Download Pre PCI hospital antithrombotic therapy for ST elevation myocardial

Pre PCI hospital antithrombotic therapy for
ST elevation myocardial infarction: striving
for consensus
S. Michael Gharacholou, Brenda
J. Larson, Christian C. Zuver, Ryan
J. Wubben, Giorgio Gimelli & Amish
N. Raval
Journal of Thrombosis and
Thrombolysis
A Journal for Translation, Application
and Therapeutics in Thrombosis and
Vascular Science
ISSN 0929-5305
J Thromb Thrombolysis
DOI 10.1007/s11239-012-0744-4
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Author's personal copy
J Thromb Thrombolysis
DOI 10.1007/s11239-012-0744-4
Pre PCI hospital antithrombotic therapy for ST elevation
myocardial infarction: striving for consensus
S. Michael Gharacholou • Brenda J. Larson
Christian C. Zuver • Ryan J. Wubben •
Giorgio Gimelli • Amish N. Raval
•
Ó Springer Science+Business Media, LLC 2012
Abstract Strong evidence exists in favor of rapid transfer
of a patient suffering an ST-elevation myocardial infarction
(STEMI) to the nearest hospital with primary percutaneous
coronary intervention (PCI) capability, assuming the time
from first medical contact to balloon inflation can be
achieved in less than 90 min. In many areas, PCI hospitals
have successfully collaborated with regional non-PCI
hospitals to provide primary PCI for STEMI; however,
significant variations exist in how these programs are
executed. For example, the pre PCI hospital administration
of antithrombotic agents by emergency medical personnel
can include aspirin, clopidogrel, unfractionated heparin,
low molecular weight heparin, partial or full dose fibrinolytics or combinations thereof. There is little consensus on
the optimal cocktail, dose and route of administration.
Standardizing the pre PCI antithrombotic regimen across
hospital systems may be one approach to improve timely
administration of these therapies, and potentially improve
STEMI outcomes.
S. M. Gharacholou (&) B. J. Larson G. Gimelli A. N. Raval
Division of Cardiovascular Medicine, University of Wisconsin
Hospital and Clinics, 600 Highland Avenue, Madison,
WI 53792, USA
e-mail: [email protected]
C. C. Zuver R. J. Wubben
Division of Emergency Medicine, University of Wisconsin
School of Medicine and Public Health, Madison,
WI 53792, USA
Introduction
Half a million people suffer ST-elevation myocardial
infarction (STEMI) every year. Rapidly restoring blood
flow in the occluded culprit coronary artery offers the best
opportunity to preserve ventricular function, prevent heart
failure and reduce mortality [1]. Primary percutaneous
coronary intervention (PCI) is preferred over fibrinolysis
provided that experienced operators can implement this
treatment within 90 min from first medical contact. However, approximately 75 % of STEMI patients (roughly
350,000 patients per year) initially present to health care
facilities incapable of performing primary PCI [2]. Furthermore, it is estimated that between 7 and 30 % of
patients fail to receive lifesaving fibrinolytic therapy or
primary PCI, despite having no contraindications [3, 4].
One-fifth of STEMI patients have contraindications to
fibrinolytics and 70 % of these fail to receive timely primary PCI [2, 5]. These sobering statistics have reinforced
the importance of standardized, system-wide delivery of
evidence-based STEMI care.
The ‘‘hub and spoke’’ care model for STEMI has
recently emerged in many regions of the US. This structure
allows hospitals without onsite PCI capabilities (spokes) to
coordinate patient care with PCI hospitals (hubs) [6, 7].
The American Heart Association (AHA), in collaboration
with emergency medicine and third-party insurers, has
advocated for collaborative regional system approaches for
STEMI management [2]. The role of emergency medical
service (EMS) in any effective regional STEMI program is
multifaceted and includes: recognition of probable STEMI,
rapid transport to the most appropriate PCI capable facility,
and administration of active therapy en route [1, 8, 9]. EMS
transport of STEMI patients from the scene to a PCI hospital has been associated with improved outcomes, even
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S. M. Gharacholou et al.
among patients who are administered fibrinolysis and are
transferred for PCI within 6 h of fibrinolysis [10]. Furthermore, there is interest in EMS-directed initiatives to
transport STEMI patients directly to centers capable of
performing PCI, rather than invoking interhospital transfer
from regional non-PCI hospitals; however, no controlled
trials testing this strategy have been performed. Generally,
paramedic units responding to calls for probable STEMI
are likely to initiate preparatory antithrombotic agents;
however, variations exist in the type of medications, doses
and routes of administration.
A principle goal in regional STEMI programs is to
increase the proportion of STEMI patients who receive
timely and successful reperfusion; however, a unified perspective on the optimal pre PCI hospital antithrombotic
regimen has not been offered. Herein, we will review
contemporary antiplatelet and antithrombotic therapy in
patients with STEMI referred for PCI. We will explore the
potential time-dependent benefits of agents administered in
the pre-hospital setting and highlight newer antithrombotic
agents and their potential implications for STEMI management. Finally, we will share the rationale behind our
own regional, standardized approach to pre PCI hospital
antiplatelet and antithrombotic management.
