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108 PART III Coronary Artery Disease
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100 U heparin) should be considered. If the patient has been
treated recently with a thrombolytic agent and the concentration
of fibrinogen levels is low or clotting factors depleted, administration of cryoprecipitate (10 U) or fresh frozen plasma (2 to 4 U)
may be required. Aminocaproic acid (Amicar), an antifibrinolytic
agent that competes with plasminogen for lysine binding sites
on fibrin, should be reserved for patients with refractory bleeding unresponsive to other measures because it can precipitate
thrombosis. If used, it should be given in a loading dose of
5 g intravenously, followed by 0.5 to 1.0 g/h until bleeding has
stopped.
60
PRIMARY PERCUTANEOUS
CORONARY INTERVENTION
Primary Percutaneous Coronary Intervention
for STEMI
Rationale and Feasability. First-line therapy for STEMI in the
late 1980s was coronary thrombolysis. Nevertheless, limitations
of fibrinolysis alone were readily apparent: experience with
fibrinolysis alone demonstrated that in approximately 15% of
patients, recanalization fails completely and for 50% of patients,
restoration of flow in the infarct-related artery is suboptimal.
Last, in 10% of patients in whom recanalization is initially
successful, reinfarction occurs.61 However, in influential early
TIMI trials in which strategies of PCI were performed with
balloon angioplasty after thrombolysis, no clinical benefit was
observed with either immediate or delayed PCI compared with
conservative therapy.
higher incidence of bleeding and emergency coronary artery
bypass graft surgery.
Given the discouraging early results of combined balloon
angioplasty and fibrinolysis, several investigators explored the
possibility that stand-alone balloon angioplasty would be a safe
and effective alternative to stand-alone fibrinolysis for patients
with STEMI. Early results by O’Neill and coworkers in comparisons of angioplasty to intracoronary streptokinase demonstrated
that balloon angioplasty was superior in improving ventricular
function and reducing residual stenosis in the setting of acute
66
Over the next 15 years, multiple trials directly comparing
MI.
stand-alone fibrinolysis to primary PCI were undertaken, eventually validating the utility of primary PCI and its superiority
compared with thrombolysis in inducing more complete and
more frequent recanalization of the infarct-related artery.
Key Clinical Trials. In 1993, Primary Angioplasty in Myocardial
Infarction (PAMI)—a multicenter, randomized trial that compared primary PCI with intravenous tPA in 395 patients—found
no difference in the primary endpoint of posttreatment radionuclide left ventricular function, but demonstrated a trend of
decreased hospital mortality with primary PCI (6.5% compared
with 2.6%, P = .06), significantly decreased in-hospital and
6-month incidence of death and reinfarction, and a decreased
incidence of ICH (0% compared with 2.0%).
Despite the favorable results with PCI in this early trial, primary
PCI was not widely adopted immediately as a treatment strategy
62–65
In fact, immediate PCI led to a much
67
for patients with STEMI.68 This was partly because of the substantial resources required for offering primary PCI around the
clock and the relative scarcity of experienced operators able to
perform emergency PCI in a high-risk setting. However, numerous
studies comparing fibrinolytic therapy with primary PCI were
performed throughout the later 1990s and early 2000s. The Global
Use of Strategies to Open Occluded Coronary Arteries in Acute
Coronary Syndromes (GUSTO-IIb) trial randomized 1138 patients
to either primary PCI or fibrinolytic therapy with accelerated
administration of tPA. With respect to the primary endpoint, a
composite outcome of death, nonfatal MI, and disabling stroke
at 30 days, primary PCI was found to be superior to fibrinolytic
therapy.69 However, the study did not demonstrate a reduction
in mortality comparable to that seen in the earlier PAMI trial.
The mechanistic benefit of primary PCI as compared to
fibrinolysis is clear: PCI restores TIMI grade 3 flow in more than
90% of infarct-related arteries, whereas TIMI grade 3 flow restoration is only approximately 50% to 60% after fibrinolysis. With
the advent of stenting in 1993, the acute reocclusion rate fell to
less than 5%, and the stent era ushered in increased use of PCI
in general and potentiated the benefits of primary PCI.70 Trials
of primary PCI compared with thrombolysis were reviewed by
Keeley et al. in 2003.71 The authors evaluated 23 trials involving
7739 patients. Most patients (76%) randomized to the thrombolytic arms of these trials were treated with fibrin-specific
thrombolytic agents. Primary PCI was superior with respect to
short-term mortality (7% compared with 9%; P = .0002), reinfarc-
tion (3% compared with 7%; P < .0001), and stroke (1% compared
with 2%; P = .004). With long-term follow-up, the benefits of
primary PCI remained robust, with substantial reduction in
mortality (P = .0019), nonfatal reinfarction (P < .0001), and
recurrent ischemia (P < .0001). Adjunctive stenting in primary
PCI was utilized in 12 of the 23 trials. The ACC/AHA guidelines
in 2013 for the care of patients with STEMI list primary PCI as
a class I recommendation with the highest level of supporting
evidence when performed by experienced operators in a timely
fashion.
1
Adjunctive Therapy and Approach
Marked improvements in primary PCI over the past 2 decades
have been a result of advancing technology (stents), pharmacology,
and access approaches, as well as an emphasis on time to reperfusion (Fig. 11.3).72 Stents, both bare metal and later drug eluting,
have improved thrombus resolution and long-term outcomes
after primary PCI.
both the plasma protein-based coagulation system and the
activation and aggregation of platelets. Adjunctive therapy for
primary PCI has been a source of controversy for the past decade;
the current ACC/AHA/European Society of Cardiology (ESC)
guidelines have endorsed a broad number of effective options.
