Download Primary Prophylaxis - Society of Hospital Medicine

Michael Laposata, M.D., Ph.D.
Director of Clinical Laboratories
Massachusetts General Hospital
Clot Formation
Vessel Wall Injury
Vessel Wall Contraction
--- -- ---
Platelet Adhesion
Fibrin Formation
Platelet Aggregation
The Appropriate Level of
Hemostasis
Bleeding
Thrombosis
Balance
Too Much Anticoagulation
in a Thrombotic Patient
1
2
Bleeding
Balance
Thrombosis
The Acquired Risk Factors
•Surgery / Trauma
•Immobilization
•Malignancy
•Pregnancy
•Oral Contraceptives
•Estrogen Replacement Therapy
•Lupus Anticoagulant
•Anticardiolipin Antibody
•Obesity
•Nephrotic Syndrome
•Polycythemia Vera
•Smoking
The Hereditary Risk Factors
Activated protein C resistance
Nearly always the factor V Leiden mutation May be heterozygous or homozygous
Prothrombin G20210A mutation May be heterozygous or homozygous
Hyperhomocysteinemia Acquired Form: From decreased intake of
folate, vitamin B6 and/or vitamin B12
Congenital Form: From enzyme deficiencies
in homocysteine degradative pathways
The Hereditary Risk Factors
•Protein C deficiency Essentially always heterozygous
•Protein S deficiency Essentially always heterozygous
•Antithrombin deficiency Esssentially always heterozygous
•Rare: Plasminogen deficiency
Dysfibrinogenemia
The “Second HIT” Theory for
Initiation of Thrombosis
The presence of more than one risk
factor is needed to manifest thrombosis
in most patients
EXAMPLE:
1 Congenital
1 Acquired
+
= Thrombosis
Risk Factor
Risk Factor
First Point in Diffential Diagnosis:
Coagulation Factors vs. Platelets
Primary
Prophylaxis
Preventing the first
thrombotic event
Primary Prophylaxis
Indications
Post Surgery
Trauma
Medical Patients
Multiple genetic
+/- acquired
Risk factors
Secondary
Prophylaxis
Preventing a
recurrence of a
thrombotic event
Secondary
Prophylaxis
Indications
A first thrombotic event –
may be lifelong therapy
Treatment of an
Existing
Thrombosis
Treatment of an
Existing Thrombosis
• Venous Thrombosis – Deep
Vein Thrombosis and
Pulmonary Embolism
• Acute Coronary Syndrome
• Arterial Thrombosis
Anticoagulants in Use or Nearly Available
Prophylaxis
Treatment
Oral/IV/SQ
Coumadin
X
X
Oral
Unfractionated heparin
X
X
IV/SQ
LMW heparin (Lovenox,
Fragmin, Innohep)
X
X
SQ/IV
Fondaparinux (Arixtra)
X
X
SQ
Hirudin – related
compounds (Lepirudin,
Refludan)
X
IV
Argatroban (Novostan)
X
IV
X
Oral
Ximelagatran (not yet
FDA approved)
X
For Each
Anticoagulant
•Drug Action
•Use in Prophylaxis
•Use in Treatment
Coumadin:
Drug Action
ACTION OF VITAMIN K
CH2
Vitamin K
Factor as
unmodified CH
2
protein
COOH
Factor with
CH2
gamma
carboxyHC - COOH Vitamin K
glutamic
Epoxide
acids
COOH
Coumadin
Vitamin K
epoxide
reductase
activity
Anticoagulants Inhibit the
Coagulation Cascade
XII
XIIa
XI
Warfarin
(Coumadin)
XIa
IX
IXa
Warfarin
(Coumadin)
X
VIIa
III
VII
Xa
II
Fibrinogen
IIa (Thrombin)
Fibrin Clot
ALGORITHM FOR WARFARIN USE
Maintain As Necessary
No
Maintain
INR at 2.0 - 3.5
Overdose?
Yes
Significant
bleeding?
Discontinue
Yes warfarin - give
plasma to stop
bleeding
Yes
No
Discontinue
Desire to regain the
warfarin &
anticoagulated state Yes
allow
as soon as possible?