Pre-PCI hospital oral antiplatelet considerations
Aspirin
Aspirin irreversibly inhibits cyclooxygenase resulting in
the inhibition of thromboxane A2 production, thereby
reducing the thromboxane A2-mediated amplification of
platelet aggregation [11]. Aspirin levels peak within 1 h of
oral administration to exert its antiplatelet effect, which
highlights the importance of pre PCI hospital administration [12]. Non-enteric coated formulations of aspirin are
preferred and patients should be instructed to chew aspirin
to increase absorption and bioavailability. As compared to
placebo, aspirin monotherapy has been shown to reduce
short term vascular mortality after myocardial infarction
(MI) (absolute risk reduction of 2.4 %; number needed to
treat (NNT) of 47; p \ 0.001) [13]. Antiplatelet therapy
administered in the pre-hospital setting improves ST-segment resolution prior to primary PCI and increases rates of
arterial patency [14].
The optimal initial dose of aspirin in STEMI remains
uncertain. A retrospective study by Berger et al. [15] in
48,422 fibrinolytic-treated STEMI patients showed no
difference in 30-day mortality or ischemic-related outcomes in patients treated initially with 162 mg of aspirin as
compared with 325 mg of aspirin; however, the higher
dose of aspirin was independently associated with greater
123
risk of moderate to severe bleeding (OR 1.14; 95 % CI
1.05–1.24, p = 0.003). There was no difference in 30-day
cardiovascular death, MI, or stroke in the Clopidogrel and
Aspirin Optimal Dose Usage to Reduce Recurrent
Events—Seventh Organization to Assess Strategies in
Ischemic Symptoms (CURRENT-OASIS 7) trial that
compared open-label high-dose (300–325 mg daily) aspirin
to low-dose (75–100 mg) aspirin in patients with acute
coronary syndromes undergoing planned PCI [16, 17]. For
suspected STEMI, aspirin 162–325 mg as the initial dose
should remain the standard, with the exception of patients
with true allergy to aspirin [18].
P2Y12 inhibitors
These agents work through inhibition of adenosine
diphosphate (ADP) induced platelet aggregation by inactivating the P2Y12 receptor on the platelet surface, thereby
preventing cross linking, and have led to improved outcomes when combined with aspirin in patients treated with
intracoronary stents [19, 20]. Ticlopidine was a first generation ADP receptor antagonist for patients undergoing
PCI and as secondary prevention in patients with a history
of stroke. However, severe side effects including neutropenia and thrombotic thrombocytopenic purpura combined
with twice daily dosing limited its use.
Clopidogrel, which is now more commonly used than
ticlopidine, is effective in reducing cardiovascular events
in high-risk patients with acute coronary syndromes when
combined with aspirin. Clopidogrel reduces risk irrespective of upfront PCI or medical therapy, with benefits
observed as early as 24 h after initiating therapy [19, 21].
Several clinical trials have subsequently evaluated whether
the benefits of clopidogrel treatment in unstable angina/
non-STEMI could also be observed in patients with
STEMI. The Clopidogrel and Metoprolol in Myocardial
Infarction Trial (COMMIT-CCS 2) randomized [45,000
patients with suspected MI (93 % had STEMI or leftbundle branch block) to clopidogrel 75 mg daily without a
loading dose or placebo on a background of antiplatelet
therapy (aspirin 162 mg daily) and found a significant
reduction in the composite outcome of death, reinfarction,
or stroke (OR 0.91; 95 % CI 0.86–0.97; NNT = 112) [22].
Sabatine et al. [23] showed improved ischemic outcomes
and greater patency of the infarct-related artery when
clopidogrel was added to a standard regimen of fibrinolytic
therapy, aspirin, and dose-adjusted unfractionated heparin
(UFH) in patients with STEMI. Clopidogrel benefits
patients with STEMI receiving fibrinolytic therapy,
resulting in a 36 % reduction in the odds of death, recurrent
MI, or an occluded infarct artery [24]. In a pre-specified
subgroup of the Clopidogrel as Adjunctive Reperfusion
Therapy—Thrombolysis
in
Myocardial
Infarction
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Pre PCI hospital antithrombotic therapy for ST elevation myocardial infarctions
(CLARITY-TIMI 28) trial, 1,863 patients underwent PCI
after treatment with fibrinolysis, half of whom received
clopidogrel (300 mg loading dose followed by 75 mg
daily) while the other half received placebo [25]. Pretreatment with clopidogrel, as compared to placebo, was
associated with fewer rates of death, MI, or stroke at
30 days (3.6 vs. 6.2 %; adjusted OR 0.54; 95 % CI
0.35–0.85, NNT = 39) and greater patency in the infarct
artery (86.9 vs. 80.8 %, p \ 0.001) [25]. Of note, there is
insufficient evidence to support a loading dose of clopidogrel in older adults (age [75 years) undergoing fibrinolysis for STEMI [26]. Although the optimal loading dose
for clopidogrel has not clearly been established [27], a
600 mg load as compared to a 300 mg load achieves
greater inhibition of platelet aggregation at onset
(approximately 2 h) and peak (approximately 6 h), and has
been associated with both lower rates of cardiovascular
events without an increase in bleeding and improved short
term outcomes in STEMI patients undergoing PCI [28, 29].
