From The Cardiovascular Institute, Mountain View, Calif.
With
the demonstration that the timely administration of
thrombolytic therapy after coronary
arterial occlusion results in myocardial salvage and
improved survival, the treatment of patients with evolving AMI has
forever been changed. To overcome the inherent limitations of
thrombolytic therapy (TIMI 3 flow rates of
Despite these attributes, balloon-induced medial
disruption and platelet activation result in recurrent
ischemia in 10% to 15% of patients treated with primary PTCA
before hospital discharge, including reinfarction in 3% to 5% of
patients.4 Although improvements in operator
technique, exclusive use of ionic contrast, and attention to
anticoagulation status can minimize these
complications,5 the significant residual
stenosis remaining in many patients after balloon angioplasty,
in concert with intimal hyperplasia, unopposed vessel recoil, and late
remodeling, results in angiographic restenosis in 30% to 50%
of infarct vessels within 6 months.4 As a result,
With the demonstration that the implantation of
balloon-expandable slotted-tube stents can reduce clinical and
angiographic restenosis compared with PTCA in patients
undergoing elective intervention,6 7 it might be
natural to conclude that shifting from primary PTCA to a primary
(routine) stent strategy in patients with AMI would similarly improve
late outcomes. However, these early randomized trials of elective
stenting were careful to exclude patients with acute ischemic
syndromes (including AMI) and lesions containing thrombus, given the
prior demonstration that subacute thrombosis rates are increased
with the implantation of a metallic endoprosthesis into a
thrombotic environment.8 With the reduction in
subacute thrombosis rates realized with improved stent
technique9 and the application of more effective
antiplatelet regimens, including
ticlopidine,10 the thrombus-laden lesion no
longer represents a strict contraindication to stenting.
As a prelude to initiation of randomized trials, the feasibility,
safety, and efficacy of primary stenting in AMI have been examined in a
number of observational and registry studies, the largest of which is
the prospective PAMI Stent Pilot Trial. In this 9-center international
cooperative effort, stenting (primarily with the Johnson & Johnson
Palmaz-Schatz stent) was found to be feasible in 240 (77%) of 312
consecutive patients undergoing primary PTCA, with a 98% procedural
success rate.11 Among the stented patients,
93.7% were event-free (alive, without reinfarction or TVR) at 30 days,
and 83.3% were event-free at 6 months. When outcomes in the PAMI Stent
Pilot Trial were compared with the 1100-patient PAMI-2 trial (99% of
patients treated with PTCA only), the routine stent strategy was
associated with improved clinical outcomes.12
Similarly favorable results were reported from the 18-center PAMI
Heparin Coated Stent Pilot Trial, in which the 30-day and 7-month
event-free rates in 101 patients with AMI were 97.0% and 81.2%,
respectively, after implantation of heparin-coated Palmaz-Schatz
stents.13
While the PAMI investigators were toiling with pilot studies,
Suryapranata and colleagues from the Hospital De Weezenlanden, Zwolle,
The Netherlands, were boldly per- forming the first
randomized trial of primary PTCA versus primary stenting (using the
Palmaz-Schatz stent), the results of which are published in this issue
of Circulation.14 Because this group
has previously demonstrated the ability to achieve superb outcomes with
primary PTCA alone,15 any findings favoring a
primary stent strategy by these investigators would be particularly
meaningful. At first glance, it is therefore quite remarkable that
among the 227 randomized patients, the 6-month cardiac event–free
rates were 95% after primary stenting versus 80% after primary PTCA
(P<0.002). This difference in the composite primary end
point was driven by reduced rates of reinfarction (1% versus 7%;
P<0.04) and TVR (4% versus 17%; P<0.002) in
the stent cohort, with no difference in mortality. Does this study
represent the proof of the promise of primary stenting in
AMI?
