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DES Controversy: Are We Asking the Wrong Questions?

Alan D. Troy, MD, FACC, FSCAI Thorndale, Pennsylvania
Alan D. Troy, MD, FACC, FSCAI Thorndale, Pennsylvania
Discussion In the aftermath of two presentations on the long-term safety and efficacy of drug-eluting stents (DESs) both presented in the fall of 2006 at the World Congress of Cardiology in Barcelona, Spain there have been passionate opinions expressed. With the recent publication of BASKET-LATE in JACC1 and a flurry of articles in The New England Journal of Medicine, additional fuel has been poured onto the fire of controversy.2-9 Many patients, physicians, and friends have approached me about this issue. Harkening back to the FDA approval of these devices, one can easily recall the unanswered questions about incomplete endothelialization and fears of thrombogenicity. Justification for these concerns emanated from the pathological specimens collected by Dr. Renu Virmani10 during that period. With the widespread clinical acceptance of two types of drug-eluting stents, the interventional cardiology community embraced deployment of DESs as the optimal form of percutaneous coronary revascularization when prudence dictated limiting the likelihood of repeat revascularization. Not unexpectedly, a competitive battle between two manufacturing giants erupted, directing vast resources toward proving the products of each superior to that of the other. In essence, each has shown comparably dramatic improvements in target vessel revascularization (TVR) over its respective bare-metal ancestors. But as is often the case in such battles many clinical issues were relegated to secondary status, the most important of which are only now drawing the attention of physicians, legislators, patients, families, and not the least the manufacturers of anti-platelet pharmacology. When comparing hard endpoints (death, myocardial infarction [MI]) with softer ones (ischemia, repeat procedure, cost-effectiveness), one should step back and recall that bare-metal stents also exacted a toll when compared to their ancestor, balloon angioplasty. After all, stent thrombosis with bare-metal stents was believed to present predominantly as ST-elevation MI with mortality approaching 20%.11,12 While such catastrophic events could occur within an expanded time frame of three to four weeks, balloon angioplasty rarely gave way to such scenarios after hospital discharge. Why is the current discussion so much more heated than the previous bare-metal stent vs. balloon angioplasty debate? It seems likely that acceptance of bare-metal stents for coronary revascularization followed two important events. First was Dr. Colombo’s demonstration of what an optimally-deployed stent should look like. Intravascular ultrasound (IVUS), unforgiving in showing us deficiencies that coronary angiography failed to show, opened up a whole new world of viewing the vessel and its deployed stent. Second was recognition of stent activation of the platelet IIb/IIIa receptor, leading to the STARS study’s proof of the adequacy of aspirin and thienopyridine therapy for the prevention of stent thrombosis.13 IVUS evolved beyond being merely a tool for coronary stenting. In fact, those operators who used IVUS and took the lessons of IVUS seriously began to perform coronary interventions with a new respect for vessel size, deployment pressures, post-deployment inflation pressures, and in many cases, to choose a specific type of pre-deployment treatment strategy for any given coronary artery. From the lessons of IVUS, the astute interventional cardiologist learned to value ˜ideal’ stent deployment, with its attendant optimal minimum lumen diameter (MLD), as the best intraprocedural endpoint for providing patients with the lowest risk of stent thrombosis and target-vessel revascularization (TVR).14 Regarding the issue of anti-platelet therapy, the interventional community has adhered stringently to the same type of regimen for years. Although the role of aspirin with clopidogrel is critical in coronary stenting, its inability to eliminate stent thrombosis entirely is a clear sign that pharmacology is not a substitute for optimal stent deployment.15 Through the late 1990s, stent technology blossomed, with newer stents becoming far more user-friendly than their ancestors. It was a tribute to this technology to see how these devices could be delivered to anatomical locations that would have been challenges for angioplasty balloons only 10 or 15 years earlier. Enter the DIRECT16 study, which paved the way for an accepted strategy of direct stenting without pre- or post-deployment dilation. Although not a randomized trial, this study likely influenced interventional cardiologists to display their prowess in the form of faster procedures, with angiographically-gratifying results. Furthermore, interventionalists could not help but to become enamored of the low TVR rates associated with direct stenting and, in that regard, life was becoming easier for the interventionalist perhaps too easy. What would the IVUS have looked like on a collection of directly-stented lesions using compliant deployment balloons that did not match the radial force of semi- and non-compliant balloons, such as those frequently used for post-deployment inflations in the bare-metal stenting days? We know that the SIRIUS and TAXUS families of trials did show struts lacking vessel-wall apposition in long-term IVUS follow-up. Intermediate-term results suggested that this might not be of clinical significance.9 But now the longer term and post-clopidogrel follow-up is coming back to haunt us, by telling us that such unapposed struts might be of clinical significance. Finally, it is conceivable that more aggressive post-deployment inflation might stimulate the vessel wall to provide neointimal coverage to a stent strut which would have otherwise remained unapposed or uncovered by neointima. Although there are no formally-established characteristics available to describe the ‘deployability’ of drug-eluting stents, those of us who deign to take on challenging, tortuous anatomy have learned of the curse of polymer coatings which make these stents too stiff to negotiate some vasculature. And when that is the case, a user-friendly bare-metal stent has been substituted and practically ‘flies’ around the bend in the vessel. Is it not possible even likely that the polymeric stiffening of the 316L stainless steel will also render drug-eluting stents relatively resistant to their deformation to full deployment? The point is this: there is a definite need to revisit the issue of how drug-eluting stents are deployed. In my personal experience, with help from IVUS and multi-view angiography, it seems that higher pressures might be required to optimize drug-eluting stent deployment. Strategies that alter vessel-wall compliance, such as rotational atherectomy, might also facilitate more satisfactory stent deployment. While such strategies might not affect TVR rates much in the era of drug-eluting stents, they will surely impact rates of stent thrombosis at least as much as they did for bare-metal stents. Substantial investigatory resources have been spent on development of stent technology. Comparable additional resources continue to be spent on comparing two very similar devices, and pharmaceutical manufacturers continue to pursue better anti-platelet therapies. Perhaps a registry of drug-eluting stent procedures recording deployment techniques pre-dilations, atherectomy, use of IVUS, post-dilation, extent of plaque coverage, extent of stent overlap, etc. would actually prove more useful in enhancing the long-term safety of drug-eluting stents. In the era of drug-eluting stents, the strategy has been to cover longer segments of disease than with bare-metal stents, and more metal could incur more thromboses and myocardial enzyme elevations. Collecting data such as these on patients who sustained stent thromboses could help identify some of the reasons for the higher incidence of stent thromboses with drug-eluting stents. Clearly, such approaches would be more helpful than asking which stent? Another issue worth evaluating is the cost-effectiveness of a bare-metal 3.5 mm stent implanted with IVUS guidance versus a drug-eluting stent. Based on the CRUISE sub-study of STARS, the TVR rates should be quite competitive. The cost of the bare-metal stent with IVUS would, however, be substantially (about $1,000) less. At our institution, the cardiac catheterization laboratory is directly across the hall from the cardiac operating suite. When opportunity permits, I remind myself to step across the hall to look at a live human heart in the flesh to actually look at the coronary arteries as they are being grafted. While in the cardiac operating room, my eyes roam between the patient’s coronaries and the surgeon’s face, his loops focused intently on the meticulous details of creating an optimal distal anastomosis. Are we, as interventional cardiologists, as intense about the quality of our stent deployments as the surgeons are about the quality of their distal anastomoses? I the interventional cardiologist whose work is visually guided by the mere shadows of these vessels must make use of every technical pearl that I can garner, be it technique, use of IVUS, additional angiograms, assessment of fractional flow reserve, etc. Perhaps we need to think more like the cardiac surgeons with their loops, and, using the kinds of tools we have at our disposal, do a better job of actually seeing what we are doing in the coronary circulation. In this fashion, we might change the focus from Which stent? or How much anti-platelet therapy? to How effectively are we deploying our stents? This last question deserves an answer. Reprint requests and correspondence: Dr. Alan D. Troy Brandywine Valley Cardiovascular Associates 3025 Zinn Rd. Thorndale, PA 19372 alantroy (at) mac. com
References
1. Pfisterer M, Brunner-La Rocca HP, Buser PT, et al, for the BASKET-LATE investigators. Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: An observational study of drug-eluting versus bare-metal stents. J Am Coll Cardiol 2006;48:2584-2591.

