Trading Restenosis for Thrombosis? New Questions about Drug-Eluting Stents
http://www.100md.com
《新英格兰医药杂志》
In September, at the World Cardiology Congress in Barcelona, Donald Baim, a cardiologist who is the new chief medical and scientific officer of Boston Scientific, was talking to a reporter when he mentioned disturbing new findings regarding the risk of late thrombosis associated with drug-eluting coronary stents. The revelation fueled a newly ignited controversy. Lauded as a means of preventing restenosis, drug-eluting stents have been implanted in nearly 6 million patients worldwide since they were introduced 3 years ago. The Food and Drug Administration (FDA) responded to the controversy by issuing a statement that drug-eluting stents are "safe and effective when used for the FDA-approved indications," which involve discrete and relatively short lesions (up to 28 mm in the case of one approved stent and up to 30 mm in the other) in relatively small, native blood vessels (2.5 to 3.5 or 3.75 mm in diameter), but drug-eluting stents are also widely used on an off-label basis for longer lesions, larger vessels, and multivessel lesions. The FDA plans to discuss questions about the safety of drug-eluting stents at an open meeting of its Circulatory System Devices Advisory Panel on December 7 and 8, 2006, to be attended by physicians, scientists, and the two leaders — and fierce rivals — in the $5.5 billion stent industry, Boston Scientific and Johnson & Johnson.
In approving drug-eluting stents, the FDA obliged manufacturers to track all subjects in their pivotal clinical trials for 5 years, and it was Boston Scientific's review of the data on its paclitaxel-eluting Taxus stent to which Baim was alluding. Four years of data on nearly 3500 patients randomly assigned to receive the Taxus stent or a bare-metal stent showed that the risk of thrombus formation more than 6 months after stent placement was significantly higher in the Taxus group. The difference in risk increased by about 0.2% per year, so that 3 years after stent placement, patients with the Taxus stent had a risk that was about 0.5% higher than that of their counterparts with the bare-metal stent. In early August, the FDA met with Boston Scientific to review these findings.
Concerned about the risks of myocardial infarction and death associated with stent thrombosis, the FDA also met with Johnson & Johnson to discuss that company's data. Dennis Donohoe, vice president of clinical and regulatory affairs at Cordis Corporation, the division that makes Johnson & Johnson's sirolimus-eluting Cypher stent, said that his company reviewed its long-term data set — 4 years of follow-up on nearly 1750 patients randomly assigned to the Cypher stent or a bare-metal stent — and found "numerically" more thromboses in the Cypher group. "While we did not see a significant difference in rates between Cypher and bare metal . . . we did see a trend suggesting more events occurring with Cypher than bare metal," said Donohoe.
(Figure)
Contrasting Mechanisms of Obstruction of Bare-Metal Stents and Drug-Eluting Stents.
Bare-metal stents may be narrowed or obstructed by ingrowth of tissue. With drug-eluting stents, this process is inhibited, but since the struts remain uncovered, they may be prone to thrombosis after antiplatelet therapy is discontinued.
Julie Zawisza, the FDA's assistant commissioner for public affairs, confirmed that in the past few months, the agency has received data from both manufacturers showing "a small additional risk of late stent thrombosis after a year" when stents are used according to their FDA-approved indications and that since summer, the FDA has undertaken extensive reviews of its data on stents. In October, Andrew Farb, a physician with the FDA's Division of Cardiovascular Devices, said that the agency became concerned about the stents, owing to an as-yet-unreleased preliminary analysis of data that FDA staff completed this fall involving off-label use of the stents in patients included in registries that the FDA requires the manufacturers to maintain. "Many of the patients will have more than one complex situation," said Farb. "They'll have multivessel disease and elevated creatinine, they'll be post- and have a bifurcation lesion — so clearly it's a different type of patient than in the initial trials." The new FDA analysis shows that such patients have a greater rate of stent thrombosis than do patients with less complex conditions who participated in trials.
Academic investigators have also been re-reviewing whatever data are available, although some are concerned about the completeness of the information, since the companies have no obligation to make patient-level trial data accessible to independent investigators.
