which cyanotic patient needs anticoagulation? -...
TRANSCRIPT
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