Clopidogrel, especially when administered with concomitant antiplatelet and antithrombotic therapies, has been
associated with increased risk of major bleeding. In the
Clopidogrel in Unstable Angina to Prevent Recurrent
Events (CURE) trial, the combination of clopidogrel and
aspirin as compared to aspirin alone was associated with
higher rates of major bleeding (3.7 vs. 2.7 %, respectively;
relative risk (RR) 1.38; 95 % CI 1.13–1.67; p = 0.001) and
higher rates of blood transfusion C2 U (2.8 vs. 2.2 %,
respectively; RR 1.30; 95 % CI 1.04–1.62; p = 0.02),
without observed differences in life-threatening or fatal
bleeding [21]. Efforts to minimize bleeding with clopidogrel therapy require appropriate dosing of anticoagulants in
the acute setting and adhering to lower maintenance doses
of aspirin, as stacked antithrombotics markedly increase
bleeding risk [30].
Despite large-scale outcome studies supporting the use
of clopidogrel across the spectrum of acute coronary syndromes, important limitations of the drug have been identified. Clopidogrel is a prodrug, requiring bioactivation
in a 2-step process from several CYP450 enzymes, chiefly
involving CYP2C19, to convert the prodrug to its pharmacologically active form (R-130964) [31]. It is important
to note that only about 15 % of the prodrug undergoes the
process of bioactivation to become potentially available to
exert its antiplatelet effect [32]. Observational studies have
shown that patients with genetic polymorphisms of
CYP2C19, particularly those with two copies of the
CYP2C19*2 and CYP2C19*3 loss-of-function alleles, are
poor metabolizers of clopidogrel, appear to exhibit less
antiplatelet effect after standard clopidogrel doses, and
have higher rates of cardiovascular events after MI and PCI
[32]. In addition, individual variability in clopidogrel
responsiveness may be associated with other genetic and
nongenetic factors, including comorbid health conditions,
age, body mass, smoking status (via CYP1A2), and medications (via CYP2C9) [33–35]. The association of genetic
polymorphisms of CYP2C19 with higher platelet reactivity
and higher event rates has prompted interest in genotyping
patients, particularly those at higher ischemic risk; however, outcomes data to guide antiplatelet strategy based on
results obtained from genotyping are lacking. Finally,
identification of CYP2C19 variants still only accounts for a
small percentage of the variability in clopidogrel responsiveness [35]. These complex issues have promoted interest
in developing more potent ADP receptor blockers with less
response variability.
Prasugrel, like clopidogrel, is a prodrug and thienopyridine that requires biotransformation to an active
metabolite; however, the efficiency of its absorption and
metabolic activation are greater than clopidogrel. Conversion to the active metabolite (R-138727) occurs through
hydrolysis by intestinal carboxylase, followed by oxidation
via the CYP450 system [36]. Importantly, the major CYP
subtypes involved in metabolic activation are CYP3A and
CYP2B6, with CYP2C19 having less importance, thus
obviating the issues related to responsiveness that have
been associated with the metabolism of clopidogrel. For
prasugrel, this has the net effect of both rapid absorption
and metabolism, and attainment of peak plasma concentration of the active metabolite in approximately 30 min
after dosing [37]. The Trial to Assess Improvement in
Therapeutic Outcomes by Optimizing Platelet Inhibition
with Prasugrel—Thrombolysis in Myocardial Infarction
(TRITON-TIMI 38) compared prasugrel to clopidogrel in
moderate-to-high risk acute coronary syndrome patients
[38]. In this study, 26 % (n = 3,534) of patients presented
with STEMI and the endpoint was the composite outcome
of cardiovascular death, MI, or stroke [38]. Prasugrel was
administered as a loading dose of 60 mg followed by a
maintenance dose of 10 mg daily as compared to clopidogrel at a loading dose of 300 mg followed by 75 mg
daily. In the TRITON study, prasugrel, as compared to
clopidogrel, was associated with significantly fewer primary outcome events (9.9 vs. 12.1 %; p \ 0.001;
NNT = 46) and fewer events of stent thrombosis (1.1 vs.
