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100 Anticoagulation Therapy
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TABLE 5-9: DTI Dosing Considerations for Open Heart Surgical
Procedures
Agent Pump
Bivalirudin
with pump
Bivalirudin
without
a
pump
Argatroban
with pump
Argatroban
without
b
pump
a
Hemofiltration can be used to decrease bivalirudin concentrations at end of procedure. In the
CHOOSE-ON trial, 50 mg was added to the priming solution with a 1-mg/kg bolus followed by
2.5 mg/kg/hr until 15 minutes before planned going of cardiopulmonary bypass.
targeted 2.5 x baseline or more. Additional bolus doses of 0.1–0.5 mg/kg could be used for
subtherapeutic ACT. With the initiation of recirculation, reconnect arterial and venous lines, clamp
arterial filter, infuse residual blood, refill CPB with saline, recirculate and add a 50-mg bolus
followed by continuous infusion of 50 mg/hr into the circuit until determined that CPB was not
necessary to reestablish.
b
Limited case reports with argatroban. Anticoagulation with argatroban has shown to be
inconsistent in CABG cases.
• Cessation of anticoagulant: commonly done prior to restoration of flow to grafts.
• If using a cell-saver device during procedure for bivalirudin, add 1 part citrate 3–4% to 6−8
parts blood to prevent clotting in the reservoir.
• Because bivalirudin is enzymatically cleared, elimination may be severely impaired during
episodes of hypothermia and may lead to some accumulation. Depending on observed ACT
measures, the infusion may actually need to be held.
• Hypothermia induced during surgery may shut down the clotting cascade. Depending on the
situation, anticoagulation may need to be reduced or turned off.
ACT: activated clotting time, CABG: coronary artery bypass graft, CPB: cardiopulmonary bypass,
x: times
12,34,35
Priming
Systemic
Bolus
Infusion
Rate During
CABG
a
50 mg to
priming
1 mg/kg 2.5 mg/kg/hr Maintain
solution
– 0.75 mg/kg 1.75 mg/kg/hr ACT:
50 mcg/kg 100 mcg/kg 5–10 mcg/
b
kg/min
5 mg 2–5 mcg/kg/
min
Suggested
Target
(High
Range ACT)
ACT:
≥2.5 x
baseline
>300 sec
ACT:
300–400 sec
ACT:
>200 sec
Adjustment
(if needed)
Rate: +/– 0.25
mg/kg/hr
or
Intermittent
bolus: 0.1–0.5
mg/kg; stop 20
min before going
off pump
Rate: +/– 0.25
mg/kg/hr
or
Intermittent
bolus: 0.1–0.5
mg/kg; stop 15
min before flow
restored down all
grafts
34
ACT values
PARENTERAL DIRECT THROMBIN INHIBITORS 101
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•
The management goals should be clearly defined at the initiation of a DTI, and
should include reassessments and revisions as needed.
•
In situations where the device requires consistent anticoagulation, the DTI should
be started at the same time heparin would have been, with frequent assessments
until the revised target range is achieved.
Additional consideration to note: Circulatory support devices can also
cause thrombocytopenia, so caution and careful assessment should occur
for changing to a DTI for suspected HIT.
Use in Pediatric Patients (see Table 5-10)
Consider alternative anticoagulant dosing in pediatric patients under HIT
conditions:
•
Body weight may be correlated with clearance.
•
Dosing in infants or neonates is unclear.
•
Higher doses may be required during ECLS or invasive procedures, including
cardiac surgery.
TABLE 5-10: Dosing Considerations for DTIs in Pediatric
Patients
Agent
Dose
Argatroban • In normal hepatic function, doses similar to observations in adults may
Bivalirudin
apply; younger patients <6 months may have lower clearance and require
a lower dose; higher doses may be used in selected situations.
• A bolus of 0.1–0.25 mg/kg has been used.
•
Infusion rate 0.15 ± 0.07 mg/kg/hr (average ranges between 0.05 and
0.31 mg/kg/hr have been observed).
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Use in Pregnant and Lactating Patients (see Table 5-11)
TABLE 5-11: Direct Thrombin Inhibitors in Pregnancy and
Lactation
Drug Pregnancy Risk
Category
Pregnancy Information Lactation Information
Bivalirudin B Although animal studies
have not shown harm
to the fetus, safety and
efficacy for use in pregnant
women have not been
established. Bivalirudin is
used in conjunction with
aspirin, which may lead to
maternal or fetal adverse
effects, especially during
the third trimester. Use
during pregnancy only if
clearly needed.
