Drug eluting stents versus bare metal stents: an update

Sponsored by Boston Scientific Corporation

Since December 2006 when the U.S. Food and Drug Administration (FDA) convened a special panel on drug-eluting stents (DES), much has been written in peer-to-peer journals comparing the mortality rates of DES versus bare-metal stents (BMS). These recently published studies are worthy of note because they show a significant advantage for DES over BMS with lower rates of re-intervention.

Boston Scientific was an active participant in the FDA’s public meeting of the Circulatory System Devices Advisory Panel on Dec. 7-8, 2006, in Gaithersburg, MD. The goal of the panel, according to the FDA, was “to improve our knowledge regarding the incidence and timing of stent thrombosis…in patients who receive drug-eluting stents.” Boston Scientific is committed to working closely with both the interventional community and the FDA to address safety concerns surrounding this revolutionary technology that continues to positively impact the lives of millions of patients worldwide. This article will highlight key points of discussion during the FDA meeting and in recent articles published in the New England Journal of Medicine and the American Journal of Cardiology.

Weighing the Benefits and Risks of DES

The FDA opened the December 2006 meeting by reviewing available data on DES currently marketed in the United States. Both Boston Scientific and Cordis Corporation presented data from randomized controlled clinical trials and “real-world” registries of the TAXUS® Stent and Cypher® Stent, respectively.

Based on the data presented, FDA advisory panel members reached consensus that the benefits of using DES within the limits of their approved labeling outweigh the risks and there is no increase in rates of death or myocardial infarction (MI) with the devices. For example, in the TAXUS Stent randomized clinical trials (RCTs), patients who received the TAXUS Stent had a 50 percent lower relative risk of re-intervention versus patients who received a BMS over four years.

The FDA advisory panel debated at length the most appropriate definition of stent thrombosis. Trial protocol definitions, as well as the Academic Research Consortium (ARC) definitions, were discussed extensively. The panel was unable to agree upon which definition should become the new standard, so multiple definitions were used to analyze stent thrombosis during the FDA panel meeting.

The FDA advisory panel addressed the question of whether late-stent thrombosis is an issue with DES in comparison to BMS. After much discussion, the panel was in general agreement that DES, when used in accordance with their approved labeling, are associated with increased rates of late-stent thrombosis (stent thrombosis after one year). However, this panel agreed that the magnitude of this increase is uncertain and that there was no overall increased risk of stent thrombosis over four years with DES versus BMS.

Other Key Findings of the FDA Panel

Comparing use of DES in accordance with their labeled indications versus BMS, the FDA advisory panel agreed among other things that DES have:

1. No increased risk of death or heart attack
2. Benefits outweighing current safety concerns
3. Statistically significant reduction in the need for repeat procedures performed

Subsequently, in a Perspective piece in the March 8, 2007 edition of the New England Journal of Medicine (NEJM), Dr. Andrew Farb and Ashley Boam (both of the FDA) summarized the findings of the FDA advisory panel, writing: “when drug-eluting stents are used for their approved indications, the risk of thrombosis does not outweigh their advantages over bare-metal stents in reducing the rate of repeated revascularization.” In addition, the authors emphasized that further “…randomized controlled trials…are needed to determine the best treatment strategies for lesions in patients with common, complex conditions” in which drug-eluting stents are now used beyond the current label indications. As examples, they cited three such trials that are already ongoing with Boston Scientific support, comparing DES to therapeutic alternatives in patient groups that lie outside current label indications.

Articles in New England Journal of Medicine

Recent articles published in the March 8, 2007 edition of the NEJM confirm the safety and efficacy of Boston Scientific’s TAXUS® ® Express2™ paclitaxel-eluting coronary stent system (TAXUS Stent) when used for the indications included in its approved labeling. The TAXUS Stent was approved by the FDA in March 2004 for use in first-time lesions up to 28 mm in length in coronary vessels between 2.5 and 3.75 mm in diameter.

In total, the findings support Boston Scientific’s own internal analyses, publications, physician communications and public presentations of the TAXUS trial data, showing that patients who received the TAXUS Stent for on-label indications had nearly a 50 percent reduction in the need for repeat procedures to treat vessel renarrowing, with no increase (in-fact a slight numerical decrease) in the risk of all-cause death or large heart attack, compared to the patients who had received the “control” BMS. These findings had previously been verified by independent examination of the data, and are now further confirmed by the additional independent analyses reported by Drs. Mauri et al, and Dr. Stone et al in the NEJM.

