Sirolimus-Eluting Stents vs Paclitaxel-Eluting Stents in Patients With Coronary Artery Disease:  Meta-analysis of Randomized Trials FREE

Although stenting has improved outcomes in patients undergoing percutaneous coronary interventions, bare-metal stents are associated with an increased risk of restenosis, in particular in high-risk subsets.^1- 2 Drug-eluting stents, which have the capacity to reduce neointimal hyperplasia via local delivery of antiproliferative agents, have recently emerged as an effective solution to the problem of restenosis.^3- 4 Numerous trials have demonstrated that the sirolimus-eluting and the paclitaxel-eluting stents, the most studied drug-eluting stents and the only stents so far approved for use by the US Food and Drug Administration, are much more effective than bare-metal stents in preventing restenosis.^5- 10 The superior efficacy of drug-eluting stents compared with bare-metal stents has also been reported in systematic reviews.¹¹

In contrast, evidence on the relative performance of the sirolimus-eluting stent and paclitaxel-eluting stent has just begun to accrue. Recently, several randomized studies addressed the issue of the potential differences in performance between the 2 drug-eluting stents, which account for more than 85% of the coronary stents currently used in the United States.¹² Meta-analysis is a valuable analytical tool for summarizing results from different, but comparable, individual studies.¹³ Herein, we report the results of a meta-analysis of recent randomized trials comparing the sirolimus-eluting stent with the paclitaxel-eluting stent in patients with coronary artery disease (CAD).

The objective of our meta-analysis was to assess the efficacy and safety of the sirolimus-eluting stent compared with the paclitaxel-eluting stent in patients with CAD.

To be selected for this meta-analysis, studies had to include patients with symptoms or objective signs of myocardial ischemia due to CAD who were assigned to treatment with a sirolimus-eluting stent or a paclitaxel-eluting stent in a randomized fashion. All studies had to report the outcomes of interest during a follow-up period of at least 6 months after the index procedure. No restriction criteria were imposed with regard to the form of study publication.

The primary outcome of interest was target lesion revascularization, which was defined as any revascularization procedure, percutaneous or surgical, involving the target lesion. Other clinical outcomes of interest were stent thrombosis, myocardial infarction (MI), death, and the composite of death or MI. The angiographic outcome of interest was binary restenosis, which was defined as diameter stenosis of at least 50% at follow-up, measured by quantitative angiography in the area, including the stented area as well as the 5-mm margins proximal and distal to the stent.

We searched PubMed and the Cochrane Central Register of Controlled Trials for randomized trials comparing the sirolimus-eluting stent with the paclitaxel-eluting stent in patients with CAD. In addition, we searched conference proceedings from the American College of Cardiology, American Heart Association, and European Society of Cardiology. Searches were restricted to the period from January 2003 to April 2005. Relevant reviews and editorials from major medical journals published within the last year were identified and assessed for possible information on trials of interest. Internet-based sources of information on the results of clinical trials in cardiology (http://www.theheart.org and http://www.tctmd.com) were also searched.

Studies were selected and data were extracted independently by 2 reviewers (A.D. and J.M.). Disagreements were resolved by consensus. We recorded the following clinical and angiographic characteristics, in addition to the number of participating patients: age, sex, diabetes mellitus, number of treated lesions, mean reference diameter of the vessel where the lesion was located, and mean lesion length. Duration of clinical follow-up and time point of follow-up angiography as well as clinical follow-up rates were also recorded. Raw data obtained from source information of the individual studies were used for all analyses.

We referred to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions 4.2.4 for our meta-analysis.¹⁴ We evaluated studies for the adequacy of allocation concealment, performance of the analysis according to the intention-to-treat principle, and blind assessment of the outcomes of interest. We used the criteria recommended by Altman and Schulz¹⁵ and Jüni et al¹⁶ to decide whether treatment allocation was adequately concealed. We did not use a summary score to identify trials of low or high quality, or perform weighting by quality scores as this practice has been discouraged by some.^16- 18 Although acknowledging that studies included in our meta-analysis cannot be absolutely equal to each other regarding their methodological quality, the gathered information allowed us to consider these trials of adequate quality regarding concealment of treatment allocation, performance of analyses according to the intention-to-treat principle, and evaluation of outcomes of interest by blinded assessors.

