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BRUCE JANCIN

B RUCE J ANCIN P RO & C ON : I S N ESIRITIDE S AFE

PRO & CON: IS NESIRITIDE SAFE? PAGE 10

Cardiology News

www.ecardiologynews.com The Leading Independent Newspaper for the Cardiologist

VO L .

3,

N O.

11

N OVEMBER

2005

for the Cardiologist V O L . 3, N O . 11 N OVEMBER 2005 The

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 TOCKHOLM — 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

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

I I N N S S I I D D E E Chest Pain Threefer

II NN SS II DD EE

I I N N S S I I D D E E
I I N N S S I I D D E E Chest Pain Threefer One
I I N N S S I I D D E E Chest Pain Threefer One
Chest Pain

Chest Pain

Threefer

Threefer

One quick scan can rule out three conditions.

One quick scan can rule out three conditions.

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ECGs for All

ECGs for All

Screening all newborns for long QT syndrome is worth it.

Screening all newborns for long QT syndrome is worth it.

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9

all newborns for long QT syndrome is worth it. PAGE 9 Avian Flu What you can
all newborns for long QT syndrome is worth it. PAGE 9 Avian Flu What you can
Avian Flu

Avian Flu

What you can do to protect yourselves and your patients.

What you can do to protect yourselves and your patients.

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VV II TT AA LL SS II GG NN SS Many Patients ‘Strongly Favor’ Physicians’
VV II TT AA LL
SS II GG NN SS
Many Patients ‘Strongly Favor’ Physicians’
Use of New Medical Technologies
51%
Home monitoring
E-mail with patient
49%
44%
Imaging by e-mail
Electronic records
42%
Personal digital device
37%
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
KEVIN FOLEY, RESEARCH

Routine Use of Drug-Eluting Stents Not Cost Effective

Certain high-risk subgroups are exceptions.

BY BRUCE JANCIN

Denver Bureau

S TOCKHOLM — Routine use of drug-eluting stents in a real- world patient setting is not good value for money, according to the findings of the first-ever ran- domized trial that compared drug-eluting stents with bare- metal stents in unselected pa- tients in a study free of industry sponsorship. 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

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

Groups Issue Appropriate Use Criteria for Imaging

BY ROBERT FINN

San Francisco Bureau

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. The panel considered which of 52 clinical scenarios were appro- priate indications for single-pho- ton emission computed tomog-

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

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News

C ARDIOLOGY

N EWS

November 2005

Analysis Raises Muraglitazar CV Safety Concerns

BY MIRIAM E. TUCKER

Senior Writer

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.

For their analysis, Dr. Nissen, Eric J. Topol, M.D., and Kathy Wolski combined the data from five clinical trials and re- 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

events in the muraglitazar groups was ap- proximately twice that of comparators. However, when broken down by 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

analyzed the data taking into account the duration of drug exposure. For CV events, there were 28.2 per 1,000 patient-years on 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.”

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.

when recruiting the 12 members of the

technical panel. In addition to specialists in nuclear cardiology, the panel included gen- eral cardiologists, experts in echocardiog- raphy, an outcomes researcher, and the chief medical officer of a health insurance provider. Although the American College of Ra- diology (ACR) was invited to send a pan- elist, they declined, Dr. Brindis said. “The ACR made a vigorous effort to

identify

a member of the college to rep- resent us in this ef-

fort,” said ACR pres- ident Milton J. Guiberteau, M.D., in an interview. “But the timing was such that we were unable to do so in a time

frame to fit the al- ready-begun process. It certainly wasn’t

a snub of the process, because we applaud

these efforts even though we have some differences in the way we approach them. I think overall it was a well-construct- ed document.” The ACR has developed appropriateness criteria for 170 clinical indications since

their first in 1993. Their approach is to take

a clinical indication, such as chest pain, and rank the available tests in terms of what would be the most appropriate. “When you just do it from a modality approach,

doesn’t tell you whether SPECT myo-

cardial perfusion imaging is preferable to

“These new technologies are terrific,” said Ralph G. Brindis, M.D., chair of the ACCF appropriateness criteria working group. “They offer new advances in diag- nosis and treatment. But we need to be able to use them in the appropriate set-

tings, [with] the right patient at the right time and for the right indication.” Dr. Brindis, a car-

diologist from Oak- land (Calif.) Kaiser Medical Center, said that the cost of care was one of the main motivations for con- sidering appropriate- ness criteria for

SPECT. “I think we owe it to our patients and to the cardiovascular community as a whole to better get our hands on the bur- geoning costs of cardiovascular care,” he said in an interview with this newspaper. “If we continue to let costs go unchecked without doing due diligence about ap- propriateness and efficiency in the use of our resources, we’re just going to bust the system.” Funded by almost $1 million from ACCF, future panels will consider other imaging modalities, including CT, MRI, and echocardiography. Dr. Brindis said that he cast a wide net

‘We need to be able to use [these new technologies] in the appropriate settings, [with] the right patient at the right time and for the

right indication.’

it

echocardiography or to a simple stress test, which is a lot cheaper,” Dr. Guib- erteau said. The ACC has already provided such a ranking in its clinical practice guidelines, countered cardiologist George A. Beller, M.D., the Ruth C. Heede Professor of Cardiology and professor of internal med- icine at the University of Virginia, Char- lottesville, who was not involved in de- veloping the appropriateness criteria.

Dr. Beller said he found few surprises in his reading of the SPECT appropriateness criteria. “I think most of the cardiologists could have predicted the results of this ex- ercise,” he said. “Where I think it might be useful is for reinforcing the clinical prac- tice guidelines for primary care physicians so they would have a better feeling for who they might refer for testing.” Dr. Brindis said that the appropriateness criteria may eventually affect pay-for-per- formance criteria, which are now based ex- clusively on quality. “I expect over time that pay-for-performance criteria will ex- tend outside of the quality arena and will include areas such as cost-effectiveness and efficiency,” he said. And Dr. Brindis said that he’s pleased with the reception the new appropriate- ness criteria have received. “I’ve had nu- clear cardiologists tell us this is too re- strictive, and I’ve had some academic nonnuclear cardiologists saying we didn’t go far enough,” he said. “If we [failed to make] both sides happy, that means we must be pretty close to the truth.”

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