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Placebo Effect could Skew Tests of New Therapies

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Duke Health News 919-660-1306

AMSTERDAM - Clinical trials that only use a cardiac
patient's quality of life as a measure of treatment success may
skewresults due to a prominent "placebo effect," researchers
caution.

In a unique study, investigators at Duke Clinical Research
Institute Durham, N.C., looked at whether a patient's
assessment ofhis or her own health status - a frequent
"endpoint" in clinical trials of novel therapies - bore any
relationship to the actual clinicaloutcome they had, based on
the treatment they received.

In a study of 1,189 patients with severe coronary artery
disease, researchers found that the treatment patients received
-aggressive or not - had no impact on their sense of
well-being. All patients in the study rated their health status
as similarlyimproved since coming under a doctor's care.

But such a bright outlook was not always reflected in
mortality figures. Death rates for patients for whom only drug
therapy wasavailable were twice as high compared to those who
received heart bypass surgery or an angioplasty procedure to
clearclogged heart passages.

The study was a surprise to researchers, who say it points
out a prominent "placebo effect" that can be slanting the
results ofclinical trials that judge success based on
quality-of-life indicators.

"Even the sickest patients in this study, those for whom
revascularization wasn't an option, felt better during the time
they werebeing followed by physicians," said Duke cardiologist
Dr. James Jollis, who led the study. "When you take care of
patients overtime and follow their progress, the placebo effect
can be strong."

He prepared his study for presentation Aug. 28 at the 22nd
annual congress of the European Society of Cardiology.
The studywas funded by Genentech Inc., of South San Francisco,
Calif.

Jollis noted that trials of several new techniques, such as
myocardial laser perforation and the use of vascular growth
factors,have relied on general health status instead of "harder
endpoints such as death or costs."

For example, recent tests of vascular growth factors have
been negative because patients in both the test and control
groupsboth have shown improvement. The unexpected improvement
among placebo patients could lead to falsely negative
findings,Jollis said. "Based on the Duke analyses, such trials
may have been positive if more patients had been included," he
added.

"There are many more things that affect the way patients
feel other than just the status of their hearts," he said.
"Variables canrange from non-cardiac illnesses to non-medical
issues, such as social, psychological and economic factors.

"Our data suggest that qualify-of-life measures vary little,
such that many patients would be required to detect a
treatmentbenefit, while mortality and cost vary greatly, such
that fewer patients would be required to detect a benefit,"
Jollis said.

This is important because the number of patients with
"end-stage" coronary artery disease - those for whom bypass
surgery orangioplasty is no longer an option - "continues to
grow" and, consequently, more therapies are being designed to
treat them,Jollis said. "It's important that these new
therapies be tested and measured in such a way that it
demonstrates theireffectiveness."

The Duke study specifically picked a group of patients with
severe coronary disease to study because they expected
thatpatients who received revascularization procedures (bypass
surgery or angioplasty) would report a higher quality of
life,compared to patients who could only be treated with
medicine. Optimal treatment for such disease is
revascularization, but inthis study, 487 patients (41 percent)
could not undergo the therapy due to their coronary anatomy or
excess risk of death.

Patients were asked to complete two questionnaires after
treatment and then at one and two years of follow-up study.
Onequestionnaire consisted of a 36-item health survey on such
topics as general health perceptions, physical functioning,
bodily painand general mental health. The other asked patients
to rank the ease with which they are able to perform common
activities ofdaily living.

Results show that patients who only received drug therapy
had a similar pattern of positive change in their
self-assessment ofphysical and emotional limitations.
Functional status also improved for all patients, independent
of their treatment.

But when data on death rates and cost of hospitalization
were tallied on the same group of 1,189 patients, it was clear
thatthose who had not qualified for a revascularization
procedure did much worse, Jollis said.

After two years, mortality in patients who were treated with
only medicine was 38 percent, compared to 15 percent in
patientswho had an angioplasty and 19 percent for bypass
surgery patients. During that follow-up period, hospital costs
of $40,471was also substantially higher in the group that
didn't have revascularization, compared to $34,785 for
angioplasty patients and$24,005 for bypass patients.

"Remarkably, despite greater disease burden and mortality,
patients with end-stage coronary artery disease do not
perceivetheir health status to change in a significantly
different fashion compared to patients still eligible for
conventionalrevascularization," Jollis said. "These findings
should inform the design of trials involving novel therapies,
suggesting thatmortality and cost be included as primary
endpoints when considering effectiveness."

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