At the Barcelona meeting, Edoardo Camenzind of University Hospital Geneva in Switzerland described a meta-analysis of the results of all published or presented trials comparing the Taxus or Cypher stent with a bare-metal stent. He reported that patients with the Cypher stent had substantially higher rates of death and myocardial infarction than those with a bare-metal stent.1 There were also nonsignificant trends toward higher rates of death and myocardial infarction among patients with a Taxus stent than among those with a bare-metal stent.
Camenzind's collaborator, Philippe Gabriel Steg of H?pital Bichat–Claude Bernard in Paris, said that in doing their meta-analysis, they were impressed "by the consistency of trends and the consistency of the data with other sources of data" such as a study of late stent thrombosis in the Basel Stent Kosten Effektivit?ts Trial, which showed increases in the risks of death and myocardial infarction with drug-eluting stents.2 In addition, an analysis of registry data on more than 8000 patients, presented in Barcelona by Peter Wenaweser of the Swiss Cardiovascular Center in Bern, showed that the incidence of stent thrombosis increased by about 0.6% per year over the course of 3 years. Steg said, "There's this meta-analysis, there's this registry data, there's this randomized clinical trial data — it all points in the same direction, and the direction is that there is a concern with late stent thrombosis and hard events occurring later with drug-eluting stents compared to bare-metal stents."
As the controversy grew, Boston Scientific and Johnson & Johnson joined forces and provided patient-level data from their pivotal clinical trials to the Columbia University-based Cardiovascular Research Foundation for a meta-analysis. The results, presented in October at the Transcatheter Cardiovascular Therapeutics Symposium in Washington, DC, confirm a significant increase in the incidence of stent thrombosis among patients with drug-eluting stents that had been implanted more than 1 year earlier: stent thrombosis occurred in five such patients in the Cypher group, as compared with none in the bare-metal group, and in nine such patients in the Taxus group, as compared with two in the bare-metal group. Stuart Pocock, of the London School of Hygiene and Tropical Medicine, noted that despite these striking findings, the absolute risk of stent thrombosis occurring months or years after stent placement is small — "about one event per 500 patient-years" — and that neither company's data set had shown that drug-eluting stents result in excess deaths or myocardial infarctions.
These data challenge the golden reputation of drug-eluting stents. The devices have reduced the need for both emergency cardiac surgery and additional angioplasty, they are associated with substantially lower restenosis rates at 6 months than are bare-metal stents, and the successful outcomes are visible on angiography. Although a drug-eluting stent costs about $2,200, as compared with $800 for a bare-metal stent, they are now used in more than 90% of angioplasty procedures. Steven Nissen, chairman of the Department of Cardiovascular Medicine at the Cleveland Clinic, thinks that the FDA and cardiologists were blindsided. "The regulators thought that if you got out 9 months and you didn't have restenosis, you were home free," he said. Instead, he added, "We've traded a short-term benefit on a relatively benign disorder, namely restenosis, for a long-term mortality disadvantage."
Some questions were raised earlier by case reports and a 2005 observational study. The study revealed that of 2229 consecutive patients in Germany and Italy who collectively received a total of 4495 sirolimus- or paclitaxel-eluting stents, 29 had stent thrombosis (occurring more than 30 days after stent placement in 15 of the patients), and 13 died — a case fatality rate of 45%.3 As cardiologist Chip Gold of Massachusetts General Hospital observed, "We accepted a technology whose long-term effects have not been studied."
Since, by definition, "very late" stent thromboses occur after the 3 or 6 months of antiplatelet therapy recommended by the stent makers, most patients with thrombosis who were identified in the recent analyses were no longer taking aspirin and clopidogrel when the thrombosis occurred — raising the question of whether extended therapy could have averted the events. Recognizing that one of the risk factors for thrombosis is premature discontinuation of antiplatelet therapy, many physicians now recommend extended or lifetime prescriptions of aspirin and clopidogrel for patients receiving drug-eluting stents. Current U.S. and European guidelines indicate that the drugs should be taken for up to 12 months, unless a patient is at high risk for bleeding.4,5
However, the companies have not markedly changed their official recommendations about the duration of drug therapy (although the FDA now recommends that patients not discontinue therapy without consulting their physician). After the December meeting, the FDA is expected to recommend a change.