Dr. Gregg Stone from Columbia University and the Cardiovascular Research Center and his co-authors examined patient level data on 3,513 patients from five clinical trials that randomly assigned them to receive either the TAXUS Stent (1,755 patients, including a small number who received a purely investigational higher dose – or moderate-release (MR) – formulation) or a similar bare-metal control stent (1,758 patients). These patients were then followed for up to four years, at which time the TAXUS Stent patients had a nearly 50 percent reduction (from 20.0%, to 10.1%) in the need for a repeat procedure to treat a renarrowing, and a trend toward lower rates of death (6.1% v. 6.6%) (p=0.68) and death or large (Q-wave) heart attack (7.3% vs. 7.5%) (p=0.93), compared to the patients who received the bare-metal control stent.

Using the original protocol definition, there was a slight numerical excess of stent thrombosis (1.3% in the TAXUS Stent arm, versus 0.9% in the bare-metal arm), which failed to reach statistical significance (p=0.30). Looking only at thrombosis events occurring beyond the first year, and including both moderate- and slow-release versions of the TAXUS Stent, the study confirmed the previously reported small (0.4%, or about one event per 500 patient years) but statistically significant (p=0.028) increase for the TAXUS Stent compared to the bare-metal control stent, which Boston Scientific’s investigators have reported since March 2005. Similar examination comparing 878 patients who received Cordis’ Cypher® Sirolimus-Eluting Coronary Stent (Cypher Stent) to 870 patients who received a bare-metal control stent also showed a significant reduction in repeat procedures and equivalent rates of death (6.7% vs. 5.3%) (p=0.23) and death or large (Q-wave) MI (8.2% vs. 6.4%) (p=0.14), and a similar and equally statistically significant (0.6%, p=0.025) increase in stent thrombosis after one year for the Cypher Stent compared to the bare-metal control stent.

Dr. Laura Mauri and co-authors from the Harvard Clinical Research Center examined patient-level data from a sub-set of 2,797 patients who were randomly assigned to receive either the commercialized (slow-release, or SR) formulation of the TAXUS Stent or a similar BMS, and then followed for up to four years. Instead of the original (protocol) definition of stent thrombosis, they used the ARC definitions of definite or probable stent thrombosis, and found no statistically significant differences in stent thrombosis overall for either the TAXUS® Stent or the Cypher® Stent compared to their respective bare-metal controls. Cumulatively in years one through four, the rates of stent thrombosis were 0.9% for the TAXUS Stent vs. 0.6% for BMS, and 0.9% for Cypher Stent vs. 0.4% for BMS.

Article in the American Journal of Cardiology

Data recently published from another study shows that DES have substantially lower rates of death, heart attack and re-intervention in real-world patients compared to BMS. The results of the study, “Comparison of Drug-Eluting Versus Bare-Metal Stents on Later Frequency of Acute Myocardial Infarction and Death,” was published in the February 1, 2007 issue of the American Journal of Cardiology.

The observational study, which was conducted by the cardiology section of the Wake Forest University School of Medicine in Winston-Salem, N.C., compared clinical outcomes among 2,359 unselected patients receiving either BMS (n=1,126) or DES (n=1,233). At nine months, DES reduced the risk of acute myocardial infarction (AMI) and death by 23 percent and 32 percent, respectively (based on hazard ratios of 0.77 and 0.68). The rate of AMI, commonly referred to as a heart attack, was 3.7 percent in DES patients versus 4.7 percent in BMS patients, while the rate of death was 4.9 percent versus 7.1 percent, respectively (p=0.03). Furthermore, the rate of revascularization, or re-intervention, in DES was less than half that in BMS patients after nine months (6 percent versus 13.3 percent, p<0.001). Finally, there was a trend toward less stent thrombosis (clotting) in DES patients compared to BMS patients, though the rates were low in both groups (0.4 percent and 0.7 percent, respectively).

In an analysis of various patient subgroups, the use of DES was associated with lower risk of death across all populations.

The Wake Forest results, suggesting lower death and MI with DES versus BMS, further support the ARRIVE registry data and help counterbalance some earlier non-randomized comparisons that suggested slightly higher mortality with DES compared to historical BMS data in somewhat simpler lesions.

Conclusion

Boston Scientific is committed to addressing the recommendations brought forth by the FDA panel, particularly concerning educating medical professionals and patients about the benefits and risks of DES, as well as compiling broad databases in order to better understand DES technology in various patient subsets. To this end, Boston Scientific has completed enrollment of the randomized SYNTAX trial comparing the TAXUS Stent to CABG in patients with complex cases of left-main and/or three-vessel disease.

FDA recommendations based on the panel’s guidance will be forthcoming. Boston Scientific remains confident in the safety and efficacy of the TAXUS Stent when used in accordance with its labeling, and hopes its detailed presentation to the panel helped to address concerns raised about DES by putting the benefits and risks of this important therapy in perspective.

For more information on the FDA advisory panel meeting, go to www.fda.gov or “Resources for Healthcare Professionals” at www.taxus-stent.com.

Cypher is a trademark of Cordis Corporation.

Sponsored by Boston Scientific Corporation