Embed Size (px)
Citation preview
EBM Rapid Fire TrackManagement of Anticoagulant Related Bleeding Complications
Amir K Jaffer, MDChief, Service of MedicineUniversity of Miami Hospital
and Division Chief, Hospital
MedicineDepartment of Medicine
Leonard M. Miller School of Medicine
University of Miami
Disclosure
Financial Interest/Affiliation
Grant/Research Support
Consultant
Speaker’s Bureau
Major Shareholder
Board Membership
Commercial Organization(s)
AstraZeneca
AstraZenecaSanofi aventis
Sanofi aventis
__
SPAQI, AC Forum
Question 1
• What are the risk factors for bleeding on warfarin or other anticoagulants?
• Who is at risk?
VIIVIIIntrinsic Intrinsic PathwayPathway
Extrinsic Extrinsic PathwayPathway
IXIX
II (prothrombin)II (prothrombin)
XIXI
XIIXIIXIIaXIIa
XX
VIIaVIIaIXaIXa
XIaXIa
IIa (thrombin)IIa (thrombin)
XaXa
Coagulation Cascade
FIBRINOGENFIBRINOGENFIBRINOGENFIBRINOGENFIBRINFIBRINFIBRINFIBRIN
TissueTissueFactorFactorTissueTissueFactorFactor
VIIIaVIIIaVIIIaVIIIa
VaVaVaVaPlateletPlatelet
ActivationActivation
Inhibition of Thrombolysis
Reactivation of Coagulation Cascade
Walenga et al. Walenga et al. Thromb ResThromb Res. 1997;86:1-36.. 1997;86:1-36.
Fondaparinux (Synthetic Pentasaccharide)
Turpie et al. NEJM 2001;344:619-25
Fondaparinux
Bleeding Rates for Selected Anticoagulants
in Clinical TrialsAgent Indication Major Bleeding
(%)
Warfarin •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
1.1. Hylek et al. Ann Intern MedHylek et al. Ann Intern Med 1994;120:897-9021994;120:897-9022. Fang et al. Ann Intern Med 2004141:745-7523. 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. Landefeld et al. Am J Med 1989;87:144-522. Levine et al. Chest 2004:126:287S-310S
Acetaminophen can cause Acetaminophen can cause Excessive Excessive
AnticoagulationAnticoagulation
INR > 6.0INR > 6.0
# 325 mg (tabs/ week)# 325 mg (tabs/ week) OROR PP
7 - 137 - 13 3.5 3.5 0.02 0.02
14 - 2714 - 27 6.9 6.9 0.001 0.001
2828 10.0 10.0 0.001 0.001
Hylek et al. JAMA. 1998; 278: Hylek et al. JAMA. 1998; 278: 657657
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
Od
ds
Ra
tio
Od
ds
Ra
tio
00
INRINRINRINR
55
1515
1010
StrokeStrokeIntracranial BleedIntracranial Bleed
11
5.05.0 6.06.0 8.08.01.01.0 2.02.0 3.03.0 4.04.0 7.07.0
Hylek EM, Singer DE. Ann Intern Med. 1994;120:897-902.Hylek EM, et al. N Engl J Med. 1996;335:540-546.
.
TimeCase-Fatality
RateMajor Bleeding
(%)
Rate ICH (%)
Initial3 mo.
9.3 (3.1 – 20.3)1.48 (1.40 –
1.56)
Subsequentto 3 mo.
9.1 (2.5 – 21.7)0.65 (0.63 –
0.68)
Duration of Treatment and Bleeding
Meta-analysis (33 studies):4,374 pt–y VTE Rx
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
• Sum the risk factors =____
Low Risk (0) Inter. Risk (1-2)High Risk (3-4)
Estimated Risk for Major Bleeding3 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)
7 Full dose Studies 17/206 96/4081 3.880.03 (1.78-8.45)
4 Adj. dose Studies 1/106 5/265 0.580.52 (0.09-3.78)
Odds Ratio PTotal Studies RI No RI (99% CI) Value
(N=348) (N=4393)
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
ARIXTRAARIXTRA®® (fondaparinux sodium) Injection Package Insert (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.ACCP=American College of Chest Physicians.Geerts WH, et al. Geerts WH, et al. ChestChest. 2004; 126:338S-400S.. 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 INR 2-3 (n = 114) (n = 268)
Major Bleed 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 Placebo (n = 45) (n = 44)
INR 1.8 - 3.2 56 % 20 %Major Bleed 4 % 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 2.5-5 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 OAT2. Give IV Vit K 1-10
mg3. 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 OAT2. Give IV Vit K 1-10
mg3. 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 life-threatening 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 EventRapid 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 mechanicalIssues
•Endoscopy, surgery,interventions
Consider prohemostatic
Agents•Antifibrinolytic agents,
DDAVP, rVIIa
Consider modalities that mayspecifically remove
Anticoagulant(Dialysis, hemoperfusion,
Plasmapheresis)Adapted from Crowther et al; Blood 2008
