Download Anticoagulation Therapy in the CICU

Anticoagulation Therapy
in the CICU:
What, When, Why?
Therese M. Giglia, MD
December 14, 2014
Propensity to Coagulopathy
Virchow’s triad:
factors that
predispose to
thrombosis (1856)
Anesth Analg 2012;114:275–85
Propensity to Coagulopathy
CPB and
Mechanical
Support
Inflammation and
Blood Stream
Infection
Thrombosis in Pediatric and Congenital Heart Disease
Fibrinolysis
Coagulation
Propensity to Coagulopathy
Special Concerns in Cyanotic Heart Disease:
• More than stroke and pulmonary embolus
• Potentially lethal complications of
– MBTS occlusion
– Fontan obstruction
• Loss of arterial and/or venous access for necessary
diagnostic and therapeutic cardiac catheterizations
• Loss of major veins may make bidirectional Glenn or
Fontan impossible
Scope of the Problem
• Overall incidence and prevalence unclear
• Associated with high mortality and morbidity
• Involves many areas of pediatric and congenital HD
– Most Studied: KD, post-cardiac catheterization, ECMO
– Recommendations extrapolated from adult guidelines:
prosthetic valves, arrhythmias, cardiomyopathy, pulmonary
embolus, pulmonary hypertension, VADs, stroke
– Of significant clinical concern but with a paucity of data:
early postoperative thrombosis, single ventricle population, infant
prosthetic valves, VADs in children, stroke in children with heart
disease
Anticoagulation in the CICU: what, when why?
Overview
1. What is available to prevent and treat thrombosis
2. When and Why (Monagle 2012, Giglia 2013, McCrindle 2014)
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Early postoperative thrombosis
Single ventricle population
VADs (Moffett 2014)
Valves (Nishimura 2014, Giglia 2012)
Stroke (Roach 2008, Sinclair 2014)
3. CHOP Initiative on Thrombosis Prevention and Treatment
Anticoagulation in the CICU: what, when why?
What is available to prevent and treat thrombosis:
Pharmacotherapy:
• Anticoagulants
• Antiplatelet agents
• Thrombolytics
Anticoagulation in the CICU: what, when why?
What is available to prevent and treat thrombosis:
1. Pharmacotherapy
2. Avoidance of risk factors
3. Suspicion and surveillance for new thrombosis
4. Collaboration and communication re thrombosis Rx
(CICU, cardiology, surgery, hematology, nursing,
pharmacy)
5. Plan for and follow-up of each thrombotic event
Anticoagulation in the CICU: what, when why?
Pharmacotherapy
Anticoagulants: fibrin, venous clots
• UFH
– IV, short half-life (1-2 hrs), binds to AT and potentiates AT’s
anticoagulate effect 1000X, challenge in neonates who have low
AT, interacts with other plasma proteins high inter and intrapatient dose response, full reversal with protamine, osteoporosis in
adults
• LMWH
– subQ, longer half-life 3-6 hrs, neonates and infants require higher
doses secondary to increased volume of distribution and increased
clearance and decreased AT, cleared by kidneys, 70% reversed by
protamine, less osteoporosis in adults, most widely studies
anticoagulant in children
Anticoagulation in the CICU: what, when why?
Pharmacotherapy
Anticoagulants
• Fondaparinux
– subQ, synthetic analog, longer half life (17hrs), no reversal agent, renal
clearance, reports of successful off-label use in HIT
• Warfarin
– oral, inhibits regeneration of Vit K needed for the synthesis of clotting
factors II, V, VII, X, C, S, Z, dosing difficult in infants; genetic
polymorphisms (metabolism, sensitivity), interaction with many drugs,
sensitivity to dietary Vit K, reversal with Vit K, initial procoagulant effect
• Direct Thrombin Inhibitors (Bivalirudin Argatroban Lepirudin)
– IV, direct/specific/reversible inhibitors of thrombin, half-life 25-60 min,
excreted by liver (bivalirudin/argatroban), kidney (lepirudin),
antibodies/anaphylaxis reported, approved in adults for HIT and coronary
thrombosis, trials in MCS
Anticoagulation in the CICU: what, when why?