In addition, the approach to primary PCI was routinely via
femoral access for the first 20 years of this reperfusion modality.
Trials over the past 5 years have emphasized potential benefits
of a radial artery access approach to limit bleeding and, potentially,
mortality among patients undergoing primary PCI.
in adjunctive therapy and approaches are summarized in the
next section.
73–75
Effective adjunctive medical therapy inhibits
76–78
Changes
1,43
CHAPTER 11 Reperfusion Therapies for Acute ST Elevation Myocardial Infarction 109
Mortality Reduction
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Antithrombin
Strategies
• Removing Dextran and Warfarin
• Removing Post PCI Heparin
• Weight-Based Heparin Dosing
• Enoxaparin and Bivalirudin
t
n
e
em
g
a
n
a
us M
mb
hro
T
Timely Stent-Based
Primary PCI
Bleedin
g Av
o
idan
c
e
• Dual Antiplatelet Therapy
• Glycoprotein Receptor Inhibition
• First and Second Generation
Oral P2Y
• Early Administration
Antagonists
12
Antiplatelet
Strategies
Fig. 11.3 Primary percutaneous coronary intervention has improved over the past 2 decades
with active investigation in areas of stent technology, time to reperfusion, as well as adjunctive
therapy and access methodology. (From Dauerman HL. Anticoagulation strategies for primary
percutaneous coronary intervention: current controversies and recommendations. Circ Cardiovasc
Interv. 2015;8.)
Oral Antiplatelet Agents: Aspirin, Clopidogrel, Prasugrel, and
Ticagrelor. Aspirin is routinely utilized in primary PCI—there
are no randomized trials comparing aspirin to placebo in this
setting and aspirin is considered de facto therapy in all patients
with STEMI unless they are known to be allergic. Results in
multiple trials have established that platelet ADP receptor
antagonism with P2Y12 receptor inhibitors is beneficial in the
setting of PCI; thus, a second oral antiplatelet therapy agent is
uniformly prescribed at the time of primary PCI. Clopidogrel
was the most commonly used P2Y12 antagonist in primary PCI:
clopidogrel is a prodrug that undergoes processing in the liver,
yielding an active metabolite. Its effect on platelet inhibition may
not occur for as long as 12 hours with a load of 300 mg. A 600-mg
load has been shown to be more effective in rapidly inhibiting
platelet aggregation. The Antiplatelet therapy for Reduction of
MYocardial Damage during Angioplasty-Myocardial Infarction
(ARMYDA-6 MI) trial compared standard (300 mg) versus high
loading dose (600 mg) regimens of clopidogrel in the setting of
primary PCI. ARMYDA-6 showed that the higher loading dose
significantly reduced infarct size in a relatively small sample of
201 patients. Thus, patients who are to undergo primary PCI
should probably be given a loading dose of 600 mg immediately
(i.e., in the emergency department) and 75 mg daily thereafter.
79,80
Similar to clopidogrel, prasugrel is a thienopyridine prodrug
requiring conversion to an active metabolite by the hepatic
cytochrome P-450 system, but prasugrel inhibits platelet activation
• Smaller Femoral Sheaths
• Early Sheath Removal
• Routine Femoral Angiography
• Vascular Closure Devices
• Radial Artery Access
Vascular
Access and
Closure
more rapidly, more consistently, and to a greater extent. Prasugrel
was compared to clopidogrel in patients presenting with acute
coronary syndromes in the large multicenter Trial to Assess
Improvement in Therapeutic Outcomes by Optimizing Platelet
Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction
(TRITON-TIMI 38) trial.52 Patients randomized to clopidogrel
(300 mg oral load followed by 75 mg per day) had increased
major adverse cardiovascular events, including stent thrombosis,
compared to patients randomized to prasugrel, with a modest
increase in the risk of bleeding. In subgroup analysis, patients
who were elderly, had a prior history of cerebrovascular events,
or were of low body weight did not derive a similar benefit from
more aggressive platelet inhibition with prasugrel. The FDA has
placed a warning urging caution regarding prasugrel treatment
for elderly and low-body-weight patients and a strict contraindication for patients with prior stroke.
Unlike the other two inhibitors of the P2Y
platelet receptor,
12
ticagrelor is a nonthienopyridine that does not require conversion
into an active metabolite. Ticagrelor (180 mg loading dose followed by 90 mg twice per day) was compared to clopidogrel
(300 mg or 600 mg loading dose followed by 75 mg per day) in
the Platelet Inhibition and Patient Outcomes (PLATO) trial of
patients with acute coronary syndrome.53 The prespecified
subgroup of patients (n = 7544) presenting for primary PCI for
STEMI or new left bundle branch block had lower risks of major
adverse cardiovascular events at 1 year of follow-up, with
110 PART III Coronary Artery Disease
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significant reductions in the risk of cardiovascular death and
stent thrombosis. However, patients randomized to ticagrelor
had higher risks of stroke and intracranial hemorrhage. Additionally, the benefit of ticagrelor appeared to be related to the dose
of aspirin, resulting in a warning from the FDA recommending
that patients taking ticagrelor receive less than 100 mg of aspirin
daily. Although the ACC/AHA guidelines give all three oral P2Y12
inhibitors equal (class 1B) recommendations for the treatment
of patients with STEMI,1 the ESC guidelines favor ticagrelor
over clopidogrel due to the favorable outcomes in trials in direct
comparison to clopidogrel.43 In order to minimize decision time
within the algorithm, we recommend the use of a ticagrelor
loading dose for all patients being considered for primary PCI
given its favorable risk profile among the oral P2Y12 inhibitors.
