Download Antithrombotic Agents In Difficult Clinical Scenarios

Antithrombotic Agents In Difficult Clinical Scenarios
Santanu Guha, Imran Ahmed, Soura Mukherjee
A
rterial and venous thromboses are major causes of
morbidity and mortality.1 In 1977, Macfarlane proposed
that ‘thrombosis is hemostasis in the wrong place’,2 and
since then pathological studies, clinical studies, and metaanalyses of randomized trials of antiplatelet, anticoagulant
and thrombolytic drugs have supported this hypothesis
by showing that platelet-fibrin hemostatic plugs are the
pathophysiological basis for both arterial and venous
thrombosis.3
Antithrombotic drugs are used for prevention and treatment
of thrombosis. These agents target the components of
thrombi, and their examples include 1. Antiplatelet drugs
Aspirin
 ADP receptor antagonist i) Irreversible - clopidogrel, prasugrel
ii) Reversible - cangrelor, ticagrelor
 Phosphodiesterase inhibitors - dipyridamole, cilostazole
 GPIIb/IIIa receptor antagonist i) IV- abciximab, eptifibatide, tirofiban
ii) oral - xemilofiban, orbofiban, sibrafiban
2. Anticoagulant drugs
Parenteral
i) Heparin, low molecular weight heparin (LMWH),
fondaparinux
ii)Direct thrombin inhibitors - lepirudin, argatroban,
bivalirudin
iii)Direct Xa inhibitors - apixaban, rivaroxaban
 Oral vitamin K antagonists (VKAs) - warfarin
3. Fibrinolytic drugs
 streptokinase, alteplase, reteplase, tenecteplase.
The prescription of these life saving drugs should be done
keeping in mind their contraindications and adverse effects.
The present article underlines the current understanding and
recommendations of prescribing antithrombotics in select
difficult clinical scenarios.
A. Antithrombotics and renal dysfunction
 In patients with severe renal insufficiency (creatinine
clearance [CrCl] < 30 mL/min) who require therapeutic
anticoagulation, the use of unfractionated heparin (UFH)
instead of LMWH is suggested.4 If LMWH is used, a 50%
reduction of the total dose is suggested.5
 Dose reduction of lepirudin and desirudin are required
in moderate renal insufficiency (CrCl 30-60 ml/min)
with monitoring of APTT levels. In patients with a CrCl
< 30mL/min, the use of lepirudin or desirudin is not
recommended.6
 Both tirofiban (PRISM-PLUS trial) and eptifibatide
(ESPRIT trial) have shown increased bleeding rates in
moderate to severe renal dysfunction.7,8 Although the
manufacturer recommends reducing both the bolus and
infusion doses of tirofiban by 50% in CrCl < 30mL/min,
the proper dose of tirofiban and eptifibatide in such
patients is uncertain.9
B. Initiation of Anticoagulation in some specific
populations including elderly
 VKAs should be initiated with doses between 5 and 10
mg for the first 1 or 2 days for most individuals, with
subsequent dosing based on INR response. In elderly
patients or those debilitated, have congestive heart
failure or liver disease, have had recent major surgery,
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Medicine Update-2011
or on drugs that increase the sensitivity to warfarin
(eg, amiodarone), the use of a starting dose of < 5 mg is
recommended.10
C. Management of nontherapeutic INR with Vitamin K
antagonists (VKAs)
 INRs above the therapeutic range, but < 5.0 and with
no significant bleeding - recommended actions include,
lowering the dose or omitting a dose, monitoring more
frequently, and resuming therapy at an appropriately
adjusted dose when the INR is at a therapeutic level.11
 For patients with INRs > 5.0 but < 9.0 and no significant
bleeding - recommended actions include, omitting the
next one or two doses, and monitoring more frequently or
alternatively, omitting a dose and administering vitamin K
(1 to 2.5 mg) orally.12,13 If more rapid reversal is required
because the patient requires urgent surgery, vitamin K
(< 5 mg) orally is suggested, with the reduction of INR
expected in 24 h.14
 For patients with INRs of > 9.0 and no significant bleeding
- recommended actions include, holding warfarin therapy
and administering a higher dose of vitamin K (2.5 to 5 mg)
orally, with more frequent INR monitoring and additional
vitamin K administered if necessary.15
 Serious bleeding and elevated INR - regardless of the
magnitude of the elevation, recommended actions
include, holding warfarin therapy and giving vitamin
K (10 mg) by slow IV infusion supplemented with fresh
frozen plasma, prothrombin complex concentrate, or
recombinant factor VIIa, depending on the urgency of
the situation. (Grade 1C).