Novel Oral Anticoagulants
• Rivaroxaban, Apixiban: direct Factor Xa inhibitors
• Dabigitran: direct thrombin inhibitor
• compared to warfarin;
• wide therapeutic window
• limited drug-drug interactions
• rapid onset
• shorter half-life
• routine monitoring not necessary in adults (unclear in children)
• no reversal agents (dabigitran partially removed with dialysis)
• approved in adults for stroke prevention from atrial fibrillation, treatment of
acute DVT, secondary prevention of DVT post elective knee and hip surgery.
PE (Apixiban). Not approved for mechanical valves. Ongoing pediatric trials.
(www.clinicaltrials.gov),
Anticoagulation in the CICU: what, when why?
Pharmacotherapy
Antiplatelet Agents: (plaque, arterial clots)
• Aspirin
oral/rectal, irreversibly inhibits platelet aggregation, hepatically metabolized/
renally excreted, no reversal agents, plt aggregation panels/mapping
techniques available, usefulness in children not established, ASA
resistance reported, 7 days needed for full plt regeneration after DC
• Clopidogrel
– oral, prevents platelet activation and therefore aggregation, plt aggregation
assays (TEG/PM, VerifyNow, Plateworks) available but not validated in children.
• Dipyridamole
– oral/IV, plt inhibition via cAMP, PGE2 release causes vasodilation
(coronary), hepatically metabolized and excreted in feces
• Abcximab IV, binds to platelet IIb/IIIa receptors preventing aggregation
Anticoagulation in the CICU: what, when why?
Pharmacotherapy
Thrombolytic Agents:
• Tissue-type plasminogen activator (t-PA)
– biosynthetic (recombinant DNA origin), only agents available in US
alteplase (TPA), recteplase (RPA) and tenecteplase (TNK), initiates local
fibrinolysis by binding to fibrin converting entrapped plasminogen to
plasmin that intern degrades fibrinogen, usually used concomitantly with
low-dose UFH, may require plasminogen supplementation, not reversible
but short half-life, pharmacokinetics not established in infants and
children/but long experience
Several modes of delivery:
• Low dose systemic
• High dose systemic
• Catheter directed
• Pharmacomechanical Thrombolysis (Angiojet, Trellis device)
Prosthetic Valve Thrombus
08/17/2012
Prosthetic Valve Thrombus
08/19/2012
Anticoagulation in the CICU: what, when why?
Early Postoperative Thrombosis:
Population
age
Incidence
Associations
Comments
Giglia
2001
pediatric
3.6%
(1930 operations)
Age < 1y, CPB
Median age 2.6m,
medial time from
OR 3 w, CL-DVT, SV
Manlhiot
2011
pediatric
11%
(1542 operations)
<31d, sat<85%,
prev thrombus, TP,
DCA, ECMO, more
days w CVL
Thrombus assoc w
longer LOS, cardiac
arrest,
reintervention,
mortality
Hanson*
2012
*VTE only
pediatric
3.8%
(1070 operations)
SV physiology,
cyanosis, more
days w CVL
37% assoc w CVL,
66% receiving anticoagulation at dx
Emani
2014
neonates
20%
(100 neonates)
SV physiology,
higher mortality
(15% cw 0%),
preop hypercoag
All received UFH
10U/kg/h X4d
Anticoagulation in the CICU: what, when why?
Early Postoperative Thrombosis
Should we anticoagulate prophylactically?
• PROTEKT trial 2003: no benefit to LMWH in preventing CVL-DVT in general
pediatric population (CHD in 23%LMWH/19% std care)
• Schroeder 2010: uFH (10U/kg/hr) not protective against CVL-DVT infants
after cardiac surgery
What can we do?
• Recognize the potential triggers of thrombosis
• Minimize these risk factors whenever possible
• Recognize the signs of perioperative thrombosis. Be suspicious in high-risk
patients and proceed to imaging studies as clinically indicated
• Treat arterial, venous and intracardiac thrombi as per guidelines
• Follow-up plan for each thrombotic event (inpatient and outpatient)
• No data for overall prophylaxis. Define high risk groups.
Thrombosis in SV Heart Disease
4.5 yr HLHS endocarditis post Stage I, EC Fontan July 2009, MSSA endocarditis July 2010,
Stent in EC Fontan Nov 2010. Outpatient Coumadin INR 2-3
Thrombosis in SV Heart Disease
Presented with MSSA Septic Shock, MOSF, Coagulopathy Apr 2011. 4 days later
had hemodynamic compromise and was taken to catheterization
Thrombolysis, homograft covered stents, 3 wks later conduit removal and BDG
Anticoagulation in the CICU: what, when why?
