Interventional Cardiology

The efficacy and safety of combination glycoprotein

IIbIIIa inhibitors and reduced-dose thrombolytic
therapy–facilitated percutaneous coronary
intervention for ST-elevation myocardial infarction:
A meta-analysis of randomized clinical trials
Mohamad C.N. Sinno, MD, Sanjaya Khanal, MD, FACC, Mouaz H. Al-Mallah, MD, Muhammad Arida, MD, and
W. Douglas Weaver, MD Detroit, MI

Objective We reviewed the literature and performed a meta-analysis comparing the safety and efficacy of
adjunctive use of reduced-dose thrombolytics and glycoprotein (Gp) IIbIIIa inhibitors to the sole use of Gp IIbIIIa
inhibitors before percutaneous coronary intervention (PCI) in patients presenting with acute ST-segment elevation
myocardial infarction (STEMI).

Background Early reperfusion in STEMI is associated with improved outcomes. The use of reduced-dose thrombolytic
and Gp IIbIIIa inhibitors combination before PCI in the setting of acute STEMI remains controversial.

Methods We performed a literature search and identified randomized trials comparing the use of combination
therapy–facilitated PCI versus PCI done with Gp IIbIIIa inhibitor alone. Included studies were reviewed to determine
Thrombolysis in Myocardial Infarction (TIMI)-3 flow at baseline, major bleeding, 30-day mortality, TIMI-3 flow after
PCI,and 30-day reinfarction. We performed a random-effect model meta-analysis. We quantified heterogeneity between
studies with I 2. A value N50% represents substantial heterogeneity.

Results We identified 4 clinical trials randomizing 725 patients; 424 patients were pretreated with combination
therapy before PCI, and 301 patients had Gp IIbIIIa inhibitor alone during PCI. Combination therapy–facilitated PCI
was associated with a 2-fold increase in TIMI-3 flow upon arrival to the catheterization laboratory compared with the
sole use of upstream Gp IIbIIIa inhibitors (192/390 patients [49%] versus 60/284 [21%]; relative risk [RR], 2.2;
P b .00001). However, post-PCI TIMI-3 flow was similar between the 2 groups (279/319 patients [87%] versus
188/212 [88%]; RR, 0.99; P = .85). Major bleeding events significantly increased in the combination therapy group
(40/420 patients [9.5%] versus 14/299 [4.7%]; RR, 2.2; P = .007). The 30-day mortality (15/424 patients [3.5%]
versus 5/301 [1.7%]; RR, 1.47; P = .46) and 30-day reinfarction rate (5/424 patients [1.1%] versus 3/301 [1.0%];
RR, 0.96; P = .96) were similar in the 2 treatment groups.

Conclusions Awaiting the results of the ongoing clinical trials, the current cumulative evidence does not support
the routine use of combination of reduced-dose thrombolytic and Gp IIbIIIa inhibitor therapy–facilitated PCI for the
treatment of STEMI. (Am Heart J 2007;153:579286.)

The primary goal of therapy for acute ST-segment
elevation myocardial infarction (STEMI) is early, rapid,
complete, and sustained restoration of infarct-related
From the Henry Ford Health System, Detroit, MI.
Submitted June 20, 2006; accepted December 26, 2006.
Reprint requests: Sanjaya Khanal, MD, FACC, Heart Center of Antelope Valley, 43807
North 10th Street West, Lancaster, CA 93536.
E-mail: skhanal1@hotmail.com
0002-8703/$ - see front matter
n 2007, Published by Mosby, Inc.
doi:10.1016/j.ahj.2006.12.024
artery (IRA) blood flow. Irrespective of whether a
mechanical versus pharmacological strategy is used,
Thrombolysis in Myocardial Infarction (TIMI) grade
3 flow in the culprit artery within 90 minutes of
presentation has been shown to correlate with im-
proved 30-day1 and long-term2 survival in patients with
acute STEMI.
Primary percutaneous coronary intervention (PCI) is
currently the preferred approach to reperfusion therapy
when delivered expeditiously in centers with docu-
mented expertise and outcomes.3 Time to treatment,
 American Heart Journal
580 Sinno et al
April 2007

