Author + information
- ↵*Reprint requests and correspondence:
Dr. Peter B. Berger, Division of Cardiovascular Diseases-W16, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA.
Mesmerized by euphoria over the promise of drug-eluting stents, cardiologists have paid surprisingly scant attention to the results of the Intracoronary Stenting and Angiographic Results-Strut Thickness Effect on Restenosis Outcome (ISAR-STEREO-2) trial since its first report in March 2002. This study randomized patients requiring stent placement to the BX Velocity stent, which has “thick” (140 μm) struts, or the Multilink stent with “thin” (50 μm) struts. There was a large, clinically and statistically significant difference in restenosis (17.9% vs. 31.4%, p = 0.001) and target vessel revascularization (12.3% vs. 21.9%, p = 0.002) favoring the Multilink stent. The lack of interest has been surprising because the issue is of great clinical (and commercial) importance, at least until drug-eluting stents become available. What lies at the heart of this important study is whether only lesion characteristics (i.e., vessel size, lesion length, stenosis severity, calcification, thrombus); procedural characteristics (i.e., final luminal diameter, acute gain, treatment length); and clinical characteristics (i.e., diabetes, perhaps renal insufficiency) determine the restenosis rate, or whether stent type plays a role. While there are clearly important differences between stents (profile, deliverability, visibility, the ease with which equipment can be advanced beyond them, access into side branches), many believe that “all stents are created equal” in terms of preventing restenosis compared with balloon angioplasty.
What fueled this belief? When only the Palmaz-Schatz stent was available, companies seeking Food and Drug Association (FDA) approval for their stents performed randomized trials in the hope of proving equivalence, or noninferiority, with the Palmaz-Schatz stent. Indeed, most were found to be equivalent (1–5). However, the fact that one stent, the Gianturco-Roubin 2, had a far higher restenosis rate (47.3% vs. 20.6%, p < 0.001) provided an early clue that not all stents reduce restenosis equally (6). Despite this, companies now need no more data to win approval by the FDA for a new stent than favorable 30-day event rates, despite significant variations from their previously-approved, better-studied predecessors.
Prior to the ISAR-STEREO-2 trial, many studies compared stents for their ability to prevent restenosis. Observational studies are of limited value since differences in deliverability, degree of coverage, radio-opacity, and so forth lead physicians to select one stent versus another for certain lesion types, introducing bias that cannot be overcome by statistical adjustment. However, several randomized trials performed after the first five trials (1–5)shed light on this issue (6–10), suggesting that the choice of stent influences the restenosis rate to a clinically and statistically significant degree. Several were single-center studies; one should generally be cautious when applying data from single-center studies to practices throughout the world.
When thinking about the ISAR-STEREO-2 trial, it is important to consider the following five questions:
1. Was the study well designed and performed?
2. Did it contain bias that influence the results?
3. Are the results consistent with prior studies?
4. Do the results support the investigators’ conclusions?
5. How should the results affect physicians’ practices?
1 Design and performance
In this issue of the Journal, the Pache et al. (11)study was a nonblinded randomized trial with wide enrollment criteria and few exclusion criteria. There were minor imbalances in baseline characteristics between the two groups; a small excess of chronic occlusions in the thick-strut group (9% vs. 5%, p = 0.06) was balanced by a greater frequency of complex lesions in the thin-strut group (82% vs. 70%, p = 0.001). Although such characteristics do influence the frequency of restenosis, these small differences would not significantly impact the results of the trial.
The fact that more of the thin-strut stents (12%) failed to cross the lesion, and that physicians then switched to the thicker-strut stent and were able to cross the lesion, introduces bias in that more severe or complex lesions were ultimately treated with the thicker-strut stent. However, the data were analyzed on an intention-to-treat basis, minimizing any true differences in the frequency of restenosis between the two stents. An analysis of the stent received was also performed, confirming significantly less restenosis with the thinner-strut stent.
An important confounder can be found in the mean balloon inflation pressure within the stents. Compliance of the delivery balloon of the thinner-strut stent is far greater. Thus, although both stents were expanded with similar balloon pressures (12.1 atm thin-strut stent vs. 12.3 atm thick-strut stent, p = 0.18), a 3.0 mm thin-strut stent delivery balloon would be 3.5 mm at 12 atm, 0.4 mm larger than a 3.0 mm thick-strut stent delivery balloon inflated to the same pressure. If the stent-delivery balloons were also used for post-deployment inflations, the results could certainly have been affected. The investigators indicated that balloon inflations were performed with semicompliant balloons rather than stent delivery balloons “in the large majority of cases.” Furthermore, the maximal balloon diameters they reported were measured by quantitative coronary angiography (QCA). Whether small differences in balloon dimensions can be accurately detected by QCA is unclear. Intravascular ultrasound is vastly superior at detecting small differences in stent expansion that might result from balloons with differing compliances, but intravascular ultrasound was performed infrequently in the ISAR-STEREO-2 trial, and the results were not reported. In summary, whether and to what degree differences in characteristics of the delivery balloons impacted the results of the Pache et al. study (11)cannot be determined; this is the most important limitation of the study.
