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370 Anticoagulation Therapy
https://t.me/med1917
In the EXTRACT-TIMI 25 trial, markedly high aPTTs ≥2.75 x control
were associated with increased bleeding risk while low aPTTs
<1.25 x control tended to be associated with increased risk of MI
at 48 hours.
•
The data supporting a heparin therapeutic range in patients with NSTE ACS
are less robust.
14-17
In the OASIS-2 trial, a target aPTT of 60–100 seconds was suggested
13
for investigators. Patients with aPTTs <60 seconds had higher rates
of recurrent ischemic events, while those with aPTTs ≥100 seconds
had an increased risk of bleeding.
In PARAGON-A, there was no statistically significant association
between aPTT and death, reinfarction, or bleeding.
In TIMI-IIIB, a large randomized trial in patients with NSTE ACS
14
15
treated with fibrinolytics or placebo, neither heparin anti-factor
Xa activity levels nor aPTT were predictive of recurrent ischemia,
reinfarction, or death.
In SYNERGY, a large randomized trial in patients with NSTE ACS
16
treated with enoxaparin or UFH (target aPTT 1.5-2 x the upper limit
of normal, approximately 50–70 seconds), the aPTT on heparin was
not associated with either ischemic or bleeding events.
•
aPTT calibration to a heparin anti-factor Xa activity level of 0.3–0.7 International
Units/mL, from which to develop a weight-based heparin nomogram, is still
recommended by both the American College of Chest Physicians (ACCP) and
the American College of Pathologists.
No data from ACS clinical trials support this target heparin anti-
18,19
However,
factor Xa activity range, which was originally developed from a
single study of venous thromboembolism treatment.
The 2012 ACCP guidelines acknowledge that the true therapeutic
range for coronary indications is unknown, but is likely associated
with heparin anti-factor Xa levels “that are about 10% lower than
those used for treatment of patients with VTE.”
18
17
Relationship Between anti-Factor Xa Activity with Low
Molecular Weight Heparin and Outcomes
The best predictor of bleeding in patients treated with low molecular weight
heparins (LMWHs) is dose (mg) per kg.
•
A desired therapeutic range for anti-Factor Xa activity with LMWHs in patients
with ACS has not been determined.
•
In TIMI-11A trial of patients with NSTE ACS, enoxaparin doses of 1.25 mg/kg
every 12 hours had a higher rate of major hemorrhage than patients receiving
a dose of 1 mg/kg every 12 hours.
In subgroup analysis of patients treated with the higher doses of
20
21
enoxaparin, patients who experienced a major bleeding event had
peak anti-factor Xa levels of 1.8 International Units/mL compared
to 1.4 International Units/mL in patients without major bleeding.
ACUTE CORONARY SYNDROMES 371
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Peak levels in patients treated with the 1 mg/kg dose were 1 Inter-
national Units/mL, and only two patients experienced bleeding.
•
The STEEPLE trial randomized patients undergoing elective PCI for stable
coronary heart disease (CAD) to a single IV dose of either enoxaparin 0.5 mg/kg
or 0.75 mg/kg.
22
Patients with anti-factor Xa levels >0.9 International Units/mL had
increased non-CABG combined major/minor bleeding.
•
A third smaller prospective study in patients with NSTE ACS suggested that
anti-factor Xa levels <0.5 International Units/mL were an independent predic
tor of 30-day mortality. However, the mean dose of enoxaparin administered to
patients with low anti-factor Xa levels was only 0.66 mg/kg.
•
Overall, no strong data suggest routine monitoring of anti-factor Xa levels
23
achieve a target anti-factor Xa therapeutic range with LMWHs if dosed accord
ing to body weight.
RISK FACTORS FOR MAJOR BLEEDING
Although validated risk prediction scores for predicting in-hospital major
bleeding, such as the CRUSADE Bleeding Risk Score and the ACTION
Registry®-GWTG™ Bleeding Risk Score, are available (see below), they are
seldom utilized clinically to alter anticoagulant or antiplatelet therapy and
no professional association guidelines recommend their use in practice at
this time.
•
Important bleeding risk predictors are renal dysfunction (low estimated creatinine clearance), anemia, low body weight, and presence of acute heart failure/
24-26
shock.
•
Use of transradial rather than transfemoral access reduces bleeding.
