Taking Pills, Even If Placebo, Predicts Better Survival in Heart Failure
DURHAM, N.C. -- In findings that can not totally be
explained but are sure to lead to future research, Duke Clinical Research
Institute investigators have found that adherence to
medical therapy, even if the medication is an inert placebo,
relates to better outcomes for heart failure patients.
This finding persisted even after the researchers
statistically controlled for a wide variety of patient and
treatment characteristics. The researchers also said that their
findings do not appear to be a statistical quirk because of the
large numbers of patients involved and the length of follow-up
in the clinical trial that served as the basis for their
In an international clinical trial of 7,599 heart failure
patients, the researchers found that good adherence was
associated with similar lower mortality rates for both the
placebo and an angiotensin receptor blocker (ARB), a medication
used to relax and dilate blood vessels, when compared to
patients who were not as adherent. Also, good adherence was
associated with lower rates of hospitalization for both placebo
and active drug.
"Adherence to medications is one of the most important
predictors of clinical outcomes for patients with complex
diseases like heart failure," said Bradi Granger, Ph.D., who
presented the results of the Duke analysis Nov. 9, 2004, at the
American Heart Association's annual scientific sessions in New
"Our finding that adherence to a placebo was an important
and independent predictor of better outcomes suggests that
adherence itself is a marker for other unmeasured variables
that can determine outcome," Granger continued. "Understanding
these factors may provide an opportunity for novel
interventions, including those targeted at improving
Also known as congestive heart failure, heart failure is a
condition characterized by the thickening of the walls of the
heart. Over time this thickening restricts the heart's ability
to pump enough blood to the body's tissues, and thereby to
provide them with oxygen and nutrients. The typical heart
failure patient takes an average of six different medications
to control their symptoms and improve their quality of life,
the researchers said.
An estimated 5 million Americans suffer from the condition,
with 400,000 new cases reported each year. Half of the patients
die within five years of the diagnosis, typically after
According to Granger, about two-thirds of all hospital
admissions for heart failure are preventable and due to
non-compliance in such areas as diet, close attention to
symptoms and adherence to drug regimens. Since it has been
known that poor adherence can limit the effectiveness of
medications for heart failure patients, the researchers studied
the issue in a large double-blind, randomized controlled
clinical trial of the ARB candesartan.
The five year trial, Candesartan in Heart Failure Assessment
of Mortality and Morbidity (CHARM), was one of the largest such
trials and had an average patient follow-up of 38 months.
Adherence was measured as the proportion of time patients took
at least 80 percent of the study medication.
Two earlier heart studies – the Coronary Drug Project in
1980 Beta-Blockers in Heart Attack in 1982 – showed similar
patterns as the new Duke analysis, and according to Granger,
researchers have attempted over the years without success to in
explain the beneficial effects of adherence in those studies.
Researchers have studied such non-medical variables as martial
status, stress, education and social isolation, but could not
uncover a statistical link to adherence, she said.
"The consensus is that there must be something that
differentiates people who adhere from people who do not,"
Granger said. "We don't know why, but they are different in
terms of outcome."
Even without an understanding of the reasons for this
phenomenon, Granger does believe that improving adherence
should help patients avoid frequent hospitalization and improve
survival. Such strategies as calling or mailing reminders to
patients about taking their medications, involving friends or
family members their care, or simplifying the drug regimen have
been shown to improve compliance, Granger said.
"These strategies can be effective, but they are expensive
and labor-intensive," Granger said. "It would be helpful if we
could determine what characteristics predict non-adherence, and
so could target our efforts toward that population of
The CHARM trial was funded by AstraZeneca, Mondal, Sweden.
Granger's analysis was supported by the Duke Clinical Research
Other members of the team were Karl Sedberg and Inger Ekman,
Sahlgrenska University Hospital, Goteborg, Sweden; Jan
Ostergren, Karolinska Hospital, Stockholm, Sweden; Salim Yusuf,
McMaster University, Hamilton, Ontario; Eric Michelson,
AstraZeneca; Christopher Granger, Duke; and Marc Pfeffer,
Brigham & Women's Hospital, Boston.