Ground-breaking Innovation Proves Superior - The Weight of Evidence Behind the Cypher Sirolimus-eluting Coronary Stent

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DOI
http://dx.doi.org/10.15420/ecr.2006.1.1u

The introduction of the Cypher┬« Sirolimus-eluting coronary stent in 2002 revolutionised the treatment of patients with coronary artery stenosis and initiated the drug-eluting stent (DES) era. Uncoated or bare metal stents (BMS), although a significant improvement on previously available therapies, are associated with significant restenosis due to neointimal hyperplasia following stent placement. The Cypher stent elutes the unique antiproliferative agent sirolimus, a potent and selective inhibitor of neointimal proliferation. Pivotal clinical trials showed that, compared with BMS, the Cypher stent significantly reduced neointimal hyperplasia (measured angiographically as late loss) and in-stent restenosis.1-4 Clinical outcomes were also significantly improved, with lower rates of major adverse cardiac event (MACE) and target lesion revascularisation (TLR).1-4 These clinical benefits have been sustained up to four years post-procedure.5-9 The following year (2003) saw the launch of Cypher Select™, the first next-generation DES, designed to provide enhanced deliverability, flexibility and conformability.

Head-to-head Superiority

The success of the Cypher stent decisively proved the DES concept, and competing DES soon appeared. The paclitaxel-eluting Taxus® stent received approval from the US Food and Drug Administration (FDA) in 2004. Unsurprisingly, the pivotal studies for Taxus showed improved outcomes versus BMS. However, these trials also demonstrated a consistently higher late loss compared with data gathered in similar Cypher studies.1,2,10-14

The results of Cypher-Taxus head-to-head studies have confirmed that the Cypher stent is significantly superior to Taxus with respect to inhibition of late loss.15-21 The superior results for in-stent late loss are strikingly consistent across a range of lesion complexities and patient types, including non-complex de novo lesions,15 long lesions,16 patients with acute myocardial infarction (AMI),17 small vessels,18 patients with diabetes19 and patients with in-stent restenosis.20

Meta-analysis of BMS and DES clinical trial data has shown that inhibition of late loss is associated with improved clinical outcomes in terms of risk of restenosis and TLR.22,23 Clinical outcomes in the Cypher-Taxus head-to-head trials show consistently lower rates of restenosis and TLR for Cypher.15-20

Other than Taxus, the zotarolimus-eluting Endeavor™ stent is the only DES to have published head-to-head trial data versus Cypher. In a large-scale trial enrolling 436 patients with non-complex de novo lesions, the Endeavor stent failed to meet its primary end-point (non-inferiority to Cypher for in-segment late loss) and demonstrated significantly inferior inhibition of in-stent late loss compared with Cypher (0.15mm versus 0.6mm, p<0.001).24

When these data are arranged in order of complexity, a consistent advantage can be seen for the Cypher stent in angiographic outcomes (binary restenosis rates) and also in clinical outcomes (rates of TLR).15-21,24,34

Superior Performance in the Broadest Range of Patients and Lesion Types

Populations in clinical trials initially tend to include low-risk patients with non-complex de novo lesions. However, 60% of patients undergoing percutaneous coronary intervention (PCI) are moderate-to-high risk and present with complex lesions (e.g. patients with diabetes, small vessels, multi-vessel disease, or in-stent restenosis). A full appreciation of the real-world clinical value of a DES therefore requires trials that focus on more challenging populations.35

Small Vessels and Long Lesions

Reference vessel diameter (RVD) and lesion length are independent predictors of TLR. Small vessels are particularly sensitive to the effects of late loss, and two key studies have established the utility of the Cypher stent in this patient subset.18,25,36 The Sirolimus-Eluting Versus Uncoated Stents for Prevention of Restenosis in Small Coronary Arteries (SES-SMART) trial enrolled 257 patients with de novo lesions in native coronary arteries less than 2.75mm in diameter, and randomised them to either Cypher stent or BMS. Quantitative coronary angiography (QCA) at eight months showed that the Cypher stent group had significantly lower in-stent late loss (0.16mm versus 0.9mm, p<0.001) and lower rates of in-stent restenosis (4.9% versus 49.1%, p<0.001). Cypher stent also showed superior clinical outcomes with lower rates of TLR (7% versus 21.1%, p=0.002) and major adverse coronary and cerebral events (MACCE) (9.3% versus 31.3%, p<0.001).25

A head-to-head trial versus Taxus (Intracoronary Stenting or Angioplasty for Restenosis Reduction in Small Arteries, ISAR-SMART 3) enrolled patients with vessel diameter less than 2.8mm and once again showed significant superiority for the Cypher stent, with lower in-stent late loss (0.25mm versus 0.56mm, p<0.001), and lower rates of in-stent restenosis (8% versus 14.9%, p=0.04) and TLR (6.6% versus 14.7%, p=0.008).18

