Significant progress in acute coronary syndrome (ACS) intervention has been made in the past decade. Mechanical revascularization yields high procedural success rates with low restenosis and reduced downstream embolization. New classes of pharmacologic agents have further improved the outcome of ACS intervention. In the setting of acute myocardial infarction, the concept of "facilitated intervention" has the potential of extending the benefits of thrombolysis to patients in community hospitals.
Dr. Pienvichit is a Staff Interventional Cardiologist at
Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. He
received his MBBS degree in 1992 from the All India Institute of
Medical Sciences. He completed his interventional fellowship at
Lahey Clinic Medical Center, Burlington, MA.
Intervention in acute coronary syndrome (ACS) involves not only
the mechanical treatment of an epicardial lesion, but also the
pharmacologic management of a complex biological process involving
plaque rupture, platelet activation, and thrombus formation.
The role of antiplatelet agents is crucial, and they are now the
standard of care in unstable angina (UA).
The widespread use of intracoronary devices has improved the
results of mechanical revascularization. Despite these advances,
many questions remain unanswered. This article will review the
current information and controversies in ACS intervention.
The strategy: To cath or not to cath
The optimal ACS management strategy has been the subject of many
debates. For acute myocardial infarction (AMI), the current data is
consistently in favor of primary percutaneous coronary intervention
(PCI) in institutions where a cardiac catheterization laboratory
and a well-trained staff are available. Meta-analysis of clinical
trials comparing primary PCI with intravenous thrombolysis
demonstrated lower mortality (4.4% versus 6.5%;
= 0.02) and risk of death or reinfarction (7.2% versus 11.9%;
<0.001) with PCI.
The optimal strategy for UA and non-Q-wave myocardial infarction
(NQWMI) patients is less clear due to conflicting results from
randomized trials. The question is whether a routine, early
invasive strategy offers an advantage over the conservative,
ischemia-driven approach. Early PCI has the potential of aborting
ischemia, salvaging myocardium, and preventing near-term events at
the expense of procedure-related complications and up-front cost.
With more than 1.3 million cases of UA and NQWMI presenting in the
United States annually, this issue has substantial financial
The findings of previous UA/ NQWMI trials were not in favor of
an early invasive strategy. The multicenter Veterans Affairs
Non-Q-Wave Infarction Strategies in Hospital (VANQWISH) trial found
higher incidence of death or nonfatal MI (
= 0.05) with the invasive strategy.
There was no significant difference in mortality from all causes at
long-term follow-up (mean follow-up 23 months) between the two
arms. In the Thrombolysis In Myocardial Infarction (TIMI) IIIB
trial, the incidence of death or MI in the two strategy arms were
not statistically different at 1 year (10.8% versus 12.2%;
However, the early invasive patients had significantly fewer repeat
admissions (26% versus 33%;
<0.001) and received fewer medications.
More contemporary trials, FRISC II (Fragmin and fast
Revascularisation during InStability in Coronary artery disease)
and TACTICS-TIMI (Treat Angina with Aggrastat and determine Cost of
Therapy with an Invasive or Conservative Strategy) 18, demonstrated
better outcomes with an early invasive strategy for UA or non-ST
segment elevation MI (NSTEMI).
These trials involved the use of glycoprotein (GP) IIb/IIIa
receptor blockers, low molecular weight heparin (LMWH), and stents,
reflecting the current interventional practice. In FRISC II, the
rate of death or nonfatal MI at 6 months was lower in the invasive
group compared with the conservative group (9.4% versus 12.1%;
= 0.031). Fewer patients in the invasive group had angina and with
less severity than the conservative group. TACTICS-TIMI 18 trial
administered (in addition to aspirin and heparin) tirofiban, a
platelet GP IIb/IIIa agent, to UA/NSTEMI patients. The trial showed
an 18% relative reduction in the primary endpoint (death, MI, or
re-hospitalization for ACS) at 6 months with an invasive strategy
compared with conservative strategy (15.9% versus 19.4%;
= 0.025). More importantly, patients with elevated cardiac troponin
T (cTnT) had more than a 40% reduction in the primary endpoint with
an invasive strategy, while cTnT-negative patients did equally well
with either management strategy.