Table I. Summary of characteristics in trials comparing simultaneous use of thrombolytics and glycoprotein IIb/IIIa inhibitors vs glycoprotein
IIb/IIIa Inhibitors alone for PCI

No. of females/ Symptom onset

No. of Patients Total (%) Mean Age yrs. to drug, mins.
Combination IIb/IIIa Combination IIb/IIIa Combination IIb/IIIa Combination IIb/IIIa
Inclusion therapy inhibitors therapy inhibitors therapy inhibitors therapy inhibitors
Study Criteria group group group group group group group group

ADVANCE-MI STEMI b6hrs. 74 74 24/148 (16) 28/148 (19) 58 55 - -

SPEED STEMI b12hrs. 191 63 49/254 (19) 21/254 (8) 59 57 153 138

BRAVE STEMI b12hrs. 125 128 28/253 (11) 33/253 (13) 63.1 62.3 160 164

APAMIT STEMI b6hrs. 34 36 8/70 (11) 6/70 (9) 55 56 205 259

however, remains an important determinant of clinical
outcome in patients with acute STEMI.
Despite the better outcomes, primary PCI has not
become the treatment of choice for most patients with
STEMI because of logistical issues and the limited
availability of institutions that can offer this treatment
modality in a timely and efficient manner. In the current
US practice, only 4.2% of transferred patients with acute
STEMI were treated within 90 minutes in the National
Registry of Myocardial Infarction 3/4 registry.4 The idea
of prehospital ambulance triage of patients with STEMI
to PCI hospitals has been suggested to decrease inherent
time delay that ensues when these patients are seen in
non-PCI hospitals. Nallamothu et al5 obtained PCI status
of hospitals from the American Hospital Association
annual survey and established the location of the
population from the 2000 US census and found that 79%
of the adult population lived within 60 minutes of a PCI
hospital. Among those with non-PCI hospitals as the
closest facility, the additional time to arrive to a PCI
hospital was 30 minutes.5,6 However, with the variability
of the emergency medical system in the United States,
getting electrocardiograms in the ambulance for patients
with chest pain and training paramedics to interpret
these electrocardiograms is the major issue. Pharmaco-
logical therapy, however, can be carried out expedi-
tiously and without site-specific variations in outcome in
patients with STEMI.7 Therefore, it is logical to think that
initial early pharmacological therapy followed by PCI
may deliver both expediency and efficacy that is desired
in treating myocardial infarction (MI) patients.
In fact, many institutions have current policies of
providing initial primary PCI alone, thrombolytic thera-
py alone, or combination therapy followed by PCI based
on estimated time to treatment. In addition to standard
therapy of aspirin, heparin, clopidogrel during primary
PCI, the range of initial pharmacotherapy encompasses
thrombolytic and glycoprotein (Gp) IIbIIIa inhibitors.
The use of Gp IIbIIIa inhibitors has been shown to
improve short-term outcomes in most studies of primary
PCI.8,9 However, full-dose fibrinolysis-facilitated PCI has
recently been shown to result in worse outcome than
primary PCI alone.10 The results with combination of
reduced-dose thrombolytic and Gp IIbIIIa inhibitors
before PCI in patients with MI are however not clear. A
recent meta-analysis comparing primary and multiple
regimens of thrombolytic-facilitated PCI for STEMI
showed a higher TIMI grade 3 flow on initial angiogra-
phy, but this translated into higher major bleeding
events, increased mortality, nonfatal reinfarction, urgent
target revascularization, and stroke11 compared with
primary PCI alone. This study, however, does not
provide guidance about the common practice of the use
of reduced-dose fibrinolytic and Gp IIbIIIa inhibitors
before PCI in patients with acute STEMI. We performed
a meta-analysis of randomized clinical trials12-15 testing
the safety and efficacy of combination therapy (reduced-
dose thrombolytic + Gp IIbIIIa inhibitors)–facilitated PCI
versus PCI performed only with Gp IIbIIIa inhibitors.
Methods
Study objectives and design
Our primary aim was to compare simultaneous administra-
tion of Gp IIbIIIa inhibitors and reduced-dose fibrinolytics
before PCI to primary PCI done with Gp IIbIIIa inhibitors in
patients with STEMI. ST-segment elevation myocardial infarc-
tion was defined according to the inclusion criteria of the
trials concerned.
Search strategy
All randomized, controlled trials comparing facilitated PCI to
primary angioplasty were identified using a 2-level search
American Heart Journal
Sinno et al 581
Volume 153, Number 4