Whether or not prehospital loading of ticagrelor is superior to
loading of the antiplatelet agent in the emergency room or
catheterization laboratory is unclear based upon a single randomized clinical trial.
81,82
Intravenous Antiplatelet Agents. Abciximab is a chimeric
antibody to the glycoprotein IIb/IIIa receptor that strongly and
irreversibly binds to the receptor. In multiple trials comparing
abciximab to heparin-alone strategies, patients given abciximab
had higher pre-PCI infarct-related artery patency rates, better
6-month left ventricular ejection fraction, and less need for urgent
target vessel revascularization. Other studies suggested broadbased benefits of abciximab in PCI, including improvements in
microvascular function and selected mortality benefits, but more
recent comparisons to bivalirudin/heparin/oral antiplatelet
therapy show less clear benefit of routine abciximab in PCI for
STEMI and a significant increase in bleeding complications.
70,83–88
Eptifibatide and tirofiban are two other commercially available
intravenous glycoprotein IIb/IIIa inhibitors. Tirofiban/heparin
has been recently compared to bivalirudin for primary PCI
without clear evidence of benefit from tirofiban.89 The 2013
ACC/AHA guidelines support selective use of any glycoprotein
IIb/IIIa inhibitor (class IIA) in STEMI primarily in patients with
inadequate loading of oral P2Y12 inhibitors or in the setting of
massive thrombus discovered during primary PCI as a bailout
1
option.
Cangrelor is an intravenously administered nonthienopyridine
P2Y12 receptor antagonist. It has a rapid onset/offset of action
with a half-life in blood of 3 to 5 minutes. The Cangrelor versus
Standard Therapy to Achieve Optimal Management of Platelet
Inhibition (CHAMPION PHOENIX) trial randomized 10,939
patients to cangrelor versus placebo (clopidogrel 300–600 mg
orally loaded 2 hours after PCI vs. cangrelor 2-hour infusion)
with 1991 patients presenting with STEMI. While the overall
trial results favor cangrelor across the spectrum of PCI, these
results are limited by the control group: patients loaded prior
to angiography with any P2Y12 antagonists (i.e., ticagrelor or
clopidogrel 600 mg) were excluded.90 Furthermore, these results
conflict with the negative results of CHAMPION PCI due to
changes in protocol, definitions, or unknown factors.91 For STEMI,
the use of cangrelor may be similar to glycoprotein IIb/IIIa
inhibitors in that it should be considered when there is inadequate
loading of the oral P2Y12 inhibitors at the time of PCI.
Antithrombins. Bivalirudin, unfractionated heparin, fond-
aparinux, and enoxaparin are antithrombotic agents used during
primary PCI. The features of these antithrombotic agents are
summarized in Table 11.1 and have been examined in multiple
clinical trials.
72,83,88,89,92–94
When used as adjunctive therapy in
combination with glycoprotein IIb/IIIa inhibitors, unfractionated heparin should be given as a bolus in a weight-adjusted
dose of 50 to 70 U/kg to target an activated clotting time of
more than 200 seconds. The use of UFH alone is recommended
by the ACC/AHA 2013 guidelines (class IC). Compared with
unfractionated heparin, low-molecular-weight heparins are
easier to administer because subcutaneous depot injections
with weight-adjusted dosing is effective. The Acute STEMI
Treated with Primary PCI and IV Enoxaparin or UFH to
Lower Ischemic and Bleeding Events at Short- and Long-Term
Follow-up (ATOLL) trial comparing unfractionated heparin
and enoxaparin for primary PCI failed to demonstrate superiority of enoxaparin compared to unfractionated heparin.92
Enoxaparin cannot be strongly recommended for primary
PCI; the ESC/ACC/AHA guidelines either discourage or only
cautiously recommend the use of low-molecular-weight heparins
(Box 11.2).
1,43
Bivalirudin is a bivalent direct thrombin inhibitor that is
given intravenously, usually with a bolus load and continuous
infusion. The Harmonizing Outcomes with RevascularIZatiON
and Stents (HORIZONS) trial randomized 3602 patients with
STEMI undergoing primary PCI to bivalirudin versus UFH
and GP IIb/IIIa inhibitor comparators. Patients randomized
to bivalirudin fared significantly better in the analysis for the
primary endpoint, driven by significantly less bleeding at the
expense of increased stent thrombosis.88 These results were
mostly replicated in the follow-up European Ambulance Acute
Coronary Syndrome Angiography (EUROMAX) trial, except for
the mortality endpoint.
83,95
On the other hand, more recent trials
have failed to show any benefit of bivalirudin as compared to
unfractionated heparin alone in the setting of primary PCI and
again noted an increased risk of acute stent thrombosis with a
bivalirudin-based regimen.
96,97
Radial, Femoral, and Multivessel Primary PCI. The evolution
of primary PCI has involved marked changes in pharmacology,
times to treatment, and, most recently, access site. These changes
are summarized in Fig. 11.3. Recently, there have been multiple
large clinical trials comparing radial versus femoral access in
acute coronary syndromes, including primary PCI.
76,78,98
access has been uniformly demonstrated to decrease access-site
bleeding complications compared to the femoral approach. Agents
and approaches that reduce bleeding complications have been
associated with mortality reductions99; the radial versus femoral
primary PCI trials have also suggested a reduction in death with
the radial approach, presumably due to less bleeding complica-
76,78
tions.
