New SIRIUS: Evolving new standards in coronary artery disease.

Introduction Professor Eduardo Sousa, Sao Paulo, Brazil, gave everyone a glimpse of the potential of drug-eluting stents when he presented the early findings from the First-in-Man (FIM) ¹ feasibility study at the American College of Clinical Cardiology, in March 2000. Subsequently, this cohort of 30 patients was expanded to include an additional 15 patients from Professor Patrick Serruys’ catheterization laboratory at the Thoraxcenter, Rotterdam, Netherlands. This, the longest running clinical trial of any drug-eluting stent (with results out to 3 years) is justifiably recognized as the foundation from which all other drug-eluting stent programs have evolved. The early optimism of FIM was confirmed when Dr Marie Claude Morice (Interventional Cardiologist and Director Cardiovascular Institute Massy, France and Principal Investigator) signaled the beginning of the era of drug-eluting stents when she presented the 6-month follow-up results from RAVEL ² (at the European Society of Cardiology Congress (Stockholm, 2001). In contrast, the development of several promising therapies (actinomycin D, Batimastat, QP2 and non-polymer formulations of paclitaxel) has been discontinued in view of poor results obtained in the early phases of clinical trials. All of which clarifies the important role controlled clinical trials play in assessing a new technology in terms of safety and efficacy. As clinical trial programs continue to develop, the lessons learned from extended clinical experiences will play a vital role in helping interventional cardiologists maximize long-term clinical outcome. Among the various drug-eluting stents currently investigated for the treatment of CAD, SES was the first to be approved for use in Europe (April 2002) and the USA (April 2003). Indeed, the longest follow-up data available in the largest group of patients (out to 3 years ³) has been conducted with SES, the most recent results coming from the more complex patient population and challenging lesions treated in New SIRIUS. Further studies designed to evaluate the technology in expanding indications such as ARTS II, comparing multi-vessel SES revascularization vs. CABG, TROPICAL for In-stent Restenosis, FREEDOM and DECODE for diabetes, and bifurcation are in varying stages of implementation and will be added to the evidence base generated by the 40 SES clinical trials funded by Cordis Corporation. Results: Sirolimus-eluting coronary stent The findings from the First-in-Man experience as well as four major international multi-center, controlled clinical trials - RAVEL, SIRIUS, C-SIRIUS and E-SIRIUS (combined 8-month angiographic and 9-month clinical results of two independent trials with an identical protocol, C-SIRIUS and E-SIRIUS, is known as New SIRIUS) provide the world’s largest database on the use of the SES in a wider range of patients and lesions. Since commercialization, additional clinical experience has been gained from the treatment of more than 160,000 patients with the SES. RAVEL: 24 - month clinical follow-up Involving 238 patients with de novo coronary artery lesions and conducted in 19 centers across Europe and Latin America, RAVEL was the first multi-center, randomized, controlled, double-blind study with the SES. The remarkable 0% angiographic binary restenosis and Target Lesion Revascularization (TLR) rates reported in the initial 6-month follow-up results for RAVEL surprised the interventional cardiology community. The 2-year follow-up results on the RAVEL patients demonstrated an excellent 2.5% TLR rate ⁴ further confirming the efficacy of the SES. The lessons learned from the RAVEL trial are: SES is effective - it really works SES demonstrates efficacy in diabetic patients and small vessels SIRIUS: 12-month clinical follow up Following presentation at TCT 2002 of the 9-month data from the SIRIUS trial, the pivotal US trial, the 12-month clinical follow-up was presented at ACC 2003 ⁵. This multi-center, randomized, controlled, double-blind study involving 1058 patients demonstrated exceptional efficacy and safety across all angiographic, IVUS and clinical endpoints at 8-9 months. The 12-month follow-up confirmed the durability of the results in this challenging patient population, with the remarkable 75% reduction in TLR seen at 9 months being sustained out to 12 months. Only 4.9% of patients treated with the SES compared to the 20% of the patients in the bare-metal stent control arm required TLR out to one year post implantation. This translates into 150 out of every 1,000 patients may avoid repeat intervention. Reductions were consistent across the different patient populations (diabetics, non-diabetics, female, male, prior PCI, hypertensives etc.) and vessel size. Significant reductions, 62%, in Major Adverse Cardiac Events (MACE) reported at 9 months were also sustained out to 1 year. At one year, 91.7% of patients treated with SES were MACE-free, compared to 77.7% of patients in the control, bare-metal, stent arm. Of note, there was no increase in stent thrombosis between 9 and 12 months. When compared to RAVEL, several key differences between the two trials can be observed. First, there is the difference in restenosis rates (an important point to remember when assessing the New SIRIUS data. At first glance, 8.9% (SIRIUS) compared to 0% (RAVEL) was somewhat surprising. However, closer examination of the data reveals some important differences between the two trials. In summary they are: More challenging patients treated in the SIRIUS trial, 28.6% diabetics treated in SIRIUS compared to the 16% in RAVEL); Different time of angiographic follow-up, SIRIUS was at 8 months as compared to 6 months for RAVEL; When Drs. Martin Leon and Jeffrey Moses (co-principal investigators) presented the SIRIUS data at TCT 2002 ⁶, they introduced the concept of peri-stent restenosis. The results in the 533 SES patients were: proximal margin 5.8%; in-stent 3.2%; and distal margin 2.0%; all of which serve to highlight the importance of avoiding peri-stent trauma and the provision of good lesion coverage. E-SIRIUS 8-month QCA and 9-month clinical results E-SIRIUS ⁷ , the European, multi-center, randomized, controlled, double blind study with the SES in de novo coronary lesions, provides insights into the treatment of an even more challenging patient