trials were also excluded. Outcome data had to be available on

culprit artery patency evaluated on admission by TIMI flow
grades, bleeding, and mortality. Two authors (M.S., M.M.)
independently reviewed abstracts or complete articles. Only
Combined 4 nonoverlapping studies met the inclusion criteria. Two
Clinical End reviewers performed independent data extraction; all discrep-
Trial Angiographic Point (Time to ancies were identified and resolved by consensus or, as
Agents eight % End Points Follow up) needed, with a third investigator and confirmed by consensus.
Tenecteplase, 20 TIMI 3 Death, Reinfarction
Eptifibatide flow grade or new CHF End points and definitions
@ 30 days The primary angiographic end point was TIMI flow grade 3
Reteplase, 35 TIMI 3 Death, Reinfarction
Abciximab flow grade or urgent on the first angiogram, which defined open culprit artery on
Revascularization
admission. The TIMI grade 3 flow was also assessed after PCI.
@ 30 days
Reteplase, 35 TIMI 3 Infarct size by SPECT, The clinical end points were all-cause mortality, reinfarction
Abciximab flow grade Death, Reinfarction, rate, and major bleeding events at 30 days follow-up.
major Bleeding, and
hemorrhagic Stroke
Alteplase, 10 TIMI 3 ACE= Death, Statistical analysis
Abciximab flow grade Reinfarction, TVR, The meta-analyses were performed by computing relative
Stroke and major
Bleeding
risks (RRs) using random-effects model. Quantitative analyses
were performed on an intention-to-treat basis and were
confined to data derived from the period of follow-up. Relative
risk for all-cause mortality, TIMI-3 flow, and major bleeding
strategy. First, we searched public domain databases including
were calculated along with 95% confidence intervals (CIs).
MEDLINE (from 1966 to December 14, 2005), the Cochrane
Between study heterogeneity was analyzed by means of I 2 =
Central Register of Controlled Trials (second quarter 2005),
[( Q df) / Q]  100%, where Q is the v 2 statistic, and df is its
Database of Abstracts of Reviews of Effects (second quarter
degrees of freedom. This describes the percentage of the
2005), Cochrane Database of Systematic Reviews (second
variability in effect estimates that is due to heterogeneity rather
quarter 2005), EMBASE (from 1980 to 2005 week 6), and BIOSIS
than sampling error (chance). A value greater than 50% may be
Previews (from 1969 to 2005 week 8). We used the following
considered substantial heterogeneity. Publication bias was
key words: acute MI; ST elevation; primary angioplasty;
assessed graphically using a funnel plot. All analyses were
facilitated angioplasty; thrombolytics including the following
performed with RevMan Analyses Version 4.2.7 (2004 the
individual medications: streptokinase, alteplase, r-TPA, and
Cochrane Collaboration).
TNK; and Gp IIbIIIa inhibitors including the following individual
medications: abciximab, tirofiban, and eptifibatide. In addition,
relevant studies were identified through a hand search of
secondary sources including references of initially identified Results
articles and proceedings from national cardiology meetings at Trial patient characteristics and study design
the American Heart Association, American College of Cardiolo- Of the 1427 potentially relevant articles initially
gy, European College of Cardiology and Transcatheter Thera-
identified, 126 full-text articles were reviewed. Four
peutics from 2001 through 2005. The search was performed
trials were identified with a design including randomi-
without any language restrictions. When an abstract from a
meeting and a full article referred to the same trial, only the full zation to combination therapy (reduced-dose thrombo-
article was included in the analysis. When there were multiple lytic + Gp IIbIIIa inhibitors) versus upstream Gp IIbIIIa
reports from the same trial, we used the most complete and/or inhibitors alone for PCI.12-15 The trial names, acronyms,
recently reported data. patient characteristics, and details of the study groups
are shown in Table I.
Study selection and data extraction Enrollment criteria of chest pain (b6 or b12 hours) with
We restricted our meta-analysis to trials that performed a ST elevation or new left bundle-branch block on the
randomized comparison between simultaneous administration electrocardiogram were used in all the trials (Table I).
of Gp IIbIIIa inhibitors and reduced-dose fibrinolytics and sole Trial design was broadly similar in all studies; however,
use of Gp IIbIIIa inhibitor before PCI in STEMI. A randomized there were some differences regarding the type and dose
controlled trial was defined according to the National Library of thrombolytic and/or Gp IIbIIIa inhibitors used. The
of Medicine criteria (http://www.nlm.nih.gov/mesh/ same-dose regimen was used throughout the 3 trials that
pubtypes2001.html). To be included in the meta-analysis, the
used abciximab in both arms of the study—0.25 mg/kg IV
trials should have randomized patients within 12 hours of
bolus followed by 12 hour infusion at 0.125 mg kg 1
symptom onset to either Gp IIbIIIa inhibitors or combination
therapy (thrombolytic + Gp IIbIIIa inhibitor) followed by min 1. Eptifibatide was used in the ADdressing the Value
preplanned angiography and angioplasty if indicated. We of facilitated ANgioplasty after Combination therapy or
excluded trials where postfacilitation angiography was not Eptifibatide monotherapy in acute Myocardial Infarction
done. We also excluded trials that compared facilitated PCI (ADVANCE-MI) trial with 2 boluses of 180 mg/kg IV
with thrombolytic therapy alone. Symptom-driven angioplasty 10 minutes apart, then 2.0 mg kg 1 min 1 infusion.
 American Heart Journal
582 Sinno et al
April 2007