The results from MATRIX radial versus femoral access study
demonstrated a significant 17% relative risk reduction in net clini
cal adverse events (defined as major adverse CV events or major
bleeding) with radial versus femoral access, primarily due to a 33%
reduction in major bleeding. Mortality was also improved with the
radial approach (1.6% vs. 2.2%, p=0.045).
Transradial access is preferred access site for patients with ACS.
28
27
27,28
-
-
-
GUIDELINE-BASED SELECTION OF
ANTICOAGULANT THERAPY
Guideline-recommended anticoagulants for ACS and monitoring are
described in Tables 15-4 through 15-8 and guideline-recommended
antiplatelets for ACS are described in Tables 15-9 through 15-11.
On-line calculator:
CRUSADE Bleeding Risk Score29: http://
crusadebleedingscore.org/index.html
372 Anticoagulation Therapy
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Primary PCI without GP IIb/IIIa inhibitor:
ACT 250–300 sec with HemoTec and
300–350 sec with Hemochron
Primary PCI with GP IIb/IIIa inhibitor:
ACT of 200–250 sec
Discontinue at end of
procedure
No dose reduction for renal
dysfunction used in clinical trials; may
consider reduction in infusion to 1
mg/kg/hr for patients with CrCl <30
mL/min and to 0.25 mg/kg/hr for
patients receiving dialysis; may also
be used in patients previously treated
with UFH; preferred for patients with
history of HIT; pretreatment with
P2Y12 inhibitor preferred; lower rate
of bleeding and mortality reduction
compared to UFH
Until end of PCI
procedure (preferred);
option to continue at
same IV infusion dose
for 4 hr post-procedure;
option to continue
lower dose 0.2 mg/kg/
hr for an additional 20
hr post-procedure
30
Contraindications Dose (Class Recommendation) Duration Comments (Class Recommendation)
Guidelines Class
Recommendations
Agent 2013 ACC/AHA STEMI
TABLE 15-4: Primary PCI for STEMI
Primary PCI (without GP IIb/IIIa)
inhibitor): 70–100 units/kg to achieve
a therapeutic ACT
Primary PCI (with GP IIb/IIIa inhibitor):
50–70 units/kg IV bolus to achieve a
therapeutic ACT
1.75 mg/kg/hr with or without prior
HIT
UFH IC Active bleeding,
Active bleeding 0.75-mg/kg IV bolus followed by
Preferred over UFH with
Bivalirudin IB
UFH treatment (for patients receiving
UFH; discontinue UFH and wait 30
min prior to starting bivalirudin)
An additional 0.3 mg/kg IV bolus
may be given
GP IIb/IIIa inhibitor in
patients with high risk of
bleeding (IIA)
ACT: activated clotting time, CrCl: creatinine clearance, GP: glycoprotein, PCI: percutaneous coronary intervention, UFH: unfractionated heparin
ACUTE CORONARY SYNDROMES 373
Not FDA-approved.
CrCl: creatinine clearance, HIT: heparin-induced thrombocytopenia, MI: myocardial infarction, PCI: percutaneous coronary intervention, sub-Q: subcutaneous, UFH:
unfractionated heparin
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following administration of fibrinolytics, administer
additional IV bolus doses to PCI ACT targets
Avoid in patients previously treated with UFH; for
secondary PCI during hospitalization following
fibrinolytics, if the last sub-Q dose was administered
at least 8–12 hr earlier, administer an IV dose of
0.3 mg/kg; if the last sub-Q dose was administered
within the prior 8 hr, no additional enoxaparin should
be given; lower rate of death or MI but higher
bleeding rate compared to UFH
Similar death or MI rate and similar bleeding
rate compared to UFH; for secondary PCI during
hospitalization, administer with additional UFH as for
primary PCI
30
Contraindications Dose Duration Comments
AHA STEMI
Guidelines Class
Recommendations
48 hr aPTT 1.5–2 x control (50–70 sec); for secondary PCI
Minimum
of 48 hr
and up to
8 days
bolus followed by 12 units/kg/hr IV
infusion (max 1,000 units/hr)