It must also be remembered that QCA is not entirely automated but requires operator input. Physicians performing QCA analyses can generally tell the difference between two stents on an angiogram, even if they are meant to be blinded. This introduces additional bias, although this too is unlikely to account for the relatively large difference in restenosis rates seen in the trial. Furthermore, the target vessel revascularization rates, described as being clinically driven “in all cases,” are consistent with the reported angiographic restenosis rates and lend validity to the differences reported by the QCA core laboratory.
3 Prior literature
The p value of 0.05 for the difference in restenosis means that there is a 1 in 20 chance that the lower restenosis rate of thin-strut stents was the play of chance. Examination of prior studies of these stents may provide a clue as to whether indeed chance is more or less likely than 1 in 20 to explain the observed results. The ISAR-STEREO-2 trial was neither the first study nor the first randomized study in which one of these two stents was included. Table 1lists all of the studies that included one of these stents and QCA analyses (1,10,12–18)and shows that the late loss associated with the BX Velocity stent in the ISAR-STEREO-2 trial is larger than the late loss seen in any prior studies of that stent. However, there were important differences among these studies in clinical, angiographic, and procedural characteristics that influenced late loss and restenosis, limiting our ability to draw definite conclusions by comparing studies. In addition, the large late loss associated with the BX Velocity stent was “anchored” by a correspondingly high frequency of ischemia-driven repeat revascularization, and some prior studies of the thicker-strut BX Velocity stent also raised concern about the degree of late loss, angiographic restenosis, and/or target vessel revascularization, suggesting the results of the ISAR-STEREO-2 trial are unlikely to be entirely due to chance.
4 Investigators’ conclusions
The investigators reported that the difference in restenosis rates was due to differences in strut thickness. This may be true, but should be considered hypothetical rather than proven. There are many differences between the stents studied in the ISAR-STEREO-2 trial; only one of them is strut thickness. The two stents studied in the ISAR-STEREO-1 trial, the Multilink and Duet stents, were more similar in design (except for strut thickness) than those studied in the ISAR-STEREO-2 trial, and the difference in restenosis rates in the ISAR-STEREO-1 trial likely resulted from strut thickness. However, metal content and purity, surface area, design, delivery balloon, degree to which the delivery balloons extend proximally and distally, and so forth may all differ between the stents studied in the ISAR-STEREO-2 trial, and restenosis rates may have been influenced by these factors as well.
5 How should the results affect physicians’ practices?
Several important points need to be emphasized when considering what impact the ISAR-STEREO-2 trial should have on the practice of interventional cardiologists. First, the thin-strut Multilink stent evaluated in the ISAR-STEREO-2 trial is no longer available. Second, physicians might consider the trade-off of greater ability to place a stent versus a lower restenosis rate differently. Indeed, one of the reasons that the Multilink was withdrawn from the market was that it was not easy to deliver (as was apparent in the ISAR-STEREO-2 trial), and being so thin and difficult to see, stent dislodgement occurred more frequently than with the BX Velocity and other currently available stents. Third, it should not be assumed that more recent generations of stents, even those with thinner struts than the BX Velocity, will have a lower restenosis rate than the BX Velocity and the same low restenosis rate as the Multilink stent in the ISAR-STEREO-2 trial. That hypothesis remains to be proven. Unfortunately, some stent sales representatives have been using data from the ISAR-STEREO-2 trial to support sales of their stents in place of the BX Velocity, although they have never been directly compared with it. These considerations, among others, undoubtedly contribute to the observation that the ISAR-STEREO-2 trial has apparently had little impact on sales of BX Velocity stents in the U.S.
6 Implications for the future
The extent to which these issues will remain relevant is unclear, since within months, drug-eluting stents will be available in the U.S. In fact, the first such stent likely to be approved by the FDA will elute sirolimus from the BX Velocity, which had the high restenosis rate in the ISAR-STEREO-2 trial. Is that relevant? Apparently it is not.
The frequency of in-stent restenosis with the sirolimus-eluting stent in the first-in-man experience (n = 45) and Randomized Study with the Sirolimus-Coated Bx Velocity Balloon-Expandable Stent in the Treatment of Patients with de Novo Native Coronary Artery Lesions (RAVEL) trial (n = 238) was 0 (17,19). In the much larger Multicenter, Randomized, Double-Blind Study of the Sirolimus-Coated Bx Velocity Balloon-Expandable Stent in the Treatment of Patients with De Novo Native Coronary Artery Lesions (SIRIUS) trial (n = 1,058), only 2% developed restenosis within the sirolimus-eluting stent, although another 7% developed restenosis at the edge of the stent, in most cases proximally. Some have wondered whether the peri-stent restenosis might be due to the delivery balloon extending 1 mm beyond the stent; this is unlikely, however, as restenosis occurred more frequently proximally than distally (even though vessels are usually smaller distally than proximally) and did not occur in the RAVEL trial. “Geographic mismatch”—pre- or post-deployment balloon inflations more proximal to where the stent was deployed—may be a factor. Regardless, it appears that the thick struts of the BX Velocity stent are not important when used as a platform for sirolimus.
The ISAR-STEREO-2 trial is at least the sixth appropriately sized randomized trial comparing stents indicating that not all stents are equal in their ability to reduce restenosis. More such trials should have been performed when interventional cardiologists had scant data to differentiate between bare stents. Happily, however, what are now needed are comparisons between drug-eluting stents, as the future of bare stents, the greatest advance in interventional cardiology since the development of balloon angioplasty, is not as bright as it once was.
↵* Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
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