BOSTON -- A blizzard of words in a quintet of studies, and more, all released online today by the New England Journal of Medicine offered evidence that drug-eluting coronary stents seem safe when used as indicated, but the issue of high risk patients remains in question.
BOSTON, Feb. 12 -- A blizzard of words in a quintet of studies, and more, all released online today by the New England Journal of Medicine, offered evidence that drug-eluting coronary stents seem safe when used as indicated, but the issue of high risk patients remains a question.
To give a sense of the nature and complexity of the debate over the late-thrombosis safety of the drug-eluting devices, the NEJM, in addition to the five studies, issued two perspectives, one editorial, and an audio "debate." All were put into the medical literature nearly a month ahead of the March 8 publication date.
There was plenty of evidence to fuel both sides of the safety debate, which erupted in full fury last September at an international heart meeting in Barcelona and led to a special FDA safety advisory committee meeting late in the year.
Among the findings (often from different authors, analyzing the same data) in the NEJM:
All of the studies agreed on one point-drug-eluting stents almost eliminate the problem of restenosis and significantly reduce the need for revascularization compared with bare-metal stents.
Findings of all of the studies have been previously reported and all five were presented to the FDA advisory committee during two days of hearings.
But the editors of the NEJM said their motivation for publishing the studies now was "the recent concern that the implantation of drug-eluting stents, as compared with bare-metal stents, may be associated with a small increased risk of late stent thrombosis."
Three of the five papers analyzed data from pivotal trials of Cypher (sirolimus-eluting) stent and/or the Taxus (paclitaxel-eluting) stent. In each of these pivotal trials the drug-eluting stent was compared with a bare-metal stent.
Another was an analysis of data from 14 published randomized controlled trials-both pivotal and post-marketing trials-of Cypher or Taxus compared with bare metal stents.
The final study was a report from a registry of more than almost 20,000 stent patients-both bare-metal and drug-eluting-who were treated in Sweden in 2003 and 2004.
Using data supplied by Cordis, the Johnson & Johnson subsidiary that makes Cypher, and Boston Scientific, which makes Taxus, Gregg W. Stone, M.D., of the Cardiovascular Research Foundation and Columbia University in New York, reported that the four-year rate of stent thrombosis was 1.2% in the Cypher group versus 0.6% in the bare metal group (P=0.20) and 1.3 for Taxus verus 0.9% for bare metal (P=0.30).
But, after a year, there were five episodes of stent thrombosis for Cypher versus none in the bare-metal arm (P=0.025). Likewise, after 12 months there were nine cases of late stent thrombosis reported for Taxus versus two in the bare-metal comparator arm (P=0.028).
Importantly, there were no "significant differences in the cumulative rates or death or myocardial infarction at four years," Dr. Stone said.
Dr. Stone's analysis used the original protocol definitions of stent thrombosis, but when Laura Mauri, M.D., of the Harvard Clinical Research Institute analyzed the same data using a different definition of stent thrombosis-the numbers changed.
Dr. Mauri used a definition developed by the Academic Research Consortium-a group that represents investigators and stent makers but does not have input from professional organizations such as the American College of Cardiology or American Heart Association.
The per protocol or traditional definition of late-stent thrombosis included any thrombosis that occurred more than 30 days post-procedure in a target vessel that had not undergone revascularization.
Bare-metal stents have a significantly higher revascularization rate than drug-eluting stents, so the per protocol definition was biased because-Dr. Mauri and others reasoned-a significant number of bare-metal stent thromboses occurred in revascularized vessels, which were not counted. That bias, she said, underestimated the thrombosis rate for bare metal stents.
The new definition classified stent thrombosis as definite, probable, or possible and as early (zero to 30 days), late (31 to 360 days) and very late (more than 360 days).
Definite thrombosis was defined as acute coronary syndrome with angiographic or autopsy evidence of thrombus or occlusion, while probable was defined as unexplained death within 30 days or acute myocardial infarction involving the target vessel. Possible stent thrombosis was defined as any unexplained death occurring 30 days or more post-procedure.
Using this definition, Dr. Mauri said the pivotal trial data provided no evidence of significant differences in the incidence of stent thrombosis between the drug-eluting stent and bare metal stent treatment groups.
In fact, the new definition found a slightly higher-but not statistically significant- rate of stent thrombosis for the bare-metal stent, 1.7% versus Cypher, 1.5% (P=0.70). For Taxus the rate was 1.8% versus 1.4% for bare-metal (P=0.52).
Christian Spaulding, M.D., of Hpitaux de Paris Couchin Hospital, Medical School Ren Descartes University, and INSERM Unit performed a pooled analysis of data from four of the Cypher pivotal trials and reported that overall survival and event rates were not significantly different.
But those same data confirmed a significant difference in survival for 428 patients with diabetes.
Among diabetic patients use of Cypher was associated with almost a tripling of mortality (hazard ratio 2.9; 95% CI 1.38-6.10; P=0.008).
When Adnan Kastrati, M.D., of Deutsches Herzzentrum, Technishe University in Munich analyzed data from 14 published trials comparing Cypher with bare-metal stents, he found that Cypher use was associated with more than a 50% reduction in the combined risk of death, MI, or reintervention (HR 0.43; 95% CI, 0.34 to 0.54).
Dr. Kastrati said that while there was not a significant difference in the risk of stent thrombosis for Cypher versus bare-metal stents, there was "evidence of a slight increase in the risk of stent thrombosis" associated with Cypher after 12 months.