For patients <75 yr old: 30-mg IV
bolus followed by 1 mg/kg sub-Q
q 12 hr
For patients ≥75 yr old: 0.75 mg/kg
sub-Q q 12 hr (omit IV bolus)
For patients weighing >100 kg and
<75 yr old: Cap first two doses at
100 mg
serum creatinine ≥2.5
mg/dL in men or ≥2
mg/dL in women
Minimum
of 48 hr
and up to
For patients weighing ≥100 kg and
≥75 yr old: Cap first two doses at
75 mg
If during therapy CrCl <30 mL/min:
Decrease dose to 1 mg/kg sub-Q
once daily
2.5 mg IV followed by 2.5 mg sub-Q
daily starting day 2
creatinine clearance
< 30 mL/min
IB Active bleeding,
a
8 days
Agent 2013 ACC/
TABLE 15-5: STEMI with Fibrinolytics
UFH IC Active bleeding, HIT 60 units/kg (max 4,000 units) IV
Enoxaparin IA Active bleeding, HIT;
Fondaparinux
a
374 Anticoagulation Therapy
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(continued)
31
Contraindications Dose Duration Comments
aPTT 1.5–2 x control (50–70 sec)
At least 48 hr or until
hospital discharge,
60-units/kg (max 4,000
units) IV bolus followed by
HIT
For PCI, if the last sub-Q dose was administered at
least 8–12 hr earlier, administer an IV dose of 0.3
mg/kg; if the last sub-Q dose was administered
within the prior 8 hr, no additional enoxaparin
discontinue after PCI
Continue for the duration
of hospitalization (up to 8
days); discontinued after
PCI
12 units/kg/hr IV infusion
(max 1,000 units/hr)
1 mg/kg sub-Q q 12 hr;
reduce dose to 1 mg/kg
q 24 hr if CrCl <30 mL/
min; consider dose cap
HIT
should be given; not studied in patients receiving
dialysis; similar death or MI rate and higher
bleeding risk compared to bivalirudin for high-
risk patients treated with an early interventional
strategy; lower death, MI or urgent revascularization
and higher bleeding risk compared to UFH for
patients undergoing an early conservative strategy;
similar death or MI risk and higher bleeding risk
compared to fondaparinux for patients undergoing
an early conservative strategy
of 120 mg (higher doses
associated with bleeding
risk in CRUSADE registry)
ACC NSTEMI
ACS Guideline
Recommendation
Agent 2014 AHA/
TABLE 15-6: NSTE ACS
UFH IA Active bleeding,
Enoxaparin IA Active bleeding,
ACUTE CORONARY SYNDROMES 375
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Increased risk of catheter thrombosis during PCI
if used as sole anticoagulant; administer 50–60
units/kg IV heparin bolus during PCI; similar death
or MI risk and lower bleeding risk compared to
fondaparinux for patients undergoing an early
conservative strategy
Not studied for initial conservative strategy;
preferred for patients with PCI and initial invasive
strategy; similar efficacy and lower bleeding rate
compared to UFH or enoxaparin for early invasive
strategy; no dose reduction for renal dysfunction
infusion to 1 mg/kg/hr for patients with CrCl <30
mL/min and to 0.25 mg/kg/hr for patients receiving
dialysis; preferred for patients with history of HIT;
pretreatment with a P2Y12 inhibitor (clopidogrel or
ticagrelor pre-PCI) preferred
Contraindications Dose Duration Comments
ACC NSTEMI
ACS Guideline
Recommendation
Agent 2014 AHA/
TABLE 15-6: (Continued)
of hospitalization (up to 8
days); discontinued after
PCI
2.5 mg/kg sub-Q daily Continue for the duration
Until end of PCI procedure
(preferred); option to
followed by 0.25 mg/kg/
CrCl <30 mL/min
IB Active bleeding,
a
Fondaparinux
IB Active bleeding 0.1-mg/kg IV bolus
b
Bivalirudin
continue at same IV
infusion dose for 4 hr
postprocedure; option to
continue lower dose 0.2
mg/kg/hr for an additional
20 hr postprocedure
hr infusion until diagnostic
angiography performed;
at time of PCI, administer
additional IV bolus of
0.5 mg/kg and increase
infusion rate to 1.75 mg/
kg/hr
Not FDA-approved for initial conservative strategy.
Not FDA-approved.
