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September 2008
Taxus Clinical Update
Experts discuss the current role of the Taxus stent.
By Mark A. Turco, MD, FSCAI, FACC, and Eberhard Grube, MD, FSCAI, FACC
To date, nearly 5 million Taxus stents (Boston Scientific Corporation, Natick, MA) have been implanted worldwide (Boston Scientific Corporation 2008 data on file). The TAXUS Clinical Trial Program consists of randomized controlled trials (RCTs) and monitored registries and has enrolled more than 44,000 patients.
The Taxus stent consists of a balloon-expandable, polymer-based stent on either the first-generation Express platform or the second-generation Liberté platform. The Liberté platform has smaller, more uniform open cells and thinner struts (.0052-inch vs .0038-inch) intended to improve stent flexibility and conformability, allowing for possibly more uniform drug distribution versus the Taxus Express. The Liberté platform is currently marketed in the European Union and is awaiting FDA regulatory approval in the US. Both stents contain 1 µg/mm² of paclitaxel, which inhibits neointimal formation by stabilizing microtubules and inhibiting intracellular signaling to block smooth muscle cell migration and proliferation.1-4
REVIEW OF CURRENT CLINICAL DATA
Standard-Risk Patients
The Taxus Express stent was evaluated in the TAXUS IV, V, and VI studies and compared with the bare-metal Express stent (Table 1).5-8 TAXUS IV, the pivotal trial, studied standard-risk patients with relatively uncomplicated lesions who were implanted with a single stent. TAXUS V and VI included patients with increasing complexity, including in-stent restenosis, long lesions, and small vessels. A meta-analysis of the TAXUS RCTs9 with up to 4 years of follow-up showed significant reductions with the Taxus Express versus bare-metal stents (BMS) in target lesion revascularization (TLR) and binary restenosis, with no significant differences in death (Table 2) or myocardial infarction (MI). Despite early concerns of late stent thrombosis (ST), recent data from 5 years of follow-up demonstrate no significant difference between the Taxus Express and BMS for the risk of ST (Figure 1).10
In the TAXUS ATLAS trials, Taxus Liberté was noninferior to the Taxus Express stent for efficacy and had comparable safety in standard-risk lesions (Table 1).11 At the primary endpoint of 9 months, the event rates were similar between the Taxus Liberté and Express for major adverse cardiac events (11% Liberté vs 10.5% Express; P=.71), MI (3.7% Liberté vs 3.9% Express; P=.9), and cardiac death (0.8% Liberté vs 0.9% Express; P>.99).11
High-Risk Subgroups Treated With Paclitaxel
Diabetes. Patients with diabetes have an increased risk of atherosclerosis and cardiac death.12 Past studies demonstrated that diabetic patients have increased restenosis risk compared to nondiabetics after BMS implantation.13,14 Diabetics treated with Taxus in the randomized controlled trials have shown no increase in intimal hyperplasia compared to nondiabetic patients (Figure 2).15 Furthermore, a meta-analysis of patients with diabetes in the TAXUS Express trials showed Taxus reduced restenosis and did not affect safety (Table 2) compared with BMS. This is corroborated by comparable TLR rates in diabetic patients compared to nondiabetic patients in the ARRIVE registries (8.1% vs 7.7%; P=.63; unadjusted results)16 and the TAXUS ATLAS Liberté study (6.6% vs 4.6%; P=.15; propensity adjusted),17 suggesting that Taxus offers comparable benefit in patients with and without diabetes. Paclitaxel may be able to inhibit restenosis independently of the pathways affected by diabetes,4 which might provide a potential mechanism for these effects.
Small vessels. As with diabetes, interventions in small-diameter vessels carry an increased risk of restenosis.18 Patients with vessels ≤ 2.5 mm were studied in the TAXUS meta-analysis, with results reported up to 5 years.19 In these patients, TLR and late loss were significantly reduced with Taxus, with no differences in death, MI, or ST. In addition, results of the TAXUS ATLAS study suggest that the Liberté stent performs better than the Express stent in small vessels. At 9 months, the TLR rate with Liberté (5.8%) was significantly lower than either Taxus Express (13.7%; P=.02) or a BMS (17.6%; P<.001), with no differences in cardiac death, MI, or ST.20 Based on these results, the Taxus Atom 2.25-mm stent (Liberté stent platform) is pending approval in the US.
Long lesions and multiple stents. Patients with long lesions are also at increased risk for restenosis.21 Use of multiple stents in these patients has been associated with increased risk of periprocedural non–Q-wave MI, predominantly in patients who had overlapping stents or emergent need for multiple stenting, as seen in TAXUS V.6,22 This increased MI rate did not translate into differences in overall mortality up to 5 years and was believed to be secondary to loss of small side branches that had spontaneous reperfusion at later follow-up.10 In the TAXUS ATLAS Long Lesion study, the periprocedural non–Q-wave MI rate was reduced in Taxus Liberté compared to Taxus Express (0% vs 4.1%; P=.01), with comparable TLR (6% vs 7%; P=.73), suggesting that a thinner strut stent may reduce periprocedural MI rates.
