Primary percutaneous coronary intervention

versus fibrinolysis in acute ST elevation

myocardial infarction

1.INTRODUCTION
2.LIMITATIONS OF FIBRINOLYSIS
3.PRIMARY PCI VERSUS FIBRINOLYTIC TRIALS
a. Primary PCI with balloon angioplasty versus fibrinolysis
b. Primary PCI with stenting versus primary PCI with balloon angioplasty
c. Primary PCI with stenting versus fibrinolysis
d. PCI after fibrinolysis
4.SELECTING A REPERFUSION STRATEGY

INTRODUCTION

Primary percutaneous coronary intervention (PCI), if performed in

a timely fashion, is the reperfusion therapy of choice in patients
who have had an acute ST elevation myocardial infarction
(STEMI) or an MI with new or presumably new left bundle branch
block or a true posterior MI.

LIMITATIONS OF FIBRINOLYSIS

The net effect in major fibrinolytic trials was an approximate 30%

reduction in the 7-10% short-term mortality

The benefit of fibrinolysis is greatest when therapy is given within

the first four hours after the onset of symptoms, particularly
within the first70 minutesas the resistance of cross-linked
fibrin to fibrinolysis is time-dependent

Although patency is restored in up to 87% of infarct-related

arteries, normalization of blood flow (as assessed by the TIMI flow
grade) occurs in only 50-60%.

In contrast, TIMI 3 flow is achieved in 93-96% of patients who

undergo primary PCI.

LIMITATIONS OF FIBRINOLYSIS

The absolute reduction in mortality was greatest among patients who presented within 1 h of symptom
onset.
Benefit in this group was estimated at 65 lives saved per 1000 treated patients.
Fibrinolytic therapy appeared to be beneficial up to at least 12 h

Boersma et al, Lancet. 1996

LIMITATIONS OF FIBRINOLYSIS
normalization of blood flow (TIMI grade
3) occurs in only 50-60%

LIMITATIONS OF FIBRINOLYSIS

Associations between early patency of the infarct-related artery,

better preservation of ventricular function and improved survival

The GUSTO Angiographic Investigators,

N Engl J Med. 1993

LIMITATIONS OF FIBRINOLYSIS
TIMI 3 flow is achieved in 93-96% of patients
who undergo primary PCI

CADILLAC Investigators, N Engl J Med. 2002

LIMITATIONS OF FIBRINOLYSIS
After apparently successful fibrinolysis, there has
been observed in
20-30%

of patients evidence of early

recurrence of ischemia (pain or ST segment
shifts)

5-15%

of patients frank fibrinolytic coronary

reocclusion

3-5%

reinfarction

Reinfarction

is associated with higher rates of

in-hospital, short-term, and long-term

LIMITATIONS OF FIBRINOLYSIS

Major hemorrhagic complications occur in 2-3%. The most serious is

intracerebral hemorrhage
1%

overall

1.4%
over

of older adults
4% in patients with multiple risk factors

As many as 20-30% of patients presenting with an acute STEMI,

particularly older adults, are not candidates for fibrinolytic therapy
because of contraindications such as active internal bleeding, a
recent stroke, or hypertension

Efficacy of fibrinolytic therapy has not been demonstrated in patients

in cardiogenic shock (unless coronary perfusion pressure is increased
with an IABP) or those with prior CABG

PRIMARY PCI VERSUS FIBRINOLYTIC

TRIALS
1.Meta-analysis of Primary PTCA vs Thrombolysis
10 RCTs, n=2606, 1985-1996
balloon angioplasty was associated
with
lower mortality at 30 days, 4.4 vs
6.5% (34% reduction)
lower rate of death or nonfatal
reinfarction (7.2 vs 11.9%)
lower rate of total stroke (0.7 vs
2.0%) and hemorrhagic stroke (0.1
vs 1.1%)

PRIMARY PCI VERSUS FIBRINOLYTIC

TRIALS
2. Primary PCI with stenting versus primary PCI with balloon
angioplasty
10 RCTs, n=6192, pre-drug-eluting-stent era, 1998-2005

Compared with balloon angioplasty, BMS was associated with

reduced rates of
reocclusion
restenosis
target

(6.7% vs 10.1)

(23.9% vs 39.3%)

vessel revascularisation (TVR, 12.2% vs 19.2%)

BMS was not associated with reduced rates of

mortality

(5.3% vs 5.1%)

reinfarction

(3.9% vs 4%)

