(Circulation. 1999;100:896-898.)
© 1999 American Heart Association, Inc.
Editorials |
Stent-Versus-Stent Equivalency Trials
Are Some Stents More Equal Than Others?
From Harvard-MIT Division of Health Sciences and Technology (E.R.E.), Cambridge Mass, and Brigham and Women's Hospital, Harvard Medical School (C.R.), Boston, Mass.
Correspondence to Dr Elazer R. Edelman, MIT, 16-343, Cambridge, MA 02139. E-mail eedelman{at}mit.edu
Key Words: Editorials • stents • arteries • restenosis
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Introduction |
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 Top Introduction Bench-Top DataAnimal ExperimentsStent-Versus-Stent TrialsConclusionsReferences |
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New endovascular stent designs are displacing tried-and-true devices for use in an ever-broader array of lesions. Yet disagreement remains as to which device is most advantageous and whether design determines outcome. Preclinical research says that this should be the case, but clinical trials have failed to validate design dependence. Is this yet another demonstration of the dichotomy between preclinical and clinical experience, or can divergent data be reconciled?
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Bench-Top Data |
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TopIntroductionBench-Top DataAnimal ExperimentsStent-Versus-Stent TrialsConclusionsReferences |
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More than 50 different stent configurations are available, with 12 having received regulatory approval in the United States and a larger number in Europe. The very processes of industrial development and federal regulatory evaluation support the importance of design. Stents are made from a spectrum of materials with a range of manufacturing techniques, providing variable surfaces, dimensions, surface coverage, and strut configurations. Classifications have been proposed, but the number of parameters involved may doom the number of subsets to approach the number of designs. Moreover, each device seems to have a unique optimal mode of placement. It is not surprising, then, that differences have been reported in flexibility, tracking ability, expansion, radiovisibility, side-branch access, and resistance to compression and recoil for different devices. Regulatory approval includes safety standards for toxicity, biocompatibility, structural and material analysis, and fatigue testing, and it has been suggested that hoop strength, surface cracking, uniformity of expansion, and other features become standardized as well.
The evolution of stent design, which has produced increasingly safer and easier-to-use devices, indicates that there is not a single safety threshold but rather a continuous spectrum of performance. Every device that has been introduced into the clinic has undergone revision. In every case, designs that met regulatory guidelines were changed to make devices easier and perhaps safer to use. From what we know of the vascular response to injury, we anticipate that differences in these parameters will impart variable injury and shape to the vessel and therefore elicit different responses.
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Animal Experiments |
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TopIntroductionBench-Top DataAnimal ExperimentsStent-Versus-Stent TrialsConclusionsReferences |
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The central element of stent-vessel biology is the degree to which each strut incises the vessel wall with expansion. Deeper penetration generates greater late tissue growth.1 Correlation between injury and response is retained across species from rabbits, pigs, and dogs to nonhuman primates and is so sensitive that differences in injury for adjacent struts can explain differences in overlying intima. Stents designed to produce lesser injury produce correspondingly less tissue growth. We compared 2 prototype stents differing only in geometry2 and found one superior for every parameter evaluated, including injury score, thrombosis, endothelial denudation, inflammation, and intimal thickening. When 3 commercial stents were evaluated in an experimental model, they also exhibited variable effects on injury and repair.3
Whether diseased human arteries are subject to the same deep stent-induced injury as animals is debatable. However, the impact of design may extend far beyond the induction of injury. Variable tissue growth along stent length can be accounted for by variation in lumenal geometry imposed by repeating stent subunits.4 5 Vessel-device-hemodynamic interactions produce variable neointima, perhaps in an attempt to restore laminar flow even in the absence of deep injury. Animal models have conclusively shown that material, surface coating, and texture can affect biological responses.6 7 8 9 10 The question then is whether the compelling rationale and extensive data from preclinical studies indicating design-dependent responses can be confirmed or refuted in the clinical arena.
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Stent-Versus-Stent Trials |
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TopIntroductionBench-Top DataAnimal ExperimentsStent-Versus-Stent TrialsConclusionsReferences |
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Four different direct comparisons of first-generation Palmaz-Schatz slotted-tube stents and second-generation stents have been made.11 12 13 14 15 In 3,11 13 14 15 there were no significant differences in restenosis at follow-up, including minimal luminal diameter (MLD), percent diameter stenosis, late loss, or binary restenosis rate. In the fourth study,12 restenosis was far greater for the Gianturco-Roubin II (GR-II) stent (Cook) than the Palmaz-Schatz stent (Cordis-Johnson & Johnson). Interestingly, the data for all stents bunch across trials: with the exception of the GR-II stent, variability between the test stent groups was no greater than the variability between the Palmaz-Schatz stent groups in the different trials.
Three distinct possibilities exist to explain the absence of clinical evidence that different designs behave differently: (1) no differences in clinical outcomes exist between devices; (2) differences exist but are so slight as to be clinically meaningless; and (3) differences exist that may be clinically meaningful, but trials performed to date were not designed to detect them.
Changes in Stent Design Make No Difference
With the exception of GR-II data, trials performed to date
comparing stents do not demonstrate a statistical difference between
designs. One might reason that "a stent is a stent is a stent,"
shoring up diseased or dissected arteries; how it does so is immaterial
and irrelevant, only that it does so is important. Why might this be
the case? Either preclinical data are mechanistically different from
and not predictive of human vascular diseases, or engineering
differences between stents are not sufficient to make a clinical
difference. As in the decades-old discussion surrounding attempts to
harness restenosis, it is difficult if not impossible to
extrapolate directly from animal data to human responsiveness. Animal
models provide mechanistic insight. The notion that controlled vascular
injury in a laboratory animal can resemble human disease may be
appealing but is simplistic. It is not possible in an animal either to
reproduce the multifactorial processes that enable complex human
lesions to evolve over decades or to mimic precisely the acute,
high-intensity injuries of vascular interventions.