PT to decline
No
Stop warfarin
Decrease dose
& administer
from before
vitamin K
Coumadin:
Use in Prophylaxis
Recommended Intensity of Oral
Anticoagulation for Common
Indications
Indication
DVT / PE
MI
Cardiogenic Embolus
Tissue Heart Valve
Valvular Heart Disease
Atrial Fibrillation
Mechanical Heart Valve
INR
2.0 - 3.0
2.0 - 3.0
2.5 - 3.5
2.0 - 3.0
2.0 - 3.0
2.0 - 3.0
2.5 - 3.5
Monitoring of Anticoagulants
Used for Prophylaxis Against
Venous Thrombosis
Coumadin to
INR 2.0 – 3.0
Monitoring with INR no
less than once/month
after stabilization of INR
Coumadin to
INR 1.5 - 2.0
Monitoring with INR
once every other month
Coumadin:
Use in Treatment
How Long Until Warfarin
Affected Factors Decrease?
VII
Approximate
Half Life
4 - 7 hours
IX
12 - 24 hours
X
40 - 45 hours
II
60 – 70 hours
Factor
Differences Between Rabbit Brain/lung
Thromboplastins in the U.S.
1 Plasma Sample Split into 3 for
PT Determinations in 3 Different Laboratories
Hospital A
Hospital B
Hospital C
13 Seconds
15 Seconds
17 Seconds
1 Sample Tested Using 3 Different Lots of Same
Thromboplastin Reagent from Same Manufacturer
14 Seconds
15 Seconds
16 Seconds
The International Normalized Ratio - INR
Patient PT
INR = Mean of Normal
PT Range
ISI
ISI: International Sensitivity Index for Thromboplastin
Used for PT Determination
Low ISI = High Sensitivity
High ISI = Low Sensitivity
to Factor Deficiencies
to Factor Deficiencies
Example:
ISI = 2
17.3
3.0 = 10
INR = 3.0
2
PT = 17.3 Seconds
ISI = 3
14.4
3.0 = 10
3
PT = 14.4 Seconds
Consequences of an INR
Miscalculation
INR Goal = 3.0 and PT = 20 sec
Actual ISI = 2.0 and Mistaken ISI = 1
2
20 = 4
10
(Actual)
1
20 = 2
10
(Mistaken)
For INR = 4, withhold dose
For INR = 2, increase dose
Unfractionated
Heparin:
Drug Action
The Antithrombin Pathway
+
+
AT
+
+
Heparin
+
+
AT
Xa
AT
Antithrombin
Conformational
Change
Heparin
Inhibition
of Xa
Heparin
AT: Antithrombin
+
+
AT
Thrombin
(IIa)
Inhibition
of Thrombin
+
Heparin
Anticoagulants Inhibit the
Coagulation Cascade
XII
XIIa
XI
Unfractionated
Heparin
XIa
III
IX
IXa
VIIa
X
Xa
II
Fibrinogen
VII
Unfractionated
Heparin
IIa (Thrombin)
Fibrin Clot
Unfractionated
Heparin:
Use in Prophylaxis
This has essentially no meritpossible exceptions include
patients with renal failure and
those anticipating epidurals
Unfractionated
Heparin:
Use in Treatment
Heparin to
Coumadin
Heparin
Clot
Warfarin
Algorithm for Heparin Use
Prophylaxis
Yes
No Monitoring
No
Low molecular weight
heparin prophylaxis or
therapy in non-obese adults
with normal renal function?
Yes
Maintain
as Necessary
No
Full-dose
unfractionated
heparin
PTT to > 1.5 X
mean of
normal range
Significant
Overdose?
Yes bleeding?
Yes
No
Discontinue
heparin - & watch
carefully for at
least 2 hours
Stop heparinNeutralize with
protamine sulfate
Persistent
bleeding?
Yes
Decrease
heparin dose
No
Yes
Bleeding?
No
More
protamine
sulfate
Heparin response
curves of different
lot numbers of
Ortho Activated
Thromboplastin over
the years. Each year
represents a different
lot number.