Argatroban B Adverse events were not
observed in animal studies
and there are no adequate
and well-controlled studies
in pregnant women.
Argatroban should be used
in pregnant women only if
clearly needed.
Excretion in breast milk
unknown; use caution.
Excretion in breast
milk unknown/not
recommended.
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SIDE EFFECTS, PRECAUTIONS,
CONTRAINDICATIONS (SEE TABLE 5-12)
TABLE 5-12: Side Effects, Precautions, and Contraindications
Argatroban Bivalirudin
Side Effects
>10%
Cardiovascular—chest pain,
hypotension
Gastrointestinal—gastrointestinal
bleed
Genitourinary—genitourinary bleed
and hematuria
>10%
Cardiovascular—hypotension
Central nervous system—pain,
headache
Gastrointestinal—nausea
Neuromuscular and skeletal—back
pain
1−10%
Cardiovascular—atrial fibrillation,
angina, bradycardia, CABGrelated bleeding, cardiac arrest,
cerebrovascular disorder, myocardial
infarction, myocardial ischemia,
vasodilation, ventricular tachycardia,
thrombosis
Central nervous system—fever,
headache, intracranial bleeding pain
Dermatologic—skin reactions
Gastrointestinal—abdominal pain,
diarrhea, nausea, vomiting
Genitourinary—urinary tract infection
Hematologic—hemoglobin
decreased, hematocrit decreased
Local—bleeding at injection or access
site
Neuromuscular and skeletal—back
pain
Renal—abnormal renal function
Respiratory—dyspnea, cough,
hemoptysis, pneumonia
Miscellaneous—sepsis, infection
Precautions Patients with increased risk of
hemorrhage:
•
Bleeding disorders
• GI ulcers hepatic impairment
• Lumbar puncture
• Major surgery
• Severe hypertension
• Spinal anesthesia
1−10%
Cardiovascular—hypertension,
bradycardia, angina
Central nervous system—insomnia,
anxiety, fever, nervousness
Gastrointestinal—vomiting,
dyspepsia, abdominal pain
Genitourinary—urinary retention
Hematologic—major hemorrhage;
transfusion required,
thrombocytopenia
Local—injection site pain
Neuromuscular and skeletal—pelvic
pain
• Thrombus formation
• Preexisting disease states
associated with increased risk
of bleeding
• Elderly patients; increased risk
of bleeding events
•
Avoid IM use due to increased
risk of bleeding
Contraindications • Overt major bleeding
CABG: coronary artery bypass graft, GI: gastrointestinal, IM: intramuscular
• Hypersensitivity to argatroban
• Active major bleeding
• Hypersensitivity to bivalirudin
or its components
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REFERENCES AND KEY ARTICLES*
1. Kaplan KL. Direct thrombin inhibitors. Expert Opin Pharmacother. 2003;4:653-666.
Mann MJ, Tseng E, Ratcliffe M, et al. Use of bivalirudin, a direct thrombin inhibitor,
2.
and its reversal with modified ultrafiltration during heart transplantation in a patient
with heparin-induced thrombocytopenia. J Heart Lung Transplant. 2005;24:222-225.
*3.
Dager WE, Dougherty JA, Nguyen PH, et al. Heparin-induced thrombocytopenia:
a review of treatment options and special considerations. Pharmacotherapy.
2007;27:564-587.
4.
Gosselin RC, Dager WE, King JH, et al. Effect of direct thrombin-inhibitors:
bivalirudin, lepirudin and argatroban, on prothrombin time and INR measurements.
Am J Clin Path. 2004;121:593-599.
Linkins LA, Dans AL, Moores LK, et al. Treatment and prevention of heparin-induced
*5.
thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis. 9th ed.
American College of Chest Physicians Evidence-based Clinical Practice Guidelines.
Chest. 2012;141(suppl 2):e495S-e530S.
6. Keyl C, Zimmer E, Bek MJ, Wiessner M, et al. Argatroban pharmacokinetics and
pharmacodynamics in critically ill cardiac surgical patients with suspected heparininduced thrombocytopenia. Thromb Haemost. 2016;115(6):1081-1089.