Differences in Stents Are Slight and Without Clinical
Significance
Another interpretation is that engineering differences between
stents have the potential to elicit different biological effects in
humans, but these differences are too small to be detected in clinical
trials. Subtle changes in stent configuration might make a device more
flexible and less injurious but insignificantly so relative to the full
extent of the injury imparted during vessel dilation and stent
implantation. In this argument, design is not dismissed as an important
feature of a stent but becomes moot within the greater context of the
overall procedural vascular injury. Effects of vascular
anatomy, lesion morphology and location, deployment strategy,
and patient comorbidity may dwarf any impact of stent design.
Clinical Trials Have Not Been Designed to Illustrate the Biological
Difference Between Stents
Equivalency Trials
Stent-versus-stent trials are equivalency trials, designed to show
that a test device performs "as well as" a standard, currently
acceptable device. This is a valid regulatory threshold but not the
means to evaluate the full potential of a device. Equivalency trials
must by definition commence with a patient population for whom the
standard device is safe. Trials with currently approved devices as the
standard necessitate that patient entry and lesion selection be
determined by limitations of the standard, not the test, device. As
depicted in the Figure
, the only way to
observe a difference in such a trial is when the test device performs
worse than the standard. For the test device to perform better, both
the test and the standard must be challenged. This was not the case for
the trials in which the average reference vessel size was
3.0±0.05 mm and American College of Cardiology
type B2 and C lesions accounted for only 
65% of lesions. These
lesions are those for which the Palmaz-Schatz stent is approved and
technically suited, but they represent only a minority of those
lesions now receiving stents. Whether similar results would be obtained
with broadened indications is impossible to know, because the standard
stent could not be used.
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Furthermore, the conception that none of the trials showed a difference
is incorrect. As used in the study, the GR-II stent did not perform as
well as the Palmaz-Schatz stent. MLD at follow-up was higher, and the
percent stenosis and late loss were lower for the Palmaz-Schatz
stent. Much has been said to explain this difference, including issues
of predilation, stent sizing, and length, but the data unequivocally
show that one stent design provoked a different biological response
from the other. The most telling parameter was the late
loss index. In virtually all trials for interventional devices to date,
this value has been 0.5. In the GR-II stent trial, this value was
0.76 for the GR-II stent, 33% greater than that observed with the
Palmaz-Schatz stent. Stent design made a difference, and these data set
the stage for other stents to demonstrate a difference, better or worse
than the standard.
Although the GR-II data alone should be convincing enough, the other
stent-comparison trials should not be dismissed out of hand. The
magnitude of differences between different stents was equivalent to the
magnitude of difference between angioplasty and stenting in BENESTENT
(BElgian NEtherlands STENT Study) and STRESS (STent REStenosis
Study).17 18 Binary restenosis rates, for example,
in ASCENT (ACS multi-link Stent Clinical Equivalence in de Novo lesions
Trial)14 and NIRVANA (medinol NIR primo stent Vascular
Advanced North America trial)13 were lower for the test
stents than for the standard stents (16.5% versus 20.8% and 15.7%
versus 25.4%, respectively). In addition, mortality at 1 and 6 months
was design dependent: in the ASCENT trial, 1.2% of patients died
within 1 month and 3.1% within 6 months of Palmaz-Schatz standard
stent placement, whereas patients receiving the Multi-Link (Guidant)
test stent had mortality rates of 0% and 1.5%,
respectively.15 Similarly, subacute thrombosis was
undetected in the group receiving NIR (Medinol) test stents compared
with a 1.2% thrombosis rate for Palmaz-Schatz standard devices. There
may be a significant difference between the thrombotic potential of 2
stents, but because one can do no better than "no thrombosis," this
difference is invisible. It is only when the thrombotic potential
becomes a significant problem based on lesion selection that one might
see a difference between 2 devices (Figure
).
Complexity, Equivalence, and Better
In truth, it may be most appropriate to think about
parameters of device success and safety as a continuum,
describing a correlation between events such thrombosis or
restenosis and a continuous measure of indication, vessel
dimension, or lesion complexity (Figure). A given device may be
represented by a characteristic response over a range of
indications. When there is a lateral offset to the curves, differences
in potential performance are anticipated. Curves might even
cross, rather than run parallel, indicating that devices might be
matched to lesions and indications. Open trials would consider the
entire range of the curves; equivalency trials are limited to a small
region of the curve.
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Conclusions |
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TopIntroductionBench-Top DataAnimal ExperimentsStent-Versus-Stent TrialsConclusionsReferences |
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The first-generation stents were a major innovation in interventional cardiology, and their place in medical history and biotechnology is unassailable. Demonstration that new stents are better than old will require that evaluations be performed in lesions for which current devices have marginal or limited application. Complex or acutely unstable lesions, small arteries, and diseased bypass grafts are the next great challenges of interventional cardiology. Perhaps in these settings, future stent trials will provide firm evidence that the manner in which blood vessels are manipulated dictates biological sequelae. Proof that stent design can alter clinical outcomes may then unleash the potential to change the way in which we consider design, approval, and use of new devices.
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Acknowledgments |
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We are indebted to Beverly Huss, Richard Kuntz, Jeffrey Popma, Jacob Richter, Frederick Welt, and Michael Williams for helpful comments and considered insight in preparing this document and discussing these issues.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionBench-Top DataAnimal ExperimentsStent-Versus-Stent TrialsConclusionsReferences |
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