Before we banish primary balloon angioplasty to the basement of the
Museum of Natural History (along with other well-known interventional
dinosaurs), the present report must be carefully analyzed
in terms of its limitations and questions left unanswered. The authors
would be the first to acknowledge the small sample size of the study
(resulting in wide CIs) and the fact that it was performed at a single
institution by operators highly experienced with acute infarct
intervention. As such, the favorable results of the present study
must be reproduced in larger, multicenter trials. In addition, the
appropriately cautious entry criteria used resulted in a relatively
low-risk population being enrolled. In this regard, the authors are to
be commended for carefully registering and tracking outcomes of the
patients excluded during the course of the study. Of note, only 50% of
the patients with AMI undergoing primary PTCA by Suryapranata et
al14 were considered to be clinically and
anatomically eligible for stenting (in contrast to 77% of screened
patients in the PAMI Stent Pilot Trial). As demonstrated in Tables 1
and 2 of their article, randomized patients compared with excluded
patients were younger, more frequently male, more likely to have
single-vessel disease, and less likely to be
hemodynamically unstable. Reference-vessel size, a
major determinant of late outcome after percutaneous
intervention,16 was also significantly larger in
the randomized cohort. Indeed, 124 patients (27%) were excluded for
small vessel size or diffuse disease, in contrast to 11% of screened
patients in the PAMI Stent Pilot.11 The results
of the present study cannot therefore be necessarily extended to
the sizable group of patients with excluded characteristics.
Perhaps more importantly, given sample-size considerations, the
possible play of chance cannot be ignored. In this regard, the 5%
incidence of adverse cardiac events at 6 months in the stent arm of the
present study (including 4% bypass surgery and 0% repeat PTCA) is
among the lowest event rates (if not the lowest) ever
reported after stenting in any population, and markedly less than the
17% to 19% rate of 6- to 7-month adverse outcomes in the 341 stented
patients from the two PAMI pilot trials, which also used the
Palmaz-Schatz stent. Moreover, despite the low-risk nature of the
randomized population and the fact that 13% of patients assigned to
primary PTCA received stents for suboptimal results, in-hospital
reinfarction in the PTCA group still occurred in 3.5% of patients. In
contrast, no patient in the first Zwolle randomized
trial15 developed reinfarction after primary
PTCA, despite enrollment of a higher-risk cohort who were treated with
PTCA only without stent availability. Furthermore, intra-aortic balloon
counterpulsation was used in 9 more patients (8%) in the stent group
than in the PTCA group in the present study, which may also have
contributed to the lower incidence of recurrent
ischemia.17
In addition to requiring that these favorable results be confirmed in
other large-scale trials, many additional questions remain to be
answered before primary stenting is routinely adopted. What patient and
lesion characteristics respond best to acute infarct stenting? Given
the obligatory amount of neointimal hyperplasia that occurs
after stenting, will certain lesion subtypes, such as small vessels or
long lesions, have equivalent or even worsened outcomes after primary
stenting compared with PTCA? If an optimal PTCA result is obtained (eg,
stenosis <30% without major dissection), is there any benefit
to stent implantation? Will routine stenting improve or degrade the
outcomes achieved with primary PTCA by the low-volume or
less-experienced AMI interventionist? Compared with PTCA alone,
stenting is more technically demanding and carries its own set of
complications.11 Does stenting improve myocardial
salvage compared with PTCA? No data have been presented yet
from any study in this regard. Importantly, is primary stenting alone
superior to primary PTCA plus glycoprotein IIb/IIIa
receptor blockade? Of note, only 1% of the patients in the present
report received abciximab. Results from the recently completed RAPPORT
trial suggest that abciximab may also improve the early safety profile
of primary PTCA.18 Is glycoprotein
IIb/IIIa inhibition beneficial if a stent is implanted during AMI? What
is the optimal stent design for AMI use, and are procedural success and
clinical outcomes affected by stent configuration? What are the
trade-offs in this setting of flexibility and deliverability versus
scaffolding and radial strength versus wall coverage and side-branch
access? Does stenting reduce the rates of angiographic
restenosis compared with primary PTCA (follow-up angiographic
data were not reported in the present study), and in this regard,
are all stents created equal? Does an inherently
thromboresistant device, such as the heparin-coated stent,
offer significant clinical benefits compared with noncoated stents?
What is the optimal anticoagulation and antiplatelet regimen after
primary stenting? Is postprocedural heparin or enoxaparin required?
Finally, is primary stenting cost-effective compared with primary
PTCA?