Svilaas et al, Heart. 2007

PRIMARY PCI VERSUS FIBRINOLYTIC

TRIALS
2. Primary PCI with stenting versus primary PCI with balloon
angioplasty

Svilaas et al, Heart. 2007

PRIMARY PCI VERSUS FIBRINOLYTIC

TRIALS
3. Primary PCI with stenting versus fibrinolysis
DANAMI-2
Danish Multicenter Randomized Study on Fibrinolytic
Therapy versus Acute Coronary Angioplasty in
Acute Myocardial Infarction

PRIMARY PCI VERSUS FIBRINOLYTIC

TRIALS
3. Primary PCI with stenting versus fibrinolysis
1572 patients,1997-2001,24 referral hospitals without angioplasty
facilities and 5 invasive-treatment hospitals
front-loaded alteplase or primary PCI with stenting
median time between randomization and arrival in the catheterization
laboratory 67 minutes, with 96% 120 minutes.
discontinued prematurely - significant reduction in the primary end
point of mortality, reinfarction, or stroke at 30 days with primary PCI
(8.0 vs 13.7)

PRIMARY PCI VERSUS FIBRINOLYTIC

TRIALS
3. Primary PCI with stenting versus fibrinolysis

DANAMI-2 Investigators, N Engl J Med.

PRIMARY PCI VERSUS FIBRINOLYTIC

TRIALS
3. Primary PCI with stenting versus fibrinolysis
The mortality benefit was noted only in the subgroup of high-risk
patients with a TIMI risk score 5 at presentation
The benefit remained significant at 3 years (19.5 vs 25.2%) and was
primarily due to less clinical reinfarction (8.9 vs 12.3%)
At median follow-up of 7.8 years, the combined end point of death or
reinfarction was significantly lower in the primary PCI group (34.8 vs
41.3%), attributable to a significantly lower reinfarction rate (11.7 vs
18.5%)

PRIMARY PCI VERSUS FIBRINOLYTIC

TRIALS
3. Primary PCI with stenting versus fibrinolysis
DANAMI-2
3 years follow-up
Differences in mortality

In the low-risk group, there was no difference in mortality:

primary angioplasty, 8.0% - fibrinolysis, 5.6%
in the high-risk group, there was a significant reduction in mortality with primary angioplasty
25.3% versus 36.2%
DANAMI-2 Investigators, Circulation.

PRIMARY PCI VERSUS FIBRINOLYTIC

TRIALS
3. Primary PCI with stenting versus fibrinolysis
DANAMI-2
Median follow-up 7.8 years
The fibrinolysis group was treated according
to the documented optimal standards in
1997 to 2001. The DANAMI-2 study had a
very low rate of crossover between the 2
groups, and <50% of patients in the
fibrinolysis arm had PCI performed within
the first 3 years of follow-up.

DANAMI-2 Investigators, Circulation.

PRIMARY PCI VERSUS FIBRINOLYTIC

TRIALS
3. Primary PCI with stenting versus fibrinolysis
Is primary angioplasty for some as good as primary angioplasty for all?
10 RCTs
68% of all mortality benefits could be captured by treating only those patients in the
highest quartile of mortality risk and 87% of the benefit could be captured by treating those
in the highest half.
A mortality benefit was unlikely in patients with a 30-day mortality risk of about 2% or less,
which is seen with a TIMI risk score of 0 to 2
With this risk-benefit relationship, treatment of only the 39% of patients with the highest
risk would yield equivalent mortality outcomes to population-wide angioplasty.
CONCLUSION: Most of the incremental benefits of primary angioplasty can be achieved by
treating high-risk patients.
Kent et al, J Gen Intern Med. 2002

PRIMARY PCI VERSUS FIBRINOLYTIC

TRIALS
3. Primary PCI with stenting versus fibrinolysis
Is primary angioplasty for some as good as primary angioplasty for all?