Heparin Concentration (u/mL)
Low Molecular Weight
Heparin:
Drug Action
FDA Approved Low Molecular
Weight Heparin Preparations
• Enoxaparin (Lovenox)
• Dalteparin (Fragmin)
• Ardeparin (Normiflo)
• Tinzaparin (Innohep)
Pharmacology
• When injected subcutaneously, the
bioavailability of unfractionated
heparin ranges from 10 to 90%,
depending on the dose given
• In contrast, the bioavailability of
LMW heparin is greater than 90%
and is independent of dose
Anticoagulants Inhibit the
Coagulation Cascade
XII
XIIa
XI
XIa
III
IX
IXa
VIIa
X
Xa
II
Fibrinogen
VII
Low Molecular
Weight Heparin
Fondaparinux
IIa (Thrombin)
Fibrin Clot
Low Molecular Weight
Heparin:
Use in Prophylaxis
Comparison: Unfractionated (UF)
Heparin vs. Low Molecular
(LMW) Heparin
• Efficacy approximately the same with a
trend to better efficacy for LMW heparin
• Much lower incidence of heparin-induced
thrombocytopenia (HIT) with LMW
heparin
• Essentially no bleeding risk with
prophylactic doses of either anticoagulant spinal puncture is a noteworthy exception
Dosage Options &
Conversions
Approximate
Equivalence:
Between LMW heparins
2500 U Fragmin QD 
40 mg Lovenox QD
5000 U Fragmin QD 
30 mg Lovenox BID
Low Molecular Weight
Heparin:
Use in Treatment
Which Heparin or LMW
Heparin can be used for
Treatment of an Existing
Venous Thrombosis?
UFH or LMWH
Warfarin
Unfractionated (UF) Heparin vs.
Low Molecular Weight
(LMW) Heparin
• Shorter half
life for unfractionated
heparin (1-2 hr) than LMW heparin
(3-5 hrs), so preference is for UFH for
briefly interrupted anticoagulation
Monitoring of Anticoagulants used
as Treatment for Existing
Venous Thrombosis
None, unless serum creatinine
> 2.0, obesity (BMI >30), very
low BMI, pregnancy, child esp
LMW neonate, long term treatment Heparin if monitoring is needed, use
anti-factor Xa assay with target
range 0.5 - 1.0 U/mL
Dosage Options &
Conversions
Approximate Anticoagulant
Equivalence: Between LMW
heparins
100 U Fragmin/kg BID 
1 mg Lovenox/kg BID
200 U Fragmin/kg QD 
1.5 mg Lovenox/kg QD
Reversal of LMW Heparin
• Protamine sulfate (1% solution)
cannot reverse all of the anti-Xa
activity, but it is recommended when
emergent reversal of anticoagulation
is required
• The protamine dose is 1 mg per mg
enoxaparin, 1 mg per 100 units
ardeparin, or 1 mg per 100 units
dalteparin by slow intravenous injection
Adverse Effects
• Heparins have three major adverse
effects: bleeding, heparin-induced
thrombocytopenia (HIT), and
osteoporosis
• Most of the clinical trials have
reported similar or decreased
bleeding with LMW heparin as
compared to unfractionated heparin
Adverse Effects
Less bone resporption by
LMW heparins may
account for the decreased
frequency of osteoporosis
relative to unfractionated
heparin
Adverse Effects
• Although the incidence of HIT is
lower with LMW heparin than
unfractionated heparin, it is
advisable to also follow the platelet
count in patients receiving LMW
heparin
• It is not currently known how often
the platelet count should be
determined in such patients
Proposed
mechanism
for the
pathogenesis of
heparin-induced
thrombocytopenia
Adverse Effects
• In patients who develop HIT
from unfractionated heparin,
the HIT antibody frequently
cross-reacts with LMW heparin
• Therefore, LMW heparin should
not be used in patients with HIT
Cost
• A dose of LMW heparin in the USA
is significantly more expensive than
a dose of unfractionated heparin
• Despite the higher cost per dose,
LMW heparin may actually be most
cost-effective than unfractionated
heparin
Fondaparinux:
Drug Action
FONDAPARINUX ACTION
Fondaparinux
• Does not increase PT or PTT
• Cleared renally and
contraindicated in patients
with a CrCl < 30
• Reversal using Factor VIIa
and possibly FFP
Fondaparinux:
Pharmacokinetic Profile
in Healthy Young Volunteers
• Tmax=1 to 3 hours following SC injection
• t1/2=17 to 21 hours
– Once-daily dosing
• Predominantly eliminated unchanged in the
urine
Fondaparinux:
Use in
Prophylaxis
Fondaparinux: Overall Efficacy and Odds
Reduction in DVT/PE Prophylaxis
Fondaparinux
better
Study
Hip fracture1
THR2
Enoxaparin
better
–62%
–58%
THR3
–28%
Major knee
surgery4
–63%
All studies
P=10-17
–55%
–80
–60
–40
–20
0
20
40
(%)