Long lesions are difficult to treat by angioplasty, and comprise approximately 20% of cases treated by interventional cardiologists today. A large-scale randomised trial has compared the Cypher stent head-to-head with Taxus in patients with lesions greater than 25mm long. Cypher was associated with lower in-stent late loss (0.1mm versus 0.43mm, p<0.001), and significantly lower rates of binary restenosis (3% versus 10.3%, p=0.0007), TLR (3.5% versus 7.8%, p=0.014), and MACE (3% versus 7.8%, p=0.027).16

Diabetes

Although many trials of the Cypher stent have included patients with diabetes, two have enrolled exclusively diabetic populations.19,26 In the Diabetes and Sirolimus-eluting Stent (DIABETES) trial, 160 patients with non-insulin-dependent diabetes mellitus (N-IDDM) (67.5%) or IDDM (32.5%) were randomised to Cypher stent or BMS. Patients who received the Cypher stent had significantly superior angiographic outcomes (late loss 0.09mm versus 0.67mm, p<0.0001; restenosis 4.9% versus 31.0%, p<0.0001).26 The ISAR-DIABETES head-to-head study versus Taxus showed that Cypher out-performs Taxus in this high-risk population, with significantly lower in-stent late loss (0.19mm versus 0.45mm, p<0.001) and in-lesion restenosis (6.9% versus 16.5%, p=0.03), and a lower TLR rate (6.4% versus 12%).19

Acute Myocardial Infarction

Ruptured vulnerable plaque in acute myocardial infarction (AMI) is a complex lesion with a pathophysiology of inflammation, which may increase the risk of neointimal hyperplasia and restenosis.27 The results of two clinical trials (presented in 2006) have shown that the Cypher stent is superior to both BMS and Taxus in this high-risk patient subset.17,28

The Trial to Assess the Use of the Cypher Stent in Acute Myocardial Infarction Treated with Angioplasty (TYPHOON) enrolled 712 patients less than 12 hours after onset of AMI, and randomised them to either Cypher stent or BMS. Patients receiving Cypher stent had significantly lower in-stent late loss (0.13mm versus 0.83mm, p<0.0001), and lower rates of binary restenosis (16.4% versus 37.1%, p<0.0001), TLR (3.7% versus 12.6%, p<0.0001) and MACE (5.9% versus 14.6%, p<0.001).28

An indication of CypherÔÇÖs likely performance versus Taxus in AMI comes from PROSIT, an on-going study based in South Korea that shows significantly lower in-stent late loss at six months (0.16mm versus 0.43mm, p=0.007). Nine-month clinical data for this study show that the Cypher stent has superior MACE rates compared with Taxus (6.9% versus 14.8%, p=0.06).17

In-stent Restenosis, Chronic Total Occlusion and Bifurcating Vessels

The development of in-stent restenosis following placement of a BMS is a significant clinical problem. Both the Cypher and Cypher Select coronary stents are CE-marked for the treatment of in-stent restenosis. Recently published clinical trial data have confirmed the efficacy of the Cypher stent in these complex lesions. Patients in the Sirolimus-eluting Cypher Stent Versus Intravascular Brachytherapy in the Treatment of Patients with In-stent Restenotic Coronary Artery Lesions (SISR) trial were enrolled with in-stent restenosis at least four months after stent placement, and were randomised to receive either Cypher stent or brachytherapy. Patients with Cypher stent had significantly lower rates of TVF (12.4% versus 21.6%, p=0.023) and MACE (10% versus 19.2%, p=0.015) at nine months.29 Cypher is also significantly superior to Taxus in this indication, with superior angiographic and clinical outcomes.20

Chronic total occlusions (CTO) are among the most difficult lesions to treat in cardiology. Recanalisation can improve symptoms and left ventricular function, increase long-term survival, reduce the need for coronary artery bypass graft surgery (CABG) and reduce predisposition to arrhythmias.

The Prospective Randomized Trial of Sirolimus-eluting and Bare Metal Stents in Patients with Chronic Total Occlusions (PRISON II) trial randomised 200 patients with coronary artery CTO to either Cypher stent or BMS. Cypher was significantly superior to the BMS with respect to binary in-stent restenosis (7% versus 36%, p<0.001), in-stent late loss (0.05mm versus 1.09mm, p<0.0001), TLR (4% versus 19%, p=0.009) and MACE (4% versus 20%, p<0.001).30

CORPAL-BIF was a prospective randomised trial designed to evaluate the efficacy of Cypher versus Taxus in 205 patients with bifurcation lesions (significant stenosis in both main and side vessels). At follow-up (six months post-stent) the quantitative angiographic data showed that Cypher was associated with significantly lower late loss in the main vessel (0.31mm versus 0.60mm, p<0.05) and significantly lower levels of binary restenosis (9% versus 29%, p<0.05). Six-month clinical outcomes showed significant superiority for Cypher in TLR (4% versus 13%, p<0.05).31

Multivessel Disease

Multivessel disease is a highly complex presentation that is currently routinely treated by CABG. The Arterial Revascularization Therapies Study part II (ARTS II) trial analysed MACCE-free survival at one year in 606 patients with multivessel disease receiving the Cypher stent, and compared it with the outcomes of the ARTS I study, where similar patient cohorts received either BMS or CABG.