Kent et al, J Gen Intern Med. 2002

PRIMARY PCI VERSUS FIBRINOLYTIC

TRIALS
3. Primary PCI with stenting versus fibrinolysis
Meta-Analyses of Primary PCI and Fibrinolysis
23 RCTs (8140 patients) and 32 observational studies (185 900 patients) up
to May 2008.
PCI was associated with reductions in short-term (<or =6-week) mortality of
34% in RCTs, and 23% lower mortality in observational studies.
PCI was associated with reductions in stroke of 63% in RCTs and 61% in
observational studies.
At long-term follow-up (>or =1 year), PCI was associated with a 24%
reduction in mortality and a 51% reduction in reinfarction in RCTs.
However, there was no conclusive benefit of primary percutaneous coronary
intervention in the long term in the observational studies.
Huynh et al, Circulation 2009

PRIMARY PCI VERSUS FIBRINOLYTIC

TRIALS
3. Primary PCI with stenting versus fibrinolysis
Meta-Analyses of Primary PCI and Fibrinolysis

Huynh et al, Circulation 2009

PRIMARY PCI VERSUS FIBRINOLYTIC

TRIALS
3. Primary PCI with stenting versus fibrinolysis
Meta-Analyses of Primary PCI and Fibrinolysis

Huynh et al, Circulation 2009

PRIMARY PCI VERSUS FIBRINOLYTIC

TRIALS
3. Primary PCI with stenting versus fibrinolysis
Meta-Analyses of Primary PCI and Fibrinolysis

Huynh et al, Circulation 2009

PRIMARY PCI VERSUS FIBRINOLYTIC

TRIALS
3. Primary PCI with stenting versus fibrinolysis
Meta-Analyses of Primary PCI and Fibrinolysis

Huynh et al, Circulation 2009

PRIMARY PCI VERSUS FIBRINOLYTIC

TRIALS
3. Primary PCI with stenting versus fibrinolysis
Meta-Analyses of Primary PCI and Fibrinolysis

Huynh et al, Circulation 2009

PRIMARY PCI VERSUS FIBRINOLYTIC

TRIALS
3. Primary PCI with stenting versus fibrinolysis
Meta-Analyses of Primary PCI and Fibrinolysis
The long-term attenuation of the early reductions in mortality and reinfarction associated
with primary PCI may be due to optimal long-term medical therapy that may have delayed
the long-term progression of coronary artery disease equally in both treatment arms.
The reduced magnitudes of risk reductions associated with primary PCI in observational
studies compared with those in RCTs might reflect real-world practice.
Greater use of in-hospital PCI (>30%) after fibrinolytic therapy in observational studies may
partially explain the smaller reductions in short-term mortality and reinfarction associated
with primary PCI.
In the real world, primary PCI also may be less successful when performed in less-thanoptimal conditions.
In observational studies, the lack of conclusive long-term benefits with primary PCI may be
explained by optimal medical therapy and/or the judicious use of coronary interventions in
patients who received fibrinolytic therapy.
Huynh et al, Circulation 2009

PRIMARY PCI VERSUS FIBRINOLYTIC

TRIALS
4.PCI after Fibrinolysis
Rescue or salvage PCI, for apparent failure of fibrinolysis
Urgent PCI, for threatened reocclusion or hemodynamic instability
Facilitated PCI, in which a fibrinolytic drug is given prior to planned PCI in an
attempt to achieve an open infarct-related artery before arrival in the
catheterization laboratory.
Adjunctive PCI, in which PCI is performed within hours after fibrinolysis
A pharmacoinvasive approach refers to the routine administration of a
pharmacologic agent (eg, fibrinolytic therapy or a glycoproteinIIb/IIIainhibitor)
prior to planned PCI for STEMI in an attempt to achieve an open infarct-related
artery before arrival in the catheterization laboratory.
Early elective PCI, in which PCI is performed within a few days after fibrinolysis,
usually because of recurrent ischemia or a positive stress test.
Late elective PCI to achieve an open artery

PRIMARY PCI VERSUS FIBRINOLYTIC

TRIALS
4.PCI after Fibrinolysis
Rescue PCI
o Primary failure of fibrinolysis has most often been defined in clinical trials as
persistent occlusion of the infarct-related artery (TIMI grade 0/1) by angiography
performed at approximately 90 minutes, which occurs in 40 to 50% of patients.
o However, angiography is not routinely performed after fibrinolysis outside of clinical
trials. Thus, primary failure is more often suspected clinically by persistent, severe,
worsening chest pain, hemodynamic instability, or ECG markers of persistent
ischemia (<50% resolution in the ECG lead showing the greatest degree of STsegment elevation at presentation is considered as a marker of failure of
fibrinolysis)
o PCI in this setting is called rescue or salvage PCI and is the best therapeutic
intervention for primary fibrinolytic failure.

