P RO & C ON : I S N ESIRITIDE S AFE ?
PAGE 10
VO L . 3 , N O. 1 1
The rate of ischemic events at 3 months was 52% greater in
quinopril- than placebo-treated patients, said Dr. Wiek H. van Gilst.
No Benefit of Early
ACEI After Bypass
BY BRUCE JANCIN
Denver Bureau
S T O C K H O L M — The initiation
of ACE inhibitor therapy within
7 days of coronary artery bypass
graft surgery does not improve
clinical outcomes in low-risk pa-
tients without a conventional in-
dication for it, Wiek H. van Gilst,
M.D., said at the annual congress
of the European Society of Car-
diology.
In fact, just the opposite was
observed in the 2,553-patient
Ischemia Management With Ac-
cupril Post Bypass Graft via
Inhibition of Angiotensin-Con-
verting Enzyme (IMAGINE) tri-
al, conducted in Europe and
Canada. The incidence of is-
chemic events was 52% greater in
the quinapril (Accupril) group
than with placebo during the first
3 months of follow-up, although
at the end of the full 43 months,
there was no significant differ-
ence between the two treatment
groups, noted Dr. van Gilst, pro-
fessor of cardiovascular and clin-
ical pharmacology at University
Medical Center, in Groningen,
the Netherlands.
The rationale behind the
IMAGINE trial was that the
post–coronary artery bypass
graft (CABG) period is known to
be a time of increased local and
systemic inflammation, throm-
botic activity, and endothelial dys-
function, and ACE inhibitors
Cardiology News www.ecardiolog ynews.com
T he Leading Inde p endent Ne wspaper for the Cardiologist
B RUCE J ANCIN
have been shown to curb en-
dothelial dysfunction and exert
an anti-inflammatory effect. The
hypothesis of the study was that
quinapril, at a target dose of 40
mg once daily, would slow ath-
erosclerotic progression and re-
duce ischemic events.
This specific issue had not been
examined before. The earlier
Heart Outcomes Prevention
Evaluation (HOPE), European
Trial on Reduction of Cardiac
Events With Perindopril in Stable
CAD (EUROPA), and Prevention
of Events With Angiotensin-
Converting Enzyme Inhibition
(PEACE) trials included collec-
See Bypass page 9
VITAL SIGNS
Many Patients ‘Strongly Favor’ Physicians’
Use of New Medical Technologies
Home monitoring
E-mail with patient
Imaging by e-mail
Electronic records
Personal digital device
Note: Based on a nationwide survey of 2,048 adults conducted Sept. 30
to Oct. 4, 2005.
Sources: The Wall Street Journal Online, Harris Interactive
INSIDE
Routine Use of
Drug-Eluting Stents
Not Cost Effective
Certain high-risk subgroups are exceptions.
Chest Pain BY BRUCE JANCIN
Threefer Denver Bureau
One quick scan can rule out
three conditions. S T O C K H O L M — Routine use
of drug-eluting stents in a real-
PAGE 21 world patient setting is not good
value for money, according to
the findings of the first-ever ran-
ECGs for All domized trial that compared
Screening all newborns drug-eluting stents with bare-
for long QT syndrome is
worth it.
metal stents in unselected pa-
tients in a study free of industry
sponsorship.
PAGE 9 The results of the Basel Stent
Cost Effectiveness Trial (BAS-
KET) suggest that the use of
drug-eluting stents (DESs) could
reasonably be restricted to se-
lected high-risk patient sub-
groups, Matthias Pfisterer, M.D.,
said at the annual congress of the
Groups Issue Appropriate
Avian Flu Use Criteria for Imaging
What you can do to protect
BY ROBERT FINN
yourselves and your patients. San Francisco Bureau
PAGE 31
D riven by concerns over the
rising cost of cardiovascular
care and looming pay-for-perfor-
mance rules, a technical panel
convened by the American Col-
lege of Cardiology Foundation
and the American Society of
Nuclear Cardiology has released
the first set of appropriateness
criteria for a cardiac-imaging
modality.
