Efficacy and Safety of Rapamycin as Compared to Paclitaxel-Eluting Stents: A Meta-Analysis

   ABSTRACT: Objective. To compare the efficacy of rapamycin-eluting stents (RES) and paclitaxel-eluting stents (PES) in patients undergo percutaneous coronary intervention. Background. RES and PES differ significantly with respect to polymer coating and antiproliferative drugs. It is not yet clear whether there are any differences between RES and PES with regard to clinical outcomes. Methods. Systematic searches were conducted of randomized, controlled trials (RCTs) comparing RES with PES in Medline and the Cochrane Database of systematic reviews. A meta-analysis was done of all available randomized studies comparing PES with RES. Information on study design, inclusion and exclusion criteria, number of patients and clinical outcomes was extracted by two investigators. Disagreements were resolved by consensus. The primary outcome was reintervention, target lesion revascularization (TLR) and target vessel revascularization (TVR). Stent restenosis, myocardial infarction (MI) and all-cause mortality were secondary endpoints. Results. Twenty-one RCTs of RES versus PES with a total number of 10,147 patients were included in this meta-analysis. Indication for angioplasty was either acute coronary syndrome or stable angina. The mean follow-up period ranged from 6 to 24 months. The rates of TLR were 4.9% vs. 7.0%; p = 0.0009 and the rates of TVR were 5.1 vs. 8.3%; p J INVASIVE CARDIOL 2010;22:312–316