7.
Beiderlinden M, Treschan TA, Görlinger K, Peters J. Argatroban anticoagulation in
critically ill patients. Ann Pharmacother. 2007 May;41(5):749-754. Erratum in: Ann
Pharmacother. 2007;41(7):1320.
Keegan SP, Rolik EM, Ernst NE, et al. Effects of critical illness and organ failure on
8.
therapeutic argatroban dosage requirements in patients with suspected or confirmed
heparin-induced thrombocytopenia. Ann Pharmacother. 2009;43:19-27.
9.
Ansara AJ, Arif S, Warhurst RD. A weight-based argatroban dosing nomogram for the
treatment of heparin induced thrombocytopenia. Ann Pharmacother. 2009;43:9-18.
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patients with acute isolated heparin-induced thrombocytopenia: an analysis of 3
prospective studies. Blood. 2004;104:3072-3077.
Huhle G, Hoffmann U, Hoffmann I, et al. A new therapeutic option by subcutaneous
11.
recombinant hirudin in patients with heparin-induced thrombocytopenia type II: a
pilot study. Thromb Res. 2000;99:325-334.
*12. Hassell K. The management of patients with heparin-induced thrombocytopenia who
require anticoagulant therapy. Chest. 2005;127:1S-8S.
13. 2015 ESC guidelines for the management of acute coronary syndromes in patients
presenting without persistent ST-segment elevation: Task Force for the Management
of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment
Elevation of the European Society of Cardiology (ESC). Eur Heart J. 2016;37(3):267-
315. doi:10.1093/eurheartj/ehv320.
14. Amsterdam EA, Wegner NK, Brindis RG, et al. 2014 AHA/ACC Guideline for the
management of patients with non-ST-elevation acute coronary syndromes: a report of
the American College of Cardiology/American Heart Association Task Force on Practice
Guidelines. Circulation. J Am Coll Cardiol. 2014;64(24):e139-228.
15. Tsu L, Dager W. Bivalirudin dosing adjustments for reduced renal function with or
without hemodialysis in the management of heparin-induced thrombocytopenia. Ann
Pharmacother. 2011;45:1185-1192.
PARENTERAL DIRECT THROMBIN INHIBITORS 105
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16. Runyan CL, Cabral KP, Riker RR, et al. Correlation of bivalirudin dose with creatinine
clearance during treatment of heparin-induced thrombocytopenia. Pharmacotherapy.
2011;31:850–856.
Hursting MJ, Murray PT. Argatroban anticoagulation in renal dysfunction: a literature
17.
analysis. Nephron Clin Pract. 2008;109:c80–c94.
18. Fischer KG. Hirudin in renal insufficiency. Semin Thromb Hemost. 2002;28:467-482.
19.
van Cott EM, Roberts AJ, Dager WE. Laboratory monitoring of parenteral direct
thrombin inhibitors. Semin Thromb Hemost. 2017 [Epub ahead of print].
Kiser TH, Burch JC, Klem PM, et al. Safety, efficacy, and dosing requirement of
20.
bivalirudin in patients with heparin-induced thrombocytopenia. Pharmacotherapy.
2008;28:1115-1124.
21.
Kiser TH, Fish D. Evaluation of bivalirudin treatment for heparin-induced
thrombocytopenia in critically ill patients with hepatic and/or renal dysfunction.
Pharmacotherapy. 2006;26:452-460.
Vanholder R, Camez A, Veys N, et al. Pharmacokinetics of recombinant hirudin in
22
hemodialyzed end-stage renal failure patients. Thromb Haemost. 1997;77:650-655.
23. Grouzi E. Update on argatroban for the prophylaxis and treatment of heparin-induced
thrombocytopenia type II. J Blood Med. 2014;5:131-141.
24. Murray PT, Reddy BV, Grossman EJ, et al. A prospective comparison of three
argatroban treatment regimens during hemodialysis in end-stage renal disease. Kidney
Int. 2004;66:2446-2453.
25.
Klingele M, Bomberg H, Lerner-Gräber A, et al. Use of argatroban: experiences in
continuous renal replacement therapy in critically ill patients after cardiac surgery. J
Thorac Cardiovasc Surg. 2014;147:1918-1924.