Patients in ARTS II had a one-year MACCE rate of 10.4%, compared with 11.6% in the ARTS I CABG group and 26.5% in the ARTS I PCI group. The composite end-point of death/CVA/MI in Cypher stent patents was significantly lower than in ARTS I CABG (p<0.001).32,33

The Weight of Evidence

The Cypher stent has been implanted in more than two million patients worldwide. The efficacy and safety of the Cypher stent has been demonstrated in more than 6,000 patients in controlled trials, and in more than 45,000 patients in registries. These figures mean that the Cypher stent is one of the most studied medical devices in history.

The accumulating weight of evidence has now firmly established Cypher as the leading DES, with proven clinical efficacy in the broadest range of lesions and patient types, including the most challenging and complex presentations. Ôûá

References
  1. Morice M C et al., A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization, N Engl J Med (2002);346: pp. 1,773-1,780.
    Crossref | PubMed
  2. Moses J W et al., Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery, N Engl J Med (2003);349: pp. 1,315-1,323.
    Crossref | PubMed
  3. Schofer J et al., Sirolimus-eluting stents for treatment of patients with long atherosclerotic lesions in small coronary arteries: double-blind, randomised controlled trial (E-SIRIUS), Lancet (2003);362: pp. 1,093-1,099.
    Crossref | PubMed
  4. Schampaert E et al., The Canadian study of the sirolimus-eluting stent in the treatment of patients with long de novo lesions in small native coronary arteries (C-SIRIUS), J Am Coll Cardiol (2004);43: pp. 1,110-1,115.
    Crossref | PubMed
  5. Fajadet J et al., Maintenance of long-term clinical benefit with sirolimus-eluting coronary stents: three-year results of the RAVEL trial, Circulation (2005);111: pp. 1,040-1,044.
    Crossref | PubMed
  6. Weisz G et al., Two-year outcomes after sirolimus-eluting stent implantation: results from the Sirolimus-Eluting Stent in de Novo Native Coronary Lesions (SIRIUS) trial, J Am Coll Cardiol (2006);47: pp. 1,350-1,355.
    Crossref | PubMed
  7. Sousa J E et al., A randomised, double-blind study with the sirolimus-eluting Bx Velocity balloon expandable stent in the treatment of patients with de novo native coronary artery lesions: RAVEL 4-Year Follow-up, presented at EuroPCR 2005.
  8. Sousa J E et al., Four-year angiographic and intravascular ultrasound follow-up of patients treated with sirolimus-eluting stents, Circulation (2005);111: pp. 2,326-2,329.
    Crossref | PubMed
  9. Leon M B et al., Long-Term Clinical Benefit of Cypher Sirolimus-eluting Coronary Stents: Three-Year Follow-Up of the Sirius Study, presented at ACC 2005.
  10. Schofer J, NEW SIRIUS, presented at ACC 2004.
  11. Moses J, DIRECT, presented at ACC 2004.
  12. Colombo A et al., Randomized study to assess the effectiveness of slow- and moderate-release polymer-based paclitaxeleluting stents for coronary artery lesions, Circulation (2003);108: pp. 788-794.
    Crossref | PubMed
  13. Stone G W et al., A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease, N Engl J Med (2004);350: pp. 221-231.
    Crossref | PubMed
  14. Dawkins K D et al., Clinical efficacy of polymer-based paclitaxel-eluting stents in the treatment of complex, long coronary artery lesions from a multicenter, randomized trial: support for the use of drug-eluting stents in contemporary clinical practice, Circulation (2005);112: pp. 3,306-3,313.
    Crossref | PubMed
  15. Morice M C et al., Sirolimus- vs paclitaxel-eluting stents in de novo coronary artery lesions: the REALITY trial: a randomized controlled trial, JAMA (2006);295: pp. 895-904.
    Crossref | PubMed
  16. Hong M K, Randomized Comparison of the Efficacy of Sirolimus-Eluting Stent Versus Paclitaxel-Eluting Stent in the Treatment of Long Native Coronary Lesions (LONG-DES II) Trial, presented at ACC 2006.
  17. Lee J H et al., Randomized trial of sirolimus- versus paclitaxel-eluting stents for the treatment of acute ST-Elevation myocardial infarction, presented at ACC 2006.
  18. Mehilli J et al., Randomized trial of paclitaxel- and sirolimus-eluting stents in small coronary vessels, Eur Heart J (2006);27: pp. 260-266.