Asked why his company didn't discover the increased risk sooner, Baim said, "It's a phenomenally-low-frequency event." But Steg pointed out that access to data is more restricted in device trials than in drug trials. As a result, patient-level trial data on drug-eluting stents have not been subject to open scrutiny, and it has been difficult for independent researchers to discover the numbers and causes of deaths. Gold said that preclinical data on arterial reactions to the stents, which could illuminate the pathophysiology of late thrombosis, have also been hard to obtain.
Although crucial issues such as independent investigators' access to data and control of analyses could be aired at the FDA meeting in December, the session seems poised to degenerate into a series of debates between industry representatives and investigators about the validity and meaning of the findings. The two companies may also be expected to debate each other, their mutual animosity inflamed by their competition to acquire Guidant Corporation last spring and by a resulting lawsuit launched by Cordis this fall. Daniel Schultz, director of the FDA's Center for Devices and Radiological Health, acknowledged the rivalry but said he hopes "the companies will take the high road here."
Outside the United States, several second-generation drug-eluting stents have been approved, including Medtronic's Endeavor (coated with zotarolimus), Abbott's Xience V (coated with everolimus), and Conor Medsystem's CoStar (coated with paclitaxel); however, given the concerns about late stent thrombosis, the FDA could ask companies for longer-term data before considering newer stents for approval in the United States. How long that term should be is likely to be one more contentious issue at the FDA meeting.
Meanwhile, as clinicians sort through the new information and await the FDA's pronouncements, they are already reducing their use of the current technology slightly: sales of drug-coated stents have dipped by 5% for Boston Scientific and 6% for Cordis, while sales of bare-metal stents are edging up.
Source Information
Dr. Shuchman is an assistant professor in the Department of Psychiatry at the University at Buffalo School of Medicine and Biomedical Sciences, Buffalo, NY.
References
Camenzind E, Steg PG, Wijns W. A meta-analysis of first generation drug eluting stent programs. Presented at Hotline Session I, World Congress of Cardiology 2006, Barcelona, September 2–5, 2006.
Pfisterer ME, Brunner-La Rocca HP, Buser PT, et al. Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: an observational study of drug-eluting vs. bare-metal stents. J Am Coll Cardiol (in press).
Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005;293:2126-2130.
Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction -- executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1999 guidelines for the management of patients with acute myocardial infarction). J Am Coll Cardiol 2004;44:671-719.
The Task Force for Percutaneous Coronary Interventions of the European Society of Cardiology. Guidelines for percutaneous coronary interventions. Eur Heart J 2005;26:804-847.(Miriam Shuchman, M.D.)
In approving drug-eluting stents, the FDA obliged manufacturers to track all subjects in their pivotal clinical trials for 5 years, and it was Boston Scientific's review of the data on its paclitaxel-eluting Taxus stent to which Baim was alluding. Four years of data on nearly 3500 patients randomly assigned to receive the Taxus stent or a bare-metal stent showed that the risk of thrombus formation more than 6 months after stent placement was significantly higher in the Taxus group. The difference in risk increased by about 0.2% per year, so that 3 years after stent placement, patients with the Taxus stent had a risk that was about 0.5% higher than that of their counterparts with the bare-metal stent. In early August, the FDA met with Boston Scientific to review these findings.
Concerned about the risks of myocardial infarction and death associated with stent thrombosis, the FDA also met with Johnson & Johnson to discuss that company's data. Dennis Donohoe, vice president of clinical and regulatory affairs at Cordis Corporation, the division that makes Johnson & Johnson's sirolimus-eluting Cypher stent, said that his company reviewed its long-term data set — 4 years of follow-up on nearly 1750 patients randomly assigned to the Cypher stent or a bare-metal stent — and found "numerically" more thromboses in the Cypher group. "While we did not see a significant difference in rates between Cypher and bare metal . . . we did see a trend suggesting more events occurring with Cypher than bare metal," said Donohoe.