Single Ventricle Heart Disease:
• BTS occlusion post stage I and thrombosis post Fontan well
described
• Coagulation abnormalities documented in HLHS across all
three stages (Odegard 2002, 2009)
• Manlhiot 2012-cross-sectional analysis across 3 stages
– Children at each stage are at increased risk
– Combined over all three stages, 51% of survivors had one or more
thrombotic events
– Early post-operative peak in thrombosis after each stage followed by
lower but constant risk
• Second peak in patients after the Fontan (5-15 yrs)
Thrombosis in SV Heart Disease
enoxaparin
Stage I
40% incidence TE
Enox assoc w dec risk
BDG
28% incidence TE
Enox assoc w dec risk
Fontan
79% 5-yr freedom from TE
94% on Rx , 77% warfarin
Warfarin assoc w dec risk
Manlhiot 2012
Anticoagulation in the CICU: what, when why?
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Prevention and Treatment of Thrombosis in Pediatric and Congenital
Heart Disease A Scientific Statement From the American Heart
Association (Giglia 2013)
Aspirin is recommended therapy for the prevention of long-term shunt
thrombosis in infants and children (Class I; Level of Evidence B).
Antiplatelet therapy may be reasonable in infants and children after a
superior cavopulmonary anastomosis (Class IIb; Level of Evidence C).
Antiplatelet therapy is reasonable after the Fontan procedure (Class IIa;
Level of Evidence C).
Warfarin or LMWH may be reasonable for 3 to 12 months after the Fontan
procedure (Class IIb; Level of Evidence C).
Warfarin may be reasonable after the Fontan procedure for patients with
anatomic or hemodynamic risk factors (Class IIb; Level of Evidence C).
– flow stasis, ventricular dysfunction, arrhythmias, bilateral bidirectional cavopulmonary
anastomoses, hypoplastic cardiac chambers with flow stasis, presence of a blind ended
pulmonary artery stump, Kawashima connection, history of previous thrombosis, proteinlosing enteropathy, prolonged pleural effusions, and prolonged immobilization.
Anticoagulation in the CICU: what, when why?
• Risk may change over time necessitating repeated clinical
screening (Kaulitz 2005)
• An increase in the magnitude of antithrombotic therapy may be
warranted if anatomic and/or hemodynamic risk factors become
present.
• Certain patients appear to be “clotters” and their propensity for
thrombosis may warrant a higher level of surveillance and
possibly a higher level of prophylaxis
• Understanding of risk factors, patients at particular individual
risk (“clotters”), alternative agents, as well as alternative
management strategies are essential.
Chair’s Initiative on Thrombosis Prevention
and Treatment
• Multidisciplinary (Card, Heme, Surg, Nursing, Pharmacy) initiative
to define the incidence and complications of thrombosis in
cardiac patients (CICU, CCU) and to improve both inpatient and
outpatient anticoagulation monitoring and thrombosis therapy
• Dedicated NP
• Weekly Cardiac Thrombosis Rounds
• Red Cap database to track all inpatient thrombi using PC4 for
denominator data
• Pathways for femoral arterial clots post cath (Glatz 2014) and
acute catheter-related VTE
• Pilot initiative using Epic to optimize management of
anticoagulation of cardiac center outpatients
Anticoagulation in the CICU: what, when why?
Prevent, Find, Treat, Follow the Clots
Prosthetic Valve Thrombus
M C-L
7 yr SLL, DORV, VSD, PS, Ebstein’s anom TV
• 26 w gestation
• BTS (10/2006)
• Senning/Rastelli (LV to Ao, homograft RV to PAs) 10/2008
– Chylothorax, TD ligation
• Subaortic resection >> CHB>>>pacemaker
– Arrest during cath>>>ECMO
– VSD closure w Amplatzer on ECMO
– MVR 21 mm St Jude
• MV thrombus 2009 to OR in extremis for thrombectomy
• 6/30/2012 heparin bridge for PM revision
– 5/31/2012 MV mean gradient 5 mm Hg