2.4 %; p \ 0.001; NNT = 77) but at a cost of more major
bleeding (2.4 vs. 1.8 %; p = 0.03; NNH = 167), including
life-threatening and fatal bleeding. The greater antiplatelet
effect with prasugrel increased the susceptibility of bleeding in certain important subgroups such as those age
C75 years, prior stroke or transient ischemic attack, or low
body weight (\60 kg) such that net clinical benefit with
prasugrel as compared to clopidogrel in these patients was
not observed. However, these subgroups suffered more
bleeding complications irrespective of the treatment
assignment [38]. Information regarding pre-hospital
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administration of study medication was not reported in
TRITON-TIMI 38, although patients with STEMI and
intending to undergo primary PCI could be treated with
study medication up to 24 h prior to their procedure. Most
patients (74 %) received first dose of study medication
after insertion of intracoronary guidewire and up to 1 h
after PCI (i.e., over half of patients were loaded after PCI),
thus few patients were ‘‘pre-treated’’ with study medication
[38, 39]. Importantly, there were no significant differences
between treatment assignment with regards to cardiovascular mortality or overall mortality in TRITON-TIMI 38,
with results driven by differences in nonfatal MI between
treatment groups. Prasugrel should be administered cautiously given the apparent increased bleeding in at-risk
subgroups such as the elderly, those with a history of
cerebrovascular disease, and low body weight [27, 40].
Ticagrelor is a reversibly binding noncompetitive oral
P2Y12 receptor antagonist, does not require metabolic
activation, is rapidly absorbed with a maximum plasma
concentration at 90 min, and has linear and predictable
pharmacokinetics [41]. Ticagrelor was compared to clopidogrel in the Platelet Inhibition and Patient Outcomes
(PLATO) trial which tested the hypothesis that ticagrelor
would be superior to clopidogrel on the composite outcome
of cardiovascular death, MI, or stroke in 18,624 patients
with acute coronary syndrome [42]. At 12 months, treatment with ticagrelor (180 mg load followed by 90 mg
twice daily), as compared to clopidogrel (300 mg load
followed by 75 mg daily), was associated with a lower rate
of the composite outcome (9.8 vs. 11.7 %; p \ 0.001;
NNT = 53), MI (5.8 vs. 6.9 %; p = 0.005; NNT = 91),
and cardiovascular death (4.0 vs. 5.1 %; p = 0.001;
NNT = 91). In the subgroup of patients receiving intracoronary stents, treatment with ticagrelor resulted in lower
rates of stent thrombosis (1.3 vs. 1.9 %; p = 0.009;
NNT = 167). In a secondary analysis of the 41 % of
patients from PLATO that presented with STEMI
(n = 7,544) and underwent primary PCI, there was a trend
towards similar benefits as observed in the parent trial, with
a 1.4 % absolute risk reduction (13 % RR reduction) in the
primary endpoint favoring ticagrelor (HR 0.87; 95 % CI
0.75–1.01; p = 0.07), including a 0.8 % absolute risk
reduction (34 % RR reduction) in definite stent thrombosis
with ticagrelor (HR 0.66; 95 % CI 0.45–0.95; p = 0.03)
[43]. Adverse events reported in follow up included higher
rates of dyspnea in patients treated with ticagrelor that
appeared to be self-limiting and non-serious but was
associated with a higher rate of study drug discontinuation.
There was no difference in major bleeding between
patients treated with ticagrelor as compared to patients
treated with clopidogrel, including no differences in
intracranial hemorrhage, fatal bleeding, or transfusion rates
between groups [43]. Non-procedure related major and
123
minor bleeding rates were, however, higher with ticagrelor
as compared to clopidogrel (5.1 vs. 3.7 %, respectively;
p = 0.02; NNH = 72) [43]. Since the timing from first
dose of study drug to PCI in patients with STEMI was a
median of 15 min in the PLATO trial, the study was not
designed to evaluate the role for administration of ticagrelor in the pre-hospital setting in patients with probable
STEMI. Its use in primary PCI are likely to be limited to
scenarios where perceived bleeding risk is low, concomitant anticoagulant use has been appropriately dosed and
monitored, and the clinician is planning to treat the patient
with maintenance doses of aspirin B100 mg daily. If these
conditions are satisfied, ticagrelor may become an attractive alternative to clopidogrel due to its superior efficacy
and could be adopted in pre-hospital administration of
STEMI patients undergoing primary PCI.
Glycoprotein IIb/IIIa inhibitors
Glycoprotein (GP) IIb/IIIa inhibitors exert their antiplatelet
effect through inhibition of the GP IIb/IIIa platelet surface
receptor, thus inhibiting the final common pathway in
platelet aggregation. The current role for GP IIb/IIIa
inhibitors in patients with STEMI referred for primary PCI
is less clear, since prior studies of GP IIb/IIIa use in this
population did not represent a high percentage that were
also being treated on a background of both dual antiplatelet
therapy (i.e., aspirin and thienopyridine) and anticoagulation [27]. Therefore, net clinical benefit (benefits minus
risks/adverse sequlae) of GP IIb/IIIa inhibitors are less well
established in the contemporary era of STEMI patients
undergoing primary PCI. Initial development of GP IIb/
IIIa’s in early phase clinical trials were of oral GP IIb/IIIa
inhibitors; however, these agents were associated with
higher rates of both bleeding and mortality [44]. Abciximab and the small molecule GP IIb/IIIa inhibitors, primarily eptifibatide and tirofiban, have been shown in a
pooled meta-analysis of randomized trials and observational registries to have comparable efficacy for reduction
of death and MI and similar rates of in-hospital major
bleeding in STEMI patients undergoing primary PCI,
suggesting non-inferiority of small molecule agents as
compared to abciximab [45]. Abciximab, as compared to
placebo, did not reduce infarct size or clinical events at
30 days in a contemporary randomized double-blinded
study of STEMI patients undergoing PCI who had been
pre-treated with 600 mg of clopidogrel and 500 mg of
aspirin [46]. The timing of administering GP IIb/IIIa’s in
STEMI patients was recently evaluated in 2,453 STEMI
patients assigned to half-dose fibrinolysis plus abciximab
prior to PCI, abciximab prior to PCI, or abciximab
administered at the time of PCI [47]. There were no
Author's personal copy
Pre PCI hospital antithrombotic therapy for ST elevation myocardial infarctions
observed benefits and higher rates of bleeding with
upstream abciximab as compared to abciximab at the time
of PCI, suggesting that timing for use of GP IIb/IIIa’s
should be relegated to selective use in the catheterization
lab based on angiographic and clinical factors. Thus,
invoking use of GP IIb/IIIa inhibitors at STEMI-referral
sites prior to transfer for primary PCI may not improve
outcomes and could potentially introduce greater transfer
delay due to dosing considerations and use of cumbersome
intravenous drips.