Real-World Results From TAXUS Registries
The ARRIVE Registries. The results from the TAXUS Express RCTs were corroborated by 2-year outcomes in the ARRIVE real-world registries.16 Patients in these registries can be divided into two categories: "simple use" (eg, conditions similar to those in the TAXUS RCTs) and "expanded use," which included patients with more complex lesions and comorbidities. In the simple-use cohort, the rates of death (4.2%), MI (2.2%), ST (1.4%), and TLR (7.7%) were comparable or lower than in the RCTs. Intriguingly, in the expanded-use cohort, TLR rates were even lower than that seen in the RCTs, even in this well-monitored registry (9.2%), and rates of all-cause mortality (7.8%) were similar to those in higher-risk subgroups of the Taxus Express meta-analysis (Table 2). These data therefore suggest that the Taxus Express maintains acceptable safety and efficacy even in high-risk patients.
The Olympia Registries. The Olympia registries are evaluating real-world usage of the Liberté stent among >22,000 patients in 59 countries. Preliminary 1-year results are available for 7,000 patients.23 Comorbidities included patients with diabetes (33%), multivessel disease (58%), previous acute MI (18%), and type B2/C lesions (57%); and nearly three quarters of patients were expanded use. At 1 year, stent-related interventions were lower than in the TAXUS ATLAS RCT (2.5% Olympia vs 6.1% TAXUS ATLAS). The rate of all-cause mortality was higher in real-world use of the Taxus Liberté (2% Olympia vs 1% TAXUS ATLAS). Overall, the stent-related cardiac death (1.1%), MI (0.9%), and ST (0.8%, definite only) were low at 1 year, indicating that outcomes in real-world usage of Taxus Liberté are roughly comparable to the results from the RCTs.
CHALLENGES FOR DRUG-ELUTING STENTS
During the past several years, some researchers have raised safety concerns surrounding very late ST and mortality with drug-eluting stents (DES) compared to BMS. As previously discussed (Figure 2), updated analyses of Taxus versus BMS find no significant difference in ST rates between the Taxus Express and BMS out to 5 years.10 Furthermore, it has been suggested that a modest increase in very late ST events in Taxus compared to BMS is offset by the significant revascularization reduction, resulting in no net difference in mortality.24 In fact, results from recent large-scale real-world studies suggest that the risk of death and MI is not increased with DES,25 but may instead be decreased compared to BMS.26,27
Among the remaining challenges for DES is defining the upper limit of efficacy and/or safety with DES in very high-risk patients, such as those with multivessel disease, unprotected left main disease, or acute coronary syndromes. Additional remaining challenges include the need for reduced duration of postprocedure dual-antiplatelet therapy and methods to identify patients at increased risk for ST.
FUTURE DIRECTIONS OF CLINICAL TRIALS
Future studies with Taxus are evaluating the efficacy and safety of Taxus in higher-risk subgroups. The SYNTAX study compares outcomes of PCI with Taxus Express versus coronary artery bypass surgery in patients with left main and/or three-vessel disease.28 The primary endpoint results from this trial will be presented at the 2008 European Society of Cardiology meeting in September 2008. The HORIZONS AMI study evaluates the use of Taxus Express in patients with ST-elevation MI,29 and results will be presented at the October TCT 2008 meeting in Washington, DC. Finally, Taxus Element is a third-generation, paclitaxel-eluting stent incorporating a platinum platform intended to improve deliverability and radiopacity. This stent is currently being evaluated in the PERSEUS clinical trial program,30,31 and enrollment is expected to be complete in late 2008.
CONCLUSION
As demonstrated, the Taxus program has been a robust clinical program that is now expanding to newer platforms. Over the next few years, further information will evolve as to the clinical safety and efficacy benefits of these new platforms.
Acknowledgements
The authors would like to acknowledge Vicki M. Houle, PhD, and Kristin L. Hood, PhD, for assistance with the manuscript.
Mark A. Turco, MD, FSCAI, FACC, is Director, Center for Cardiac & Vascular Research, Washington Adventist Hospital, Takoma Park, Maryland. He has disclosed that he receives grant and research funding, and is a speaker/consultant for Boston Scientific Corporation. Dr. Turco may be reached at (301) 891-6636; mturco@adventisthealthcare.com.
Eberhard Grube, MD, FSCAI, FACC, is from HELIOS Klinikum Siegburg, Siegburg, Germany. He has disclosed that he holds no financial interest in any product or manufacturer mentioned herein. Dr. Grube may be reached at +49 (224) 118-2322; grubee@aol.com.
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