The efficacy of radial access is linked to the volume
of radial approaches performed at the institutions utilizing the
approach98: for operators and sites that do have this expertise,
though, there appears to be no harm and considerable potential
benefit to routine use of radial access as a primary bleedingavoidance strategy for primary PCI.
Radial
CHAPTER 11 Reperfusion Therapies for Acute ST Elevation Myocardial Infarction 111
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TABLE 11.1 Anticoagulation Options for Primary PCI
Mechanism of
Anticoagulant
Unfractionated
heparin
Low-molecular-
weight heparin:
enoxaparin
Fondaparinux Indirect inhibitor of
Bivalirudin Direct antithrombin Half-life of 25 min More reliable thrombin-inhibitory
Modified from Dauerman HL. Anticoagulation strategies for primary percutaneous coronary intervention: current controversies and
recommendations. Circ Cardiovasc Interv. 2015;8.
ADMIRAL, Abciximab Before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long-Term Follow-up; ATOLL, Acute
STEMI Treated with Primary PCI and IV Enoxaparin or UFH to Lower Ischemic and Bleeding Events at Short- and Long-Term Follow-up;
CADILLAC, Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications; EUROMAX, European Ambulance Acute
Coronary Syndrome Angiography; HEAT-PCI, How Effective Are Antithrombotic Therapies in Primary Percutaneous Coronary Intervention;
HORIZONS, Harmonizing Outcomes with RevascularIZatiON and Stents; OASIS-6, Sixth Organization to Assess Strategies in Acute Ischemic
Syndromes; PAMI, Primary Angioplasty in Myocardial Infarction.
Action Pharmacokinetics Advantages Disadvantages
Activation of
antithrombin:
indirect antithrombin
Inhibition of Factor
Xa and IIa
4 : 1 ratio of effect,
predominantly
acting on Factor Xa
Factor Xa
Half-life of ~60 min but
depends upon bolus
amount
Anti-Xa effects
negligible after 8
hours
Half-life of ~20 hours Daily dosing Heparin-induced
Inexpensive and extensively
studied
Reversible
Easily measurable anticoagulant
effects
More reliable thrombin-inhibitory
effect than heparin
Partially reversible
effect than heparin
Does not activate platelets
Short half-life
No associated thrombocytopenia
Heparin-induced
thrombocytopenia (rare)
Platelet activation
Inactive against
clot-bound thrombin
Optimal dosing unclear
Heparin-induced
thrombocytopenia (rare)
Difficult to measure
anticoagulant effect
thrombocytopenia (rare)
Difficult to measure
anticoagulant effect
Catheter-related
thrombosis
Expensive
Not reversible
Short half-life
Acute stent thrombosis
risk
Key Primary PCI
Clinical Trials
PAMI
CADILLAC
ADMIRAL
HEAT
ATOLL
ATOLL
OASIS 6
HORIZONS
EUROMAX
HEAT-PCI
BOX 11.2 European and US Recommendations for Anticoagulation in Primary PCI
UFH: Class I recommended, level of evidence C
• With GP IIb/IIIa receptor antagonist planned: 50–70 U/kg IV bolus to achieve
therapeutic ACT
• With no GP IIb/IIIa receptor antagonist planned: 70–100 U/kg bolus to
achieve therapeutic ACT
Bivalirudin: Class I recommended, level of evidence B
• 0.75 mg/kg IV bolus, then 1.75 mg/kg/h infusion with or without prior
treatment with UFH. An additional bolus of 0.3 mg/kg can be given if
needed
• Reduce infusion to 1 mg/kg/h with estimated CrCl <30 mL/min
• Preferred over UFH with GP IIb/IIIa receptor antagonist in patients at high
risk of bleedingl class IIA, level of evidence B
Fondaparinux: not recommended as sole anticoagulant for primary PCI class III:
not recommended, B
Enoxaparin: not mentioned; no recommendation level given
Bivalirudin: Class I recommended, level of evidence B
• With use of GP IIb/IIIa blocker, restricted to bailout
• Recommended over UFH and a GP IIb/IIIa blocker
Fondaparinux is not recommended for primary PCI; class III, level of evidence B.
ACT, Activated clotting time; CrCl, creatinine clearance; GP, glycoprotein; IV, intravenous; PCI, percutaneous coronary intervention; UFH,
unfractionated heparin.
• Bivalirudin 0.75 mg/kg IV bolus followed by IV infusion of 1.75 mg/kg/h
for up to 4 hours after the procedure as clinically warranted. After cessation
of the 1.75 mg/kg/h infusion, a reduced infusion dose of 0.25 mg/kg/h may
be continued for 4–12 hours as clinically necessary
Enoxaparin: Class IIB, level of evidence B
• With or without routine GP IIb/IIIa blocker
• May be preferred over UFH
• Enoxaparin 0.5 mg/kg IV bolus
UFH: Class I recommended, level of evidence C
• With or without routine GP IIb/IIIa blocker
• Must be used in patients not receiving bivalirudin or enoxaparin
• UFH 70–100 U/kg IV bolus when no GP IIb/IIIa inhibitor is planned
• 50–60 U/kg IV bolus with GP IIb/IIIa inhibitors
112 PART III Coronary Artery Disease
Intracoronary versus
Thrombectomy versus
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While early STEMI reperfusion strategies focused upon rapidity
and completeness of culprit artery patency, many patients with
STEMI have multivessel coronary artery disease: the role of
nonculprit artery PCI is controversial and evolving. While the
guidelines initially expressed caution and/or concern about risk
of nonculprit artery PCI during STEMI,1 more recent clinical
trials suggest that complete revascularization may be attempted
safely at the time of primary PCI.