Closer examination of the older trials points to severe
limitations of the VANQWISH and TIMI IIIB trials.
The mean time to revascularization in the early invasive group was
36 hours after admission in the TIMI IIIB trial and 8 days for
VANQWISH. The delays could reduce the potential of myocardial
salvage. These trials did not employ GP IIb/IIIa receptor blockers,
LMWH, or stents as FRISC II and TACTICS-TIMI 18 did. Furthermore,
the worse outcome in the VANQWISH invasive arm was attributable to
the higher mortality (11.6%) in patients undergoing coronary artery
bypass graft (CABG) surgery compared with those in the conservative
group undergoing CABG (3.4%). Even with the drawbacks, one could
conclude from VANQWISH and TIMI IIIB that the early invasive
strategy performed at least as well as the conservative
Given the advances in PCI, an early invasive strategy leads to
better outcomes, particularly in high-risk patients. For low-risk
patients, the risks and financial cost of PCI must be balanced
against the potential benefits.
Anticoagulation and antiplatelet medications play a critical
role in ACS intervention and account for a large part of the
improvement made in the clinical outcomes. UA patients treated with
the standard regimen of aspirin, heparin, and beta-blockers have a
30-day death and nonfatal MI rate of 8% to 16%.
GP IIb/IIIa receptor blockers, LMWH, and thienopyridine derivatives
can improve these outcomes significantly. Disagreement remains,
however, regarding the choice of agent and the optimal time for
Ticlopidine and clopidogrel
Currently, the thienopyridine derivatives (ticlopidine and
clopidogrel) are used mainly for preventing subacute stent
thrombosis. The STARS (Stent Anticoagulation Regimen Study) and
ISAR (Intracoronary Stenting and Antithrombotic Regimen) trials
demonstrated <1% stent closure at 30 days with ticlopidine and
Studies suggest that they may have additional benefits in ACS apart
from their use in stenting.
Ticlopidine in UA is effective in reducing vascular death and
nonfatal MI at 6 months when used in combination with conventional
therapy (nitrates, ß-blockers, and calcium-channel blockers).
The benefit, however, is not superior to that of aspirin. The
efficacy of clopidogrel in the treatment of UA was demonstrated in
the CURE (Clopidogrel in Unstable Angina Prevent Recurrent Events)
The primary composite endpoint (cardiovascular death, MI, or
stroke) was reduced by 20% with the clopidogrel plus aspirin
combination compared with aspirin alone (9.3% versus 11.5%;
= 0.00005). This apparent benefit started within 2 hours and
reached 20% by the first day after randomization. Whether the
positive outcome would be blunted with concomitant use of a GP
IIb/IIIa is not known. Also unknown is the bleeding complication of
those on clopidogrel who underwent CABG. Nevertheless, the results
of the trial are encouraging, and expand on the implications of the
the Clopidogrel versus Aspirin in Patients at Risk of Ischemic
Events (CAPRIE) trial.
CAPRIE demonstrated long-term safety and efficacy of clopidogrel in
reducing the annual risk of stroke, MI, and vascular death compared
with aspirin (5.32% versus 5.83%;
= 0.043; relative risk reduction 8.7%) in patients with
atherosclerotic cardiovascular disease.
Thienopyridine derivatives are indispensable to current
interventional practice where stenting has dominated over other
devices. They improve the outcome of ACS independent of stent
usage. With a favorable hematologic profile, clopidogrel is the
preferred agent over ticlopidine.
Low molecular weight heparin
There are many theoretical advantages of LMWH over
unfractionated heparin (UH).
LMWH in ACS has proven to be beneficial in clinical studies.
Meta-analysis of the TIMI 11B and ESSENCE (Efficacy and Safety of
Subcutaneous Enoxaparin in Non-Q-wave Coronary Events) trials
demonstrated sustained and significant reduction in the composite
endpoint (death and nonfatal MI) of about 20% at 43 days (7.1%
= 0.02) with the use of enoxaparin in UA/NQWMI compared with UH.
The FRISC-II trial randomized UA/NSTEMI patients to subcutaneous
dalteparin (120 IU/kg) twice daily or placebo for 3 months. Among
the noninvasive arm patients, there was a significant difference in
the rates of death, nonfatal MI, and revascularization between
dalteparin and placebo at 1 month (19.5% versus 25.7%;
= 0.001) and 3 months. At 6-month follow-up, however, these
differences ceased to be significant.