All analyses were performed based on the intention-to-treat principle. There was no need for data imputation. Odds ratios (ORs) with 95% confidence intervals (CIs) were computed as summary statistics. The pooled OR was calculated with the Mantel-Haenszel method for fixed effects¹⁹ and the DerSimonian and Laird method for random effects.²⁰ To assess heterogeneity across trials, we used the Cochran Q test based on the pooled OR by Mantel-Haenszel. Heterogeneity was also assessed by means of I² statistic as proposed by Higgins et al.²¹ Results were considered statistically significant at P<.05. A funnel plot as well as the adjusted rank correlation test, according to the method of Begg and Mazumdar,²² were used to assess publication bias with respect to the primary outcome of interest, target lesion revascularization. Statistical analyses were performed with Stata software version 8.2 (Stata Corp, College Station, Tex).

Our search identified 6 randomized trials, which compared the sirolimus-eluting stent with the paclitaxel-eluting stent in 3669 patients with CAD.^23- 28 (After this paper was accepted for publication, 2 of the trials included in the meta-analysis as abstracts from conference proceedings^25,27 were published.^29- 30) Angiographic restenosis was the primary end point in 3 trials.^23- 24,26 Late lumen loss in follow-up angiography was the primary end point in 1 trial.²⁵ The combined incidence of death, MI, and target lesion revascularization was the primary end point in the remaining 2 trials.^27- 28 Target lesion revascularization was a secondary end point in all of the trials.

The diagnosis of stent thrombosis was based on the presence of an acute coronary syndrome plus angiographic evidence of stent occlusion in 4 studies.^23- 25,27 In 2 trials, this definition was expanded to include patients with unexplained sudden death²⁸ or patients who had a Q-wave MI in the territory of the stented vessel.²⁶ The diagnosis of MI was based on the appearance of new Q waves in the electrocardiogram or elevation of creatine kinase and its creatine kinase-MB isoenzyme levels 2 to 3 times the upper limit of normal.

A loading dose of 300 to 600 mg of clopidogrel was administered to all patients either before or at the end of the procedure in all but 1 trial.^24- 28 In 1 trial, 500 mg of ticlopidine was administered 1 day before the procedure.²³ Maintenance therapy with clopidogrel consisted of a daily dose of 75 mg. In 5 of 6 trials, the duration of clopidogrel therapy was similar (6 to 12 months) for patients of both drug-eluting stent groups.^23- 25,27 In only 1 of the trials,²⁶ the duration of clopidogrel therapy was different in the 2 groups; it was shorter in the group of sirolimus-eluting stent (at least 2 months) than in the group of paclitaxel-eluting stent (at least 6 months). In all studies, patients were administered aspirin indefinitely.

All trials reported the clinical outcomes of interest from a 6-month up to a 13-month follow-up period. One trial was interrupted prematurely because study investigators observed no significant difference between the 2 stents in the first 202 patients.²⁸ Overall clinical follow-up rate was 98.2% among patients treated with the sirolimus-eluting stent and 97.8% among those treated with the paclitaxel-eluting stent. With the exception of 1 trial that did not perform routine follow-up angiography,²⁸ the other trials reported the incidence of angiographic restenosis after a follow-up period of 6 to 8 months. Routine follow-up angiography was part of the study protocol in 3 studies.^24- 26 In the other 2 studies,^23,27 follow-up angiography was performed only in patients participating in the angiographic substudies. Angiographic restenosis rates were reported for 3229 treated lesions.

Patients included in our meta-analysis were representative of the whole clinical and angiographic spectra of CAD. No restriction criteria were applied in the SIRTAX,²⁷ CORPAL,²³ and TAXI²⁸ trials. The ISAR-DIABETES trial²⁵ included only patients with diabetes mellitus while the ISAR-DESIRE trial²⁴ included only patients with in-stent restenosis. In the REALITY trial,²⁶ patients with in-stent restenosis, ostial lesions, or totally occluded vessels were excluded.