 Life-threatening bleeding (eg intracranial hemorrhage)
and elevated INR - regardless of the magnitude of
the elevation, recommended actions include, holding
warfarin therapy and administering fresh frozen plasma,
prothrombin complex concentrate, or recombinant
factor VIIa supplemented with vitamin K, 10 mg by slow
IV infusion, repeated, if necessary, depending on the
INR.14,16,17
 Patients on long-term warfarin with a variable INR
response - suggested actions include, a trial of daily lowdose oral vitamin K (100-200 µg) with close monitoring
of INR and warfarin dose adjustment.18
 INR in antiphospholipid syndrome - ordinarily, a
therapeutic target INR of 2.5 (INR range, 2.0 to
3.0) is recommended.19 Those who have recurrent
thromboembolic events with a therapeutic INR or other
additional risk factors for thromboembolic events, a
target INR of 3.0 (INR range, 2.5 to 3.5) is suggested.20
D. Perioperative management of patients who are on
anticoagulant drugs
 VKAs before surgery - In patients who require temporary
interruption, VKAs should be stopped approximately
5 days before surgery to allow adequate time for the
INR to normalize.21 It is recommended to resume VKAs
approximately 12 to 24 h (the evening of or the next
morning) after surgery.22
 VKA interrupted before surgery but with INR still
elevated (> 1.5) - suggested action is to administer lowdose (1 to 2 mg) oral vitamin k to normalize the INR.23
 In patients with a mechanical heart valve or atrial
fibrillation (AF) or venous thromboembolism (VTE) at high
or moderate risk for embolism - recommended actions
include, bridging anticoagulation with therapeutic-dose
LMWH (preferred) or IV UFH.24,25
 Patients with a mechanical heart valve or AF or VTE at
low risk for thromboembolism - low-dose SC LMWH is
recommended over bridging with therapeutic-dose SC
LMWH or IV UFH.24
 Stoppage of bridging anticoagulation during surgery last preoperative dose of LMWH, is recommended to be
administered 24 hrs before surgery and approximately
half the total daily dose is given instead of 100% of the
total daily dose.26 Bridging anticoagulation with UFH
should be stopped approximately 4 h before surgery.27
 In patients undergoing major surgery or with high
bleeding risk - recommended actions include, delaying
the initiation of therapeutic-dose LMWH/UFH for 48 to
72 h after surgery when hemostasis is secured.28
E. Perioperative management of patients who are on
antiplatelet drugs
 Aspirin or clopidogrel before surgery - If interruption is
required, it should be done 7-10 days before surgery.29,30
It is recommended to resume aspirin or clopidogrel
approximately 24 h (or the next morning) after surgery
when there is adequate hemostasis.31
 Patients at high risk of cardiac events (exclusive of
coronary stents) - recommended actions include,
continuing aspirin up to and beyond the time of surgery;32
if patients are receiving clopidogrel, it should be
interrupted at least 5 days and, preferably, within 10
days prior to surgery.33
 In patients scheduled for elective CABG - recommended
actions include, continuing aspirin up to and beyond the
time of CABG;34 if aspirin is interrupted, it should be
reinitiated between 6 h and 48 h after CABG.35 If patients
are receiving clopidogrel, it should be interrupted at
Medicine Update-2011





least 5 days and, preferably, within 10 days prior to
CABG.36
In patients scheduled for percutaneous coronary
intervention (PCI) - suggested actions include, continuing
aspirin up to and beyond the time of the PCI; if clopidogrel
is interrupted prior to PCI, it should be resumed after
PCI with a loading dose of 300 to 600 mg.37,38
In patients with a coronary stent ( to prevent stent
thrombosis) - It is recommended to continue aspirin and
clopidogrel in the perioperative period in those with bare
metal coronary stent who require surgery within 6 weeks
of stent placement, and in those with a drug-eluting
coronary stent who require surgery within 12 months of
stent placement.39,40 In patients with a coronary stent