Dosing of LMWH during PCI and safety in combination with other
pharmacologic agents were addressed in the National Investigators
Collaborating on Enoxaparin (NICE) 3 and NICE 4 trials.
In the NICE 3 trial, enoxaparin (0.3mg/kg intravenously) was given
in combination with a GP IIb/IIIa receptor blocker during coronary
angiogram if more than 8 hours had elapsed from the last enoxaparin
dose. The clinical outcomes and bleeding frequency were similar to
those reported in large GP IIb/IIIa receptor blocker trials. The
NICE 4 trial used 0.75 mg/kg of enoxaparin intravenously in
combination with abciximab during PCI and had similar major
bleeding rate as that of EPILOG.
GP IIb/IIIa receptor antagonists
GP IIb/IIIa receptor blockers can reduce the risk of adverse
cardiac events from coronary intervention.
Our knowledge of these agents in ACS comes from clinical trials
that are divided into "upstream," and "downstream" trials. The
downstream trials are designed to study the benefits of GP IIb/IIIa
antagonists on PCI when given in the perioperative period. Only a
subset of the enrolled patients had ACS. The upstream trials are
designed primarily as medical management of UA/NQWMI, but varying
percentages of the patients (23% to 30%) went on to have PCI,
blurring the distinction from the downstream studies.
Confusion arises when these trials yield conflicting results.
Eptifibatide and tirofiban reduce the risk of adverse events
when used in an upstream fashion. In the PURSUIT (Platelet
glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression
Using Integrilin Therapy) trial, eptifibatide showed significant
reduction in the composite endpoint (death or MI) compared with
placebo at 30 days (14.2% versus 15.7%;
In the PRISM-PLUS (Platelet receptor inhibition in ischemic
syndrome management in patients limited by unstable signs and
symptoms) trial, tirofiban plus heparin had a significant reduction
in the composite endpoint (death, MI, or refractory angina) at 30
days compared with heparin (18.5% versus 22.3%;
The issue of upstream abciximab is less clear. The results from
the CAPTURE (c7E3 Fab Antiplatelet Therapy in Unstable Refractory
Angina) and the more recent GUSTO IV ACS (Global Utilization of
Streptokinase and t-PA for occluded coronary arteries trial IV in
Acute Coronary Syndromes) trials point to different conclusions.
The CAPTURE trial randomized refractory UA patients to abciximab
bolus followed by continuous drip or placebo for 18 to 24 hours
before PCI and for 1 hour after the procedure. Abciximab reduced
the risk of cardiac event (deaths or MI) at 30 days (5.4% versus
= 0.012) compared with placebo. The more recent GUSTO IV ACS trial
randomized NSTEMI patients to medical treatment with placebo or 24-
or 48-hour abciximab infusion. Among the three arms, there was no
significant difference in the primary endpoint (death or MI) or the
need for revascularization at 30 days (8%, 8.2%, and 9.1%,
= not significant).
One theory to explain the different conclusions of the two
trials is suboptimal continuous infusion dosing of abciximab in the
GUSTO IV ACS trial. The initial benefit derived from the bolus dose
is thought to be lost over time. This scenario was seen in the
Au-Assessing Ultegra (GOLD) study, which monitored the
effectiveness of standard GP IIb/IIIa antagonists dosing. After 8
hours of continuous drug infusion, the degree of platelet
inhibition was highly variable. The risk of adverse events (death,
MI, or urgent target vessel revascularization [TVR]) tripled for
those patients with <70% platelet inhibition compared with those
with >70% inhibition (25% versus 8.1%;
Subgroup analysis of the CAPTURE trial reveals important
findings. The cardiac troponin T (cTnT) positive patients
(>0.1ng/mL) randomized to placebo had higher event rates
compared with cTnT-negative patient at 30 days (19.6% versus 4.9%),
similar to the GUSTO III trial, which showed higher 30-day
mortality for the cTnT-positive patients (15.7% versus 6.2%;
The benefit of abciximab was confined to those with elevated cTnT,
reducing the adverse events from 19.6% to 5.8% at 30 days (
The use of abciximab downstream (during intervention) is well
supported by the EPIC (Evaluation of Platelet IIb/IIIa Inhibition
for Prevention of Ischemic Complication), EPILOG (Evaluation in
PTCA to Improve Long-term Outcome with Abciximab GP IIb/IIIa
Blockade), and EPISTENT (Evaluation of Platelet IIb/IIIA Inhibitor
for Stenting) trials.