100,101
Defining the efficacy and
safety—along with the timing and method of nonculprit artery
PCI—requires further investigation; larger randomized clinical
trials are ongoing in this controversial area.
102,103
Thrombectomy and Route of Drug Administration. The need
to provide more complete coronary and microvascular reperfu-
104
sion
spurred developments of newer fibrinolytic agents, primary
PCI methodologies, and adjunctive antiplatelet/antithrombin
agents. In addition, two other avenues have been pursued to
improve primary PCI-based reperfusion—thrombectomy and
intracoronary administration of glycoprotein IIb/IIIa inhibitors.
The purpose of these two methods has not been to improve
TIMI grade 3 coronary reperfusion but to decrease infarct size
via decreased microvascular obstruction that occurs even in the
setting of normal epicardial coronary flow. Six trials have
addressed thrombectomy and intracoronary drug administration—
smaller trials
105,106
have suggested beneficial effects for these
methodologies. But, as shown in Fig. 11.4, these trials have since
been superceded by much larger randomized clinical trials that
have failed to show any clear benefit for these approaches.
107–110
Current guidelines do not support the routine use of either
intracoronary drug administration or thrombectomy to aid
reperfusion during primary PCI.
1,43
PHARMACOINVASIVE THERAPY FOR STEMI
Current ACC/AHA guidelines recommend that primary PCI be
performed when patients present with a goal of first medical
contact to device time of 90 minutes and with the availability
of skilled operators who perform more than 75 PCI procedures
per year in a hospital that performs more than 36 PCI procedures
for STEMI annually.1 Fulfilling these requirements is not feasible
in many US and worldwide hospitals: cost of PCI, transfer
distance, transfer times, and lack of 24/7 PCI capability are among
the issues that may limit universal adoption of primary PCI for
STEMI in both the United States and globally.
111–115
Two options
are available for patients presenting to non-PCI hospitals: rapid
transfer systems and pharmacoinvasive therapy.
The available approaches for urgent treatment of STEMI—
fibrinolytics and primary PCI—have often been described as
competing strategies. Although numerous trials directly comparing the two have been performed over the last two decades, the
two approaches are not mutually exclusive. In 2003, Dauerman
and Sobel first outlined an approach called “pharmacoinvasive
therapy” to describe a strategy that might combine the universal
availability of fibrinolysis and the efficacy of PCI for patients
that are not candidates for rapid performance of primary PCI.
As noted earlier, the two most significant factors determining
infarct size and risk of mortality in patients with STEMI are the
time to induction of patency of the infarct-related artery and
the completeness of reperfusion.
6,41
Pharmacoinvasive therapy
is designed to provide universal early reperfusion (fibrinolysis)
as an initial step before routine postlytic PCI performed 3 to 24
hours after fibrinolysis.
118
This strategy differs from two other terms: facilitated PCI
and rescue PCI. Rescue is a strategy of emergent PCI after
fibrinolysis if reperfusion fails (as defined by refractory chest
pain and/or persistent ST elevations); evidence supporting the
strategy of rescue PCI for patients after failed fibrinolytic reperfusion came from the Middlesbrough Early Revascularization to
Limit Infarction (MERLIN) trial.
119
It included 307 patients
randomized to conservative therapy, including repeat fibrinolysis,
compared with immediate angiography with or without PCI.
Although there was only a numerical trend favoring rescue PCI
for the primary endpoint of 30-day mortality (9.8% compared
with 11%; P = .70), rescue PCI was superior to conservative
116,117
Intravenous Abciximab Trials
2500
2000
1500
1000
500
Randomized Patients
0
INFUSE
AMI
CICERO
AIDA
STEMI
No Thrombectomy Trials
12000
10000
8000
6000
4000
2000
0
Randomized Patients
INFUSE
TAPAS TASTETOTAL
AMI
Fig. 11.4 Attempts to improve
microvascular reperfusion in acute ST
elevation myocardial infarction primary
percutaneous coronary intervention
have focused on intracoronary administration of glycoprotein IIb/IIIa inhibitors
and thrombectomy devices. Initial
trials suggested benefit, but much
larger trials with greater than 5-fold
enrollment have not shown these to be
beneficial treatment strategies.
105–107,109
CHAPTER 11 Reperfusion Therapies for Acute ST Elevation Myocardial Infarction 113
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treatment with respect to the combined secondary endpoint of
death, reinfarction, stroke, heart failure, and urgent revascularization. These results were corroborated by those in the larger Rescue
Angioplasty versus Conservative Treatment or Repeat Thrombolysis (REACT) trial, which demonstrated lower mortality in
patients undergoing rescue PCI compared with the combined
medical therapy or repeat thrombolysis treatment groups (hazard
ratio, 0.48; 95% CI, 0.23–0.99).
120
On the other hand, facilitated PCI is PCI for STEMI performed
early and routinely after reperfusion has been facilitated by fibrinolysis: comparison of facilitated PCI with primary PCI shows
no benefit of facilitating early flow with fibrinolysis (compared
to primary PCI alone). Thus this strategy is not recommended.
The Assessment of the Safety and Efficacy of a New Treatment
Strategy for Acute Myocardial Infarction (ASSENT-4 PCI) Trial
randomized patients to either primary PCI or PCI facilitated
by fibrinolytic therapy given immediately before transfer of
patients to the catheterization laboratory. After only 1600 of the
planned 4000 patients had been enrolled, the study was stopped
prematurely by the data safety monitoring board because of
increased in-hospital mortality in the facilitated PCI arm (6%
compared with 3%; P = .01). The incidences of stroke, reinfarction,
and urgent target vessel revascularization were also unexpectedly
higher in the treatment arm.