Key words: angioplasty, drug-eluting stents, reintervention, stent restenosis    In patients undergoing percutaneous coronary intervention (PCI), compared to balloon angioplasty and bare-metal stenting, the use of drug-eluting stents (DES) is associated with less restenosis and less need for recurrent revascularization. There is, however, uncertainty about which of the two currently approved and most widely used DES — rapamycin-eluting stents (RES, Cypher, Cordis), and paclitaxel-eluting stents (PES, Taxus, Boston Scientific Corp., Natick, Massachusetts) — is safest and most effective.    RES and PES differ importantly with respect to polymer coating and antiproliferative drugs.¹ A number of large randomized studies have demonstrated that both rapamycin- and paclitaxel-eluting stents significantly decrease restenosis rates in a variety of lesion types.^2–17 A recent meta-analysis of 16 randomized trials1 showed that RES, compared to PES, significantly reduced the risk of reintervention and stent thrombosis and trended toward a lower risk of MI without affecting mortality. However, since then, several new randomized trials have been conducted, presented and published, and their results were not included in that meta-analyses. The purpose of the present study was to compare both stents in a large series of patients with coronary artery lesions at high risk for restenosis. Methods    Literature review. We obtained results from all randomized trials on RES (Cypher, Cordis, Johnson & Johnson, Miami Lakes, Florida) and PES (Taxus, Boston Scientific Corp.). The literature was scanned by formal searches of electronic databases (Medline, Central, Embase, and the Cochrane Central Register of Controlled trials, https://www.mrw.interscience.wiley.com/cochrane), to October 2008, the scientific session abstracts in Circulation, Journal of College of Cardiology, European Heart Journal and American Journal of Cardiology from January 1990 to October 2008. Furthermore, oral presentations and/or expert slide presentations were included, searched on the Transcatheter Cardiovascular Therapeutics (TCT, www.tctmd.com), EuroPCR (www.europcr.com), ACC (American College of Cardiology; www.acc.org), AHA (American Heart Association; www.aha.org), and ESC (European Society of Cardiology; www.escardio.org) websites to October 2008.    The websites https://clinicaltrials.gov and www.tctmd.com were also assessed in an attempt to locate unpublished studies. Information on study design, inclusion and exclusion criteria, number of patients and clinical outcomes was extracted by two investigators. Disagreements were resolved by consensus. In cases of incomplete or unclear data, authors, where possible, were contacted. Finally, all coauthors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.    Endpoints/data abstraction. The primary clinical endpoint was reintervention; target lesion revascularization (defined as reintervention for stenosis within the stent or its 5 mm borders), target vessel revascularization (defined as reintervention driven by a lesion in the same epicardial vessel as initially treated). Secondary endpoints were stent restenosis, MI and all-cause death.    Statistical analysis. For clinical outcomes, we used the intention-to-treat analysis, so that the denominator of the incidence was the total number of patients randomized to a given therapy. There were generally fewer patients available for the determination of several outcomes; therefore, to determine the incidence of these outcomes more accurately, we used the treatment-received (or protocol) analysis. The Mantel-Haenszel model was used to construct random effects summary odds ratios (ORs) and risk differences. Potential publication bias was examined by constructing a “funnel plot”, in which sample size was plotted against ORs (for incidence of target lesion revascularization, if available from a study).    Clinical data were initially analyzed among all the studies. All outcomes were analyzed at the maximal extent of clinical follow up. All p-values were two-tailed, with statistical significance set at 0.05, and confidence intervals (CI) were calculated at the 95% level. All analyses were performed using SPSS 16. Results    A total of 21 randomized trials, including 10,147 patients, were analyzed (Table 1). The indications for PCI included the entire clinical spectrum of coronary artery disease. As shown in Figures 1–4, not every study mentioned all the outcomes that we planned to analyze. We performed analysis on available data.    TLR occurred in 189/3,864 (4.9%) vs. 266/3,812 (7.0%) in the RES and PES groups, respectively. Allocation to the RES group was associated with an OR of 0.66 (95% confidence interval [CI] 0.51–0.84; p = 0.0009) (Figure 1A). TVR occurred in 147/2,900 (5.1%) versus 237/2,850 (8.3%) in the RES and PES groups, respectively. Allocation to the RES group was associated with an OR of 0.53 (95% CI 0.39–0.73; p Discussion    In this meta-analysis we compared the clinical outcomes after implantation of RES versus PES in a large patient population, representative of the whole clinical spectrum of coronary artery disease.    Reintervention was clinically driven in three studies^2,8,17 and two additional studies mentioned clinically- as well as angiographically-driven reintervention.^13,14 In all the other studies reintervention was angiographically driven.    RES, as compared to PES, was associated with a lower need for reintervention, less frequent stent restenosis and a trend towards a lower risk of MI, without affecting the risk of all-cause mortality. These results confirm a previous meta-analysis of 16 randomized trials.¹ In the current meta-analysis, compared with the previous one, we add results of five more recent trials^18–22 and data from two trials that were recently fully published.^16-17 Furthermore, we analyzed the rates of TLR and TVR separately.    Use of DES. Because the incidence of stent thrombosis may be higher in patients with DES than in those with bare-metal stents (BMS), and because the incidence of stent thrombosis may be higher in patients undergoing PCI,²³ there have been concerns about using DES. However, various registries, randomized trials and recent meta-analyses on patients undergoing primary PCI have demonstrated that the use of DES is safe and is associated with significantly reduced rates of restenosis and repeat intervention without an increased risk of MI or stent thrombosis at intermediate-term follow up.^24–26 Additional large trials with hard clinical endpoints and longer follow up are needed before routine DES use can be recommended in more patients undergoing primary PCI.    Mechanisms. Delayed healing characterized by persistent fibrin deposition, poorer endothelialization and local hypersensitivity reaction may explain the late occurrence of thrombosis-related events with DES.²⁷ Previous reports showed that these phenomena are more pronounced with PES than RES.²⁸    Although both sirolimus and paclitaxel inhibit cell proliferation and other cellular processes, the working mechanism is different. Sirolimus induces G1 cell cycle inhibition, and paclitaxel mainly induces M-phase arrest. An in vitro study suggested that sirolimus reduces neointimal hyperplasia through a cytostatic mechanism, while paclitaxel produces apoptotic cell death.²⁹ A study in diabetic patients using intravascular ultrasound suggested that sirolimus inhibits neointimal hyperplasia more effectively.³⁰ Three studies compared RES with PES in patients with diabetes showed that in these patients, RES are more effective.^4,19,20    Furthermore, differences in the early systemic inflammatory response after PCI may partially explain the differences in clinical outcomes after RES and PES implantation. A recent study showed that implantation of both types of DES induce an acute inflammatory response, as assessed by CRP and IL-6 plasma concentrations, where RES implantation resulted in lower inflammatory responses compared with PES implantation. This may be of clinical relevance since this difference was associated with the degree of restenosis at 8-months follow up.³¹    In addition, another ’olimus- (everolimus) eluting stent has been shown to be superior to PES. The SPIRIT III trial demonstrated a significant reduction in the in-segment late loss with everolimus-eluting stents (EES) compared with PES at 8 months and noninferiority to PES for the clinical endpoint of target vessel failure at 1 year, and resulted in a significant reduction in major adverse cardiac events.^32,33 The Spirit IV trial, that presented during the 2009 annual Transcatheter Cardiovascular Therapeutics (TCT), showed a 2.6% absolute difference in the rate of target lesion failure between the two stents, statistically favoring the EES.³⁴ Furthermore, the COMPARE trial³⁵ showed that use of EES versus PES in real-world patients was associated with a relative risk reduction (RR) of 31% in the composite of safety and efficacy (all-cause mortality, MI and TVR) within 12 months. The difference was driven by lower rates of: early stent thrombosis, 0.7 vs. 2.5% (RRR 74%); fewer MIs, 2.8% vs. 5.3%; and fewer TLRs, 2.3% vs. 6.0%. Based on our meta-analysis and the above-mentioned studies, RES may be preferable to PES.    Study limitations. This meta-analysis was not performed on individual patient data. Caution should be exercised in the interpretation of the results, given the potential clinical heterogeneity among trials, the varying patient population and the varying definition of variables. The results of our meta-analysis may only be applied to patients who fulfill the criteria of these studies and may not be applied to registries. Furthermore, the meta-analysis is limited by the design of the original studies, particularly in terms of the short follow-up period of several studies. Conclusions    This meta-analysis shows that use of RES, as compared to PES, is associated with a significantly lower need for reintervention and less frequent stent occlusion, without affecting the risk of MI or all-cause mortality. From the Department of Cardiology, Isala Klinieken, Zwolle, the Netherlands and Klinik Kardiovaskular, Cinere Hospital, Jakarta, Indonesia. The authors report no conflicts of interest regarding the content herein. Manuscript submitted January 22, 2010, provisional acceptance given Feb- ruary 8, 2010, final version accepted March 1, 2010. Address for correspondence: Dr. J. P. Ottervanger, Department of Cardiol- ogy, Isala Klinieken, Locatie Weezenlanden, Groot Wezenland 20, 8011 JW Zwolle, The Netherlands. E-mail: v.r.c.derks@isala.nl References

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