Transcript Exclusion Criteria

EBM Rapid Fire Track
Management of Anticoagulant
Related Bleeding Complications
Amir K Jaffer, MD
Chief, Service of Medicine
University of Miami Hospital and
Division Chief, Hospital Medicine
Department of Medicine
Leonard M. Miller School of Medicine
University of Miami
Disclosure
Financial Interest/
Affiliation
Commercial
Organization(s)
Grant/Research Support
AstraZeneca
Consultant
AstraZeneca
Sanofi aventis
Speaker’s Bureau
Sanofi aventis
Major Shareholder
__
Board Membership
SPAQI, AC Forum
Question 1
•
•
What are the risk factors for bleeding
on warfarin or other anticoagulants?
Who is at risk?
Coagulation Cascade
XIIa
XII
Extrinsic
Pathway
XIa
XI
Intrinsic
Pathway
IXa
IX
Inhibition of
Thrombolysis
Platelet
Activation
Reactivation of
Coagulation Cascade
Walenga et al. Thromb Res. 1997;86:1-36.
Tissue
Factor
VIIa
VII
X
Xa
VIIIa
IIIIa
(prothrombin)
(thrombin)
FIBRINOGEN
FIBRIN
Va
Fondaparinux (Synthetic Pentasaccharide)
Fondaparinux
Turpie et al. NEJM 2001;344:619-25
Bleeding Rates for Selected
Anticoagulants in Clinical Trials
Agent
Warfarin
Indication
Major Bleeding (%)
•Mechanical Valves
1-8.3
•Atrial Fibrillation
1-6.6
•VTE Treatment
1-3
Unfractionated
Heparin (UFH)
•VTE Prophylaxis
3.5
•VTE Treatment
2.0
•ACS
4.5
LMWH
(Enoxaparin)
•VTE Prophylaxis
1.7
•VTE Treatment
2.1
•ACS
4.7
Fondaparinux
•VTE Prophylaxis
2.7
•VTE Treatment
1.2
•ACS
2.2
Vitamin K Antagonists (VKA):
Risk Factors for Bleeding
• Intensity of Anticoagulation (Level of
INR)1
• Age2
• Medical Conditions3
– HTN
– Cerebrovascular disease
– Chronic Renal Insufficiency
– Malignancy
1.
2.
3.
Hylek et al. Ann Intern Med 1994;120:897-902
Fang et al. Ann Intern Med 2004141:745-752
White et al. Arch Intern Med 1996;156(11):1197-201
Vitamin K Antagonists (VKA):
Risk Factors for Bleeding
• Length of time on warfarin1
• Concomitant drugs2
– ASA + VKA
– NSAIDs + warfarin
– Metabolized by the Cytochrome P-450
– Thienopyridines
• Occult pathologic lesion1
1.
2.
Landefeld et al. Am J Med 1989;87:144-52
Levine et al. Chest 2004:126:287S-310S
Acetaminophen can cause
Excessive Anticoagulation
INR > 6.0
# 325 mg (tabs/ week)
OR
P
7 - 13
3.5
0.02
14 - 27
6.9
0.001
 28
10.0
0.001
Hylek et al. JAMA. 1998; 278: 657
Age and Risk of Warfarin associated
Extracranial Hemorrhage
Fang et al. J Am Geriatric Soc 2006;54:1231-1236
Age and Risk of Warfarin associated
Intracranial Hemorrhage
Fang et al. J Am Geriatric Soc 2006;54:1231-1236
Intensity of Anticoagulant Effect
INR Values at the Time of Stroke or ICH in AF Pts
Odds Ratio
15
Stroke
Intracranial Bleed
10
5
1
0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
8.0
INR
Hylek EM, Singer DE. Ann Intern Med. 1994;120:897-902.
Hylek EM, et al. N Engl J Med. 1996;335:540-546.
Duration of Treatment and Bleeding
Meta-analysis (33 studies):4,374 pt–y VTE Rx
.
Case-Fatality Rate
Major Bleeding (%)
Rate ICH (%)
Initial
3 mo.
9.3 (3.1 – 20.3)
1.48 (1.40 – 1.56)
Subsequent
to 3 mo.
