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PAMI Trial
 Three randomized trials, all in 1993, provided a stimulus for
expanded application of the primary angioplasty strategy.
 The largest (N = 395), the Primary Angioplasty in Myocardial
Infarction (PAMI) trial, achieved TIMI-3 flow in 97% ( [TIMI-3
flow]) within 60 minutes in the angioplasty group.
 No significant improvement in LV function during rest or
exercise at 6-week follow-up
 there was a trend for a reduction of in-hospital mortality (2.6
vs. 6.5%, P=0.06) in the angioplasty group in comparison
with tissue plasminogen activator (t-PA).
 There was a significant reduction in combined death or
reinfarction (5.1 vs.12%, P=0.02) and ICH (0 vs.2.0%,
P=0.05) with angioplasty. Patients classified as “not low
risk” (age older than 70 years, anterior infarction or heart
rate more than 100 beats/min) had a lower mortality rate
(2.0 vs.10.4%, P=0.01) with angioplasty.
PCAT meta-analysis
Evidence favoring the primary angioplasty
strategy was derived from the PCAT (Primary
Coronary Angioplasty Trialists) meta-analysis of
10 randomized trials (conducted from 1989 to
1996).
Primary POBA significantly reduced 30-day
mortality (4.4 vs. 6.5%, P=0.02; 34% risk
reduction) and the combination of death plus
reinfarction (7.2 vs.11.9%, P < 0.001, 40% risk
reduction).
These effects were not significantly affected by
the thrombolytic regimen. Primary angioplasty
was also associated with a reduction in total
stroke (0.7 vs. 2.0%, P=0.007) and a marked
decrease in hemorrhagic stroke (0.1 vs. 1.1%, P <
0.001).
PCAT Analysis
E
What About Stents vs.
Lytics?
These studies were done before the adoption of
more advanced PCI techniques.
More recent trials have compared thrombolysis
with stents and (GP) IIb/IIIa receptor inhibitors.
For example, the Stent vs. Thrombolysis for
Occluded Coronary Arteries in Patients with Acute
Myocardial Infarction (STOPAMI) trial compared
patients reperfused with a stent plus abciximab
with patients receiving t-PA.
Scintigraphic infarct size was significantly reduced
in the PCI group because of a larger salvage
index. In addition, the composite endpoint of
death, reinfarction, and stroke was lower in the
stent group (8.5 vs. 23.2% at 6 months, P=0.02).
Review by Keeley
 A quantitative review by Keeley has combined the PCAT
analysis with 13 more recent investigations (1997 to 2002),
in which stents were used in 12 of 13 and GP IIb/IIIa
inhibitors in 7 of 13 trials.
 Of the total group (N = 7739), most patients (76%)
randomized to thrombolytic therapy received t-PA.
 The summary results a significant reduction in death,
reinfarction, stroke, and hemorrhagic stroke for patients
treated with primary PCI. Major hemorrhage (5 vs. 7%,
P=0.032) was the only endpoint increased in the PCI
patients.
 The benefit was similar, irrespective of the thrombolytic
regimen. The survival advantage for primary PCI over
thrombolysis (20 lives saved for every 1000 patients
treated) is similar to the magnitude of benefit for
thrombolysis compared to placebo.
 Long-term (6 months) outcomes in several trials have been
persistently favorable for the PCI patients.
Combination Lytic & GP
Modification of pharmacological reperfusion using
a reduced dose lytic agent and addition of a GP
IIb/IIIa inhibitor has resulted in higher TIMI-3 flow
rates.
This combination therapy was tested in the
GUSTO-V and ASSENT-3 trials.
Despite a decrease in early ischemic events
(including reinfarction), there was no reduction in
30-day or 1-year mortality compared with
standard lytic therapy.
Combination therapy also increased the risk of
hemorrhage (including intracranial) in elderly
patients.
TIMI Flow Grades
 Grade 0: No perfusion. There is no antegrade flow beyond
the point of occlusion.
 Grade 1: Penetration without perfusion. Contrast material
passes beyond the area of obstruction but fails to opacify
the entire coronary bed distal to the obstruction for the
duration of the cine filming sequence.
 Grade 2: Partial perfusion. Contrast material passes across
the obstruction and opacifies the coronary distal to the
obstruction. However, the rate of entry of contrast material
into the vessel distal to the obstruction and/or its rate of
clearance from the distal bed (or both) is perceptibly slower
than its flow into or clearance from comparable areas not
perfused by the previously occluded vessel.