121
Based on ASSENT IV and similar
negative trials, routine use of full- or half-dose fibrinolytic therapy
to facilitate primary PCI for STEMI cannot be recommended.
122
Guidelines from the 1990s recommended that only patients
who have symptomatic, inducible ischemia after thrombolysis
undergo angiography and possible PCI.
123
However, PCI early
after thrombolysis can establish recanalization when lysis has
failed and can consolidate benefit when it has succeeded. Thus,
a radical change is suggested by the pharmacoinvasive approach:
after fibrinolysis is given to a patient at a non-PCI center, patients
are routinely transferred to a PCI center for emergent PCI if there
are ongoing symptoms (rescue PCI) or urgent PCI (3 to 24 hours
after fibrinolysis) as opposed to the conservative approach of
fibrinolysis alone and watchful waiting at the non-PCI center. This
comparison—stand-alone fibrinolysis versus a pharmacoinvasive
approach for patients requiring transfer to a PCI center—has
been tested in multiple large randomized clinical trials and
demonstrated a clear benefit for reinfarction and recurrent
ischemia with pharmacoinvasive therapy. For example, the Trial
of Routine Angioplasty and Stenting after Fibrinolysis to Enhance
Reperfusion in Acute Myocardial Infarction (TRANSFER-AMI)
demonstrated a nearly 50% reduction in reinfarction (6.0% vs.
3.3%; P = .04) for patients treated with pharmacoinvasive therapy
as compared to fibrinolysis alone (Table 11.2).
124,125
Most important, the early concerns about PCI after fibrinolysis
being linked to high rates of general bleeding and abrupt closure
are not seen in the era of routine stenting and oral antiplatelet
therapy.
65,66,74,125–127
On the other hand, the risk of any fibrinolytic
strategy for intracranial bleeding is real and should be considered
before undertaking the pharmacoinvasive approach. Recently,
the Strategic Reperfusion Early after Myocardial Infarction
(STREAM) trial compared primary PCI to pharmacoinvasive
therapy and demonstrated similar outcomes for the primary
ischemic endpoint with the two approaches. An increased risk of
TABLE 11.2 TRANSFER-AMI: Fibrinolysis
Alone Versus Pharmacoinvasive Therapy
Standard
Endpoint
Primary endpoint 16.6 10.6 .0013
Death 3.6 3.7 .94
Reinfarction 6.0 3.3 .044
Recurrent ischemia 2.2 0.2 .019
Death/MI/ischemia 11.7 6.5 .004
New/worsening CHF 5.2 2.9 .069
Cardiogenic shock 2.6 4.5 .11
Pharmacoinvasive therapy (fibrinolysis with either emergent or urgent
percutaneous coronary intervention 3–24 hours after thrombolytics) is
superior to stand-alone fibrinolysis as shown by decreased recurrent
infarction and ischemia.
CHF, Congestive heart failure; MI, myocardial infarction.
(%)
124
intracranial bleeding was noted with pharmacoinvasive therapy
early in the trial, however, leading to a protocol change: for
patients older than 75 years, only a half dose of fibrinolytic
therapy was utilized, leading to a significant reduction in risk of
intracranial bleeding.
128
A recent registry performed in Ottawa,
Ontario showed similar results: ischemic/mortality/reinfarction
outcomes were comparable with pharmacoinvasive therapy
versus primary PCI, but enhanced risk of intracranial bleeding
is noted with fibrinolysis (1.3% vs. 0%; P = .004).
approaches incorporating pharmacoinvasive therapy (as opposed
to primary PCI with transfer) should (1) be restricted to those
patients who require a greater than 60-minute transfer time,
(2) be restricted to patients not at high risk for intracranial
bleeding, and (3) utilize half-dose fibrinolysis for those older than
75 years.
Pharmacoinvasive
(%) P Value
127
Thus, regional
REGIONAL SYSTEMS IN STEMI CARE
The choice between stand-alone fibrinolysis, pharmacoinvasive
therapy, and primary PCI should not be rendered on a patientby-patient basis. A time-dependent decision tree is required for
each hospital (Fig. 11.5).
trauma to cardiac tissue and requires the automation and systems
of care needed for similar time-sensitive situations (stroke,
trauma). Thus the 2013 ACC/AHA Guidelines recommend that
hospitals and regions decide on a best-practice standard to provide
a system of STEMI care for the vast majority of their patients:
“All communities should create and maintain a regional system
of STEMI care that includes assessment and continuous quality
improvement of EMS and hospital based activities” (class I, level
of evidence B) (Fig. 11.6).
Regional programs in primary PCI were first tested in the
Danish Trial in Acute Myocardial Infarction-2 (DANAMI-2)
130
trial.
This Danish trial randomized patients to fibrinolysis
alone; primary PCI, if they arrived at a PCI center; and primary
PCI after transfer to a PCI center from a non-PCI center. The
regions of Denmark involved in this trial were organized in a
spoke-and-hub model in which non-PCI centers were designated
a specific referring PCI program (mean distance of approximately
1,43,112,118,129
1
STEMI is a time-sensitive
114 PART III Coronary Artery Disease
2013 ACC/AHA Guideline for the Management of ST
FMC-to-device time system
goal of 120 minutes or less.