Baseline characteristics and length of clinical follow-up are shown in Table 1. There were no significant differences between patients treated with the sirolimus-eluting stent and the paclitaxel-eluting stent regarding main entry clinical characteristics. Overall proportion of patients with diabetes mellitus was 31.6%; proportion of men was 75.5%. Similarly, patients assigned to the 2 drug-eluting stent types did not differ with respect to the main angiographic characteristics of the lesions (Table 2).

Target lesion revascularization, the primary outcome of interest, was needed in 95 (5.1%) of 1845 patients assigned to the sirolimus-eluting stent group and 142 (7.8%) of 1824 patients assigned to the paclitaxel-eluting stent group (pooled OR, 0.64; 95% CI, 0.49-0.84; P = .001) by the fixed-effect model (Figure 1). There was no significant heterogeneity between trials (P = .41). No evidence of publication bias with respect to target lesion revascularization was found using the Begg funnel plot and rank correlation test (P = .89).

Sirolimus-eluting stents were significantly more effective in the reduction of angiographic restenosis (Figure 2). The incidence of angiographic restenosis was 9.3% (151 of 1616 lesions) among patients treated with the sirolimus-eluting stent and 13.1% (211 of 1613 lesions) among those treated with the paclitaxel-eluting stent. The pooled OR in favor of the sirolimus-eluting stent was 0.68 (95% CI, 0.55-0.86; P = .001) by the fixed effects model, with no significant study heterogeneity (P = .33).

In contrast, patients treated with sirolimus-eluting and paclitaxel-eluting stents did not differ significantly with respect to other outcomes of interest. There were 17 cases (0.9%) of stent thrombosis reported among patients who received sirolimus-eluting stents and 20 cases (1.1%) among patients who received paclitaxel-eluting stents (OR, 0.85; 95% CI, 0.46-1.59; P = .62; P = .27 for heterogeneity) (Figure 3). Few deaths occurred in the 2 stent groups (25 [1.4%] in the sirolimus-eluting stent group and 29 [1.6%] in the paclitaxel-eluting stent group; OR, 0.85; 95% CI, 0.50-1.46; P = .56; P = .48 for heterogeneity) (Figure 4). The composite of death or MI was reported in 91 patients (4.9%) in the sirolimus-eluting stent group and 106 (5.8%) in the paclitaxel-eluting stent group (OR, 0.84; 95% CI, 0.63-1.12; P = .23; P = .94 for heterogeneity) (Figure 5).

Currently approved sirolimus and paclitaxel drug-eluting stents have become the predominant percutaneous treatment strategy for patients with CAD.¹² Recently, the results of several randomized trials comparing these 2 drug-eluting stents in patients with various clinical and angiographic presentations have been made public. We performed a meta-analysis of these trials that included 3669 patients. The number of patients in each of the drug-eluting stent groups of our meta-analysis is higher than the overall number of patients who received the sirolimus-eluting stent or the paclitaxel-eluting stent in previous randomized trials that compared these drug-eluting stents with bare-metal stents. There was no significant heterogeneity among the trials. We found that the sirolimus-eluting stent was associated with a decreased risk of restenosis compared with the paclitaxel-eluting stent.

Patients who received sirolimus-eluting stents had a 36% reduction in the odds of target lesion revascularization compared with paclitaxel-eluting stents. The better clinical efficacy of the sirolimus-eluting stent was angiographically demonstrated by a 32% reduction in the odds of angiographic restenosis. Two of the studies included in our meta-analysis reported a considerable reduction in the rates of target lesion revascularization and angiographic restenosis among patients assigned to the sirolimus-eluting stent group.^24,27 In the other 4 studies,^{23,25- 26,28} a nonsignificant difference in clinical and angiographic restenosis was observed between patients who underwent sirolimus-eluting stent or paclitaxel-eluting stent implantation, with a clear trend toward a lower incidence of restenosis with the sirolimus-eluting stents in 2 of these studies.^23,25

The superiority of the sirolimus-eluting stent over the paclitaxel-eluting stent in reducing the rate of restenosis found in our meta-analysis might be explained by the greater reduction of late lumen loss with the sirolimus-eluting stent uniformly demonstrated by both angiographic follow-up data^23- 27 and intravascular ultrasound findings reported in 1 of the studies.²³

