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120 Anticoagulation Therapy
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SIDE EFFECTS, PRECAUTIONS, AND
CONTRAINDICATIONS
Review of absolute and relative contraindications for thrombolytic therapy
should also take place prior to administration. These criteria should be easily
retrieved to ensure rapid assessment (see Table 6-4).
TABLE 6-4: Contraindications to Thrombolytic Therapy
Absolute Contraindications
•
Any prior ICH
Known structural cerebral vascular lesion (e.g., arteriovenous malformation)
•
•
Known malignant intracranial neoplasm (primary or metastatic)
Ischemic stroke within 3 months EXCEPT acute ischemic stroke within 4.5 hours of
•
symptom onset
Suspected aortic dissection
•
•
Active bleeding or bleeding diathesis (excluding menses)
Significant closed-head or facial trauma within 3 months
•
•
Intracranial or intraspinal surgery within 2 months
Severe uncontrolled hypertension (unresponsive to emergency therapy)
•
•
For streptokinase, prior treatment within the previous 6 months
Relative Contraindications
• History of chronic, severe, poorly controlled hypertension
Significant hypertension on presentation (SBP >180 mmHg or DBP >110 mmHg)
•
•
History of prior ischemic stroke greater than 3 months, dementia, or known intracranial
pathology not covered in contraindications
• Traumatic or prolonged (greater than 10 minutes) CPR or major surgery (within less than 3
weeks)
Recent (within 2–4 weeks) internal bleeding
•
• Noncompressible vascular punctures
• Pregnancy
• Active peptic ulcer
• Oral anticoagulant therapy*
10-15
*Current guidelines published in 2018 note that the use of IV alteplase in patients taking a direct
thrombin inhibitor or direct-acting oral anti-Xa inhibitor has not been firmly established, but may
be harmful (IIIC recommendation). IV alteplase should not be administered to patients taking
direct thrombin inhibitors or direct factor Xa inhibitors unless laboratory tests such as aPTT, INR,
platelet count, ecarin clotting time, thrombin time, or appropriate direct factor Xa activity assays
are normal or the patient has not received a dose of these agents for >48 hr (assuming normal
renal metabolizing function). (Alteplase could be considered when appropriate laboratory tests
such as aPTT, INR, ecarin clotting time, thrombin time, or direct factor Xa activity assays are
normal or when the patient has not taken a dose of these ACs for >48 hr and renal function is
normal.) For patients receiving warfarin with a INR ≤1.7 who present in the 3- to 4.5-hr window, IV
alteplase appears safe and may be beneficial (IIB recommendation).
CPR: cardiopulmonary resuscitation, DBP: diastolic blood pressure, ICH: intracranial hemorrhage,
SBP: systolic blood pressure
THROMBOLYTIC CONSIDERATIONS WHEN USED WITH ANTICOAGULANTS 121
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RISK OF BLEEDING
9-15,45,46
Patient Characteristics That Increase the Risk of Bleeding
with Thrombolytic Agents
•
In patients experiencing stroke and myocardial infarction, the most important
bleeding complication is intracranial hemorrhage (ICH) (see Table 6-5).
•
Due to the low number of patients who have been enrolled in randomized
clinical trials for PE (<2,000 total patients), the actual incidence of ICH as well
as risk factors for bleeding are less well defined compared to acute coronary
syndrome (ACS) and stroke.
•
Risk factors for bleeding are heavily dependent on the indication for thrombolysis, with patients treated for stroke having a much higher rate of ICH than
patients experiencing STEMI.
•
Characteristics predicting increased bleeding in patients with stroke:
Larger neurologic deficit has been associated with a higher rate
of ICH
Older age has in some, but not all, analyses been associated with
a higher rate of ICH
Diabetes
Higher doses of thrombolytic agents
•
Characteristics predicting increased bleeding in patients with STEMI:
Older age
Lower body weight
Prior stroke
Increased systolic or diastolic pressure
Female gender
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Risk of Intracranial Hemorrhage Between Agents
TABLE 6-5: Rates of Intracranial Hemorrhage Observed in
Various Patient Populations
Urokinase Streptokinase Alteplase
(rt-PA)
Reteplase Tenecteplase
(TNK)
STEMI: NA—
Contemporary
information not
available
PE: NA—
Contemporary
information not
available
DVT: NA
Stroke: NA
DVT: deep vein thrombosis, ICH: intracranial hemorrhage, NA: not applicable, NINDS: National
Institute of Neurological Disorders and Stroke, PE: pulmonary embolism, STEMI: ST-segment
elevation myocardial infarction
STEMI: 0.6% in
GUSTO I trial
PE: N/A—
Contemporary
information not
available
DVT: NA
Stroke: NA
STEMI: 0.7% for
rt-PA vs. 0.6%
for streptokinase
in GUSTO I trial
PE: 3% for rt-PA
vs. 0.3% for IV
UFH
DVT: NA
Stroke: 6.4% for
rt-PA vs. 0.6%
for placebo
symptomatic
ICH within 36 hr
in NINDS t-PA
study
STEMI: 0.8%
for reteplase
vs. 0.4% for
streptokinase in
INJECT trial
0.6% for
reteplase vs.
