niwa, JACC 1999)

UCLA 77 35 46%

1999 (Cantor, AJC 1999)

Toronto 109 12 11%

2007 (Broberg, JACC 2007)

London,

Brompton

55 27 49% 28% combined

Courtesy of Prof. Jane Somerville, London

Hemoptysis: Most Common Mode of Death

From: Past and current cause-specific mortality in Eisenmenger syndrome Eur Heart J. Published online April 18, 2017. doi:10.1093/eurheartj/ehx201

8% 7%

Eisenmenger Syndrome:

Cause of the Death in the Modern Era

Hjortshoj CMS et al.

Eur Heart J 2017; in press

Vascular Factors • Arteriolar Dilatation

• Increased Tissue

Vascularity

Endothelial

Dysfunction

Platelet Abnormalities • Low Platelet Count

• Platelet Dysfunction

Coagulation

Pathway

Ischemia / Thrombosis

Bleeding

Intrapulmonary Hemorrhage

THROMBUS

BLEEDING /

HEMOPTYSIS

Thrombosis of

subclavian vein

Therapeutic

anticoagulation

Mechanical

Fall:

Hematoma

D/C Warfarin

48 y/o man:

CCHD:

Non-Eisenmenger

Physiology

Thrombosis of

subclavian vein:

Therapeutic

anticoagulation

Mechanical

Fall:

Hematoma

D/C Warfarin

Ischemic stroke

Anticoagulation?

PRO

• Thrombus formation

– Laminated thrombus

Cons

• Retrospective data

• Intrinsic coagulopathy

• Eisenmenger syndrome ≠ IPAHT

• Monitoring of INR!!

• Target INR?

• Dismal hemoptysis

– Warfarin related deaths (Somerville

1998)

No clinical trial

to support the benefit of

routine anticoagulation

in cyanotic CHD

Sandoval J, et al.

Congenit Heart Dis 2012; 7:268-76

p=0.22

Univariate Predictors of

Death:

• Functional Class III/IV

• Clinical evidence of heart

failure

• MCV < 80fL

• Higher mean PAP

Sandoval J, et al.

Congenit Heart Dis 2012; 7:268-76

Hemorrhagic Complications

Anticoagulated Patients:

• Severe bleeding: 4

– Two fatal bleedings

(hematothorax -1

cardiac tamponade -1)

• Minor bleeding: 3

– Epistaxis, gingival bleeding,

bruising

Non-anticoagulated Patients:

• NO serious bleeding

• Minor bleeding: 3

– Epistaxis (2)

– Mild hemoptysis (1)

Sandoval J, et al.

Congenit Heart Dis 2012; 7:268-76

No Survival Benefit for Pts on OAK / ASA

• Study population: n = 153

– Mean age 23.0 14.3 yrs

– Oral anticoagulation: 17.6%

– ASA: 23.5%

Diller GP, et al.

Eur Heart J 2016;371:1449-55

HR 0.93

(0.47-1.82) HR 1.07

(0.52-2.22)

Key Questions

• Is there a survival benefit?

– Probably not

• Increased morbidity?

– Probably yes

• Is monitoring of INR simple?

– NO!!!!

Strong Indication for Anticoagulation

Which Cyanotic Patients Should Be

Anticoagulated?

Therapy

No risk factors

No

anticoagulation

Prophylaxis

Risk factors •AFli / AFla

Anticoagulation

• Vein thrombosis

• Thromboembolic

events

Optimal INR?

• No prospective study

• Therapeutic aPTT: 1 x control

• Target INR: 2.0 – 2.5

– Narrow therapeutic range because of increased risk of

bleeding!

Laboratory Precautions Hematocrit – Plasma Volume

Cyanotic Congenital Heart Disease

70% 60%

40%

Laboratory Precautions

70%

To adjust the amount

of sodium citrate

Clinical and

Laboratory

Standards Institute

Summary

• High prevalence of silent thromboembolic events

– Underreported prevalence of CVA and pulmonary

thrombosis

– Prevalence of both cerebral and pulmonary thrombosis of

around 30% - 40% (Jensen et al, Heart 2015)

• Fragile balance of hemostasis:

– Bleeding vs thrombus formation

Summary

• ‘Anecdotal’ experiences

– No prospective data

– Small case series / limited follow-up

• Routine anticoagulation remains controversial

without proven benefit / strong indication

• Meticulous monitoring remains a challenge

RISK REDUCTION Strategy for

Thrombosis and Bleeding

• Assessment of integrity of hemostasis

• Assessment of thromboembolic risk

• Risk reduction strategy for:

– Bleeding complications

– Thromboembolic events

• Multidisciplinary team approach!

INDIVIDUAL RISK

ASSESSMENT AND

STRATIFICATION

ANTICOAGULATION:

YES or NO