Administration of fibrinolysis (half or full-dose) upfront
with or without GP IIb/IIIa inhibitors with the intent of
proceeding directly to PCI has been referred to as facilitated PCI, though current recommendations advise against
using labels such as facilitated or rescue in contemporary
STEMI management [27]. The use of facilitated PCI in
STEMI regional care systems has been described [48];
however, higher rates of bleeding complications remain a
significant impediment to more widespread adoption and
the totality of current evidence does not support this
approach routinely [49]. The addition of GP IIb/IIIa
inhibitors to fibrinolysis compared to fibrinolysis alone in a
facilitated PCI strategy has been tested [50]. Despite
improved infarct-related artery flow at the time of angiography, clinical harm due to ischemic and bleeding
complications result in greater risk with a facilitated
strategy [49, 50], and current guidelines do not recommend
facilitated PCI as a routine reperfusion approach [27].
Instead, the transfer of fibrinolytic treated STEMI patients
to the nearest PCI-hospital for possible rescue PCI (i.e.,
PCI performed after failure of fibrinolysis based on presence of clinical symptoms and incomplete (\50–70 %)
resolution of ST-segment elevation) is recommended since
at least a 40 % fibrinolytic failure rate can be expected
[27].
Pre-hospital anticoagulant considerations
There are several anticoagulant options for patients with
STEMI referred for PCI, including UFH, enoxaparin,
fondaparinux, and bivalirudin (Table 1); however, optimal
use of anticoagulation relies on institutional-specific algorithms for managing anticoagulation at the STEMIreceiving center in order to reduce medication and dosing
error, optimize anti-ischemic benefit while reducing
bleeding risk, and to maintain flexibility in adapting the
anticoagulation strategy based on clinically related factors
(i.e., renal insufficiency, bleeding risk, adjunctive GP IIb/
IIIa use) [27, 51]. Familiarity with all major anticoagulants
is essential given that a proportion of patients co-administered anticoagulants at the time of fibrinolysis may subsequently be referred for rescue PCI. In this case,
appropriate anticoagulation at the correct doses will need to
be continued during the PCI procedure.
The use of UFH for acute MI has demonstrated reductions in mortality and reinfarction in an era prior to standard use of aspirin, yet added benefits for UFH in the era of
fibrinolytic therapy have not been convincing [52]. UFH
has become the comparator in non-inferiority and activecontrol superiority studies of alternative anticoagulant
Table 1 Anticoagulants in the Pre PCI setting in STEMI
Anticoagulant
Bolus dose
Maintenance dose
Renal adjustment
Cath lab considerations
UFH
60 U/kg IV
(maximum
4,000 U)
12 U/kg/h (maximum 1,000 U/h)
OR may be omitted at non-PCI
hospital to minimize transfer delay
None
Supplemental boluses administered in
Cath lab to maintain ACT [ 250 if
GP IIb/IIIa use is not planned OR
switch to bivalirudin
Enoxaparin
30 mg IV (for
age
\75 years)
1.0 mg/kg SQ Q12H if \75 years
old (first dose to be administered
15 min after IV bolus) or 0.75 mg/
kg SQ Q12H if [75 years old
Advise against using
enoxaparin if
SCr [ 2.5 mg/dL in men
or [2.0 mg/dL in women
If last SQ dose of enoxaparin was
given within 8 h, no additional
enoxaparin needed. If last SQ dose of
enoxaparin was given 8-12 h earlier,
administer 0.3 mg/kg IV
Fondaparinux
2.5 mg IV (if
SCr \ 3.0 mg/
dL)
2.5 mg SQ Q24H
Not recommended if
SCr [ 3.0 mg/dL
(patients were excluded
from OASIS-6 [55])
Supplement the fondaparinux-treated
patient with anticoagulant that
possesses anti-IIa activity (either
UFH or bivalirudin).