    Crossref | PubMed
  19. Dibra A et al., Paclitaxel-eluting or sirolimus-eluting stents to prevent restenosis in diabetic patients, N Engl J Med (2005);353: pp. 663-670.
    Crossref | PubMed
  20. Kastrati A et al., Sirolimus-eluting stent or paclitaxel-eluting stent vs balloon angioplasty for prevention of recurrences in patients with coronary in-stent restenosis: a randomized controlled trial, JAMA (2005);293: pp. 165-171.
    Crossref | PubMed
  21. Windecker S et al., Sirolimus-eluting and paclitaxel-eluting stents for coronary revascularization, N Engl J Med (2005);353: pp. 653-662.
    Crossref | PubMed
  22. Mauri L et al., Robustness of late lumen loss in discriminating drug-eluting stents across variable observational and randomized trials, Circulation (2005);112: pp. 2,833-2,839.
    Crossref | PubMed
  23. Moreno R et al., Late Loss after Drug Eluting Stent Implantation. Does it Have Clinical Significance?, presented at AHA 2005.
  24. Kandzari D E, ENDEAVOR-III. A Prospective Randomized Comparison of Zotarolimus-Eluting and Sirolimus-Eluting Stents in Patients With Coronary Artery Disease, presented at TCT 2005.
  25. Ardissino D et al., Sirolimus-eluting vs uncoated stents for prevention of restenosis in small coronary arteries: a randomized trial, JAMA (2004);292: pp. 2,727-2,734.
    Crossref | PubMed
  26. Sabate M et al., Randomized comparison of sirolimus-eluting stent versus standard stent for percutaneous coronary revascularization in diabetic patients: the diabetes and sirolimus-eluting stent (DIABETES) trial, Circulation (2005);112: pp. 2,175-2,183.
    Crossref | PubMed
  27. Spratt J C et al., Plaque stabilisation by systemic and local drug administration, Heart (2004);90: pp. 1,392-1,394.
    Crossref | PubMed
  28. Spaulding C, Trial to Assess the Use of the Cypher Stent in Acute Myocardial Infarction Treated with Balloon Angioplasty (TYPHOON) Trial, presented at ACC 2006.
  29. Holmes D R Jr. et al., Sirolimus-eluting stents vs vascular brachytherapy for in-stent restenosis within bare-metal stents: the SISR randomized trial, JAMA (2006);295: pp. 1,264-1,273.
    Crossref | PubMed
  30. Suttorp M J et al., Primary Stenting of Occluded Native Coronary Arteries the PRISON II Study., presented at TCT 2005.
  31. Pan M, CORPAL-BIF, presented at AHA 2005.
  32. Serruys P W et al., Five-year outcomes after coronary stenting versus bypass surgery for the treatment of multivessel disease: the final analysis of the Arterial Revascularization Therapies Study (ARTS) randomized trial, J Am Coll Cardiol (2005);46: pp. 575-581.
    Crossref | PubMed
  33. Serruys P W, ARTS II. Part II of the Arterial Revascularization Therapies Study of the Cypher Stent in the treatment of patients with de novo coronary artery lesions., presented at ACC 2005.
  34. Goy J J et al., A prospective randomized comparison between paclitaxel and sirolimus stents in the real world of interventional cardiology: the TAXi trial., J Am Coll Cardiol (2005);45(2): pp. 308-311.
    Crossref | PubMed
  35. Rogers C et al., "Pushing drug-eluting stents into uncharted territory: simpler than you think--more complex than you imagine", Circulation (2006);113: pp. 2262-2265.
    Crossref | PubMed
  36. Kastrati A et al., "Predictive factors of restenosis after coronary implantation of sirolimus- or paclitaxel-eluting stents", Circulation (2006);113: pp. 2293-2300.
    Crossref | PubMed

Sirolimus-eluting Stent made by Cordis pursuant to a licence from Wyeth Pharmaceuticals. TAXUS® is a registered trademark of Boston Scientific Corporation or its affiliates.

ENDEAVOR™ is a registered trademark of Medtronic inc. Important information: Prior to use, refer to the 'instruction for use' supplied with these devices for indications, contraindications, side effects, suggested procedure, warnings and precautions. As part of the Cordis policy of continuous product development we reserve the right to change product specifications without prior notification. CYPHER┬« Select™ Sirolimus-eluting Stent is not for sale in the USA. This publication is not intended for distribution in the USA.