0.4% for rt-PA in
GUSTO III trial
PE: NA
DVT: NA
Stroke: N/A
STEMI: 0.9% for
TNK vs. 0.9% for
rt-PA in ASSENT
II study
PE: 2% for
tenecteplase vs.
0.2% for placebo
DVT: NA
Stroke: NA
DOSING AND MONITORING STRATEGIES
FOR ANTICOAGULANT/ANTIPLATELET
AGENTS TO MINIMIZE RISK OF BLEEDING
AND OPTIMIZE OUTCOME
9-15, 24-27
The use of adjunctive antithrombotic therapy (antiplatelet and anti-thrombin
agents) is often necessary to maintain patency of the affected artery or vein.
However, specific recommendations exist for how and when adjunctive
therapies should be initiated in different indications. It is crucial to ensure
adjunctive therapies are timed appropriately in relation to thrombolytic
administration to optimize safety and efficacy (see Table 6-6).
THROMBOLYTIC CONSIDERATIONS WHEN USED WITH ANTICOAGULANTS 123
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(continued)
Bivalirudin
NA
2.5 mg sub-Q once daily
started in conjunction with
thrombolytic agent; therapy
should be continued for
minimum of 48 hr and
ideally up to 8 days;
contraindicated in patients
with a CrCl <30 mL/min
Enoxaparin is the preferred
agent and should be
given in conjunction with
fibrinolytic agent for a
minimum of 48 hr and
ideally up to 8 days.
Patients <75 yr: 30-mg IV
bolus followed by 1 mg/kg
sub-Q q 12 hr (maximum of
100 mg for first two doses)
Patients >75 yr: No IV
bolus, therapy should be
0.75 mg/ kg sub-Q q 12 hr
(maximum of 75 mg for first
two doses)
Any patient with CrCl <30
mL/min, regardless of age:
Maintenance dose should
be 1 mg/kg sub-Q q 24 hr
UFH LMWH Fondaparinux
Bolus: 60 units/kg,
maximum dose 4,000 units
Continuous IV infusion:
12 units/ kg/hr, maximum
initial rate of 1,000 units/hr
UFH should be given
in conjunction with
thrombolytic agents for a
minimum of 48 hr; patients
receiving fibrin specific
agents such as rt-PA,
reteplase, and TNK should
receive UFH; patients
receiving streptokinase
should receive UFH only
if at high risk of systemic
emboli (AF, LV, thrombus).
Clopidogrel
+
dose using chewable
formulation; maintenance
dose 81–325 mg daily
Clopidogrel: Loading
dose of 300–600 mg
may be considered in
patients <75 yr of age;
loading dose should be
omitted in patients ≥75 yr;
maintenance dose of 75
mg daily
Recommended for all
patients for up to 14 days
if no subsequent PCI is
ASA or ASA
Patient Group
TABLE 6-6: Dosing of Antithrombotic Agents with Thrombolytic Therapy
STEMI ASA: 162–325 mg initial
performed.
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Bivalirudin
No data available regarding
concomitant administration;
however, in a patient with
active HIT and PE, consider
a dose of 0.15–0.25 mg/
kg/hr, titrated to an aPTT
of 1.5–2.5 x control and
-
able regarding using
fondaparinux with systemic
thrombolysis in PE;
however, if used, standard
treatment doses for VTE
Minimal data are avail
could be considered:
continued until warfarin
therapy is therapeutic;
these recommend doses
come from ACS and HIT
data (see Chapter 18 on
HIT)
≤50 kg: 5.0 mg sub-Q
once daily
51–100 kg: 7.5 mg
sub-Q once daily
>100 kg: 10 mg
sub-Q once daily
-
(continued)
Standard treatment doses
of LMWH agents apply
UFH LMWH Fondaparinux
recommended maximum
dose
Clopidogrel
+
ASA or ASA
Patient Group
TABLE 6-6: (Continued)
PE NA Bolus: 80 units/kg, no
tion.
Dalteparin 200 units/kg
Enoxaparin 1 mg/kg sub-Q
q 12 hr or daily for patients
with a CrCl 20−30 mL/min
(maximum of 75 mg for first
two doses). Caution with
CrCl <20 mL/min due to
lack of data in this popula
-
mended maximum dose.