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Patient with STEMI presents
to a STEMI referral center
The 2-hour rule:
If transfer hospital system cannot demonstrate routine PCI within 2
hours of initial presentation, a pharmacoinvasive approach is used
Initial treatment with aspirin, P2Y
antagonist, and antithrombin
Transfer for primary PCI:
initial contact/door to final balloon
< 120 minutes
Elevation Myocardial Infarction
I
IIaIIbIII
I
IIaIIbIII
I
IIaIIbIII
Fig. 11.6 American College of Cardiology (ACC)/American Heart
Association (AHA) ST elevation myocardial infarction (STEMI)
guidelines endorse regional systems of care and first medical
contact goals of <90 minutes for direct presenters to percutaneous
coronary intervention hospitals and <120 minutes for patients
requiring transfer to a percutaneous coronary intervention hos-
1
pital.
EMS, Emergency medical services; FMC, first medical
contact; PCI, percutaneous coronary intervention.
All communities should create and maintain
a regional system of STEMI care that includes
assessment and continuous quality
improvement of EMS and hospital-based
activities.
EMS transport directly to a PCI-capable hospital for
primary PCI with an ideal
goal of 90 minutes or less.
Immediate transfer to a PCI-capable hospital for
primary PCI with an FMC-to-device time system
30 miles from non-PCI center to PCI center). The results of
stand-alone fibrinolysis versus primary PCI arms of the trial
were not surprising: there was a 45% relative risk reduction in
the primary endpoint of death/MI or stroke at 30 days with
primary PCI. What was somewhat surprising was the similar
40% reduction in the primary endpoint with transfer-mediated
primary PCI compared to fibrinolysis alone, suggesting that
incorporating a defined delay (<120 minutes from initial presentation to PCI in over 90% of the DANAMI 2 transfer population)
in primary PCI as part of a regional strategy could provide the
best results.
These results did not immediately translate into broader
incorporation of primary PCI into regional and nationwide
12
FibrinolysisNo fibrinolysis
Initial treatment with aspirin, fibrin-specific
lytic, 300 mg clopidogrel, and
Transfer for pharmacoinvasive PCI:
immediately (rescue) or 3-24 hours after
heparin
fibrinolysis
programs due to concerns about replicating the transfer times
and coordinated spoke-and-hub models seen in the DANAMI-2
trial. Efforts to establish statewide primary PCI programs in
North Carolina, Minnesota, and Vermont to replicate and expand
the DANAMI-2 experience were undertaken in the mid-2000s;
the results confirmed the feasibility of the DANAMI-2 approach
for many hospitals and transfer patients.
helped define the need for the following key elements of successful
regional primary PCI programs
• SimpliedpharmacologicalgorithmstoprecedeprimaryPCI
and initiated in the ambulance or non-PCI center
• Automatedtransferprograms(i.e.,nowaitingforbedavailability at PCI center)
• Dedicatedalgorithmsfor care that wereshared at multiple
hospitals: all hospitals using a 24-hour-a-day, 7-day-a-week
predictable approach to transfer for primary PCI
• Singlecall activation oftheprimaryPCIteamtoallowfor
timely, automatic transfer to the catheterization laboratory
• Prehospital activation of the catheterization laboratory by
emergency medical services
As the Door-to-Balloon Alliance addressed the timeliness of
reperfusion among patients presenting to primary PCI centers
(door-to-balloon goal <90 minutes),
created in the United States to address coordination of regional
programs for primary PCI and timeliness of reperfusion from
first medical contact to PCI among both direct presenting and
transfer hospitals.
countries demonstrating nationwide incorporation of regional
transfer programs for primary PCI and improvement in STEMI
outcomes.
138
Based upon DANAMI-2 and these regional programs,
the ACC/AHA/ESC guidelines were revised recently to specifically
include the guideline that patients presenting to non-PCI centers
may be referred for primary PCI if the transfer process would
allow the goal of first medical contact (or first presentation) to
PCI time of less than 120 minutes (class I).
expansion of primary PCI regional systems in the United States
Fig. 11.5 Regional acute ST elevation
myocardial infarction (STEMI) care
algorithms begin with a 2-hour rule
(time from presentation to percutaneous coronary intervention [PCI] <2 hours)
and then triage patients to a primary
percutaneous coronary intervention
or pharmacoinvasive strategy accordingly. (Modified from Dauerman HL,
Sobel BE. Toward a comprehensive
approach to pharmacoinvasive therapy
for patients with ST segment elevation
acute myocardial infarction. J Thromb
Thrombolysis. 2012;34:180–186.)
131–134
These experiences
129,135
:
9,136
Mission: Lifeline was
113,129,137
Similar efforts occurred in European
1,43
Of note, the
CHAPTER 11 Reperfusion Therapies for Acute ST Elevation Myocardial Infarction 115
E
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and some countries in Europe has not necessarily been replicated
in developing countries due to cost and access issues.
112,115,139,140
While the efforts to improve times to reperfusion for patients
presenting directly to primary PCI centers have been generally
successful such that over 90% of patients are achieving doorto-balloon times less than 90 minutes in the United States,
7,136
the success of regional coordination programs in achieving the
guideline-mandated goal of 120 minutes has been less robust.
In a recent analysis of transfer STEMI patients within 60 minutes
of a PCI center, two-thirds of patients have reached the 120-minute
goal (even when using first presentation as the starting point,
as opposed to the more difficult first medical contact [as measured
by emergency medical services’ provision of a first electrocardiogram]).