ACC: American College of Cardiology, AHA: American Heart Association, aPTT: activated partial thromboplastin time, CrCl: creatinine clearance, IV: intravenous, PCI:
a
b
percutaneous coronary intervention, sub-Q: subcutaneous, UA/NSTEMI: unstable angina/non-ST-segment elevation myocardial infarction, UFH: unfractionated heparin
376 Anticoagulation Therapy
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TABLE 15-7: Injectable Anticoagulant Monitoring
Agent Monitoring
UFH Daily weight, clinical signs and symptoms of bleeding, aPTT or heparin anti-
factor Xa activity levels at baseline and q 4–6 hr until in desired range then
daily thereafter, ACT during PCI; baseline and daily platelet count, baseline
INR
Enoxaparin Daily weight, clinical signs and symptoms of bleeding, baseline and daily
CrCl, baseline platelet count, baseline and daily CBC, baseline INR
Fondaparinux Daily weight, clinical signs and symptoms of bleeding, baseline and daily
CrCl, baseline and daily CBC, baseline platelet count, baseline INR
Bivalirudin Daily weight, clinical signs and symptoms of bleeding, baseline and daily
CrCl, baseline and daily CBC, baseline platelet count, baseline INR
ACT: activated clotting time, aPTT: activated partial thromboplastin time, CBC: complete blood
count, INR: international normalized ratio, PCI: percutaneous coronary intervention
TABLE 15-8: Interventional Issues: Arterial Femoral Sheath
Management Following Cardiac Catheterization
Agent Recommended Sheath Management
UFH ACT <180 sec
Enoxaparin 1. 4 hr after last IV dose or 6–8 hr after last
sub-Q dose
2. Can consider immediate removal with
arterial closure device if single 0.5 mg/
kg IV dose used
If continuing treatment, give next scheduled
dose no sooner than 6 hr after sheath
removed.
32-35
a
a
Bivalirudin 1.
a
Follow with direct manual groin compression (preferred over mechanical compression device).
ACT: activated clotting time, IV: intravenous, UFH: unfractionated heparin
Immediate removal using an arterial
closure device, or
Remove 2 hr after discontinuation
2.
without ACT monitoring
a
ACUTE CORONARY SYNDROMES 377
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TABLE 15-9: Concomitant Aspirin Therapy
30,31
ACS Initial Dose Subsequent Doses Starting
Day 2 and Duration of
Therapy
NSTE ACS
STEMI with fibrinolysis)
STEMI primary PCI
a
Higher doses are not associated with improved efficacy and are associated with increased
bleeding risk (Grade IIaB recommendation).
TABLE 15-10: Concomitant P2Y12 Inhibitor
31
30
162–325 mg nonenteric
coated formulation either oral
or chewed
30
162–325 mg nonenteric
coated formulation either oral
or chewed
162–325 mg nonenteric
coated formulation either oral
or chewed
30
81–162 mg/day indefinitely
81 mg/day preferred
a
With ticagrelor 81 mg/day
75–100 mg/day indefinitely
81 mg/day preferred
a
With ticagrelor 81 mg/day
81–325 mg/day indefinitely
81 mg/day preferred
a
With ticagrelor 81 mg/day
30,31,36
ACS Initial Dose Subsequent Doses Starting Day
2 and Duration of Therapy (Class
Recommendation)
NSTE ACS (initial
ischemia guided
31
strategy)
Clopidogrel 300 mg or
600 mg
Ticagrelor 180 mg
Clopidogrel 75 mg daily in addition to
aspirin for up to 12 months
90 mg bid in addition to aspirin for up to
12 months
a-c
a,b
Ticagrelor preferred over clopidogrel (Grade
IIaB recommendation)
NSTE ACS PCI stent
Clopidogrel 300 mg or
600 mg
Ticagrelor 180 mg
Clopidogrel 75 mg daily in addition to
aspirin for up to 12 months
90 mg bid in addition to aspirin for up to
12 months
a-c
a,b
31
Ticagrelor preferred over clopidogrel
(Grade IIaB recommendation)
Prasugrel 60 mg
Prasugrel 10 mg daily in addition to aspirin
for up to 12 months
a
; dose reduction to
5 mg daily for patients weighing <60 kg;
contraindicated in patients with prior
stroke/TIA
Prasugrel preferred over clopidogrel in
patients who are not at high risk for bleeding
(Grade IIaB recommendation)
STEMI fibrinolysis
For patients age >75 yr:
Clopidogrel 75 mg
Clopidogrel 75 mg daily for at least 14 days
and up to 1 year
30
For patients age ≥75 yr:
Clopidogrel 300 mg
(continued)
378 Anticoagulation Therapy
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TABLE 15-10: (Continued)
ACS Initial Dose Subsequent Doses Starting Day
2 and Duration of Therapy (Class
Recommendation)
STEMI primary PCI30Clopidogrel 600 mg
Ticagrelor 180 mg
Prasugrel 60 mg
Clopidogrel 75 mg daily in addition to
aspirin for up to 12 months
90 mg bid in addition to aspirin for up to
12 months
a-d
Prasugrel 10 mg daily in addition to aspirin
for up to 12 months,
a,b,d
a,d
dose reduction to
5 mg daily for patients weighing <60 kg;
contraindicated in patients with prior
stroke/TIA
For patients
undergoing elective
CABG surgery
31
For patients
undergoing urgent
CABG surgery
31
Clopidogrel
Ticagrelor
Prasugrel
Clopidogrel
Ticagrelor
Prasugrel
Discontinue at least 5 days before surgery
Discontinue at least 5 days before surgery
Discontinue at least 7 days before surgery
Ideally discontinue at least 24 hours before
surgery
Ideally discontinue at least 24 hours before
surgery
No recommendation given (unlikely to be
used as only given following angiography/
PCI)
a
Earlier discontinuation (i.e. <12 months) is reasonable if morbidity from bleeding outweighs
anticipated benefit (Grade IIaC recommendation).