Figure 1

Relative risk of TIMI grade 3 flow with combination therapy versus Gp IIbIIIa inhibitors.

Figure 2

Relative risk of major bleeding with combination therapy versus Gp IIbIIIa inhibitors.

Alteplase used in the Asia-Pacific Acute Myocardial
Infarction Trial (APAMIT) was 15 mg of standard bolus
followed by a reduced dose of 35 mg over 60 minutes. The
ADVANCE-MI study group used half dose of tenecteplase,
whereas reteplase was used in the remaining 2 trials. The
Strategies for Patency Enhancement in the Emergency
Department study group tested multiple doses of rete-
plase, but we included the 5 U + 5 U dose regimen in our
analysis because it was associated with a better safety
profile and was confirmed as the better dose in phase B of
the trial. The same 5 U + 5 U dose of reteplase was used in
the Bavarian Reperfusion Alternatives Evaluation
(BRAVE) trial as well. The 4 trials randomized 725 patients.
Four hundred twenty-four patients were initially ran-
domized to the combination therapy–facilitated PCI
group, and the rest (301) were randomized to the Gp
IIbIIIa inhibitor–facilitated PCI. There were 92% (390/
424) assigned to the combination therapy–facilitated PCI
group and 94% (284/301) in Gp IIbIIIa inhibitor group
that had postfacilitation angiography. We decided to
include the APAMIT trial despite being labeled as a rescue
angioplasty trial because all the patients in both groups
had angiography and only those patients with TIMI-3 flow
post reduced-dose alteplase did not have angioplasty. In
American Heart Journal
Volume 153, Number 4
Figure 3
Relative risk of 30-day mortality with combination therapy versus Gp IIbIIIa inhibitors.
Figure 4
Relative risk of reinfarction with combination therapy versus Gp IIbIIIa inhibitors.
the ADVANCE-MI trial, the results were analyzed both in
the bas randomizedQ and bas treatedQ fashion. We included
the data from the former group to reduce bias and
maintain an intention-to-treat analysis.
Clinical outcomes and angiographic end points
All 4 trials reported 30-day mortality, 30-day major
bleeding events, and TIMI-3 flow upon arrival to the
catheterization laboratory. Patients who received com-
bination therapy more often had patent arteries upon
arrival on the catheterization laboratory (RR, 2.18; 95%
CI, 1.70-2.81; P b .00001; I 2 = 0%). However, that did
not affect the procedural success rate because the
postprocedural TIMI-3 flow rate was similar between the
Sinno et al 583
2 groups in 3 trials (RR, 0.99; 95% CI, 0.86-1.14; P = .85;
I 2 = 81.7%). The postprocedural TIMI-3 flow was not
reported in the ADVANCE-MI trial.
The increased original vessel patency (TIMI-3 flow on
presentation) was not associated with increased surviv-
al. Each of the 4 trials reported all-cause mortality. The
30-day all-cause mortality was the same in patients
randomized to either treatment group with no hetero-
geneity between the different trials (RR, 1.47; 95% CI,
0.52-4.14; P = .46; I 2 = 0). The incidence of 30-day
reinfarction was similar between the 2 groups (RR, 0.96;
95% CI, 0.23- 4.02; P = .96; I 2 = 0).
The safety of this approach was also assessed.
Combination therapy–facilitated PCI was associated