Bivalirudina
0.75 mg/kg IV
1.75 mg/kg/h (infusion usually
terminated at end of procedure)
Reduced to 1 mg/kg/h
(CrCl \ 30 mL/min) or
0.25 mg/kg/h if on
dialysis (bolus remains
unchanged)
Confirm oral antiplatelet therapy
(aspirin and thienopyridine) have
been administered
UFH unfractionated heparin, ACT activated clotting time, GP glycoprotein, SQ subcutaneously, IV intravenously, CrCl creatinine clearance,
OASIS Organization for the Assessment of Strategies for Ischemic Syndromes
a
Primarily started in the cardiac catheterization laboratory upon patient arrival
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S. M. Gharacholou et al.
strategies, yet drawing conclusions regarding comparative
efficacy has been limited due to differences in dosing
across studies, characteristics of the study population, differences in duration of therapy in treatment arms, and
monitoring strategies of anticoagulant effect [26].
For STEMI, UFH has been a preferred anticoagulant in
the pre-hospital setting or when transitioning from the
emergency department directly to the catheterization laboratory for primary PCI [18]. The recommended dosing for
UFH is 60 U/kg intravenously (not to exceed a 4,000 U
bolus) followed by an infusion of 12 U/kg/h (not to exceed
1,000 U/h) with a goal activated partial thromboplastin
time of 1.5–2.0 times the local laboratory reference values,
which usually approximates 50–70 s [18, 53]; however, the
initial bolus may be modified based on whether adjunctive
GP IIb/IIIa inhibitors are going to be used.
There are limited data for either enoxaparin or fondaparinux as the sole anticoagulant in patients with STEMI
undergoing primary PCI, yet these therapies may be started
upstream, at the non-PCI hospital, and strategies for
switching, supplementing, or continuing the anticoagulant
will need to be considered. Enoxaparin, a low molecular
weight heparin with a higher ratio of anti-Factor Xa to antiFactor IIa activity than UFH, has been studied in fibrinolytic-treated patients with STEMI, and includes a specific
dosing regimen adjusted for age and renal function
designed to avoid excess bleeding events due to accumulation of drug and extended anti-Factor Xa activity
(Table 1) [54]. For the enoxaparin treated patient with
STEMI that is referred for primary PCI and receives the
30 mg IV loading dose prior to transfer, the weight-based
supplemental subcutaneous dose should be administered in
15 min by paramedic or emergency department personnel,
if not given immediately after the IV loading dose. The
rationale for the IV loading dose of enoxaparin in STEMI
is related to the pharmacokinetic activity of enoxaparin,
which results in peak anti-thrombin and anti-Factor Xa
activity 3–5 h after subcutaneous injection.
Fondaparinux, a synthetic pentasaccharide that binds
antithrombin and inhibits Factor Xa, exerts its antithrombotic effect through antithrombin-mediated neutralization
of Factor Xa and subsequent inhibition of thrombin formation. Subcutaneous injection results in near complete
bioavailability of the drug and therapeutic drug concentrations are reached approximately 2–3 h post-dose.
Fondaparinux has been compared to placebo and UFH in a
randomized trial of STEMI patients, including non-reperfused, fibrinolytic-treated, and patients undergoing PCI
[55]. In the subset of the stratum that underwent primary
PCI, death or reinfarction rates among fondaparinux-treated patients were similar to patients treated with UFH (8.5
vs. 8.2 %, respectively, p = 0.61), yet there were higher
rates of guide catheter thrombus events in the fondaparinux
123
group as compared to those treated with UFH (22.0 vs.
0 %, respectively, p \ 0.001) [55]. In addition, there were
numerically greater coronary complications in the fondaparinux group as compared to the UFH group (270 vs. 225,
respectively, p = 0.04). On this basis, supplemental anticoagulation with UFH or bivalirudin is advised in fondaparinux-treated STEMI patients undergoing planned PCI.
If STEMI patients receive fondaparinux at the non-PCI
hospital, it is critical to communicate this information to
the PCI hospital so that appropriate supplemental antithrombotic therapy with anti-IIa activity can be provided to
support the PCI procedure (Table 1).
Bivalirudin has recently emerged as an important anticoagulant in primary PCI for STEMI. In the Harmonizing
Outcomes with Revascularization and Stents in Acute
Myocardial Infarction (HORIZONS-AMI) trial, bivalirudin
(with provisional GP IIb/IIIa inhibitor for no-reflow or
thrombus after PCI) was compared to UFH plus a GP IIb/
IIIa inhibitor (dose-adjusted eptifibatide or abciximab per
the investigator’s discretion) on rates of major bleeding or
major adverse cardiovascular events at 30-days [56]. Bivalirudin resulted in a lower rate of the primary endpoint
(9.2 vs. 12.1 %, p = 0.005), driven by less major bleeding,
and an observed lower rate of cardiac death and all-cause
mortality at 30-days. There was a higher rate of acute
(\24 h) stent thrombosis in the bivalirudin treated patients
as compared to the UFH/GP IIb/IIIa group (1.3 vs. 0.3 %,
p \ 0.001). Some of the higher rate of stent thrombosis
may have been explained by a lower loading dose of
clopidogrel (300 mg instead of 600 mg) and bivalirudin
monotherapy [27]. Thus, from a pre-hospital STEMI activation standpoint in patients being referred for primary
PCI, it is important to recognize that the majority of
patients in HORIZONS-AMI (76 %) were treated with
open label UFH as the initial anticoagulant, with subsequent secondary analyses suggesting that switching from
UFH to bivalirudin, as compared to continued use of UFH
with a GP IIb/IIIa inhibitor, may not only be associated
with lower rates of major bleeding, but also lower longterm cardiac mortality and reinfarction [57]. Indeed, in the
interventional setting, patients initially treated with UFH
can be readily converted to bivalirudin to support the primary PCI procedure, with a proviso of a 30 min interval
between dosing of the anticoagulants [56].