 Grade 3: Complete perfusion. Antegrade flow into the bed
distal to the obstruction occurs as promptly as antegrade
flow into the bed proximal to the obstruction, and clearance
of contrast material from the involved bed is as rapid as
clearance from an uninvolved bed in the same vessel or the
opposite artery.
TIMI Myocardial Perfusion
Grade 0: minimal or no myocardial blush
Grade 1: Dye stains myocardium and stain
persists on the next injection
Grade 2: Dye enters myocardium but washes
out slowly so that the dye is strongly
persistent at the end of the injection.
Grade 3: normal entrance and exit of dye in
the myocardium.

Advantages of the PCI
Strategy
Superior Restoration of Flow
Treatment of the Inciting Pathobiology in AMI
Anatomical Definition and Risk Stratification
Reduction in Complications
Superior Restoration of
Flow
Critical link between early establishment of TIMI-3
flow with myocardial salvage and survival.
Primary PCI attains TIMI-3 flow in more than 90%
of patients.
 In contrast, less than 65% of patients receiving a lytic
agent achieve this benchmark.
Primary PCI efficacy is sustained in the late stages
of infarction
 thrombolysis effectiveness declines significantly within a
few hours of symptom onset.
This discrepancy provides a theoretical basis for
the incremental improvement in outcomes with
primary PCI.
Treatment of Inciting
Pathobiology
Reperfusion therapy (especially thrombolysis)
targets the thrombotic intracoronary event
that occurs in most myocardial infarctions.
However, dynamic factors, apart from
thrombus, including plaque rupture,
intramural hemorrhage, dissection, and
spasm, are effectively treated with catheter-
based reperfusion and may partially explain
the advantage of primary PCI over
thrombolysis.
After successful thrombolysis, a significant
residual stenosis (50%) remains in more than
90% of patients.
 Among patients in the TIMI trials, the
composite of death, reinfarction, and
congestive heart failure was higher with a
residual stenosis, more than 50% (7.8 vs.
2.8%, P=0.03).
Treatment of the stenosis during primary
angioplasty appears to lower the risk of
recurrent ischemic events.
Reocclusion occurs in 25 to 30% of patients
after successful thrombolysis. After primary
balloon angioplasty, reocclusion ranges from 5
to 16.7%
Stenting further decreases risk of reocclusion
(5.1% vs. 9.3% with PTCA.)
Anatomical Definition
and Risk Stratification
 Angiographic and hemodynamic data obtained at the time
of cath impart valuable decision-facilitating information and
more precise risk stratification.
 Angiography defines the coronary anatomy in patients with
equivocal or uninterpretable ECG changes.
 After urgent coronary angiography, a subset of patients will
require emergent coronary bypass surgery for severe
multivessel or left main coronary artery disease.
 Mechanical complications can also be identified during
cardiac catheterization. An additional subset of patients
exhibits spontaneous reperfusion without a significant
residual stenosis and avoids the hazards of re-perfusion
therapy, including the hemorrhagic risks of thrombolysis
Anatomical Definition
and Risk Stratification
A primary PCI strategy allows stratification of
patients into a low-risk group (age 70 years,
LVEF higher than 0.45, one- or two-vessel
disease, successful angioplasty, no persistent
arrhythmias) who can be discharged after 3
days with reduced costs and similar survival
compared with longer hospitalization (7 days).
Reduction in
Complications
Treatment with primary angioplasty appears to
reduce infarct rupture.
In a combined meta-analysis of the GUSTO-I and
PAMI-I/II trials, primary angioplasty resulted in an
86% reduction in the risk of mechanical
complications compared with patients undergoing
thrombolysis.
There was a significant reduction in acute MR
(0.31 vs. 1.73%, P < 0.001) and VSDs (0.0 vs.
0.47%, P < 0.001).
In a multivariate analysis of 1375 patients,
treatment with primary angioplasty was
Complications of
Reperfusion Therapy
Intracranial hemorrhage may be fatal in half to
two thirds of patients and remains a devastating
peril of thrombolytic therapy.
In a comparative analysis, the risk of intracranial
hemorrhage was found to be 1% with
thrombolysis and 0.05% with PCI.
Major bleeding complications were increased with
PCI compared with thrombolysis (7 vs. 5%,
P=0.032). However, these hemorrhages usually
occur at the access site and were found to
decrease in later trials.