584 Sinno et al
Figure 5
Relative risk of post-PCI TIMI 3 flow with combination therapy versus Gp IIbIIIa inhibitors.
with increased major bleeding as reported by all the
included trials except in the APAMIT trial (RR, 2.15; 95%
CI, 1.17-3.94; P = .01; I 2 = 0).
Because small trials are more prone to be affected by
publication bias, we constructed funnel plots for both
angiographic and clinical end points that exhibited a
fairly symmetrical distribution and convergence toward
the pooled effect when the weight of the trials
increased, suggesting that publication or selection bias
was unlikely (Figures 1-5).
Discussion
Time-to-treatment remains an important determinant
of clinical outcome in acute MI care, regardless of the
methodology used to establish adequate blood flow in
the IRAs. Mortality benefit of primary PCI is lost for
patients with door to balloon times exceeding 2 hours
(cannon et al) compared with patients treated with
thrombolysis. The attendant delay for primary PCI may
limit its clinical benefit over early use of thrombolysis,
especially when patients present within 3 hours after
the onset of symptoms.16,17 Thrombolysis has been
compared to primary PCI in multiple studies. These
investigations demonstrate that PCI-treated patients
experience lower short-term mortality rates, less
nonfatal reinfarctions, and less hemorrhagic strokes
than those treated with fibrinolysis alone when
performed in a timely and efficient manner.3,18 To take
advantage of early therapy of thrombolysis and the
more definite therapy of PCI, a facilitated approach
has been advocated where patients initially receive
thrombolysis while waiting for the definite primary
PCI. However, full-dose fibrinolysis-facilitated PCI has
recently been shown to be associated with higher
mortality, nonfatal reinfarctions, and urgent target
American Heart Journal
April 2007
vessel revascularization compared with primary PCI
alone for patients with STEMI.10
Gp IIbIIIa inhibitors have been shown to reduce event
rates when used in the setting of primary PCI.8,9,19-24
Moreover, the early use of Gp IIbIIIa inhibitors improved
outcomes in a recent meta-analysis that included
931 STEMI patients.25 Therefore, in addition to aspirin,
heparin, and clopidogrel, Gp IIbIIIa inhibitors have been
considered standard of care during primary PCI.
Combination of full-dose thrombolysis with full-dose
Gp IIbIIIa inhibitors results in prohibitively high risk of
bleeding complications.26 A reduced-dose combination
therefore may offer the benefit of earlier reperfusion
without increasing bleeding risks. A reduction of recur-
rent MI has been demonstrated in patients treated with
half-dose tenecteplase with abciximab when compared
to full-dose tenecteplase in patients with STEMI.26
Although the mortality rate at 30 days was the same
between the 2 groups, the combination therapy group
experienced fewer recurrent MIs. It is possible that Gp
IIb/IIIa inhibitors improve flow in the infarct artery and
prevent the prothrombotic milieu that occurs after the
thrombolytic wears off. Because administration of half-
dose thrombolysis may be safer than full-dose in patients
undergoing primary PCI, many hospitals advocate ad-
ministration of reduced-dose thrombolytic and Gp IIbIIIa
inhibitor during the delay in performing PCI. However,
the safety and efficacy of the combination of these 2
classes of drugs before PCI have not yet been validated in
a large randomized, blinded, placebo controlled trial.
The major finding of our meta-analysis is the demon-
stration of a bfacilitatingQ effect of reduced-dose fibrino-
lytic combined with Gp IIbIIIa inhibitors by improving
preprocedure TIMI-3 flow of the IRA. The TIMI flow on
initial angiography has been shown to be a major
determinant of survival in primary PCI27 and a valid end
American Heart Journal
Volume 153, Number 4
point for mortality in thrombolytic trials.28 However, in
spite of improved preprocedural TIMI-3 flow, postpro-
cedural flow was similar compared with patients