PRIMARY PCI VERSUS FIBRINOLYTIC

TRIALS
4.PCI after Fibrinolysis
Urgent PCI
Threatened reocclusion of the infarct-related artery is characterized by the
development of early recurrent ischemia after apparently successful fibrinolysis.
Thrombotic reocclusion can be manifested by recurrent ST segment elevation,
recurrent chest pain, and/or reinfarction.
After apparently successful fibrinolysis by either clinical or angiographic criteria,
early recurrence of ischemia or ST segment shifts (threatened reocclusion): 2030%
thrombotic coronary reocclusion: 5-15%
reinfarction in 3-5%
In two reviews of almost 76,000 patients from GUSTO-I, GUSTO-III, and the TIMI and
InTIME II trials,
reinfarction occurred in 4.3% of patients at a median of 2-4 days after fibrinolytic
therapy

PRIMARY PCI VERSUS FIBRINOLYTIC

TRIALS
4.PCI after Fibrinolysis
Urgent PCI

ST shift as discussed here represents a recurrent ST shift >6 h from the time of thrombolytic
therapy
Langer et al, J Am Coll Cardiol. 1998

PRIMARY PCI VERSUS FIBRINOLYTIC

TRIALS
4.PCI after Fibrinolysis
Urgent PCI
243/734 had a new ST segment shift (33%).
The 30-day mortality rate in patients with an
ST shift was significantly higher than that in
patients without an ST shift (7.8% vs 2.25%)
as was the 1-year mortality rate (10.3% vs.
5.7%)

PRIMARY PCI VERSUS FIBRINOLYTIC

TRIALS
4.PCI after Fibrinolysis
Urgent PCI

Hudson et al, Reinfarction After Fibrinolysis, Circulation. 2001

PRIMARY PCI VERSUS FIBRINOLYTIC

TRIALS
4.PCI after Fibrinolysis
Facilitated PCI

Facilitated PCI refers to pharmacologic therapy just prior to planned

primary PCI for STEMI in an attempt to achieve an open infarctrelated artery before arrival in the catheterization laboratory.
Trials have been conducted using either
fibrinolytic therapy
half-dose fibrinolytic
half-dose fibrinolytic with a GP IIb/IIIa inhibitor

PRIMARY PCI VERSUS FIBRINOLYTIC

TRIALS
4.PCI after Fibrinolysis
Facilitated PCI
Primary vs tenecteplase-facilitated PCI ASSENT-4 PCI

planned to enroll 4000 patients

primary endpoint was death or congestive heart failure or shock within 90 days
median time from bolus tenecteplase to first balloon inflation 104 min
early cessation of enrollment because of a higher in-hospital mortality in the facilitated
than in the standard PCI group (6% vs 3%)
primary endpoint in 19% of facilitated PCI vs 13% of primary PCI (relative risk 1.39).
during hospital stay, significantly more strokes (1.8% vs 0) in patients assigned facilitated
rather than standard PCI.
more ischaemic cardiac complications, such as reinfarction (6% vs 4%) or repeat target
vessel revascularisation (7% vs 3%) within 90 days in this study group.

ASSENT-4 PCI, Lancet. 2006

PRIMARY PCI VERSUS FIBRINOLYTIC

TRIALS
4.PCI after Fibrinolysis
Facilitated PCI

PRIMARY PCI VERSUS FIBRINOLYTIC

TRIALS
4.PCI after Fibrinolysis
Facilitated PCI

PRIMARY PCI VERSUS FIBRINOLYTIC

TRIALS
4.PCI after Fibrinolysis
Pharmacoinvasive strategy
An early invasive strategy after fibrinolytic therapy in STEMI patients achieves rapid
stabilization of the culprit lesion in patients who may otherwise develop recurrent ischaemic
events after an initially successful fibrinolysis. Moreover, it restores coronary flow in patients
with a persistently occluded artery, who are not always easily identifiable based on symptoms
and ST-segment changes.
Despite the consistent results confirmed by two recent additional trials, the most recent ESC
and ACC STEMI guidelines only provided a Class IIa recommendation for routine early PCI within
324 h after successful lytic therapy. This recommendation reflects the absence of a significant
reduction in hard endpoints such as death or reinfarction in any of the trials and the concern
about an increased bleeding risk raised by previous trials using the different strategy of
facilitated PCI.