Hursting MJ, Verme-Gibboney CN. Risk factors for major bleeding in patients with
26.
heparin-induced thrombocytopenia treated with argatroban: a retrospective study. J
Cardiovasc Pharmacol. 2008;52:561-566.
27.
Lincoff AM, Bittl JA, Harrington RA, et al. REPLACE-2 Investigators. Bivalirudin
and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned
glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2
randomized trial. JAMA. 2003;289:853-863.
28. Dager WE. Considerations for drug dosing post coronary artery bypass graft surgery.
Ann Pharmacother. 2008;42:421-424.
29. Arpino PA, Hallisey RK. Effect of renal function on the pharmacodynamics of
argatroban. Ann Pharmacother. 2004;38:25-29.
30. Brown PM, Hursting MJ. Lack of pharmacokinetic interactions between argatroban
and warfarin. Am J Health-Syst Pharm. 2002;59:2078-2083.
31. Gosselin RC, King JH, Janatpour KA, et al. Comparing direct thrombin inhibitors
using aPTT, ecarin clotting times, and thrombin inhibitor management testing. Ann
Pharmacother. 2004;38:1383-1388.
32. Arpino PA, Demirjian Z, Van Cott EM. Use of the chromogenic factor X assay to predict
the international normalized ratio in patients transitioning from argatroban to warfarin.
Pharmacotherapy. 2005;25:157-164.
33. Trask A, Gosselin RC, Diaz J, et al. Warfarin initiation and monitoring with clotting
factors II, VII and X levels. Ann Pharmacother. 2004;38:251-256.
106 Anticoagulation Therapy
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34. Koster A, Dyke CM, Aldea G, et al. Bivalirudin during cardiopulmonary bypass in
patients with previous or acute heparin-induced thrombocytopenia and heparin
antibodies: results of the CHOOSE-ON trial. Ann Thorac Surg. 2007;83:572-577.
Greinacher A. The use of direct thrombin inhibitors in cardiovascular surgery in patients
*35.
with heparin-induced thrombocytopenia. Semin Thromb Hemost. 2004;30:315-327.
36. Bain J, Flannery AH, Flynn J, Dager W. Heparin induced thrombocytopenia with
mechanical circulatory support devices: review of the literature and management
considerations. J Thromb Thrombolysis. 2017;44(1):76-87.
37.
Crouch MA, Kasiraja V, Cahoon W, et al. Successful use and dosing of bivalirudin
after temporary total artificial heart implantation: a case series. Pharmacotherapy.
2008;28:1413-1420.
6
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Chapter
THROMBOLYTIC
CONSIDERATIONS WHEN USED
WITH ANTICOAGULANTS
Toby C. Trujillo and Tyree H. Kiser
INTRODUCTION
Today thrombolytic agents such as recombinant tissue plasminogen activator
(rt-PA), reteplase, and tenecteplase (TNK) are crucial agents in the treatment of
acute myocardial infarction (AMI), stroke, venous thromboembolism (VTE) (including massive pulmonary embolism [PE]), and peripheral arterial thrombosis as well
as other unique thromboembolic conditions. Their ability to dissolve clot, as
opposed to preventing clot expansion, is a key distinguishing characteristic from
other anticoagulant agents, which makes them valuable options when immediate
nonsurgical reperfusion of an occluded vessel is warranted. Despite their clinical
utility, thrombolytic agents carry a high risk of bleeding, especially intracranial
hemorrhage. Patient selection must be carefully considered to optimize the risk−
benefit ratio with these agents.
PHARMACOLOGY AND PHARMACOKINETICS
•
Four thrombolytic agents are commercially available in the US: streptokinase, rt-PA
(alteplase [Activase]), reteplase (Retavase), and TNK (TNKase). Each of these agents
has distinct pharmacologic properties that impact their clinical use (see Table 6-1).
Mechanism of Action
•
All of the available agents exert their effect on the endogenous fibrinolytic system by
converting plasminogen to plasmin through hydrolysis of the arginine−valine bond in
plasminogen. Plasmin cleaves fibrin and fibrinogen leading to clot dissolution, as well
as degrading the procoagulant factors V and VIII.
