Boston Scientific Addresses Safety Concerns in Drug-Eluting Stents

The Impact of DES Since their introduction in 2003, drug-eluting stents (DES) have shown clear and substantial benefits in patients with coronary artery disease. Compared to their predecessors, bare-metal stents (BMS), DES reduce rates of restenosis and the subsequent need for repeat procedures by more than half (i.e., from 20% to 10%, or even less when no routine angiographic follow-up is performed). This represents a significant step forward in interventional cardiology, and saves many thousands of patients every year from the potential complications associated with restenosis and its treatment. Clinical trials such as Boston Scientific’s rigorous TAXUS series - including TAXUS II, IV, V, and VI - randomized a total of 3,445 patients to the TAXUS® Stent or bare metal stent, with the latest follow-up out to four years. These studies have shown greater efficacy in reducing restenosis compared to BMS, with equal safety in terms of a nearly identical cumulative rate of death (cardiac and non-cardiac) and myocardial infarction (Q-wave and non-Q wave) for the TAXUS and bare metal stent arms. Recently, the U.S. Food and Drug Administration (FDA) gave further credence to the benefits of the two approved DES in the U.S., stating that these devices have resulted in a significant reduction in the need of second procedures to treat restenosis. Furthermore, the FDA declared DES safe and effective when used in patients having clinical and coronary anatomic features similar to those treated in the pivotal trials conducted by the manufacturers for FDA approval. Recent Safety Questions At this year’s European Society of Cardiology (ESC) meeting in Barcelona, however, questions were raised about late stent thrombosis and potential increases in late adverse clinical events, including death and myocardial infarction (MI), with DES as compared to BMS. One concern stemmed from Boston Scientific’s observation that although its data from the 3,445-patient pooled TAXUS trials showed no significant cumulative increase in stent thrombosis (1.3% vs. 0.8% for BMS, p=0.36), it did reveal a small, but nonetheless statistically significant, 0.5 percent increase in the incidence of stent thrombosis occurring between six months and three years for the TAXUS® Stent compared to the BMS control group (p=0.02) (Figure 1). It’s important to note that this issue does not appear to be specific to the TAXUS Stent, as the largest data sets demonstrate that both the TAXUS Stent and the Cypher® Stent have similar rates of stent thrombosis. This is apparent in pooled trial data for the Cypher Stent versus BMS control groups (despite only half the number of patients studied, i.e., 1,748 rather than 3,445 with the TAXUS Stent), as well as in two independent registries (with more than 15,000 real-world cases) that showed entirely comparable rates of stent thrombosis after six months for the TAXUS and Cypher Stents. However, it is critically important to note that these same 3,445 patients in the TAXUS trials showed no evidence that this small increase in stent thrombosis occurring after six months translated into an increase in death, cardiac death, MI or any combination of these, for the TAXUS Stent in comparison to BMS (Figures 2A and 2B). Weighing the Risks and Benefits of DES The frequency of stent thrombosis occurring between six months and three years with DES should be viewed in the context of their overall benefit to patients - in terms of weighing any increased risk of death and MI against the significant benefit in reduced restenosis. Based on Boston Scientific’s 3,445 patient pooled analysis, and despite the 0.5% chance of developing stent thrombosis after six months, there does not seem to be any safety penalty for using the TAXUS® Stent vs. BMS. There are extensive data to support the benefits of DES in reducing restenosis. For example, the TAXUS trials showed a substantial (50% relative and 10 percent absolute) and durable reduction in the rate of re-intervention among patients in the TAXUS Stent group versus patients in the BMS group at three years. Other than helping to avoid the discomfort and expense associated with restenosis and its treatments, we note a recent report from the Cleveland Clinic that demonstrated that restenosis is not a benign event, finding that almost 10 percent of BMS patients with restenosis present with acute MI (Chen. Am Heart J. 2006; 151:1260) (Figure 3). Our Responsibility to Physicians and Patients At Boston Scientific, patient safety remains our number-one priority. That commitment to patient safety includes providing health care professionals transparency to all our available data, and was the foundation for a meeting we requested with the FDA and world-wide regulatory partners to proactively present our DES data. While some may not have understood our decision to go public with what we believe is a generic issue of stent thrombosis after six months among DES (at least, DES with enough patients and follow-up to detect the issue), we remain proud of this proactive and responsible approach. We also note that the FDA has requested additional information regarding the Cypher® Stent so that it can work together with both DES manufacturers to explore this important patient safety issue. Physicians should stress the importance of complying with the manufacturers’ label-recommended duration of dual anti-platelet therapy (Aspirin and Plavix® medication) for their DES patients, and should consider other newer sources of information (including the 2005 Updated PCI Guidelines from the AHA/ACC/SCAI) in evaluating the merits of longer durations of therapy in their individual patients. Boston Scientific looks forward to being an active participant in the FDA’s upcoming public meeting of the Circulatory System Devices Advisory Panel, which aims to improve our knowledge regarding the incidence and timing of stent thrombosis as well as the appropriate duration of clopidogrel use in patients who receive DES, according to the FDA. Boston Scientific is currently conducting additional clinical studies involving more than 10,000 patients to evaluate the TAXUS® Stent in an even broader range of patients and lesions. We are committed to working closely with both the interventional community and the FDA to share additional data on the safety and efficacy of this revolutionary technology that continues to positively impact the lives of millions of patients worldwide. For full directions for use, go to www.taxus-stent.com Cypher is a trademark of Cordis Corp. Plavix is a trademark of Sanofi-Aventis Corp. Sponsored by Boston Scientific Corporation.

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