Borgia et al, Early PCI after fibrinolysis, Eur Heart J. 2010

PRIMARY PCI VERSUS FIBRINOLYTIC

TRIALS
4.PCI after Fibrinolysis
Pharmacoinvasive strategy

Borgia et al, Early PCI after fibrinolysis, Eur Heart J. 2010

PRIMARY PCI VERSUS FIBRINOLYTIC

TRIALS
4.PCI after Fibrinolysis
Pharmacoinvasive strategy

Routine early referral for PCI after fibrinolysis in patients for whom
primary PCI is not readily available leads to a significant reduction in
reinfarction, recurrent ischaemia, and the combined endpoint of
death/reinfarction, during the first month after STEMI.
There was no difference in mortality at 30 days and 612 months
between the two treatment strategies
The benefits of early routine PCI after fibrinolysis occur in the absence of
an increased risk of adverse events (stroke or major bleeding) and persist
at longer follow-up (612 months).

Borgia et al, Early PCI after fibrinolysis, Eur Heart J. 2010

PRIMARY PCI VERSUS FIBRINOLYTIC

TRIALS
4.PCI after Fibrinolysis
Pharmacoinvasive strategy

Borgia et al, Early PCI after fibrinolysis, Eur Heart J. 2010

PRIMARY PCI VERSUS FIBRINOLYTIC

TRIALS
4.PCI after Fibrinolysis
Pharmacoinvasive strategy

Borgia et al, Early PCI after fibrinolysis, Eur Heart J. 2010

PRIMARY PCI VERSUS FIBRINOLYTIC

TRIALS
4.PCI after Fibrinolysis
Pharmacoinvasive strategy
The results of our meta-analysis suggest that the current conservative approach after

fibrinolysis in patients for whom PCI is not readily available, i.e. ischaemia-guided
strategy (waiting for reperfusion to occur after fibrinolysis and referring patients to
rescue PCI thereafter) is not as beneficial as early referral to PCI

Borgia et al, Early PCI after fibrinolysis, Eur Heart J. 2010

PRIMARY PCI VERSUS FIBRINOLYTIC

TRIALS
Selecting a Reperfusion Strategy
As DB-DN times increase, the mortality advantage of PPCI over fibrinolysis declines, and
this advantage varies considerably depending on patient characteristics

In 192 509 patients included in the US

National Registry of Myocardial
Infarction (NRMI) 24 registry, the
mean PCI-related time delay where
mortality
rates of the two reperfusion strategies
were comparable was calculated at
114 min.

Pinto et al, PCI-Related Delay in STEMI Circulation. 2006

PRIMARY PCI VERSUS FIBRINOLYTIC

TRIALS
Selecting a Reperfusion Strategy
Variables included in the model:
treatment type (PPCI or fibrinolysis)
age
gender
race
DM
Hypertension
angina
Killip class 2/3
Killip class 4
previous infarction
current smoking
stroke
pulse
SBP
payer
symptom duration
Pinto
et al,
PCI-Related Delay in STEMI Circulation. 2006
infarct
location

PRIMARY PCI VERSUS FIBRINOLYTIC

TRIALS
Selecting a Reperfusion Strategy

PCI-related delay (DB-DN time) at which mortality with PCI and fibrinolysis were equal

Pinto et al, PCI-Related Delay in STEMI Circulation. 2006

PRIMARY PCI VERSUS FIBRINOLYTIC

TRIALS
Selecting a Reperfusion Strategy
a patient who is 65 years old who presents with an anterior MI within 2 hours of
symptom onset only gains a mortality advantage from PPCI if the DB-DN time is 40
minutes.
It could be speculated that this finding is due to the fact that
thromboresistance has less likely emerged (better fibrinolytic efficacy),
the risk of intracranial hemorrhage is low (improved fibrinolytic safety),
and there are advantages of more rapid restoration of flow (an advantage of
fibrinolytic therapy) to preserve left ventricular function

Pinto et al, PCI-Related Delay in STEMI Circulation. 2006

PRIMARY PCI VERSUS FIBRINOLYTIC

TRIALS
Selecting a Reperfusion Strategy
Although there is tremendous
appeal in identifying a sole DB-DN
time as the optimal goal of STEMI
reperfusion care (eg, 60 minutes or
114 minutes), the present analysis
demonstrates that the significant
variability in patient characteristics
and clinical outcomes that exists
within the STEMI population may
modify the selection of an optimal
reperfusion
strategy.

Pinto et al, PCI-Related Delay in STEMI Circulation. 2006

Thank you!