Fortunately, at least 7 additional randomized trials comparing
primary stenting and PTCA have either been completed or are actively
enrolling patients,19 including 2 large
international studies designed with adequate statistical power and
geographic representation to ascertain whether primary stenting
indeed results in improved outcomes and is more cost-effective than
primary PTCA. In the PAMI Heparin Coated Stent Trial, 900 patients with
AMI at 65 sites were randomized to either primary PTCA or stenting with
the heparin-coated Palmaz-Schatz stent, with angiographic follow-up
planned in all patients. Given the properties of local stent-bonded
heparin to resist platelet and thrombus deposition, stented
patients in PAMI received no additional postprocedural
intravenous heparin, which should minimize vascular and
hemorrhagic complications and promote early discharge. The PAMI 30-day
results were to be available in March 1998, with the 6-month primary
end-point data to be reported in November 1998. In the CADILLAC trial,
2000 patients with AMI at 90 sites are being randomized in a 2x2
factorial design to primary PTCA alone, PTCA plus abciximab, primary
stenting alone, or stenting plus abciximab, with routine angiographic
follow-up in a subset of 700 patients. The stent used in CADILLAC is
the ACS Multi-Link, which is available to treat lesions
One fact is clear: as the 21st century approaches, we have
entered an age in which clinical practice is powerfully influenced by
the results of well-designed, prospective randomized trials. It is no
small irony that after the introduction of primary PTCA, 17 years were
required to randomize 2606 patients with AMI to PTCA versus
thrombolytic therapy, whereas in the course of <3
years,
Selected Abbreviations and Acronyms
Footnotes
Reprint requests to Dr Gregg W. Stone, The Cardiovascular Institute, 2660 Grant Rd, Mountain View, CA 94040.
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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© 1998 American Heart Association, Inc.
Editorials
Primary Stenting in Acute Myocardial Infarction
The Promise and the Proof
Key Words: Editorials • stents • myocardial infarction • angioplasty • trials
55% at
best, and rare but unavoidable life-threatening or incapacitating
hemorrhagic complications), mechanical reperfusion by balloon
angioplasty without antecedent thrombolysis (primary
PTCA) has been adopted at many centers. Ten prospective, randomized
trials comparing primary PTCA and lytic therapy in 2606 patients have
now been performed and examined in a recent meta-analysis by
Weaver et al,1 demonstrating that compared with
thrombolytic therapy, primary PTCA results in reduced
rates of mortality, reinfarction, and stroke. Other randomized
trials2 3 have shown that primary PTCA, by
reducing early and late recurrent ischemic events and
facilitating earlier discharge, is as or more cost-effective than
thrombolysis. 20% of patients after primary PTCA require TVR with repeat
angioplasty or bypass surgery during this time
period.4 Furthermore, not all operators have been
able to achieve optimal results of primary PTCA at their
institutions. 
65 mm in
length in vessels from 2.5 to 4.1 mm in diameter. It is thus
anticipated that >80% of screened patients will be randomized.
Patients receiving abciximab in CADILLAC (after either PTCA or stent)
will receive no postprocedural heparin and, if stable, will be
discharged on the second hospital day (day 3 in high-risk patients),
making CADILLAC the most ambitious early-discharge study yet attempted.
The CADILLAC trial began enrolling patients in late 1997, and results
are expected in 1999. In addition, formal substudies in both PAMI and
CADILLAC are examining the usefulness of intravascular ultrasound
imaging after mechanical reperfusion of AMI, and the role of
thrombectomy in occluded vein grafts is being investigated in
CADILLAC. 4000 patients will have been prospectively randomized to
primary PTCA versus stenting. The intense global interest expressed in
these ongoing trials attests to the conviction that primary stenting
holds promise to be the next major breakthrough in the treatment of
patients with AMI. Suryapranata and colleagues deserve credit for being
at the forefront of this effort.
AMI
=
acute myocardial infarction
CADILLAC
=
Controlled Abciximab and Device Investigation to Lower Late Angioplasty
Complications
PAMI
=
Primary Angioplasty in Myocardial Infarction
TIMI
=
Thrombolysis In Myocardial Infarction
TVR
=
target-vessel revascularization
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