2. Lagerqvist B, James SK, Stenestrand U, et al. Long-Term Outcomes with Drug-Eluting Stents versus Bare-Metal Stents in Sweden. N Engl J Med 2007;356:1009-1019.

3. Mauri L, Hsieh WH, Massaro JM, et al. Stent Thrombosis in Randomized Clinical Trials of Drug-Eluting Stents. N Engl J Med 2007; 356:1020-1029.

4. Stone GW, Moses JW, Ellis SG, et al. Safety and Efficacy of Sirolimus- and Paclitaxel-Eluting Coronary Stents. N Engl J Med 2007;356:998-1008.

5. Spaulding C, Daemen J, Boersma E, et al. A Pooled Analysis of Data Comparing Sirolimus-Eluting Stents with Bare-Metal Stents. N Engl J Med 2007; 356:989-997.

6. Curfman GD, Morrissey S, Jarcho JA, et al. Drug-Eluting Coronary Stents -Promise and Uncertainty. N Engl J Med 2007;356:1059-1060.

7. Maisel WH. Unanswered Questions - Drug-Eluting Stents and the Risk of Late Thrombosis. N Engl J Med 2007;356:981-984.

8. Kastrati A, Mehilli J, Pache J, et al. Analysis of 14 Trials Comparing Sirolimus-Eluting Stents with Bare-Metal Stents. N Engl J Med 2007;356:1030-1039.

9. Weissman N. Intravascular ultrasound results from the TAXUS V study: The TAXUS stent reduces neointimal proliferation in long lesions and overlapping stents. TCT 2005 (poster 317, Drug-Eluting Stents I), Washington, D.C.

10. Joner M, Finn AV, Farb A, et al. Pathology of drug-eluting stents in humans: Delayed healing and late thrombotic risk. J Am Coll Cardiol 2006;48:193-202.

11. Cutlip D, Baim D, Ho K, et al. Stent thrombosis in the modern era: A pooled analysis of multicenter coronary stent trials. Circulation 2001;103:1967-1971.

12. Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005;293:2126-2130.

13. Leon MB, Baim DS, Popma JJ, et al. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. N Engl J Med 1998;339:1665-1671.

14. Fitzgerald PJ, Oshima A, Hayase M, et al. Final results of the can routine ultrasound influence stent expansion (CRUISE) study. Circulation 2000;102:523-530.

15. Chieffo A. Influence of prolonged dual anti-platelet use on late stent thrombosis in a large real-world registry: The Milan/ Siegburg experience. Presented at TCT 2006, Washington, D.C.

16. Moses JW, Leon MB, Popma JJ, et al. Direct stenting using the sirolimus-eluting Bx VELOCITY stent: Procedural, clinical and angiographic outcomes compared to a pre-dilation strategy. Presented at ACC 2004, New Orleans, LA.