population (n=352) than SIRIUS. Patients had a higher clinical risk profile, with significantly more prior MI (42.1% vs. 30.5%, pC-SIRIUS: 8-month QCA and 9-month clinical results Results for C-SIRIUS ⁸, the Canadian multi-center, randomized, controlled, double blind study of the SES in de novo coronary lesions, were also presented as a Late Breaking Clinical Trial at ACC 2003. As with E-SIRIUS, this study involved more challenging patients (n=100) and more complex lesions than SIRIUS. Particularly challenging outcome predictors included 24.0% diabetics, post-MLD of 2.53mm, and a stented length of 26.1mm. The 8-month angiographic results were once again remarkable. A highly significant difference in 8-month in-stent MLD (primary endpoint) resulted in an exceptional reduction in in-stent late loss of 91% (0.09mm for the SES arm). There was also a significant reduction in late loss at the proximal and distal margins. Particularly noteworthy was the 100% reduction in in-stent restenosis rate (0% vs. 41.9% for control), with in-lesion results revealing only one patient (2.3%) with binary restenosis in the SES group, compared to 23 (53.5%) in the control group. At 9 months, clinical assessment demonstrated a very low clinically driven TLR rate (4.0%), representing a significant 78% reduction versus control (18%, p=0.027). This equates to 140 patients out of every 1000 may avoid the need for repeat intervention when using the SES. Similarly, MACE rates were also very low in the SES arm (4.0%), being significantly less than control (18%, p=0.029). The very low thrombosis rate (2%, n=1) was the same for both arms. NEW SIRIUS: Evolving new standards in coronary artery disease. When assessing any new technology the wealth of available clinical evidence will naturally increase over time. The SES program is no exception. The most important observation comes from the New SIRIUS (9) data. The investigators treated even more complex patients than SIRIUS, with the vessel size in New SIRIUS being on average significantly smaller (2.57 vs. 2.80mm), multiple stents were more often implanted (46.5 vs. 35.1% of patients) and the prevalence of previous MI and current smokers were higher (42.8 vs. 30.5% and 34.1 vs. 20.8% respectively) (Table 1), and still achieved consistent TLR (4.0%) and in-stent late loss (0.18mm) results, and superior in-lesion binary restenosis rate (See Table 2). Upon careful analysis of the data from SIRIUS and New SIRIUS, it is clear that the difference in in-lesion restenosis rate is primarily due to the difference in restenosis at the proximal edge (Table 2). These findings can most likely be attributed to the different technique employed in New SIRIUS, primarily the use of undersized balloons to avoid dissections; complete coverage of the lesion/the vessel segment injured by pre-dilatation; and strictly limiting post-dilatation to within the stent margins with a properly (1:1) sized balloon. In addition, direct stenting accounted for 27% of all procedures. Overall, New SIRIUS adds further support to the belief that the impressive results of both RAVEL and SIRIUS may now be extended to more complex patients with longer lesions and smaller vessel size. In fact, New SIRIUS showed greater reductions in late loss, restenosis, TLR and MACE than SIRIUS, despite the more challenging patient population. New SIRIUS has clearly established the new standard in randomized clinical trials against which other DES could be measured. At a time when interventional cardiologists use angiographic binary restenosis, as well as late loss and TLR, as key comparators between individual DES trials, every percentage point of restenosis is likely to count. Maximizing clinical outcomes with SES The fact that superior results were achieved in more challenging patient population treated in New SIRIUS supports the concept that refinement in deployment techniques may further improve clinical outcomes. The key lessons learned from New SIRIUS are: Minimize pre-stenting peri-lesion trauma: use short pre-dilatation balloons. Cover the lesion from normal vessel segment to normal vessel segment, including the segment injured by pre-dilatation. This will reduce exposed areas that may be prone to restenosis and/or disease progression. Use of a marker wire may optimise stent length selection. Remember that foreshortening of the SES varies from 0.3 -1.0 mm depending on stent length and diameter. If after measuring a lesion, the stent length is still in question, it may be preferable to choose a longer stent. Appropriate stent deployment: use a matching nominal balloon size to artery ratio of 1.1:1.0. When necessary, use short post-dilatation balloons, positioned within the stented area to prevent injury outside of the stent edges. When post-dilating, do not exceed the expansion limits of the SES: 3.75 mm for 6-cell (2.5 - 3.0 mm) and 4.75 mm for 7-cell (3.5 - 4.00 mm) SES. Overlap multiple stents, from distal to proximal placing the distal balloon marker of a second stent well inside the proximal edge of the first deployed stent, providing a 3-4 mm overlap segment avoiding gaps. Maintain current intravenous GP IIb/IIIa practice guidelines, considering the target patient population and lesion. Anti-platelet therapy (APT: Clopidogrel or Ticlopidine in addition to lifetime Aspirin) is mandatory. In RAVEL and New SIRIUS, 2 month APT was used vs. 3 months in SIRIUS. Summary Clinical experience in four randomized, controlled clinical trials with SES has demonstrated excellent efficacy, which has since been reproduced in large, post marketing surveillance registries such as e-CYPHER ¹⁰ (6700 patients and growing) and RESEARCH (11) (1600 patients). New SIRIUS demonstrated that even in a patient population at high risk of restenosis, appropriate CYPHER Sirolimus-eluting coronary stent selection and adapted technique can lead to excellent outcomes for our patients, with a late loss of 0.18mm, an in-lesion angiographic restenosis rate of 5.1% and an associated TLR rate of 4.0%.

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10. Urban P. The first internet-based post-marketing surveillance registry to monitor any drug-eluting stent: e-CYPHER; EuroPCR, 2003, Paris, France.

11. Serruys PW. Rapamycin Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) Registry; CRF 2003, Washington, USA and EuroPCR 2003, Paris, France.