Temporal Dynamics of
Reperfusion Therapy
Rapid reperfusion of the infarct artery leading
to myocardial salvage has remained the
rationale for early reperfusion.
The survival benefit of thrombolytic
reperfusion therapy decreases with increasing
delay in treatment.
 There is an inherent delay in initiation of
primary PCI reperfusion compared with
thrombolysis.
Despite the identified advantages and trial
evidence favoring a primary PCI strategy,
considerable controversy still surrounds the
relative time-dependent efficacy of this
 Examination of primary angioplasty (N = 27,080) in the
NRMI-2 database has revealed that the adjusted odds of
hospital mortality did not increase significantly with
increasing time from symptom onset to balloon inflation
(ischemic time) but mortality did increase with a door to
balloon time (treatment interval) longer than 2 hours.
 One large study (N = 2635) has demonstrated increasing
major adverse cardiac events rates with increasing
presentation delay for thrombolysis but relatively stable
event rates over time for primary angioplasty.
 A mechanistic difference in reperfusion efficacy was
illustrated by the study of Schomig and associates, who
demonstrated a consistent degree of myocardial salvage
with primary PCI (stenting), despite increasing ischemic
time.
 Conversely, myocardial salvage achieved by thrombolysis
declines markedly with increasing ischemic time, leading to
a larger apparent advantage from primary PCI with later
LOGISTIC CHALLENGE OF
EFFECTIVE REPERFUSION THERAPY.
 Despite analytical considerations, the selection of
reperfusion therapy remains a complex and controversial
decision. Local factors, patient risk, and temporal dynamics
must be considered.
 In facilities able to provide on-site primary PCI, expeditious
application clearly provides the best opportunity for
survival.
 However, only approximately 25% of U.S. hospitals have the
capacity for primary PCI.
 The advantage of primary PCI and an apparent prolonged
temporal margin of benefit have created a foundation for
expanding catheter-based reperfusion by transfer to
capable centers.
DANAMI-2
 The polarity of reperfusion strategy is exemplified by the
findings of two trials in this meta-analysis.
 The DANAMI-2 randomized 1129 patients at referral
hospitals to on-site thrombolysis or transport for PCI (PCI
delay over thrombolysis was 67 minutes).
 There was reduction in the composite endpoint of death,
reinfarction, and stroke (8.5 vs. 14.2%, P=0.002), primarily
because of less reinfarction (1.9 vs. 6.2%, P < 0.001).
 Rescue PCI occurred in only 1.9%, and 4% of screened
patients were considered unable to tolerate transport.
CAPTIM Trial
 Alternatively, the CAPTIM trial (N = 840) compared the
earliest possible initiation of thrombolysis with direct
transport for PCI. A physician initiated thrombolysis on site.
 The composite endpoint (death, reinfarction, stroke)
occurred in 6.2% with PCI and 8.2% with prehospital
thrombolysis (P=0.29). In patients randomized within 2
hours, there was a trend for mortality reduction (2.2 vs.
5.7%, P=0.058) with prehospital thrombolysis.
 Cardiogenic shock occurred less frequently with
thrombolysis in this early group (1.3 vs. 5.3%, P < 0.032).
 Notably, in the thrombolytic group, rescue PCI occurred in
26% and, by day 30, 70% underwent PCI.
Misc Considerations
Other factors should be considered with early
presentation (shorter than 3 hours). Patients
with contraindications to thrombolysis and
those with cardiogenic shock should be
transported for PCI.
Higher risk patients (e.g., anterior infarction,
elderly, hemodynamic compromise) also
experience a larger benefit from catheter-
based reperfusion, and the TIMI risk score can
identify this group.
Patients at higher risk for intracranial
hemorrhage from thrombolysis will also
accrue less hazard from primary PCI.
Patients with 2- to 3-hour or longer presentation
delays will be better served by a primary PCI
strategy if transfer and/or reperfusion can be
accomplished promptly.
Despite ACC/AHA recommendations for a
treatment interval (door to balloon) of less than
90 minutes, another study from NRMI-3/4 on
patients transferred for PCI has determined a
median door to balloon time of 180 minutes, with
only 4.2% treated within 90 minutes.[
Clinical trials have demonstrated the feasibility of
rapid transport for primary PCI. Early assessment
using prehospital 12-lead electrocardiogram (ECG)
acquisition can allow efficient triage and advance
preparation at the PCI center, with a considerable
reduction in the treatment interval.