The EPIC trial studied high-risk angioplasty and directional
atherectomy, which included UA and recent MI patients. There was a
significant reduction in death and MI at multiple follow-up points
up to 3 years (risk reduction 23%;
<0.05). The EPILOG trial extended the positive findings to
urgent and nonurgent PCI. The EPISTENT trial showed statistically
significant reduction in death, MI, and TVR with stent plus
abciximab. At 6 months, the composite endpoint was 5.6% for the
stent plus abciximab group, 7.8% for balloon angioplasty plus
abciximab, and 11.4% for stent plus placebo (
<0.01). Additionally, the EPISTENT diabetic substudy noted
significant reduction in 6-month TVR among diabetic patients
treated with stent and abciximab.
Downstream eptifibatide was studied in ESPRIT (Enhanced
Suppression of the Platelet IIb/IIIa Receptor with Integrin
Therapy), but it was not an ACS trial. The trial included only
stenting. Eptifibatide was given as a 180 µg/kg bolus, followed by
2 µg/kg/min infusion and another bolus 10 minutes later.
The primary endpoint (death, MI, urgent TVR, or GP IIb/IIIa
antagonist crossover at 48 hours) was reduced by 37% with
eptifibatide (6.6% versus 10.5%;
= 0.002). These dosages were higher than those used in the earlier
IMPACT II trial (Integrilin to Minimize Platelet Aggregation and
Coronary Thrombosis), which failed to demonstrate a positive
The trial of downstream tirofiban has been disappointing. The
TARGET trial (Do Tirofiban and ReoPro Give similar Efficacy Trial)
showed the superiority of abciximab over tirofiban in lowering the
incidence of death, MI, or urgent TVR at 30 days (6.0% versus 7.5%,
= 0.037) when these agents were used in non-AMI patients undergoing
PCI with "intent-to-stent."
Suboptimal dosing of tirofiban and non-GP IIb/IIIa effect(s) of
abciximab have been advanced as explanations for the inferiority of
tirofiban in this "equivalence" study.
GP IIb/IIIa antagonists are beneficial in ACS. The benefits are
more apparent in the high-risk patients, e.g., those with elevated
cardiac troponins. Further clinical trials designed with optimal
dosing and direct comparison would settle many questions about
these drugs. As no oral IIb/IIIa receptor blockers have proven to
be of clinical benefit, they currently have no role in the
management of ACS.
Acute myocardial infarction
The outcomes of primary PCI for acute ST-elevation MI are
superior to those of thrombolytics.
Primary PCI has consistently shown reperfusion rates in the range
of 85% to 95% for end-of-procedure TIMI 3 flow, compared with the
traditional 50% to 66% TIMI 3 flow at 90 minutes reported in the
Death or reinfarction rate at 6 months was reduced by more than 50%
with primary PCI compared with tissue plasminogen activator (t-PA)
(8.2% versus 17.0%;
= 0.02) in the PAMI trial (Primary Angioplasty in Myocardial
The composite endpoint of death, reinfarction, and stroke at 6
months was also lowered by more than 60% (8.5% versus 23.2%,
= 0.02) with PCI compared to thrombolytic therapy in the STOP-AMI
Stent versus Thrombolysis for Occluded Coronary Arteries in
Patients with Acute Myocardial Infarction) trial.
The current success of primary PCI is due in part to stenting.
In the PAMI-Stent trial, a 35% reduction in the composite endpoint
(death, recurrent MI and TVR) was seen with stenting compared to
balloon angioplasty alone (12.6% versus 20.1%;
Stenting of the culprit lesion resulted in less restenosis at 6
months compared with balloon angioplasty alone (27% versus 52%;
GP IIb/IIIa antagonists during AMI intervention show
inconsistent benefits. In the ADMIRAL (Abciximab before Direct
angioplasty and stenting in Myocardial Infarction Regarding Acute
and Long-term follow-up) trial, the stent plus abciximab group had
higher end-of-procedure TIMI 3 flow (95.1% versus 86.7%;
= 0.03) and 49% reduction in the primary endpoint (death, recurrent
MI, and urgent TVR) at 30 days (7.4% versus 14.6%;
= 0.04%) when compared with stent plus placebo.