(Figure)
Contrasting Mechanisms of Obstruction of Bare-Metal Stents and Drug-Eluting Stents.
Bare-metal stents may be narrowed or obstructed by ingrowth of tissue. With drug-eluting stents, this process is inhibited, but since the struts remain uncovered, they may be prone to thrombosis after antiplatelet therapy is discontinued.
Julie Zawisza, the FDA's assistant commissioner for public affairs, confirmed that in the past few months, the agency has received data from both manufacturers showing "a small additional risk of late stent thrombosis after a year" when stents are used according to their FDA-approved indications and that since summer, the FDA has undertaken extensive reviews of its data on stents. In October, Andrew Farb, a physician with the FDA's Division of Cardiovascular Devices, said that the agency became concerned about the stents, owing to an as-yet-unreleased preliminary analysis of data that FDA staff completed this fall involving off-label use of the stents in patients included in registries that the FDA requires the manufacturers to maintain. "Many of the patients will have more than one complex situation," said Farb. "They'll have multivessel disease and elevated creatinine, they'll be post- and have a bifurcation lesion — so clearly it's a different type of patient than in the initial trials." The new FDA analysis shows that such patients have a greater rate of stent thrombosis than do patients with less complex conditions who participated in trials.
Academic investigators have also been re-reviewing whatever data are available, although some are concerned about the completeness of the information, since the companies have no obligation to make patient-level trial data accessible to independent investigators.
At the Barcelona meeting, Edoardo Camenzind of University Hospital Geneva in Switzerland described a meta-analysis of the results of all published or presented trials comparing the Taxus or Cypher stent with a bare-metal stent. He reported that patients with the Cypher stent had substantially higher rates of death and myocardial infarction than those with a bare-metal stent.1 There were also nonsignificant trends toward higher rates of death and myocardial infarction among patients with a Taxus stent than among those with a bare-metal stent.
Camenzind's collaborator, Philippe Gabriel Steg of H?pital Bichat–Claude Bernard in Paris, said that in doing their meta-analysis, they were impressed "by the consistency of trends and the consistency of the data with other sources of data" such as a study of late stent thrombosis in the Basel Stent Kosten Effektivit?ts Trial, which showed increases in the risks of death and myocardial infarction with drug-eluting stents.2 In addition, an analysis of registry data on more than 8000 patients, presented in Barcelona by Peter Wenaweser of the Swiss Cardiovascular Center in Bern, showed that the incidence of stent thrombosis increased by about 0.6% per year over the course of 3 years. Steg said, "There's this meta-analysis, there's this registry data, there's this randomized clinical trial data — it all points in the same direction, and the direction is that there is a concern with late stent thrombosis and hard events occurring later with drug-eluting stents compared to bare-metal stents."
As the controversy grew, Boston Scientific and Johnson & Johnson joined forces and provided patient-level data from their pivotal clinical trials to the Columbia University-based Cardiovascular Research Foundation for a meta-analysis. The results, presented in October at the Transcatheter Cardiovascular Therapeutics Symposium in Washington, DC, confirm a significant increase in the incidence of stent thrombosis among patients with drug-eluting stents that had been implanted more than 1 year earlier: stent thrombosis occurred in five such patients in the Cypher group, as compared with none in the bare-metal group, and in nine such patients in the Taxus group, as compared with two in the bare-metal group. Stuart Pocock, of the London School of Hygiene and Tropical Medicine, noted that despite these striking findings, the absolute risk of stent thrombosis occurring months or years after stent placement is small — "about one event per 500 patient-years" — and that neither company's data set had shown that drug-eluting stents result in excess deaths or myocardial infarctions.
These data challenge the golden reputation of drug-eluting stents. The devices have reduced the need for both emergency cardiac surgery and additional angioplasty, they are associated with substantially lower restenosis rates at 6 months than are bare-metal stents, and the successful outcomes are visible on angiography. Although a drug-eluting stent costs about $2,200, as compared with $800 for a bare-metal stent, they are now used in more than 90% of angioplasty procedures. Steven Nissen, chairman of the Department of Cardiovascular Medicine at the Cleveland Clinic, thinks that the FDA and cardiologists were blindsided. "The regulators thought that if you got out 9 months and you didn't have restenosis, you were home free," he said. Instead, he added, "We've traded a short-term benefit on a relatively benign disorder, namely restenosis, for a long-term mortality disadvantage."