51% The panel considered which of
52 clinical scenarios were appro-
49% priate indications for single-pho-
ton emission computed tomog-
44%
CARDIOLOGY NEWS
42% 12230 Wilkins Avenue
Rockville, MD 20852
CHANGE SERVICE REQUESTED
37%
K EVIN F OLEY, R ESEARCH
N OV E M B E R 2 0 0 5
European Society of Cardiology.
“Based upon these data, we
can define some subgroups
where these stents are more at-
tractive. They are more cost ef-
fective in patients older than 65
years with three-vessel disease,
more than one treated segment,
longer lesions, and small treated
vessels. This will hold true until
the price of drug-eluting stents
falls significantly,” said Dr. Pfis-
terer of the University of Basel
(Switzerland).
In a typical catheterization lab-
oratory, perhaps two-thirds of pa-
tients fit that description, he
added.
“Turning the data around,” he
continued, “we can say that
See Routine Use page 23
raphy myocardial perfusion
imaging (SPECT MPI), which
were inappropriate indications
for SPECT, and which were un-
certain indications ( J. Am. Coll.
Cardiol. 2005;46:1587-605). The
criteria have been endorsed by
the American Heart Association.
The panel judged SPECT to be
a generally acceptable and rea-
sonable approach in 27 of the
clinical scenarios. These included
evaluation of asymptomatic pa-
tients with high Framingham risk
of coronary heart disease (CHD),
asymptomatic patients with
coronary calcium scores of 400
See Appropriate Use page 8
Presorted Standard
U.S. Postage
PAID
Permit No. 384
Lebanon Jct. KY
8 News CARDIOLOGY NEWS • November 2005

Analysis Raises Muraglitazar CV Safety Concerns

BY MIRIAM E. TUCKER For their analysis, Dr. Nissen, Eric J. events in the muraglitazar groups was ap- analyzed the data taking into account the
Senior Writer Topol, M.D., and Kathy Wolski combined proximately twice that of comparators. duration of drug exposure. For CV events,
the data from five clinical trials and re- However, when broken down by there were 28.2 per 1,000 patient-years on

C
oncerns over the cardiovascular
safety of muraglitazar have delayed
the Food and Drug Administra-
tion’s decision about licensure of the in-
vestigational diabetes drug.
Just two days after the FDA granted an
“approval” letter for muraglitazar (Parglu-
va), the combination peroxisome prolifer-
ator-activated receptor a and g activator
codeveloped by Bristol-Myers Squibb and
Merck, an article by Steven E. Nissen,
M.D., of the Cleveland Clinic Foundation
and his associates outlined increased car-
diovascular event rates among muragli-
tazar-treated patients in phase II and III
clinical trials of the drug.
The investigators advised that the drug
not be approved until its safety is docu-
mented in a dedicated cardiovascular
events trial ( JAMA 2005 Oct. 20 [Epub
doi:10.1001/jama.294.20.joc50147]).
Their analysis was based on data made
public on the Food and Drug Administra-
tion’s Web site on Sept. 8 and discussed in
detail at a Sept. 9 meeting of the FDA’s En-
docrinologic and Metabolic Drugs Advi-
sory Committee. At that time, the panel
voted to recommend approval of the drug
as monotherapy and in combination with
metformin, but not with sulfonylureas
(CARDIOLOGY NEWS, Oct. 2005, p. 10).
When the FDA issued an “approvable”
letter to the manufacturers on Oct. 18, the
agency requested more data regarding
muraglitazar’s cardiovascular safety profile.
stricted their analysis to diabetic patients
given the 2.5-mg and 5-mg doses of
muraglitazar for which the companies are
seeking licensure. The primary outcome
measure—all-cause mortality, nonfatal MI,
or nonfatal stroke—occurred in 1.47% (35)
of 2,374 subjects versus 0.67% (9) of 1,351
control patients who received either place-
bo or 30-mg pioglitazone, for a relative risk
(RR) of 2.23.
Substituting cardiovascular death for all-
cause mortality, the combined end points
occurred in 1.14% (27) of 2,374 muragli-
tazar-treated patients, versus 0.52% (7) of
1,351 controls (RR 2.21). When heart fail-
ure and transient ischemic attacks were
added to the composite, the incidence
rates were 2.11% for muraglitazar and
0.81% for controls (RR 2.62).
