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DURHAM, N.C. -- The deaths or clinical complications in
heart attack patients given potent drugs to re-open clogged
arteries is more likely to be due to individual patient
characteristics than to modest misdosing of the drugs,
researchers from the Duke
Clinical Research Institute (DCRI) have determined. Thus,
they said, physicians should not be overly worried about the
possibility of minor errors in dosing -- a concern that the
Duke physicians said likely contributes to insufficient
prescribing of the drugs to treat heart attacks.

These findings are important, the researchers said, because
approximately one in three patients rushed to emergency rooms
with heart attack symptoms do not receive these potentially
life-saving drugs. One reason cited for this under-usage is
that many physicians may be overly – albeit sometimes
justifiably -- concerned about potential adverse events due to
incorrect dosing, the researchers said.

The drugs, known as fibrinolytic agents, have been proven
effective in clinical trials in breaking apart blood clots in
coronary arteries, restoring blood flow to heart and saving
heart muscle. The doses of some of the drugs in this class are
determined by a calculation that includes body weight, which
must often be estimated in emergency situations. The amount of
drug administered is crucial, the researchers said, since too
much can cause unwanted bleeding events, while too little will
not dissolve the blood clot.

"Many physicians have assumed that modest errors in dosing
errors of these fibrinolytic drugs can cause harm, which made
them afraid to give the drugs altogether," said Duke University
Medical Center cardiologist Christopher Granger, M.D., senior
member of the research team that published the results of their
analysis in the April 13, 2005 issue of the Journal of the American Medical
Association. The DCRI's Rajendra Mehta, M.D. was the first
author of the paper.

"We have found that there does not appear to be a
cause-and-effect relationship between small dosing errors and
worse outcomes for patients," Granger continued. "These
findings should be somewhat reassuring to busy physicians in
emergency rooms who can assume that as long as the drugs are
given carefully to the right patients, small misdosings should
not lead to bad outcomes. These are a class of drugs that can
save lives, but tend to be underused."

For their study, the Duke team analyzed the results of the
16,949-patient clinical trial concluded in 1998 known as
ASSENT-2 (Assessment of the Safety and Efficacy of a New
Thrombolytic). The trial compared the effectiveness of tissue
plasminogen activator (t-PA) and TNK, a newer genetically
altered version of t-PA. t-PA works by dissolving blood clots
and is most effective when administered within hours of heart
attack symptoms.

Using the data collected from ASSENT-2, the researchers
analyzed to what extent incorrect dosing – whether over or
under – was responsible for death, stroke or major bleeding
within 30 days of treatment.

"Like previous studies, our analysis showed that about five
percent of the patients in ASSENT-2 received incorrect doses of
t-PA," Mehta said. "What is so fascinating is that we found the
nearly same excess risk of misdoses of placebo that we found in
misdosing t-PA. This suggests that most, if not all, of the
associations between incorrect dosing of t-PA and adverse
events were due to other confounding factors."

When the researchers adjusted the data for these confounding
factors, they found that the association was greatly reduced.
The patient-specific factors that appeared to bestow the
greatest risks for adverse events included advanced age, female
gender, being African-American, shorter stature, lower body
weight, and lower blood pressure.

Specifically, the 30-day mortality rate for those who
received a t-PA overdose was 9.8 percent, and 19.5 percent for
those receiving an underdose. Those receiving a correct dose
had a mortality rate of 5.4 percent. Conversely, those who
received an overdose of placebo had a 10 percent mortality
rate, and 23.5 percent rate for underdose. Those who received
the correct dose of placebo also had a 5.4 percent mortality
rate.

"These findings are counterintuitive – when given the wrong
dose of placebo, there was much worse outcome," Granger said.
"This is clearly a remarkable finding, as well as a reason to
pause – whenever we see a relationship between a treatment and
an outcome, we must be careful in ascribing cause and effect.
Other factors may also be involved, and additional studies are
needed to better understand what these factors may be."

Granger cited as a similar example the issue of hormone
replacement therapy (HRT) for post-menopausal women. Earlier
observational studies of thousands of women indicated an
association between HRT and a lowered risk of heart attack.

"However, when the randomized, scientific studies were done
the opposite was proven to be true, that there was in fact an
increased risk of blood clots and stroke," Granger said.
"Another example is vitamin E. At first, earlier studies
appeared to show that vitamin E was associated with better
outcomes, but when the proper studies were conducted, it turned
out not to be the case."

While Granger does not believe that the results of this
analysis will change clinical practice, he does believe that
hospitals and physicians should not withhold beneficial drugs
because of concern over misdosing, as long as the drugs are
given carefully and errors minimized. Less concern about minor
misdosing could lead to an increased usage of the drugs.
Additionally, he said that the patients at the highest risk for
adverse outcomes should be closely monitored while they are
receiving fibrinolytic therapy.

Mehta believes that the results of this study could also
have an impact on medical malpractice litigation, which is
often driven by adverse outcomes.

"This study finds that adverse outcomes following modest
errors in fibrinolytic dosing are often times not caused by the
error, but by clinical factors that may contribute to higher
likelihood of the error occurring," Mehta said.

The ASSENT-2 trial was funded by Boehringer Ingelheim and
Genentech, Inc. Granger's analysis of the ASSENT-2 data was
supported by the DCRI.

Other members of the team, from the DCRI, were John
Alexander, M.D., Karen Pieper, Jyotsna Garg, and Robert Califf,
M.D. Other colleagues were Frans Van de Werf, M.D., University
Hospital Lueven, Belgium, and Paul Armstrong, M.D., University
of Alberta, Edmonton.