In the CADILLAC (Controlled Abciximab and Device Investigation to
Lower Late Angioplasty Complications) trial, however, abciximab
failed to show incremental benefit to PCI in AMI patient.
Additional studies are indicated to resolve these differences.
Despite the superior results of primary PCI, it is available
only in certain referral centers. For many AMI patients,
thrombolytic therapy is the only other alternative for
Facilitated percutaneous coronary intervention
The availability of around-the-clock AMI angioplasty is limited.
Transfer of patients from community hospitals to referral centers
for primary PCI adds delay to the definitive treatment. The delay,
due mainly to the initiation of transfer (51 ± 37 minutes) and
transport time (34 ± 30 minutes), could add more than 2 hours (120
± 69 minutes) to the process, as seen in the AIR-PAMI trial.
Facilitated PCI (FPCI) strategy attempts to combine the commonly
available pharmacologic agents at the peripheral hospitals with PCI
at the referral centers. Improved pharmacologic regimen could
stabilize AMI patients and increase the vessel patency.
Furthermore, having some flow before PCI permits visualization of
the distal vessel, making the procedure easier.
More recent data has alleviated the concern of SWIFT (Should We
Intervene Following Thrombolysis) trial, TAMI (Thrombolysis and
Angioplasty in Myocardial Infarction), and TIMI IIA trials, which
demonstrated no benefit or worse outcomes with immediate/early PCI
For totally occluded vessels post-thrombolysis, the RESCUE I
(Randomized Evaluation of Rescue PCI with Combined Utilization
Endpoints) trial found lower incidence of death and severe
congestive heart failure at 30 days with rescue PCI compared with
conservative management (6.4% versus 16.6%;
Pooled data from the RESCUE I and Canadian trial demonstrated lower
mortality with rescue PCI (
Reduction in 30-day mortality was also demonstrated in the GUSTO
III trial where abciximab was added to the rescue strategy (37%
For the partially occluded vessel post-thrombolysis, the
nonrandomized TIMI 9B trial showed significantly (
<0.05) lower readmission rate (14% versus 28%), less angina (18%
versus 29%), and repeat MI (4% versus 9%), with a trend towards
lower 60-day mortality rate (0.5% versus 2.8%;
= 0.12) with PCI during the index hospitalization compared to
Many combinations of pharmacologic agents were studied as part
of the FPCI strategy. The PACT trial, using
t-PA, 50 mg followed by PCI, showed patency (TIMI 2 or 3 flow) rate
on arrival to the catheterization laboratory of 61% in the t-PA
group compared with 34% with placebo.
In the SPEED (Strategies for Patency Enhancement in the Emergency
Department) study, half-dose reteplase (r-PA) given in two divided
doses of 5 units in combination with abciximab achieved higher TIMI
3 flow (54%) than r-PA alone (47%) at 60- to 90-minute intervals.
The TIMI 14 trial achieved 77% TIMI 3 flow rate at 90 minutes with
half-dose t-PA plus abciximab.
The FPCI strategy has yet to be proved superior to transporting
patients directly for primary PCI without giving prior
thrombolytics. In the PRAGUE study, direct transportation group had
lower primary endpoint (death, reinfarction, and stroke) at 30 days
than thrombolytic therapy during transportation group or
thrombolytic therapy in the community hospital group (8%, 15%, and
The study suggested that there might be more ventricular
fibrillation during transportation of thrombolysed patients. FPCI
is a promising revascularization strategy for AMI, but more support
from clinical studies is needed.
ACS intervention continues to improve with innovative
pharmacologic and mechanical approaches. Thienopyridine
derivatives, GP IIb/IIIa antagonists, and LMWH can lower the
incidence of adverse events and have become an integral part of ACS
management. Early intervention in combination with these
pharmacologic adjuvants and stenting leads to better outcomes,
although the GP IIb/IIIa antagonist of choice remains a matter of