Antithrombotic approaches adopted by regional
primary PCI programs
Early primary PCI for STEMI and its time-dependant
benefits have been known for some time [58]. Implementing primary PCI in the US requires collaboration and
direct communication between EMSs, emergency medicine
physicians, and cardiologists. Additional complexities of
Author's personal copy
Pre PCI hospital antithrombotic therapy for ST elevation myocardial infarctions
delivering primary PCI in the US include resource utilization, staffing personnel, and economic and logistical
details regarding cardiac services in rural hospitals [6, 7].
Several organizations have developed standardized protocols within their regional network for antithrombotic
therapies to be administered before or at the time of primary PCI that aims for efficiency, simplicity, and an evidence based approach to STEMI care (Table 2). These
programs have been effective in integrating rural community hospitals with a PCI center [48, 59–62], and have been
implemented statewide [59] and across state borders [60].
One important limitation in STEMI care in the US has
been a lack of standardized guideline-driven protocols.
Instead, protocols tend to vary from region to region.
Variable dosing of antithrombotics, selection of thienopyridines versus GP IIb/IIIa inhibitors for adjunctive
antiplatelet therapy, and select use of facilitated PCI are
examples that make outcome comparisons across regional
protocols difficult (Table 2). Notably, achieving goals and
benchmarks on pre-PCI hospital care and transport
appears feasible in the conduct of clinical trials [63];
however, achieving these goals and benchmarks in the
‘‘real-world’’ setting has proven to be problematic. Registry studies show that \9 % of patients have total
(e.g., arrival at non-PCI hospital to first device at PCI
hospital) door-to-balloon times of \90 min [64]. It would
appear that the same level of coordination and motivation
that drives multi-center clinical trials is what is required
to institute protocol standards for STEMI care in the
patient care setting.
Streamlining, simplifying, and maintaining efficacy
Specific factors that are unique to certain regions must be
taken into account when designing standardized STEMI
protocols. For example, inclement weather directly impacts
the selection of transport strategies, which may be more of
a factor in the upper Midwest than in the Southeastern US
during the winter months. The local distribution of EMS
services including staffed helicopter units, paramedic units,
or ‘‘basic’’ EMS units can affect time to STEMI recognition on the electrocardiogram and qualifications to
administer antithrombotic agents, for example. Variations
exist in level of integration between health providers and
facilities, governance of local emergency systems, and
willingness to invest in regional STEMI system of care.
However, efforts to understand strategies that work and to
allow for comparative evaluation between programs
Table 2 Antithrombotic recommendations suggested for use by PCI centers for interhospital transfer patients with STEMI intended for primary
PCI
Program name
Program location
Reperfusion of Acute Myocardial
Infarction in North Carolina
Emergency Departments (RACE)
[59]
State of NC
Geisenger STEMI protocol [62, 65]
Stat Heart Program [61]
Minneapolis Heart Institute Level 1
Myocardial Infarction Program [48]
Mayo Clinic STEMI Protocol [60]
Antiplatelet strategy
Anticoagulant strategy
Aspirin 162 mg to 325 mg
Bolus: UFH 70 U/kg
Clopidogrel 300 mg to
600 mg or Prasugrel 60 mga
Maintenance: None during
transfer
Central PA
Aspirin 325 mg
Clopidogrel 600 mg
Bolus: UFH 70 U/kg
Maintenance: None during
transfer
Central IL
Aspirin 324 mg
Clopidogrel 300 mg
Bolus: UFH 70 U/kg
(maximum of 7,000 U)
GP IIb/IIIa inhibitor
(abciximab or eptifibatide)
Maintenance: 15 U/kg/h
(maximum of 1,000 U/h)
Regional sites within
200 miles of
Minneapolis, MN
Aspirin 325 mg
Bolus: UFH 60 U/kg
(maximum of 4,000 U)
Regional sites within
150 miles of
Rochester, MN
Aspirin regimen not
reported but high rates
of use ([95 %)
Clopidogrel 600 mg
Maintenance: 12 U/kg/h
(maximum of 1,000 U/h)
Clopidogrel not used
University of
Wisconsin-Madison
Regional sites within
100 miles of
Madison, WI
Aspirin 325 mg
Clopidogrel 600 mg
Bolus: UFH 60 U/kg
(maximum of 4,000 U)
Maintenance: 12 U/kg/h
(maximum of 1,000 U/h)
Bolus: UFH 60 U/kg
(maximum of 4,000 U)
Maintenance: None during
transfer
UFH unfractionated heparin, GP glycoprotein
a
Operations manual (available at http://www.nccacc.org)
123
Author's personal copy
S. M. Gharacholou et al.
require consensus on antithrombotic strategies for STEMI
patients referred for primary PCI.