undergoing primary PCI alone. Moreover, the combina-
tion therapy–facilitated PCI was also associated with
unfavorable trends for mortality and significant increase
in major bleeding events.
The reasons for neutral to worse outcomes in the
facilitated arm despite improved preprocedural TIMI-3
flow in this analysis may be the same factors that
worsen outcomes in patients undergoing facilitation
with full-dose thrombolytics. The possible explanations
may be suboptimal antithrombotic/antiplatelet therapy,
treatment delay, and increased bleeding complications
in the facilitated group compared with patients under-
going primary PCI alone. The addition of fibrinolytic
before PCI has been shown to increase nonbleeding
adverse clinical events in spite improved initial TIMI-3
flow.10 Therefore, whether hemorrhagic transformation
of the infracted muscle and increased infarct size occurs
more in the setting of reperfused arteries has to be
entertained. It has been demonstrated that the bleeding
risk is proportionately increased with increasing doses
of antithrombins (heparin and low-molecular-weight
heparin). The studies described mostly used standard
dose antithrombin therapy. It is possible that bleeding
may be reduced if lower antithrombin doses are
lowered in the facilitated therapy group.
The current meta-analysis has a number of limitations,
including inevitable clinical heterogeneity between
trials and an overall sample size of only 725 patients,
which is statistically adequate to compare TIMI grade 3
flow (power of 97%) but insufficient for clinical
outcomes like mortality. Sensitivity analyses were also
performed, and comparable results were obtained with
a random effect model or when the largest study was
excluded from the meta-analysis. Our analyses were also
limited to short-term outcomes, whereas some Gp
IIbIIIa inhibitor studies have often demonstrated in-
creased survival benefit with longer follow-up. In spite
of the various limitations, however, the individual trials
were in most cases underpowered, and the combined
analysis allows more robust conclusions. Whether
combination of reduced-dose thrombolytic and Gp
IIbIIIa inhibitor–facilitated PCI will result in better
outcomes compared with primary PCI with Gp IIbIIIa
inhibitor only will be finally be determined by ongoing
randomized studies like the Facilitated Intervention
with Enhanced reperfusion Speed to Stop Events trial.
Until the results of these studies are available, our
analysis suggests that reduced-dose thrombolytic and
Gp IIb/IIIa inhibitor combination–facilitated PCI does
not offer an advantage over primary PCI done with Gp
IIbIIIa inhibitors only.
Contrary to the previous quantitative review of
randomized trials11 on the comparison of primary and
Sinno et al 585
facilitated PCIs for STEMI, where the authors grouped all
modalities of facilitation (Gp IIbIIIa alone, thrombolytic
therapy alone, and simultaneous Gp IIbIIIa inhibitor
with thrombolytic therapy) in one arm and primary PCI
in the other; our meta-analysis was dedicated to compare
combination therapy (Gp IIbIIIa inhibitors and throm-
bolytics) to Gp IIbIIIa inhibitors alone before PCI.
Besides, in the previous quantitative review, a discrep-
ancy in the definition of primary PCI is to be noted.
Some patients received no treatment before angiogra-
phy, bclassical primary PCI,Q and others received
inhibitors of Gp IIbIIIa. Thus, in the final analysis, some
patients who received Gp IIbIIIa inhibitors in the
primary intervention group were compared with the
subset of patients who received the same treatment
modality in the facilitated intervention group.
In conclusion, similar to the results of thrombolytic-
facilitated PCI studies, facilitation of PCI with combina-
tion of reduced-dose thrombolytics and Gp IIbIIIa
inhibitors does not result in improved clinical outcome
in spite of better TIMI-3 flow in the infarct artery on
presentation. This approach, therefore, cannot be
recommended currently except in clinical trial settings.
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