Relative risk was consistently higher for
individual components of the primary end
point in the muraglitazar-treated group
versus controls. Rates ranged from 2.14 for
fatal or nonfatal MI to 7.43 for adjudicated
heart failure. However, the number of
events was small and differences for indi-
vidual components of the primary out-
come measure were not statistically signif-
icant, the investigator reported.
These and other safety data were ana-
lyzed and presented in detail at the Sept. 9
hearing by Julie Golden, M.D., a medical
officer in the FDA’s Division of Metabolic
and Endocrine Drug Products. She, too,
had noted that the percentage of CV
monotherapy (two studies) and combina-
tion therapy (three studies), the imbalance
of CV adverse events was seen only in the
combination studies, and in fact was most-
ly driven by one study in which muragli-
tazar or placebo was added to glyburide (11
vs. 0 events). At least two of these subjects
had evidence of other causes for the event.
Cardiovascular deaths occurred in 9 of
3,226 muraglitazar subjects, 1 of 591 place-
bo subjects, and none of 823 on pioglita-
zone, giving an overall death rate 1.5 times
higher with muraglitazar than with the
comparators. Overall deaths occurred in
19, 1, and 2 patients, respectively; the in-
cidence was 2.5 to 3 times higher with
muraglitazar, Dr. Golden said. However,
“the rates in the comparator groups, based
on exceedingly small numbers of events,
are highly unstable, meaning that even one
additional death in either group could im-
pact the result,” she said at the hearing.
Eight of the CV deaths were in subjects
taking 2.5 or 5 mg of muraglitazar, and six
were subjects from a single study in which
5-mg muraglitazar or 30-mg pioglitazone
was added to metformin. In that study,
which had about 580 subjects per treat-
ment arm, there was no marked difference
in overall CV events. Moreover, no clear
clinical or pathologic pattern could be
identified for either deaths or CV events,
and the pooled studies did not show a
dose-response pattern, she noted.
For its part, Bristol-Myers Squibb had
muraglitazar, compared with 33.4/1,000
for placebo and 19.7/1,000 with pioglita-
zone—a nonsignificant difference, Rene
Belder, M.D., vice president for muragli-
tazar development at Bristol-Myers
Squibb, said at the hearing.
Similarly, for the CV deaths, the rates
were 3 per 1,000 patient-years for placebo,
compared with 2.6 per 1,000 with muragli-
tazar. “By taking into account the differ-
ence in patient exposure, the apparent
imbalance in cardiovascular death is re-
versed,” Dr. Belder said.
But that analysis was challenged by
James M. Brophy, M.D. in an editorial ac-
companying the JAMA report. He pointed
out that the company’s analysis included
495 patients who had received subthera-
peutic doses of 2.5 mg or less in whom
there were no CV events, thereby diluting
the risk estimate. When the rates were re-
calculated to include just those patients re-
ceiving the proposed marketed doses of 2.5
or 5.0 mg, the muraglitazar group shows
a 20% increase in events compared with
placebo and a 67% increase compared with
the combined pioglitazone/placebo con-
trol group, said Dr. Brophy, of McGill Uni-
versity, Montreal.
Bristol-Myers Squibb and Merck said in
a joint statement, “We are eager to begin
discussions with the FDA to address more
fully the cardiovascular safety profile of the
compound and to determine what addi-
tional information may be necessary.” ■

when recruiting the 12 members of the echocardiography or to a simple stress

Cardiac SPECT Is First Modality
Appropriate Use from page 1
or greater, and patients with chest-pain
syndrome and a high pretest probability of
coronary artery disease (CAD) who are
unable to exercise or who have an un-
readable ECG.
The panel found SPECT to be general-
ly unacceptable and an unreasonable ap-
proach in 13 of the scenarios. These in-
cluded the evaluation of asymptomatic
patients with low Framingham risk of
CHD and asymptomatic patients with car-
diac calcium scores less than 100; it was
also unacceptable for preoperative risk as-
sessment of noncardiac surgery patients.
