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A Randomized, Multicenter Trial Comparing a New, Low-Pressure Stent Versus a Conventional Stent: Primary Results from the CONSER
March 2003
As compared with balloon angioplasty alone, coronary stent implantation has resulted in improved clinical outcomes and lower clinical restenosis rates.1–3 The latter is not due to less neointimal proliferation, but rather to a larger initial gain in lumen diameter, lack of recoil and prevention of negative arterial remodeling.4,5
Numerous studies have compared new stent designs to the initial stainless-steel Palmaz-Schatz™ stent and found them to be largely equivalent with respect to clinical outcome and restenosis.6–9 Nevertheless, one aspect not sufficiently studied previously is the contribution of arterial injury during high-pressure stent deployment restenosis. Directional atherectomy specimens have demonstrated that deeper arterial injury incites more restenosis,10 and in a comparison of balloon angioplasty with stent implantation for the treatment of narrowed saphenous vein grafts, there was more restenosis in grafts subjected to higher inflation pressure during stent deployment.11
Thus, we compared a new stent design — the low-pressure LP™ stent (Interventional Technologies, San Diego, California) with the Food and Drug Administration (FDA)-approved Guidant Duett™ and Tristar™ stents. This new device is etched at low temperatures in a tubular stainless-steel structure, resulting in continuous loops of radially directed trapezoid struts with excellent tensile strength. Because of the relatively low temperatures used to treat the metal, the stent reaches its maximal size at approximately 10 atmospheres (atm), unlike the 14–16 atm required for other stents.
Methods
Between November 29, 1999 and May 23, 2001, patients with symptomatic coronary artery disease undergoing percutaneous coronary intervention (PCI) were randomized (open label) after diagnostic coronary angiography to either the LP™ or the Guidant stent (Appendix 1). Important exclusion criteria were: acute myocardial infarction (AMI) within the preceding 48 hours, ineligibility for bypass surgery, target lesion in bypass graft, visible thrombus, excessive tortuosity or angulation, in-stent restenotic lesion, lesion length > 25 mm or vessel diameter > 4 mm or 250 seconds without. All patients received aspirin and thienopyridines for at least 1 month after the procedure.
Clinical and angiographic endpoints. The primary endpoint was the 6-month incidence of clinically indicated target vessel revascularization (TVR) or clinical restenosis. The need for TVR was established according to routine clinical criteria, i.e., recurrent symptoms and/or abnormal stress test.
Secondary endpoints were the ability to fully deploy the LP™ stent, 7-day and 30-day incidence of death, MI (CK-MB > 3 times the upper limit of normal or new pathological Q-waves), urgent TVR, coronary artery bypass surgery and their composite (MACE). An independent committee blinded to patient assignment adjudicated all clinical outcomes (Appendix 2).
Nested within the main trial was an FDA-mandated angiographic registry of the first 150 patients randomized to the LP™ stent in order to study the classical angiographic parameters of restenosis associated with its use. They underwent repeat angiography at 6 months (range, 20–28 weeks) after being interviewed by the investigator, who determined in advance whether revascularization would be clinically indicated. The films were reviewed at an independent angiographic core laboratory for lesion characteristics and standard quantitative measurements (Appendix 2).
Statistical analysis. Based on the FDA requirements and assuming a 6-month TVR rate of 15% for the Guidant stent, a total of 477 patients were needed in each group to demonstrate equivalency between the two stents (upper limit of the 95% confidence interval for absolute difference in TVR 70% diameter stenosis definition) or 40.9% (using the > 50% definition) and the loss index was 0.57. In a cohort randomized to the Palmaz-Schatz™ stent (n = 127) matched by age, lesion length, and incidence of diabetes mellitus and unstable angina from the Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT) trial12 analyzed at the same laboratory, the respective rates were 14.2%, 39.4% and 0.39 (p > 0.2 for all).
Discussion
This randomized clinical trial demonstrates in a large cohort of low-risk patients that, compared with the FDA- approved and widely used Guidant stent, the LP™ stent achieves similar rates of procedural success, clinical outcome and clinical restenosis (need for TVR). It did not validate the concept that lower pressure deployment limits arterial injury, and thus reduces need for TVR. The excess pre- and post-dilatation in the LP™ group may have reflected the investigators’ insecurity with respect to the stent deliverability and appropriate deployment, rather than being mandated by the angiographic or clinical setting. The potential benefit of lower-pressure deployment and decreased arterial injury may be offset by insufficient stent distention and lumen gain, in the absence of systematic intravascular ultrasound (IVUS) confirmation of optimal strut apposition. If the stent deployed at low pressure is not fully apposed to the vessel wall, the initial gain in lumen size is suboptimal and the potential for thrombus formation and subsequent restenosis increases. This scenario is very plausible, as visual estimation of vessel size frequently underestimates the true diameter.13 Indeed, in this trial, LP™ patients not undergoing post-dilatation had a higher rate of restenosis than those receiving the Guidant stent, which was deployed at higher pressure. Thus, systematic high-pressure deployment may overcome undersizing of stents and improve the initial gain in lumen diameter.
These data also focus our attention on the way equivalency between approved and new stents is established (Table 4). In general, the criteria for equivalency have been vague or not articulated at all and the focus of most comparisons has been to establish that the new stent is acceptable from the safety and regulatory point of view. Some of these studies have not even been fully published, raising important concerns regarding the adoption of new technology. In contrast, the CONSERVE trial clearly established equivalency guidelines based on the rate of events in other trials and on the consensus among practitioners with respect to clinically relevant outcomes. This is particularly germane at this time, as we face the introduction of drug-eluting stents, with a rate of restenosis well below 10%, high cost and unknown long-term effects. Forthcoming trials comparing stent designs should therefore enroll a minimum of 1,000 patients to ensure enough events, incorporate appropriate clinical and angiographic follow-up and establish a priority criteria for equivalency with meaningful confidence intervals for the expected difference in outcomes. As restenosis and revascularization become more infrequent, the number of patients enrolled may need to be appropriately increased.
The relationship between stent deployment pressure and subsequent restenosis is a complex interaction between initial lumen gain, strut apposition and exclusion of intraluminal plaque on one hand, and deep arterial injury on the other. Conflicting data regarding the use of high-pressure deployment highlight the many variables responsible for restenosis. Colombo et al.14 have shown that stents deployed at 15 ± 3 atm demonstrated optimal apposition by IVUS in 96% of patients, thus ushering the era of high-pressure deployment. In contrast, Savage et al.,11 while showing stents to be beneficial overall in the treatment of venous bypass grafts, found that the stents deployed at higher pressures (>= 16 atm) had higher restenosis rates than those deployed at lower pressures ( 1.3:1) and deployment pressure ( 15 atm) and showed that the most aggressive strategy is associated with a lower restenosis rate (12% versus 30% in the least aggressive group), again reflecting the importance of the higher initial gain in lumen size.
Study limitations. The majority of patients had low-risk clinical characteristics and lesion complexity, which diminish the applicability of our findings to more complex patients. The lack of systematic IVUS does not permit us to speculate on the relative role of stent mal-apposition during low-pressure deployment versus neointimal proliferation. The high rate of post-dilatation in the LP™ patients limits the ability to test the low-pressure deployment concept. The lower than predicted rate of TVR in the Guidant stent may have limited the power of our study.
Conclusion. Despite these limitations, we conclude that the LP™ stent appears to be associated with a low rate of clinically indicated TVR, which is not inferior to the Guidant stent. These results cannot be directly linked to lower-pressure deployment, which requires further study.
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