•
Urokinase and streptokinase produce plasminogen activation on a systemic level,
leading to global activation of plasminogen to plasmin. With doses used for systemic
effects, plasmin may be depleted and fibrin/fibrinogen degradation products may
produce a systemic anticoagulant effect.
•
Recombinant t-PA, reteplase, and TNK are all fibrin-specific thrombolytic agents. As
such, minimal amounts of plasminogen are converted to plasmin in the absence of
fibrin leading to a more localized thrombolytic effect.
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•
Of note, in patients with plasminogen levels significantly below normal (e.g.,
<50%) at therapy initiation, the therapeutic response from an exogenously
administered thrombolytic agent may be blunted or less than expected.
•
Thromboelastography (See Chapter 21, Coagulation Laboratory Considerations)
can be used to assess the level and duration of thrombolysis. It can be a useful
tool to determine if adequate lysis is present when attempting to dissolve a
thrombus, but cannot be used to determine if thrombolytic dosage is too high.
Pharmacologic and Clinical Properties of Thrombolytics
TABLE 6-1: Characteristics of Available Thrombolytic Agents
Property Urokinase+Streptokinase Alteplase
(rt-PA)
Molecular weight, kD35 47 70 39 70
Half-life, min 13–20 23 4–8 14–18 23–37
Fibrin specificity Minimal Minimal Moderate Moderate High
Reteplase Tenecteplase
(TNK)
Potential
antigenicity
Plasminogen
binding
FDA-approved
indications
Patency with TIMI
Grade 3 flow* – 90
min
+
Currently not commercially available in the United States.
*TIMI Grade 3 flow (see Table 6-3): complete perfusion defined by normal flow, which fills
the distal coronary bed completely. TIMI Grade 0 flow is no perfusion, with Grades 1 and 2
representing partial perfusion of the myocardium.
DVT: deep venous thrombosis, FDA: U.S. Food and Drug Administration, MI: myocardial
infarction, PE: pulmonary embolism, TIMI: thrombolysis in myocardial infarction
No Ye s No No No
Direct Indirect Direct Direct Direct
PE MI, PE, DVT MI, PE,
stroke,
catheter
occlusion
NA 40–50% 46–75% 60–63% 63%
MI MI
INDICATIONS, DOSING, AND
ADMINISTRATION
•
Depending on the half-life of the compound being used, administration is either
by single or multiple intravenous (IV) boluses or through a continuous IV infusion
given for a specified time frame (see Table 6-2).
•
Catheter flush is for localized (catheter-related) thrombosis.
•
Devices (e.g., ultrasound-accelerated thrombolysis catheters, mechanical circulatory support).
10-44
THROMBOLYTIC CONSIDERATIONS WHEN USED WITH ANTICOAGULANTS 109
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• Many thrombolytic agents are dosed on body
weight (actual body weight); therefore, obtaining
an accurate weight prior to the initiation of
therapy is crucial to optimize therapy.
•
A small bolus of fluid (50–100 mL normal
saline) should follow the administration of a
thrombolytic dosed for systemic effects to ensure
the entire dose is delivered to the patient and no
drug is remaining in the IV line.
In more emergent situations, it is important to
•
set up in advance the lytic to be used, dose, and
location of the drug including sustaining an
adequate supply for a given indication/situation.
MONITORING
10-21
Monitoring Parameters in ST Segment Elevation
Myocardial Infarction (STEMI)
•
General
Baseline activated partial thromboplastin time (aPTT), prothrombin
time/International Normalized Ratio (PT/INR), hematocrit, platelet
count, fibrinogen (streptokinase therapy)
Coagulation parameters during therapy: aPTT, PT/INR, fibrinogen
level (streptokinase)
Vital signs (blood pressure, heart rate [BP, HR]) at baseline and
during therapy
Bleeding, especially during planned invasive procedures, while
lytic state is in effect
•
Therapeutic
Resolution of electrocardiogram (ECG) changes
Resolution of chest pain
Appearance of reperfusion arrhythmias
Early cardiac enzyme peak (primarily creatinine phosphokinase
[CPK])
Infarct artery patency—TIMI flow (see Table 6-3)
•
Toxicity/adverse effects
Clinical evidence of bleeding (vascular access site, hematuria, GI
bleeding, positive stool guaiac)
Intracranial bleeding—impaired cognitive, motor, or sensory
function on neurologic exam
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