141
Efforts to implement the key elements of a successful
regional primary PCI program throughout 16 regions of the
United States in recent years (the STEMI ACCELERATOR
program) has also shown mixed success
142
: while significant
improvements in surrogate metrics (i.e., use of prehospital
activation, single call catheterization laboratory activation) are
STEMI:
Zone 1 primary PCI
<90 min for PCI hospital,
<120 min for transfer hospitals
CP less than 24 hours:
STE > 1 mm in 2 leads or new LBBB
Field activate
OHCA with cooling
• ROSC=Yes
• DNR=No
• Family Discussion=Yes
clearly improved through such efforts, the percentage of transfer
patients with goal-mandated reperfusion times still hovers around
50% to 60%, suggesting opportunities for further progress.
Based upon the feasibility and limitations of a regional primary
PCI program, a dedicated coordinated algorithm that respects
the need for timely reperfusion and availability of PCI-mediated
complete reperfusion is recommended. The regional algorithm
used in Vermont and upstate New York for a single PCI center
and its referring community hospitals is shown in Fig. 11.7.
This algorithm mandates that each hospital in a region declares
itself to be either a primary PCI or transfer to primary PCI
center or pharmacoinvasive center (if greater than 60-minute
transfer time to a PCI center) with dedicated pharmacologic
algorithms based upon geography, distance, and transfer timing.
This organizational scheme is similar to one developed in Minnesota: hospitals were designated zone 1 (primary PCI, by direct
presentation or transfer) and zone 2 (pharmacoinvasive therapy
with initial half-dose fibrinolysis followed by rapid transfer for
PCI) with demonstration of excellent outcomes, which has led
Zone 2
760 min
transfer time
118,143
Primary PCI
ED pharmacotherapy:
b-blockers only for hypertension without CHF
Heparin (60 U/kg) bolus
Ticagrelor 180 mg oral load preferred
Clopidogrel 600 mg if ticagrelor not available
Cath lab:
Radial access preferred by experienced operators
Bolus heparin or bivalirudin
GPI/thrombectomy for large thrombus or bailout
(<15% of patients)
Continue bivalirudin at PCI dose 2 hours post PCI
transfer emergently
Yes,
to PCI hospital
EMS, ED, Nursing
feedback:
• Within 24 hours
• Quarterly
Chest pain or persistent STE,
EMS activates cath lab
with 30 min ETA
Contraindication to thrombolytic therapy?
No
Pharmacoinvasive therapy
Full-dose fibrinolysis: half-dose lysis if age >75
b-blockers only for hypertension without CHF
Immediate transfer to PCI hospital
Rescue PCI
Upon arrival
ED pharmacotherapy:
Aspirin 325 mg
Heparin (60 U/kg) bolus and drip
Clopidogrel 300 mg
Reperfusion with
chest pain relief and
>70% resolution of ST
Pharmacoinvasive PCI
3-24 hours after lytics
Vascular closure device, aspirin 81 mg, ticagrelor 90 mg BID, statin, cardiac rehab, metoprolol 12.5 mg BID
Fig. 11.7 A sample regional algorithm for ST elevation myocardial infarction (STEMI) incorporating
a primary percutaneous coronary intervention (PCI) or pharmacoinvasive therapy strategy depending
upon transfer time >60 minutes. Adjunctive therapy, half-dose thrombolytics in the elderly, and
considerations of higher-risk groups are incorporated into this comprehensive statewide algorithm
in Vermont. BID, Twice per day; CHF, congestive heart failure; DNR, do not resuscitate; ED,
emergency department; EMS, emergency medical services; GPI, glycoprotein inhibitor; OHCA,
out-of-hospital cardiac arrest; ROSC, return of spontaneous circulation; STE, ST elevation.
116 PART III Coronary Artery Disease
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to wider adoption of these regionally coordinated algorithms to
allow for timely and complete reperfusion across a broad spectrum
of STEMI patients.
113,114,131,132
CONCLUSIONS
Reperfusion therapy improves survival in patients with STEMI.
Achieving optimal results with primary PCI depends on revascularization of the infarct-related artery within 90 minutes after
presentation of the patient to the PCI hospital (or first medical
contact). Primary PCI may be extended to transfer patients from
community hospitals if timely transport is feasible within the
goal of initial presentation to device of less than 120 minutes.
Accordingly, implementation of primary PCI is appropriate for
patients presenting to an interventional center or those who
can be transported to one via helicopter or ambulance within
60 minutes. For patients presenting to institutions that cannot
meet these primary PCI criteria and have no contraindication
to thrombolysis, treatment with fibrinolysis followed by PCI
(pharmacoinvasive approach) is warranted.
Appropriate adjunctive therapy should be implemented
for both primary PCI and pharmacoinvasive approaches. This
includes administration of aspirin and heparin for all patients
with STEMI, with use of clopidogrel (300 mg) in patients
undergoing fibrinolysis and potentially more potent antiplatelet
therapy (ticagrelor) in patients undergoing primary PCI. With
prompt and complete reperfusion as the linchpin of therapy for
STEMI, 30-day mortality is routinely less than 5% in clinical trials,
national registries, and clinical practice. While issues of timing
and efficacy of reperfusion therapies as well as delays between
symptom onset and initial presentation for treatment remain
critical, the major mortality challenge facing clinicians in the
STEMI population has moved to two specific populations: patients
with STEMI complicated by cardiogenic shock and/or cardiac
arrest. The dramatic impact of reperfusion therapy—fibrinolysis
first, followed by primary PCI and pharmacoinvasive therapy—on
the survival of patients with STEMI over the past 3 decades
provides a model for development of future approaches and
developments in this complex field.
The full reference list for this chapter is available at
ExpertConsult.com.
CHAPTER 11 Reperfusion Therapies for Acute ST Elevation Myocardial Infarction 116.e1
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