Contact

Duke Health News

919-660-1306

DURHAM, N.C. – 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.