At the University of Wisconsin-Madison, paramedics in
Dane County (Madison, WI) activate the cardiac catheterization laboratory based on their own interpretation of
electrocardiogram acquired at the scene, and administer a
standard pre-treatment regimen of antithrombotic therapy
en route (Table 2). Adjunctive medications, such as nitroglycerin and analgesics, are also administered for symptom
relief. For STEMI outside of Dane County, the decision to
travel directly by ground or helicopter (Med Flight) from
the regional non-PCI hospital, or through a Med Flight
intercept (i.e., convenient landing zone near the scene) is
rapidly determined by radio communication between
emergency room physicians and Med Flight dispatch.
Factors such as flight conditions, road conditions, and
travel distances are rapidly assessed. The University of
Wisconsin-Madison Med Flight Helicopter transport program is uniquely staffed by board-certified emergency
physicians (MD/DO) that significantly enhances the team’s
Fig. 1 STEMI referral sites and
their geographic relationship to
the University of WisconsinMadison as represented by
ground distance (mileage) and
nautical miles (rings)
123
capability to make clinical decisions and institute care
related to pre PCI hospital antithrombotics. The geographic
distribution of non-PCI centers in our STEMI referral
program at the University of Wisconsin-Madison is illustrated in Fig. 1.
In our program, we initiate antiplatelet therapy with
aspirin 325 mg chewed at first contact with EMS. In patients
unable to take oral agents and who do not have a nasogastric
tube in place, a 300 mg aspirin suppository can be administered [9]. For fibrinolytic treated patients in the non-PCI
emergency room, a clopidogrel loading dose of 300 mg in
patients B75 years of age is administered. A strategy of
administering clopidogrel 75 mg without a loading dose can
be used in patients [75 years old with STEMI undergoing
fibrinolysis, but careful attention to the adjunctive anticoagulant dose is imperative [22]. For primary PCI, we recommended rapid clopidogrel loading of 600 mg, as has
been used in contemporary primary PCI trials [46]. However, it should be noted that the optimal clopidogrel loading
dose in patients with STEMI referred for primary PCI has
Author's personal copy
Pre PCI hospital antithrombotic therapy for ST elevation myocardial infarctions
not been conclusively determined from clinical trials [27].
Our choice of clopidogrel is based on the favorable safety
profile (in comparison to prasugrel or ticagrelor), regional
provider familiarity, and regional ease of access to the drug.
On arrival in the STEMI receiving hospital’s cardiac catheterization lab, a formal checklist is entered that includes
queries that aspirin and clopidogrel were administered, their
doses and time of administration. This approach is critical to
avoid the untenable scenario of stacked dosing that may
increase bleeding risk or omission that may lead to recurrent
ischemic events or stent thrombosis [18].
Our recommended anticoagulant has remained a bolus of
UFH without maintenance infusion, similar to the anticoagulant of choice among other regional care systems, and
dose of anticoagulant is verified as part of our checklist upon
patient arrival to the cath lab. However, slight differences in
dosing regimens may be due to patient-related factors such
as obesity or perceived bleeding risk, or whether some
programs prefer starting maintenance infusions post bolus
(Table 2). We routinely switch to bivalirudin during the PCI
procedure. A greater percentage of our procedures are being
performed via the transradial approach, which in the future
may enable intensifying the antithrombotic regimen or even
a re-evaluation of facilitated PCI in selected patients. Of
important note, the above-described regional STEMI protocol has been agreed upon by the three STEMI-receiving
PCI hospitals in Madison, WI. Such integration is critical for
regional providers to avoid problems associated with conflicting protocols. However, a standardized protocol does
not usurp clinical experience or sound clinical judgment for
selecting appropriate adjunctive pharmacological therapies
or refining dosing regimens based on a risk–benefit calculus
for individual patients.
Summary
Standardized, system wide approaches to STEMI care
involve the creation of regional networks, and multi-disciplinary collaborations to improve STEMI outcomes.
Time-dependant benefits of antithrombotic agents instituted in the patient with STEMI are important co-interventions in the delivery of reperfusion therapy. Goals
should include reducing delay to coronary reperfusion,
achieving PCI as the preferred reperfusion strategy within
90 min of first medical contact, and preventing medication
dosing errors, and improving quality and performance.
Acknowledgments We would like to thank Vicki Carter and Renae
Buchheim for their assistance in creating the figure of the regional
map of STEMI referral centers that coordinate care with the
University of Wisconsin-Madison. No compensation, apart from
employment at the University of Wisconsin-Madison Hospitals and
Clinics, was provided.
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