The remaining 12 scenarios were those
that may be generally acceptable and
may be a reasonable approach, but for
which additional data are necessary.
These included evaluations of asympto-
matic patients with moderate Framing-
ham risk of CHD, asymptomatic patients
diagnosed with stenosis of unclear sig-
nificance after CT angiography, and
asymptomatic patients for the first 5 years
post revascularization.
The authors of the criteria recom-
mended that third-party payers should
definitely reimburse for the appropriate
and uncertain indications, but that reim-
bursement for indications judged inap-
propriate should require a documented ex-
ception from the physician ordering the
study.
technical panel. In addition to specialists in test, which is a lot cheaper,” Dr. Guib-
nuclear cardiology, the panel included gen- erteau said.
eral cardiologists, experts in echocardiog- The ACC has already provided such a
“These new technologies are terrific,” raphy, an outcomes researcher, and the ranking in its clinical practice guidelines,
said Ralph G. Brindis, M.D., chair of the chief medical officer of a health insurance countered cardiologist George A. Beller,
ACCF appropriateness criteria working provider. M.D., the Ruth C. Heede Professor of
group. “They offer new advances in diag- Although the American College of Ra- Cardiology and professor of internal med-
nosis and treatment. But we need to be diology (ACR) was invited to send a pan- icine at the University of Virginia, Char-
able to use them in the appropriate set- elist, they declined, Dr. Brindis said. lottesville, who was not involved in de-
tings, [with] the right patient at the right “The ACR made a vigorous effort to veloping the appropriateness criteria.
time and for the right indication.” identify ...a member of the college to rep- Dr. Beller said he found few surprises in
Dr. Brindis, a car- resent us in this ef- his reading of the SPECT appropriateness
diologist from Oak- ‘We need to be able to use fort,” said ACR pres- criteria. “I think most of the cardiologists
land (Calif.) Kaiser ident Milton J. could have predicted the results of this ex-
Medical Center, said [these new technologies] Guiberteau, M.D., in ercise,” he said. “Where I think it might be
that the cost of care in the appropriate settings, an interview. “But useful is for reinforcing the clinical prac-
was one of the main the timing was such tice guidelines for primary care physicians
motivations for con- [with] the right patient at that we were unable so they would have a better feeling for
sidering appropriate- the right time and for the to do so in a time who they might refer for testing.”
ness criteria for frame to fit the al- Dr. Brindis said that the appropriateness
SPECT. “I think we right indication.’ ready-begun process. criteria may eventually affect pay-for-per-
owe it to our patients ... It certainly wasn’t formance criteria, which are now based ex-
and to the cardiovascular community as a a snub of the process, because we applaud clusively on quality. “I expect over time
whole to better get our hands on the bur- these efforts even though we have some that pay-for-performance criteria will ex-
geoning costs of cardiovascular care,” he differences in the way we approach them. tend outside of the quality arena and will
said in an interview with this newspaper. ... I think overall it was a well-construct- include areas such as cost-effectiveness
“If we continue to let costs go unchecked ed document.” and efficiency,” he said.
without doing due diligence about ap- The ACR has developed appropriateness And Dr. Brindis said that he’s pleased
propriateness and efficiency in the use of criteria for 170 clinical indications since with the reception the new appropriate-
our resources, we’re just going to bust the their first in 1993. Their approach is to take ness criteria have received. “I’ve had nu-
system.” a clinical indication, such as chest pain, and clear cardiologists tell us this is too re-
Funded by almost $1 million from rank the available tests in terms of what strictive, and I’ve had some academic
ACCF, future panels will consider other would be the most appropriate. “When nonnuclear cardiologists saying we didn’t
imaging modalities, including CT, MRI, you just do it from a modality approach, go far enough,” he said. “If we [failed to
and echocardiography. ...it doesn’t tell you whether SPECT myo- make] both sides happy, that means we
Dr. Brindis said that he cast a wide net cardial perfusion imaging is preferable to must be pretty close to the truth.” ■
Pages 8a—8b佥