9.1 (2.5 – 21.7)
0.65 (0.63 – 0.68)
Time
Linkins LA, et al. Ann Intern Med. 2003;139:893-900.
Outpatient Bleeding Risk Index
• What risk factors are
present?
Age >65 years
history of stroke
history of GI B
Recent MI, Hct.<30%, Cr. >1.5
mg/dl or history of DM
Low Risk (0)
• Sum the risk factors
=____
Inter. Risk (1-2)
High Risk (3-4)
Estimated Risk
for Major Bleeding
3 months
2%
5%
23%
12 months
3%
12%
48%
Beyth et al. Am J Med 1998;105:91-99
Clinical Prediction rule for
Hemorrhage
HEMORR2HAGES by adding 2 points for a prior bleed and 1 point for :
hepatic or renal disease, ethanol abuse, malignancy, older (age > 75 years), reduced platelet
count or function, hypertension (uncontrolled), anemia, genetic factors, excessive fall risk, and
stroke.
Gage et al. Am Hear J 2006;151:713-9.
Heparin:
Risk Factors for Bleeding
• For every 10 second increase in aPTT,
major bleeding increases by 7%
• Age > 70
• Renal insufficiency
• Concomitant drugs
– Thrombolytics
– GP IIb/IIIa
Levine et al. Chest 2004:126:287S-310S
LMWHs and Bleeding in Renal Insufficiency (RI)
Total Studies
7 Full dose Studies
Odds Ratio
(99% CI)
P
Value
96/4081
3.88
(1.78-8.45)
0.03
5/265
0.58
(0.09-3.78)
0.52
RI
No RI
(N=348)
(N=4393)
17/206
4 Adj. dose Studies 1/106
Lim et al. Ann Intern Med 2006;144:673-684
Fondaparinux
• Contraindications:
– Low body weight (< 50 kg)
– Renal impairment (CrCl< 30ml/min)
• Renal function should be assessed
periodically in patients receiving the
drug
ARIXTRA® (fondaparinux sodium) Injection Package Insert
7th ACCP Conference
Recommendations
• We recommend consideration of
renal impairment when deciding
on doses of LMWH, fondaparinux,
the direct thrombin inhibitors, and
other antithrombotic drugs that are
cleared by the kidneys, particularly
in elderly patients or those at high
risk for bleeding (Grade 1C+)
ACCP=American College of Chest Physicians.
Geerts WH, et al. Chest. 2004; 126:338S-400S.
Question 2
•
In the setting of a coagulopathy,
when should Vitamin K be used and
through which route?
Outcomes of Ambulatory Patients with
Excessive Warfarin Anticoagulation
• Prospective observational study
• No Vitamin K
• Major bleed, 2 weeks:
– Fatal, intracranial, hospitalization + 2 U transfusion
INR > 6
Major Bleed
INR 2-3
(n = 114)
(n = 268)
4.4 %
0%
Hylek, Arch Intern Med 2000;160:1612
Treatment of Warfarin-Associated
Coagulopathy with Oral Vitamin K: a RCT
• Double-blind, INR 4.5 - 10, non-bleeding
• Outcomes
– INR 1.8 - 3.2, day after
– Major bleed, 3 m (hospitalization, transfusion)
Vit. K 1mg
(n = 45)
INR 1.8 - 3.2
Major Bleed
56 %
4%
Placebo
(n = 44)
20 %
17 %
Crowther, Lancet 2000;356:1551
Treatment of Coumarin-associated
Coagulopathy: Systematic review
• Medline, Embase between 1966-2005
• RCTs or Prospective trials
• Low dose oral Vitamin K rapidly and
reliably returned the INR to therapeutic
range in non-bleeding patients
• IV Vitamin K and coagulation factors
should really be given to those with
bleeding
Dentali et al. J Thromb Haemost 2006:4:1853-1863
Treatment Strategy for Elevated
INRs in Asymptomatic Patients
• INR 4.5—10.0
1. Hold Warfarin
2. Give oral 1mg Vit K
(or give 2.5 mg)
3. Give warfarin at
lower dose the
following day
4. Recheck INR the
next day or so
Dentali et al. J Thromb Haemost 2006:4:1853-1863
Treatment Strategy for Elevated