b
Continuation of dual antiplatelet therapy may be considered for >12 months (Grade IIbC
31
recommendation).
c
Also FDA-approved for a dose reduction to 60 mg bid after 12 months based on the results of
the PEGASUS trial, which demonstrated a 15% reduction in the composited endpoint of death,
MI or stroke at 3 years with a higher rate of bleeding.
d
Continue beyond 1 year for drug-eluting stent (Grade IIbC recommendation).
CABG: coronary artery bypass graft, NSTE: non-ST-segment elevation, PCI: percutaneous
coronary intervention, STEMI: ST-segment elevation myocardial infarction
ACUTE CORONARY SYNDROMES 379
NSTE ACS in patients with high-risk
features not pretreated with clopidogrel
NSTE ACS in patients treated with DAPT
(Class IIbB initial therapy, IIaB at time of
NSTE ACS in patients with high-risk
features not pretreated with clopidogrel
NSTE ACS in patients treated with DAPT
(Class IIbB initial therapy, IIaB at time of
NSTE ACS in patients with high-risk
features not pretreated with clopidogrel
In patients scheduled for CABG surgery, discontinue eptifibatide and tirofiban for at least 2–4 hr and abciximab at least 12 hours prior to surgery.
ACC/AHA: American College of Cardiology/American Heart Association, CABG: coronary artery bypass graft, CrCl: creatinine clearance, FDA: U.S. Food and Drug
Administration, IANSTE: non-ST-segment elevation, PCI: percutaneous coronary intervention, STEMI: ST-segment elevation myocardial infarction
In practice, infusions often omitted or duration of infusion brief <12 hours (no guideline recommendation on infusion duration).
https://t.me/med1917
; dose adjusted to
37
Comments
Agent with most data for STEMI
primary PCI; intracoronary
administration not an FDA-approved
dose.
Early routine use prior to coronary
downstream)
0.25-mg/kg IV or intracoronary bolus
followed by 0.125 mcg/kg/min
(maximum 10 mcg/min) started at
time of angiography.
30,31,37
Contraindications Dose (started at time of PCI, i.e.,
Active bleeding,
thrombocytopenia, history of
180-mcg/kg IV bolus x 2, 10 min
stroke.
Active bleeding,
1 mcg/kg/min in patients with CrCl
<50 mL/min.
Contraindicated in patients with prior
stroke.
angiography increases bleeding
and not efficacy in high-risk patients
with NSTE ACS
apart with an infusion of 2 mcg/kg/
min
thrombocytopenia, history of
stroke, kidney dialysis.
Avoid in patients on dialysis.
If CrCl ≤60 mL/min, give 25 mcg/kg
within 5 min and then 0.075 mcg/
kg/min.
High-dose bolus regimen now FDA-
High-dose bolus regimen: 25 mcg/
kg within 5 min, then 0.15 mcg/kg/
min
Active bleeding,
thrombocytopenia, history of
stroke.
approved for NSTEMI ACS, but not
for STEMI.
30,31
Recommendations
Agent ACC/AHA Guideline
TABLE 15-11: Glycoprotein IIb/IIIA Inhibitors for PCI in ACS
or ticagrelor prior to PCI (IA).
STEMI primary PCI (IIaA)
Abciximab
PCI).
or ticagrelor prior to PCI (IA).
STEMI primary PCI (IIaB)
Eptifibatide
PCI).
or ticagrelor prior to PCI (IA).
Tirofiban
STEMI primary PCI (IIaB)
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