The bad news for drug-eluting stents was delivered by Bo Lagerqvist, M.D., Ph.D., of the Swedish Coronary Angiography and Angioplasty Registry, and colleagues, which reported data from 6,033 patients treated with either Cypher or Taxus and 13,738 patients who had bare-metal stents implanted.
At six months the Swedish data favored the drug-eluting stents, which had lower event rates. But after six months, "patients with drug-eluting stents had a significantly higher event rate, with 12.7 more events per 1,000 patients per year (adjusted relative risk 1.20; 95% CI 1.05 to 1.37).
"At three years post procedure, mortality was about 18% higher for drug-eluting stent patients, "and from six months to three years, the adjusted relative risk for death in this group was 1.32 (95% CI, 1.11 to 1.57).
In the audio debate hosted on the NEJM website, Donald Baim, M.D., chief medical and scientific office at Boston Scientific, said the Swedish data reflected operator bias, because cardiologists used drug-eluting stents in patients with more complicated, longer lesions-a population in which more adverse events should be expected.
Steven Nissen, M.D., chairman of the department of cardiovascular medicine at the Cleveland Clinic, said that he believed the Swedish data reflected real world use of drug-eluting stents, noting that in the U.S. an estimated 60% of drug-eluting stents are used in patients with more severe disease. He said the data suggest the drug-eluting stents are not safe in those patients.
Samin Sharma, M.D., director of the cardiac catheterization laboratory at Mount Sinai Heart Institute in New York, said he believes the "the crux of the issue is Plavix (clopidogrel) compliance."
Dr. Sharma, who was not involved in the studies, noted that several studies reported an increase in stent thrombosis at 12 months, "which was the time in clinical practice when Plavix was most often stopped."
Going forward, he said the critical issue is the evaluation of the patient for acceptance of Plavix therapy.
"At Mount Sinai for patients coming in the door, the first consideration is evaluation of the patient for Plavix," he said.
If a patient cannot tolerate Plavix, "the patient will not receive a drug-eluting stent because I believe that without Plavix a drug-eluting stent is no better than a bare metal stent."
He added that all patients who receive drug-eluting stents at Mount Sinai are now kept on Plavix for three years because "I think that after three years endothelialization of the stent is complete and thrombosis is no longer an issue."
Dr. Sharma said his center also "discharges patients with warning cards stating that the patient is not to be taken off Plavix without first contacting his or her cardiologist."
In one of the two perspectives, Andrew Farb, M.D., and Ashley B. Boam, M.S., of the FDA's office of device evaluation at the Center for Devices and Radiological Health, noted that it was difficult to explain why data from the pivotal trials did not detect an increase in mortality when the data did identify an increase in very late stent thrombosis for drug-eluting stents.
They suggested, however, that it was "possible that the samples in the pooled studies were simply not large enough to permit detection of a difference in the groups."
Dr. Nissen agreed with this explanation, noting that his calculations suggested that the pivotal trials were significantly underpowered to detect mortality, which he said would require a trial with at least 8,000 patients.
Finally, William H. Maisel, M.D., M.P.H., of Beth Israel Deaconess Medical Center and Harvard Medical School in Boston, who chaired the FDA drug-eluting stent advisory committee hearings last December, summed up the frustration of many clinicians.
"Unfortunately, despite the five years that have elapsed since the start of the clinical trials and the implantation of millions of drug-eluting stents, much remains uncertain about the long-term safety of the devices."
Drs. Sharma, Maisel and Nissen and Ms. Boam declared no conflicts.
The Swedish registry trial was supported by the Swedish Association of Local Authorities and Regions, the Swedish Heart-Lung Foundation, the Swedish Board of Health and Welfare and the Swedish Medical Products Agency. Dr. Lagerqvist and his co-authors declared no conflicts.
The analysis of 14 published trials of Cypher versus bare-metal stents was supported by Deutsches Herzzentrum in Munich. Dr. Kastrati and co-authors declared financial support from one or more of these entities: Bristol-Myers Squibb, Cordis, GlaxoSmithKline, Lilly, Medtronic, Novartis, Sanofi-Aventis, Merck, Amersham/General Electric, Bayerische Forschungsstiftung, Cryocath, Guidant, Nycomed, and Schering.
Dr. Stone's study was supported by the Cardiovascular Research Foundation. Dr. Stone and co-authors Jeffrey W. Moses, M.D., Ajay J. Kirtane, M.D., Martin B. Leon, M.D., and Roxana Mehran, M.D., are directors of the Cardiovascular Research Foundation, which receives funding from Boston Scientific, Cordis, Sanofi-Aventis, and Bristol-Myers Squibb. Dr. Stone and colleagues reported financial support from Boston Scientific, Abbott, Guidant, Xtent, BMS Imaging, Medtronic, Cordis, Conor, Nycomed, Eli Lilly, OrbusNeich. Dr. Stone has equity interests in Devax and Xtent and is a member of the board of directors of Devax. Dr. Leon has equity interests in Conor, Medinol, and OrbusNeich.
Cordis and Boston Scientific contracted with Harvard Clinical Research Institute to perform the analysis reported by Dr. Mauri. Drs. Mauri, Joseph M. Massaro, Ph.D, and Ralph D'Agostino, Ph.D., received reimbursement for preparation time, travel, and lodging to present those data at the FDA hearing. Donald E. Cutlip, M.D., a co-author, received support from Bristol-Myers Squibb.