Overall odds reduction for proximal DVT=57.4 %[CI 72.3-35.6]; P=10-6
1 Eriksson BI, et al. N Engl J Med. 2001;345:1298-1304.
2 Lassen MR, et al. Lancet. 2002. In press.
3 Turpie, AGG, et al. Lancet. 2002. In press.
4 Bauer KA, et al. N Engl J Med. 2001;345:1305-1310.
60
80
Effect on Bleeding of Timing of
Fondaparinux Injection After Closure
P=0.028
3.0
1.8
Fondaparinux started
<6 h after closure
n=1337
Fondaparinux started
>6 h after closure
n=2229
Turpie AGG, et al. Blood. 2001;98(11):266A.
Data on file, Organon Sanofi~Synthélabo LLC.
No Effect of Timing on Overall
Venous Thromboembolism Rate
P=0.33
7.1
7-
Overall VTE rate (%)
6.3
65-
Risk reduction
>50%
over enoxaparin
in both subgroups
43210Fondaparinux started
<6 h after surgical closure
n=993
Fondaparinux started
>6 h after surgical closure
n=1680
Turpie AGG, et al. Blood. 2001;98(11):266A.
Fondaparinux:
Use in Treatment
Fondaparinux Treatment Dose
• 5 mg SQ QD
– Small size person
• 7.5 mg SQ QD
– Average size person
• 10.0 mg SQ QD
– Large size person
Hirudin – Related
Compounds:
Drug Action
Anticoagulants Inhibit the
Coagulation Cascade
XII
XIIa
XI
XIa
III
IX
IXa
VIIa
X
VII
Xa
II
Fibrinogen
IIa (Thrombin)
Hirudin
Fibrin Clot
Argatroban
Lepirudin
•Lepirudin (Refludan) is a
biotechnologically
manufactured desulfatohirudin
from S.cerevisiae
•Lepirudin has been proven as a
safe and effective thrombin
inhibitor in patients with HIT
Hirudin – Related
Compounds:
Use in Prophylaxis
Desirudin
Desirudin, which differs from
lepirudin only in the first two
N-terminal amino acids (ValVal), has a licensed indication
for the prevention of deep vein
thrombosis (DVT)
Hirudin – Related
Compounds:
Use in Treatment
Lepiruden & Refludan
Description:
Recombinant Protein
Action:
Direct Thrombin Inhibitor
Monitoring:
PTT to 1.5 - 2.5 x Mean of
normal range
Administration: Intravenous - Bolus with
Continuous Infusion
Lepiruden & Refludan
Primary Use: Patients with heparinInduced thrombocytopenia
and adequate renal function
Half-Life:
1 hour if normal renal
function and 52 hours (avg)
in end stage renal disease
Elimination: Mostly renal
Reversal:
None
Lepirudin
• Approximately 40% of patients
receiving lepirudin develop
antibodies, and the antibodies
increase activity
• Dose adjustment is necessary in
renal failure patients
Lepirudin Dosing
• 0.4 mg/kg bolus up to 110 kg
• Maintenance: 0.15 mg/kg
continuous IV infusion
• Do not use bolus in patients
with a PTT greater than 2.5
baseline – some suggest no
bolus at all
Lepirudin Dose Adjustments –
Based Upon Results of PTT
• Goal: PTT 1.5 to 2.5 baseline
• Measure first PTT 4 hours after initiation
 If PTT >2.5 baseline, stop infusion for 2
hours then restart at 50% original infusion
rate
 If PTT less than 1.5 baseline increase
infusion rate by 20%
Argatroban:
Drug Action
Argatroban
• Argatroban is a synthetic
direct thrombin inhibitor