Some questions were raised earlier by case reports and a 2005 observational study. The study revealed that of 2229 consecutive patients in Germany and Italy who collectively received a total of 4495 sirolimus- or paclitaxel-eluting stents, 29 had stent thrombosis (occurring more than 30 days after stent placement in 15 of the patients), and 13 died — a case fatality rate of 45%.3 As cardiologist Chip Gold of Massachusetts General Hospital observed, "We accepted a technology whose long-term effects have not been studied."
Since, by definition, "very late" stent thromboses occur after the 3 or 6 months of antiplatelet therapy recommended by the stent makers, most patients with thrombosis who were identified in the recent analyses were no longer taking aspirin and clopidogrel when the thrombosis occurred — raising the question of whether extended therapy could have averted the events. Recognizing that one of the risk factors for thrombosis is premature discontinuation of antiplatelet therapy, many physicians now recommend extended or lifetime prescriptions of aspirin and clopidogrel for patients receiving drug-eluting stents. Current U.S. and European guidelines indicate that the drugs should be taken for up to 12 months, unless a patient is at high risk for bleeding.4,5
However, the companies have not markedly changed their official recommendations about the duration of drug therapy (although the FDA now recommends that patients not discontinue therapy without consulting their physician). After the December meeting, the FDA is expected to recommend a change.
Asked why his company didn't discover the increased risk sooner, Baim said, "It's a phenomenally-low-frequency event." But Steg pointed out that access to data is more restricted in device trials than in drug trials. As a result, patient-level trial data on drug-eluting stents have not been subject to open scrutiny, and it has been difficult for independent researchers to discover the numbers and causes of deaths. Gold said that preclinical data on arterial reactions to the stents, which could illuminate the pathophysiology of late thrombosis, have also been hard to obtain.
Although crucial issues such as independent investigators' access to data and control of analyses could be aired at the FDA meeting in December, the session seems poised to degenerate into a series of debates between industry representatives and investigators about the validity and meaning of the findings. The two companies may also be expected to debate each other, their mutual animosity inflamed by their competition to acquire Guidant Corporation last spring and by a resulting lawsuit launched by Cordis this fall. Daniel Schultz, director of the FDA's Center for Devices and Radiological Health, acknowledged the rivalry but said he hopes "the companies will take the high road here."
Outside the United States, several second-generation drug-eluting stents have been approved, including Medtronic's Endeavor (coated with zotarolimus), Abbott's Xience V (coated with everolimus), and Conor Medsystem's CoStar (coated with paclitaxel); however, given the concerns about late stent thrombosis, the FDA could ask companies for longer-term data before considering newer stents for approval in the United States. How long that term should be is likely to be one more contentious issue at the FDA meeting.
Meanwhile, as clinicians sort through the new information and await the FDA's pronouncements, they are already reducing their use of the current technology slightly: sales of drug-coated stents have dipped by 5% for Boston Scientific and 6% for Cordis, while sales of bare-metal stents are edging up.
Source Information
Dr. Shuchman is an assistant professor in the Department of Psychiatry at the University at Buffalo School of Medicine and Biomedical Sciences, Buffalo, NY.
References
Camenzind E, Steg PG, Wijns W. A meta-analysis of first generation drug eluting stent programs. Presented at Hotline Session I, World Congress of Cardiology 2006, Barcelona, September 2–5, 2006.
Pfisterer ME, Brunner-La Rocca HP, Buser PT, et al. Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: an observational study of drug-eluting vs. bare-metal stents. J Am Coll Cardiol (in press).
Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005;293:2126-2130.
Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction -- executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1999 guidelines for the management of patients with acute myocardial infarction). J Am Coll Cardiol 2004;44:671-719.
The Task Force for Percutaneous Coronary Interventions of the European Society of Cardiology. Guidelines for percutaneous coronary interventions. Eur Heart J 2005;26:804-847.(Miriam Shuchman, M.D.)