INRs in Asymptomatic Patients
• INR > 10.0
1. Hold Warfarin
2. Give vitamin K 2.55 mg po or 1mg Vit
K IV
3. Recheck INR in 24
hrs
Dentali et al. J Thromb Haemost 2006:4:1853-1863
Treatment Strategy for Bleeding Patients
• Major but non-life
threatening bleeding
with any INR
1. Hold OAT
2. Give IV Vit K 1-10 mg
3. Consider
administration of coag
factors by using
complex concentrates
or plasma
4. Supportive therapy
with transfusions and
plts as needed
Dentali et al. J Thromb Haemost 2006:4:1853-1863
Treatment Strategy for Bleeding Patients
• Life threatening
bleeding with any
increase in INR
1. Hold OAT
2. Give IV Vit K 1-10 mg
3. Replace coag factors
by using complex
concentrates or
plasma
4. Treat remediable
causes of bleeding
5. Supportive therapy
with transfusions and
plts as needed
Dentali et al. J Thromb Haemost 2006:4:1853-1863
Question 3
•
•
How should intracranial
hemorrhage related to
anticoagulant therapy be
managed?
When can anticoagulation
be resumed?
Treatment of Warfarin-associated
Intracerebral Hemorrhage
Aguilar et al. Mayo Clin Proc 2007;82:82-93
Treatment of Warfarin-associated
Intracerebral Hemorrhage
Aguilar et al. Mayo Clin Proc 2007;82:82-93
Question 4
• When should recombinant Factor VII
(Novo-7) be used for coagulopathy
prophylactically?
• When should it be used in the setting of
bleeding?
Recombinant factor VIIa
(rFVIIa):
• Mechanism of action:
Targets sites of
exposed tissue factor
• Rapid and predictable
reversal of
anticoagulation
• Expensive
• Short duration of action
• Potential risk of
thrombosis
• Can reverse LMWH,
warfarin, fondaparinux
Hedner et al. Sem Thromb Hemost 2006;32:77-85
Approved Indications
• Patients with Factor VIII or IX inhibitor
– For vigorous or persistent bleeding or prior
to invasive procedure
– 90 microgram/kg every 2-3 hrs
Goodnough et al. Curr Opin in Heme 2007;14:505
Non-Approved Clinical Use
• Use low-dose rFVIIa (50-100 µg/kg) for lifethreatening bleeding unresponsive to
conventional therapy (platelets, FFP,
cryoprecipitate and PRBCs)
• Anticoagulation-induced hemorrhage only
after conventional therapies have failed
• Uncontrolled hemorrhage associated with
trauma, surgery or liver failure
Goodnough et al. Curr Opin in Heme 2007;14:505
Use with Caution in
•
•
•
•
•
•
Cardiac Surgery
History of CAD
History of VTE
DIC
On ECMO or VAD
Cerebrovascular disease
Goodnough et al. Curr Opin in Heme 2007;14:505
rFVIIa in Hemorrhagic Stroke
Mayer et al. NEJM 2005;352:777-85
Survival at 90 Days
Mayer et al. NEJM 2005;352:777-85
Treatment of UFH or LMWH
related Bleeding
• 1mg for every 100
units of heparin
• No greater than 50
mg of protamine at
one time
• Infusion should not
exceed 5 mg/min
• 1mg/mg of
Enoxaparin
Deloughery et al. Crit Care Clin 2005;21:497-512
Conclusion:
Anticoagulant-Associated Bleeding Event
Rapid and continuous assessment and reassessment of
patient’s condition
•Initiate life saving therapy
•Consider transfer to ICU
•Measure activity of coagulation cascade
•Withdraw anticoagulant therapy
•Consider antidote if one exists
Any mechanical
Issues
•Endoscopy, surgery,
interventions
Consider
prohemostatic
Agents
•Antifibrinolytic agents,
DDAVP, rVIIa
Consider
modalities that may
specifically remove
Anticoagulant
(Dialysis, hemoperfusion,
Plasmapheresis)
Adapted from Crowther et al; Blood 2008