derived from arginine
• Anticoagulant for prophylaxis
or treatment of thrombosis in
patients with heparin-induced
thrombocytopenia (HIT)
Argatroban
Description:
Synthetic chemical
compound
Action:
Direct thrombin
Inhibitor
Monitoring:
PTT to 1.5 - 2.5 x mean
of normal range
Administration: Intravenous
Argatroban
Primary
Use:
Patients with heparin induced thrombocytopenia,
especially those with
impaired renal function
Half-Life:
20 minutes
Elumination:
Mostly hepatic
Reversal:
None
Argatroban:
Use in Prophylaxis
None
Argatroban:
Use in Treatment
Argatroban
• Anticoagulant effects are produced
immediately upon infusion but
steady state levels are reached
within 1 – 3 hours
• Upon discontinuation of therapy,
anticoagulant parameters return to
baseline within 2 – 4 hours
Argatroban
• Hepatic impairment
decreases argatroban
clearance
• The dosage must be
reduced for patients with
liver dysfunction
Guidelines for Conversion to
Oral Anticoagulant Therapy
• All direct thrombin inhibitors,
especially argatroban, increase the
prothrombin time (PT)
• Therefore, argatroban interferes
with the International Normalized
Ratio (INR)
How to Monitor Warfarin
Effect When Argatroban
and Warfarin Are
Co-adminstered
• Use Chromogenic Factor X instead of INR
• INR 3 hours after discontinuation of
argatroban
• Use of manufacturer nomogram to
extrapolate to INR without argatroban
MGH A NTICOAGULATION
& E PIDURAL
A NESTHESIA
/A NALGESIA
G UIDELINES
MONITORING
C ATHETER P LACEMENT
AFTER
L AST D OSE
C ATHETER R EMOVAL
AFTER
P OST -O P D OSE
R ESTART M ED
AFTER
C ATHETER R EMOVAL
None
48 Hours
48 Hours
12 Hours
CLOPIDOGREL* (PLAVIX)
None
7 Days
EPTIFIBATIDE (INTEGRILIN)
None
8 Hours
8 Hours
4 Hours
FONDAPARINUX ** (ARIXTRA)
None
> 24 Hours
> 24 Hours
2 Hours
HEPARIN SC
None
HEPARIN IV
PTT
2 -4 Hours
2 -4 Hours
1 Hour
LMW HEPARIN
*** LOW DOSE
DALTEPARIN (FRAGMIN) < 5000 U QD
ENOXAPARIN (LOVENOX)< 60 mg QD
TINZAPARIN (INNOHEP)
None
12 Hours
12 Hours
2 Hours
None
> 24 Hours
DRUG (GENERIC) COMMON TRADE
NAMES
ABCIXIMAB
(REOPRO)
LMW HEPARIN
*** HIGH DOSE
BID DOSING = HIGH DOSE
DALTEPAR IN (FRAGMIN) (see below ***)
ENOXAPARIN (LOVENOX) (see below ***)
TINZAPARIN (INNOHEP)
NSAID, ASA
CELEBREX; MOTRIN; NAPROSYN; VIOXX;
ETC.
Critical Time Intervals
WITHIN 24 Hours*
No Significant R
None
24 Hours
isk
Catheter SHOULD be removed
prior to first dose. IF NOT:
wait > 24 Hours.
2 Hours
No Sign ificant Risk
THROMBOLYTICS:
STREPTOKINASE (STREPTASE)
ALTEPLASE (TPA) (ACTIVASE)
None
10 Days
10 Days
10 Days
TICLOPIDINE (TICLID)
None
14 Days
14 Days
24 Hours
TIROFIBAN (AGGRASTAT)
None
8 Hours
8 Hours
4 Hours
Check INR if treatment > 24
Same Day
Hours
* NOTE: Clopidogrel (Plavix) has a 24
-48 hour window to remove an epidural catheter once the medication is given. If it has been more than 48 hours since
dosing of Clopidogrel (Plavix), you MUST wa
it 7 days.