A few cases of stent thrombosis were reported from the studies included in our meta-analysis. Although in the REALITY trial²⁶ there was a trend toward a higher incidence of stent thrombosis in patients who underwent paclitaxel-stent implantation, the other studies reported comparable rates of stent thrombosis between the 2 drug-eluting stents and the pooled rates were also comparable. A recent study of consecutive patients treated with sirolimus-eluting and paclitaxel-eluting stents reported a trend toward a higher incidence of stent thrombosis with paclitaxel-eluting stents.³¹ The rare occurrence of stent thrombosis reduces, however, the power of our meta-analysis regarding the assessment of this complication and makes it difficult to draw any definitive conclusions on the relative safety of the sirolimus-eluting and paclitaxel-eluting stents.

We found no significant difference between the sirolimus-eluting stent and the paclitaxel-eluting stent with respect to MI, death, or their composite. Actually, none of the studies reported any difference between the 2 stent groups with respect to these outcomes of interest. The reduction in restenosis with sirolimus-eluting stent was not associated with a similar reduction in mortality or MI rate. It is likely that the low event rate and the limited length of follow-up period have not allowed the detection of potential differences in the incidences of death or MI between patients assigned to the respective drug-eluting stent groups.

Several factors may be responsible for the observed difference between the sirolimus-eluting and paclitaxel-eluting stents. Although both sirolimus and paclitaxel inhibit neointimal proliferation, there are differences in their mechanisms of action. Sirolimus is an immunosuppressive drug with anti-inflammatory properties that produces cell-cycle arrest in the G₁/S phase transition and is regarded as a cytostatic agent, while paclitaxel is an antineoplastic drug that produces cell-cycle arrest in the G₂/M phase transition and is regarded as a cytotoxic agent.^32- 33 In addition to the specific drug, another determinant of the drug-eluting stent performance is the drug delivery system, including the polymer and the stent. The different coating materials and strategies used for the sirolimus and paclitaxel stents may result in different amounts of the drug released and drug-release kinetics,³⁴ which coupled to the distinct transmural distribution patterns in the arterial wall of sirolimus and paclitaxel,³⁵ may influence their local pharmacological effects. The polymer coating of the sirolimus-eluting stent allows for elution of 100% of the drug, most of which occurs within 1 month.³⁴ The polymer coating of the paclitaxel-eluting stent allows for elution of only 10% of the drug over 2 months, with 90% of paclitaxel remaining sequestered in the polymer indefinitely.³⁴ The long-term implications of the presence of the sequestered drug are unknown.³⁴ In addition, the sirolimus-eluting stent and the paclitaxel-eluting stent have different designs: the first has a closed-cell design while the second an open-cell design.³⁴ It has been suggested that a closed-cell design may provide a more uniform distribution of the coated drug in the arterial wall compared with an open-cell design.^32,34 Other unidentified factors may as well be responsible for the observed difference in performance between the 2 stents.

A limitation of our meta-analysis is that all individual studies included were open-label studies. This limitation cannot be circumvented in studies comparing drug-eluting stents from different manufacturers due to clear differences in stent design and delivery systems. Another limitation is that not all included studies had routine follow-up angiography as part of their protocol. However, the similarity in the calculated ORs for both clinical (target lesion revascularization) and angiographic indicators of restenosis makes it highly unlikely that there was a bias associated with incomplete angiographic follow-up. In addition, head-to-head comparisons between 2 drug-eluting stents are a new focus of clinical trials in cardiology. It is possible that new trials will be performed to compare sirolimus-eluting and paclitaxel-eluting stents. With respect to the primary end point (target lesion revascularization), a future study will need to have a sample size of 1000 patients and an OR of 2.8 in favor of the paclitaxel-eluting stent before an updated meta-analysis would fail to show a significant advantage for the sirolimus-eluting stent.

In conclusion, the results of our meta-analysis show that in patients with CAD presenting with various clinical and angiographic risk profiles, sirolimus-eluting stents are better than paclitaxel-eluting stents in reducing the risk of restenosis. Although the risk of death and MI was not significantly different between these 2 drug-eluting stents, our finding needs to be confirmed by longer follow-up studies.