Therapy may be started
with or continued when
thrombolytic therapy is
Continuous IV infusion: 18
units/ kg/hr, no recom
initiated; alternatively, it
sub-Q once daily or 100
is reasonable to initiate
therapy after thrombolysis
has been administered;
in patients who had UFH
units/kg sub-Q q 12 hr;
caution in patients with
CrCl <20 mL/min
Tinzaparin 175 units/kg
sub-Q once daily; caution
in patients with CrCl <20
mL/min
end of lytic infusion
restart UFH at previous
infusion rate with no
Check the aPTT at the
interrupted for thrombolytic
administration, consider
the following approach to
If aPTT is <2 x control,
restarting UFH:
•
•
Therapy may be started
with or continued when
thrombolytic therapy is
initiated; alternatively it
is reasonable to initiate
therapy after thrombolysis
has been administered.
bolus
recheck in 4 hr and
if acceptable, restart
UFH
If aPTT >2 x control,
•
Catheter-directed or local
thrombolysis: See DVT
THROMBOLYTIC CONSIDERATIONS WHEN USED WITH ANTICOAGULANTS 125
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(continued)
Bivalirudin
No data available regarding
concomitant administration;
however, in a patient with
active HIT and PE, would
recommend a dose of 0.15–
0.25 mg/ kg/hr, titrated to
an aPTT of 1.5–2.5 x control
and continued until warfarin
therapy is therapeutic;
these recommended doses
come from ACS and HIT
data (see Chapter 18 on
HIT)
Systemic thrombolysis:
Follow recommendations
for PE
Catheter-directed or local
thrombolysis: Minimal
information available;
recommend utilizing dosing
strategies found under PE
Systemic thrombolysis:
Follow recommendations
for PE
UFH LMWH Fondaparinux
Follow recommendations
for PE
Clopidogrel
+
ASA or ASA
Patient Group
TABLE 6-6: (Continued)
DVT NA Systemic thrombolysis:
Catheter-directed or local
thrombolysis: Minimal
information available,
recommend utilizing dosing
strategies found under PE
Catheter-directed or
local thrombolysis: UFH
dosing in this setting
is not standardized;
often lower intensities
of anticoagulation were
reported in studies as
compared to standard DVT/
PE dosing (often <1,000
units/hr); in addition, goal
aPTT used in the literature
include 1.2–1.7 x baseline,
1.5–2.5 x baseline, up to
80–100 sec
126 Anticoagulation Therapy
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Bivalirudin
NA NA
(continued)
IV alteplase should not be
administered to patients
who have received a LMWH
UFH LMWH Fondaparinux
Therapeutic
anticoagulation with UFH
is not recommended in
Clopidogrel
+
ASA or ASA
should be withheld for a
minimum of 24 hr after
Patient Group
TABLE 6-6: (Continued)
Ischemic stroke ASA: Therapy initiation
treatment dose within
the previous 24 hr (IIIB
recommendation). Older
guidelines suggested it
was reasonable to start a
LMWH for VTE prophylaxes
after thrombolysis, and wait
24 hr after alteplase to start
the previous 48 hr, or
24 hr after thrombolysis
for ischemic stroke; UFH
for VTE prophylaxis may
be initiated 24 hr after
thrombolysis. Caution is
advised if considering
administering a bolus dose;
the administration of
thrombolysis; thereafter,
ASA 325 mg as an initial
dose is recommended
Clopidogrel: A dose
of 75 mg daily is only
recommended if ASA
treatment doses. Note:
Patients with substantial
renal failure may have
prolonged LMWH effects
where a longer hold prior
to the procedure may be
considered.
boluses are frequently
omitted post-ischemic
stroke.
cannot be used with the
same timing constraints as
discussed above
NA NA NA NA NA
Catheter
occlusion
THROMBOLYTIC CONSIDERATIONS WHEN USED WITH ANTICOAGULANTS 127
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Bivalirudin
NA NA NA
UFH LMWH Fondaparinux
concomitantly with intra-
arterial thrombolytic;
Clopidogrel
+
ASA or ASA
NA UFH generally administered
Patient Group
Peripheral
arterial occlusion
TABLE 6-6: (Continued)
(intra-arterial)
dosing in trials generally
consisted to a 3,000–5,000
unit bolus, followed by
a 600–1,000 units/hr
continuous infusion titrated
to a defined goal aPTT.
NA NA NA NA NA
administration)
Pleural effusion/
empyema
to aPTT of approximately
50–70 sec, but varies based
on aPTT reagent utilized
NA NA NA NA NA
Prosthetic valve
thrombosis
Frostbite IV heparin infusion titration
ACS: acute coronary syndrome, aPTT: activated partial thromboplastin time, ASA: aspirin, CrCl: creatinine clearance, DVT: deep vein thrombosis, HIT: heparin-induced
thrombocytopenia, hr: hour, IV: intravenous, LMWH: low molecular weight heparin, NA: not applicable, PCI: percutaneous coronary intervention, PE: pulmonary embolism,
sec: seconds, sub-Q: subcutaneous, UFH: unfractionated heparin, units: International Units, VTE: venous thromboembolism, x: times
128 Anticoagulation Therapy
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