who have interruption of antiplatelet therapy before
surgery, the routine use of bridging therapy with UFH,
LMWH, direct thrombin inhibitors, or glycoprotein (GP)
IIb/IIIa inhibitors is not suggested.41
Perioperative management in patients who require
minor dental, dermatologic or ophthalmologic (cataract
excision) procedures - For those on VKAs or aspirin, it is
recommended to continue them around the time of the
procedure. If patients are receiving clopidogrel, it should
be interrupted at least 5 days prior to surgery (except
for the above recommendations on those with coronary
stent). 42
Patients who are receiving VKAs and require urgent
surgery - For urgent reversal of the anticoagulant effect,
recommended actions include, treatment with low-dose
(2.5 to 5.0 mg) IV or oral vitamin K.43 For more immediate
reversal of the anticoagulant effect, treatment with
fresh-frozen plasma or another prothrombin concentrate
in addition to low-dose IV or oral vitamin K is suggested.44
For patients receiving aspirin, clopidogrel, or both,
having excessive or life-threatening perioperative
bleeding - suggested actions include, transfusion of
platelets or administration of other prohemostatic
agents.45,46
F. Antithrombotic therapy and pregnancy
 For women receiving anticoagulation for VTE who
become pregnant - it is recommended that VKAs be
substituted with UFH or LMWH.47
 Women with mechanical valves who become pregnant - it
is suggested to use either adjusted dose LMWH or UFH
throughout pregnancy, or adjusted-dose LMWH or UFH
(doses adjusted to keep APTT at least twice control or
attain an anti-Xa level of 0.35 to 0.70 U/mL) until the
thirteenth week with substitution by VKAs until LMWH or
35
UFH are resumed close to delivery.48 The use of warfarin
throughout pregnancy until the 36 weeks has also been
recommended when warfarin dose is below 5 mg per day
during the first trimester.49
 In pregnant women with high-risk mechanical valves
(eg, older-generation valve in the mitral position or
history of thromboembolism) - it is suggested to use oral
anticoagulants over heparin.50,51 This recommendation
gives equal importance to prevention of maternal VTE
to that of avoiding fetal risks. The addition of low-dose
aspirin, 75 to 100 mg/d is also suggested.52
 For women with antiphospholipid antibodies and
recurrent (three or more) pregnancy loss or late
pregnancy loss and no history of venous or arterial
thrombosis - recommended actions include, antepartum
administration of prophylactic or intermediate-dose UFH
or prophylactic LMWH combined with aspirin.53
 Lactating woman on antithrombotics - For lactating women
using warfarin or UFH, it is recommended to continue
these medications.54,55 Also, lactating women using
LMWH, danaparoid, or r-hirudin who wish to breastfeed,
it is suggested to continue these medications.56 For those
women who are on pentasaccharides (eg. fondaparinux),
alternative anticoagulants are suggested. 47
G. Cerebrovascular accident (CVA) in a patient on
antithrombotics
 Initial response - It is recommended that both Warfarin
and heparin be stopped immediately when CVA occurs
(heparin shown to have a 15-25% chance of converting a
non hemorrhagic into a hemorrhagic stroke). 57
 CT scan reveals no hemorrhage - Heparin should be
administered to maintain an aPTT at the lower end of
therapeutic level until Warfarin started. 57
 CT scan reveals hemorrhage - antithrombotic therapy
should be withheld until the bleed is stabilized (7 to 14
days). 57
 Embolic event occurring in a patient on adequate
antithrombotic therapy - the therapy should be altered
as follows 57
If on warfarin and INR 2 to 3: increase dose to achieve
INR 2.5-3.5.
If on warfarin and INR 2.5 to 3.5: add aspirin 50 to 100
mg/d
If on warfarin and INR 2.5 to 3.5, plus aspirin 80 to 100
mg/d: aspirin dose may be increased to 325 mg/d
If on aspirin 325 mg/d: switch to warfarin (INR 2 to 3).
36
Medicine Update-2011
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