Heart patients who have received drug-coated stents to hold open an artery and who stop taking the drug clopidogrel to reduce blood clotting may face more than double the risk of death or heart attack than patients who continue on the drug, according to an analysis by Duke Clinical Research Institute investigators.
The finding suggests that patients who receive "drug-eluting" stents may need to continue taking clopidogrel, a costly drug, for much longer than previously thought, maybe even for life, the researchers said.
"Patients with drug-eluting stents should consult their physicians regarding continuation or reinitiation of treatment with clopidogrel; however, these data strongly suggest that anyone with a drug-eluting stent should continue taking clopidogrel until a new randomized clinical trial can identify the implications of discontinuing it," said cardiologist Robert Califf, M.D., director of the Duke Translational Medicine Institute and senior member of the research team. "With more than 600,000 patients receiving stents each year in the United States, and many more people worldwide, the need for definitive evidence rises to the level of a major public health concern."
The researchers published the findings on Tuesday, Dec. 5, in the early online edition of the Journal of the American Medical Association, and they are also expected to present them on Friday, Dec. 8, at a meeting of the Food and Drug Administration's Circulatory System Devices Advisory Committee in Washington, D.C.
The analysis was funded by the Agency for Healthcare Research and Quality as part of the DECIDE (Developing Evidence to Inform Decisions about Effectiveness) Network in the Effective Healthcare Program.
Drug-eluting stents were approved by the FDA in 2003, and within 18 months they accounted for 80 percent of new stent implants in the United States, according to the researchers.
"As is frequently seen with new cardiac devices, a rapid increase in clinical adoption quickly outstripped what is known about the device from limited clinical trials," Califf said.
In their analysis of more than 4,600 patients who received drug-eluting stents, the researchers found that patients who had experienced no adverse effects from their devices but who stopped taking clopidogrel six or 12 months after receiving their stent were more than twice as likely to die or have a heart attack than patients who continued to take the drug.
Stents are thin metal mesh tubes that prop open a coronary artery after cardiologists have conducted "balloon angioplasty" to push the blockage against the wall of the artery. The first generation of the devices were made of bare metal, but over the past several years surgeons have in large measure switched to using drug-eluding stents that help to prevent potentially dangerous formation of tissue in the stents.
Physicians normally prescribe that clopidogrel, sold as Plavix, be used along with aspirin for three to six months following stent placement. But the drug is not free of risks, Califf said. It can cause thrombotic thrombocytopenic purpura (TTP), a rare disorder of the blood coagulation system. Also, clinical trials have revealed that use of clopidogrel can, in rare cases, increase risk of hemorrhage or experiencing decreased levels of white blood cells, and, more commonly, cause stomach pain, gastrointestinal issues, headaches and dizziness. Patients taking clopidogrel must stop taking the drug if they are scheduled to undergo surgery or some other type of invasive medical procedure that might lead to bleeding. On average, the drug costs about $1,400 per year, the researchers said.
"If the use of drug-eluting stents is committing millions of patients to lifelong clopidogrel use, then we need to understand the implications for patients and for the health care delivery system," Califf said.
Recent studies have suggested that patients who stopped taking clopidogrel three to six months after receiving their stents have higher rates of death or cardiac events, such as a heart attack. But Califf said no definitive clinical trials have been conducted to understand the effects of longer-term clopidogrel use.
In the current study, the team drew data from the Duke Database for Cardiovascular Disease, a compilation of data on heart patients with significant coronary artery disease who come to Duke University Hospital for diagnosis and treatment.
The researchers studied 4,666 consecutive patients who received a stent between Jan. 1, 2000, and July 31, 2005. Cardiologists at the hospital began using drug-eluting stents on April 1, 2003. Of the study subjects, 3,165 received a bare metal stent and 1,501 received a drug-eluting stent. Results from this analysis are generalizable to all patients receiving drug-eluting stents and do not reflect an experience particular to Duke, the researchers said.
The researchers grouped together all patients who had not had experienced an adverse cardiac event (heart attack or additional revascularization procedure) or died six months after the procedure. After two years, patients with drug-eluting stents taking clopidogrel had a death rate of 2 percent, compared with 5.3 percent for patients not taking clopidogrel, Califf said. The combined rate of death or heart attack was 3.1 percent for those taking clopidogrel, compared with 7.2 percent of those not taking clopidogrel.
The researchers conducted a similar two-year follow-up on patients who went one year without a cardiac event or death, and they found that clopidogrel had a significant positive effect on death and heart attacks in this group as well. No patients taking clopidogrel died, compared with 3.5 percent of those not taking clopidogrel. The combined risk of death or cardiac event also was similar: none for those taking clopidogrel, compared with 4.5 percent for those not taking clopidogrel.
"It's important to understand that the total absence of death or heart attacks among the patients in this group who took clopidogrel was probably a chance occurrence; thus, we are not saying that clopidogrel completely prevents these problems," said Eric Eisenstein, D.B.A., a health economist and principal author of the study report. "But our findings do provide a strong rationale for continuing clopidogrel until we have more evidence."
The study also demonstrated that patients who had received bare metal stents derived no benefit from taking clopidogrel in terms of reducing their long-term mortality or avoiding adverse cardiac events, the scientists noted.
Although the researchers say the results of the current study are suggestive, they also point to the need for a larger clinical trial to gain better understanding of possible health effects associated with the use of drug-eluting stents.
In the journal report, they outlined details for a three-year study of 10,000 patients who have received the stents. The patients would be assigned randomly into three groups, with one group taking clopidogrel for 12 months, another for 24 months, and the third for 36 months. At the end of the study, researchers would compare the rates of fatal and of nonfatal cardiac events among the three groups to determine whether longer-term clopidogrel use is beneficial.
Other researchers who participated in the current study were Kevin Anstrom, David Kong, Linda Shaw, Robert Tuttle, Daniel Mark, Judith Kramer, Robert Harrington, David Matchar, David Kandzari, Eric Peterson and Kevin Schulman.
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