**NOTE: Fondaparinux should NOT be given if regional anesthesia is anticipated or has been used. If, however, fondaparinux is given, we suggest the above
guidelines.
WARFARIN (COUMADIN)
INR (<1.5)
3 -5 day s, check INR
*** NOTE: SINGLE DAILY LMWH DOSING may be started 6
- 8 hours postoperati
vely. TWICE DAILY LMWH DOSING should be started AT LEAST 24 hours
postoperatively. Postoperative BID dosing is considered "HIGH DOSE LMWH". Epidural catheters should be removed prior to the initiation of BID dosing.
Please refer to the ASRA Guidelines
at www.ASRA.com
.
Summary
Drug Action & Use in
Prophylaxis and Treatment for:
•
•
•
•
•
•
Coumadin
Unfractionated Heparin
Low Molecular Weight Heparin
Fondaparinux
Hirudin Related Compounds
Argatroban
MGH A NTICOAGULATION
& E PIDURAL
A NESTHESIA
/A NALGESIA
G UIDELINES
MONITORING
C ATHETER P LACEMENT
AFTER
L AST D OSE
C ATHETER R EMOVAL
AFTER
P OST -O P D OSE
R ESTART M ED
AFTER
C ATHETER R EMOVAL
None
48 Hours
48 Hours
12 Hours
CLOPIDOGREL* (PLAVIX)
None
7 Days
EPTIFIBATIDE (INTEGRILIN)
None
8 Hours
8 Hours
4 Hours
FONDAPARINUX ** (ARIXTRA)
None
> 24 Hours
> 24 Hours
2 Hours
HEPARIN SC
None
HEPARIN IV
PTT
2 -4 Hours
2 -4 Hours
1 Hour
LMW HEPARIN
*** LOW DOSE
DALTEPARIN (FRAGMIN) < 5000 U QD
ENOXAPARIN (LOVENOX)< 60 mg QD
TINZAPARIN (INNOHEP)
None
12 Hours
12 Hours
2 Hours
None
> 24 Hours
DRUG (GENERIC) COMMON TRADE
NAMES
ABCIXIMAB
(REOPRO)
LMW HEPARIN
*** HIGH DOSE
BID DOSING = HIGH DOSE
DALTEPAR IN (FRAGMIN) (see below ***)
ENOXAPARIN (LOVENOX) (see below ***)
TINZAPARIN (INNOHEP)
NSAID, ASA
CELEBREX; MOTRIN; NAPROSYN; VIOXX;
ETC.
Critical Time Intervals
WITHIN 24 Hours*
No Significant R
None
24 Hours
isk
Catheter SHOULD be removed
prior to first dose. IF NOT:
wait > 24 Hours.
2 Hours
No Sign ificant Risk
THROMBOLYTICS:
STREPTOKINASE (STREPTASE)
ALTEPLASE (TPA) (ACTIVASE)
None
10 Days
10 Days
10 Days
TICLOPIDINE (TICLID)
None
14 Days
14 Days
24 Hours
TIROFIBAN (AGGRASTAT)
None
8 Hours
8 Hours
4 Hours
Check INR if treatment > 24
Same Day
Hours
* NOTE: Clopidogrel (Plavix) has a 24
-48 hour window to remove an epidural catheter once the medication is given. If it has been more than 48 hours since
dosing of Clopidogrel (Plavix), you MUST wa
it 7 days.
**NOTE: Fondaparinux should NOT be given if regional anesthesia is anticipated or has been used. If, however, fondaparinux is given, we suggest the above
guidelines.
WARFARIN (COUMADIN)
INR (<1.5)
3 -5 day s, check INR
*** NOTE: SINGLE DAILY LMWH DOSING may be started 6
- 8 hours postoperati
vely. TWICE DAILY LMWH DOSING should be started AT LEAST 24 hours
postoperatively. Postoperative BID dosing is considered "HIGH DOSE LMWH". Epidural catheters should be removed prior to the initiation of BID dosing.
Please refer to the ASRA Guidelines
at www.ASRA.com
.