Impediments to
Widespread PCI Strategies.
However, there are several impediments to
widespread application, especially in the United
States, including lack of prehospital ECG
capability (10% in the United States), economic
impact on providers, organizational issues,
regulatory policies involving certification,
interpretation of performance metrics, and the
political dynamics of achieving a broad
consensus.
Nevertheless, a geographic study has determined
that nearly 80% of the adult U.S. population lives
within 60 minutes of a PCI-capable hospital.
A recent AHA initiative is a step forward to
implement timely reperfusion via primary PCI in
THROMBOLYTIC-INELIGIBLE
PATIENTS.
A significant proportion (25 to 30%) of patients
presenting with ST elevation (or LBBB) infarction
who are eligible do not receive reperfusion
therapy.
In the Global Registry of Acute Coronary Surgery
(GRACE) 2084 patients presenting within 12 hours
of STEMI onset, thrombolytic were CI in 15% and,
overall, 30% of eligible patients did not receive
reperfusion therapy.
Correlates of the latter group included those with
prior bypass surgery, diabetes, history of
congestive failure, and age older than 75 years.
There remains a bias against thrombolysis,
particularly for the elderly.
Patients with clear-cut and relative
contraindications to thrombolysis are at higher
PCI for Those with Lytic
CI
Primary PCI also achieved significant
myocardial salvage and a favorable 6-month
mortality in a group of patients ineligible for
thrombolysis.
Primary PCI can be applied to most higher risk
patients who are not ideal candidates for
thrombolytic therapy.
The contraindications to primary angioplasty
are limited to patients who cannot receive
heparin, aspirin, or thienopyridines,
documented life-threatening contrast allergy,
or lack of vascular access.
PATIENTS IN CARDIOGENIC
SHOCK.
Multiple observational series of patients
undergoing balloon angioplasty in cardiogenic
shock have demonstrated improved
hemodynamic status and suggested enhanced
survival.
In contrast, thrombolysis appears less effective
when administered to patients in shock.
Although thrombolysis may provide a survival
benefit for patients, increasing rates of PCI (28 to
54%) and declining rates of lytic use (20 to 6%)
were associated with declining mortality (60 to
48%, P < 0.001) for 25,311 shock patients in the
NRMI database from 1995 to 2004.
In this propensity-adjusted multivariable analysis,
primary PCI was associated with a significant
reduction in hospital mortality (OR, 0.46; 95% CI,
0.40 to 0.53).
SHOCK Trial
Randomized 302 patients to an early (within 12 hours
shock onset, 36 hours of infarction onset)
revascularization strategy (PCI, 63%; bypass surgery
38%) or medical stabilization (thrombolysis, 63%) with
delayed revascularization, if appropriate.
 IABP support was recommended (86%) in both groups.
A significant survival advantage for early
revascularization was noted at 6 months and 1 year
but not at the 30-day primary endpoint.
The 30-day mortality was significantly lower with early
revascularization for patients younger than 75 year.
(41 vs. 57%, P < 0.05). There was no benefit for the 56
patients older than 75 years, but an imbalance of
baseline characteristics may have been present in this
small group.
SHOCK
Furthermore, in the larger SHOCK registry, hospital
mortality was significantly lower in elderly patients
selected for early revascularization (48 vs. 81%,
P=0.0003) and similar to that of younger patients (45
vs. 61%, P=0.002).
With exclusion of early deaths and covariate-adjusted
modeling, the relative risk with revascularization was
0.46 (95% CI, 0.28 to 0.75; P=0.002) for age of 75
years and 0.76 (95% CI, 0.59 to 0.99; P=0.045) for age
younger than 75 years.
Rapid reperfusion is critical for survival and a large
benefit (132 lives saved/1000 treated) is realized at 1
year.
Early revascularization is clearly recommended for
patients younger than 75 years and suitable for many
More Shocking Results
The survival of 82 patients undergoing PCI in
the SHOCK trial was 50% at 1 year.
One-year mortality was 38% with TIMI-3, 55%
with TIMI-2, and 100% with TIMI 0-1 flow after
PCI.
The PCI success rate was 76%. Stents (34%)
and GP IIb/IIIa inhibitors (32%) were used in
the minority during the study period (1993 to
1998).
A prospective registry of 96 shock patients
has indicated that the use of stents and
Most cardiogenic shock patients have multivessel
disease (81% in SHOCK). Survival rates for PCI
and bypass surgery in the early revascularization
arm were similar, although patients undergoing
bypass surgery had more extensive coronary
disease and a higher prevalence of diabetes.[
There was a trend for improved 30-day survival in
bypass surgery patients with complete
revascularization (63 vs. 17%, P=0.07).
Only 13% of PCI patients underwent a multivessel
procedure, with a 1-year survival of 20%
compared with 55% with single-vessel PCI.
Elderly +Lytics = Bad Jaeger
Shot
Although the relative benefit of thrombolytic therapy is
diminished in the elderly, the higher overall mortality
results in a greater absolute mortality reduction, as
noted in a meta-analysis of major trials.
Despite this evidence, age predicts failure to use
reperfusion therapy.
Observations from the Medicare and NRMI data bases
have indicated no benefit or possible harm for this
group with thrombolysis, especially in patients older
than 75 to 80 years.
 Apprehension regarding the risk of intracranial
hemorrhage remains, and the cumulative risk factors
for this complication are more common in the elderly
population.
Elderly patients undergoing thrombolysis have more
than a threefold risk of free wall rupture compared
with no reperfusion or primary PCI.
Elderly + PCI = Sexy!
In contrast, Medicare patients undergoing primary
angioplasty (N = 2038) exhibited a lower 30-day
(8.7 vs. 11.9%, P=0.001) and 1-year (14.4 vs.
17.6%, P=0.001) mortality compared with
thrombolysis (N = 18,645).
 For patients older than 75 years in the NRMI-2
registry, the combined endpoint of death and
nonfatal stroke was significantly higher in patients
treated with t-PA compared with primary
angioplasty (18.4 vs. 14.6%, P=0.001).
In the PCAT analysis of 10 randomized trials,
primary angioplasty was more effective in
reducing 30-day mortality in patients over age 70
years compared with younger patients.
Prior CABG
Mortality increased with prior CABG
Large thrombus burden in vein grafts may
also be more resistant to lytic agents.
POBA of vein grafts assoc with higher rates of
TIMI-3 flow compared with lytics, but reduced
compared to native vessel reperfusion.
GP 2b/3a Inhibitors with
PTCA
RAPPORT (ReoPro in AMI Primary PTCA
Organization Randomized Trial) assigned
people to either placebo or abciximab while
undergoing balloon angioplasty.
Incidence of death, reinfarction, or urgent TVR
was reduced significantly at 30 days (6% vs.
11%) and 6 months with reopro.
Rescue Angioplasty
Limited data regarding value of recue
angioplasty in pts who do not achieve
reperfusion after lytics.
Observation data showed suggested little
benefit and high mortality in whom attempted
RA failed.
Analysis of 4 small randomized trials of RA
identified significant reduction in early severe
HF, trend toward reduced mortality and 2 of
these trials showed signif survival benefit at 1
year.
Facilitated Angioplasty
Several trials showed adverse outcomes if
early angioplasty (compared with delayed)
after lytics with more complications (bypass
surgery and bleeding), a trend for higher
mortality, and no difference in LV function.
PACT (Plasminogen-activator Angioplasty
Compatibility Trial) – pts got ½ dose tPA had
higher TIMI-3 flow prior to angioplasty.
In ADMIRAL trial, reopro alone before cath
resulted in TIMI-3 of only 30%.
However reopro combined with ½ dose lytics
the TIMI-3 flow rates were 62-77% without an
increase in major bleeding or ICH over full
dose lytics.
SPEED
Lytics for Late
Presentation
In the NRMI data base, nearly one third of
patients with acute infarction presented more
than 12 hours after symptom onset.
Thrombolytic therapy in this group does not
significantly improve survival.
Guidelines restrict recommendations for
reperfusion with PCI to late presentation
patients (12 to 24 hours) with persistent
ischemic symptoms, heart failure, and
hemodynamic or electrical instability.
PCI for Late Presentation
Data from small RCTs evaluating the effect of
PCI more than 12 hours after MI are conflicting
and inconclusive.
Recently, the BRAVE-2 trial (N = 365)
evaluated immediate PCI in asymptomatic
patients 12 to 24 hours after symptom onset.
Scintigraphic infarct size was significantly
smaller in PCI patients (8 versus 13 percent, P
< 0.001). Death, reinfarction, and stroke were
insignificantly reduced with PCI at 30 days
(4.4 versus 6.6 percent, P = 0.37).