Imaging Criteria

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Routine Use of Drug-Eluting Stents Not Cost Effective

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B RUCE J ANCIN

Certain high-risk subgroups are exceptions.

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 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 patients without a conventional indication for it, Wiek H. van Gilst, M.D., said at the annual congress of the European Society of Cardiology. In fact, just the opposite was observed in the 2,553-patient Ischemia Management With Accupril Post Bypass Graft via Inhibition of Angiotensin-Converting Enzyme (IMAGINE) trial, conducted in Europe and Canada. The incidence of ischemic 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 difference between the two treatment groups, noted Dr. van Gilst, professor of cardiovascular and clinical 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, thrombotic activity, and endothelial dysfunction, and ACE inhibitors

have been shown to curb endothelial 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 atherosclerotic progression and reduce 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 AngiotensinConverting Enzyme Inhibition (PEACE) trials included collecSee Bypass page 9

BY BRUCE JANCIN

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 realworld patient setting is not good value for money, according to the findings of the first-ever randomized trial that compared drug-eluting stents with baremetal stents in unselected patients in a study free of industry sponsorship. The results of the Basel Stent Cost Effectiveness Trial (BASKET) suggest that the use of drug-eluting stents (DESs) could reasonably be restricted to selected high-risk patient subgroups, Matthias Pfisterer, M.D., said at the annual congress of the

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San Francisco Bureau

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riven by concerns over the rising cost of cardiovascular care and looming pay-for-performance rules, a technical panel convened by the American College 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 appropriate indications for single-photon emission computed tomog-

VITAL SIGNS Many Patients ‘Strongly Favor’ Physicians’ Use of New Medical Technologies 51%

Home monitoring

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E-mail with patient Imaging by e-mail Electronic records Personal digital device

European Society of Cardiology. “Based upon these data, we can define some subgroups where these stents are more attractive. They are more cost effective 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. Pfisterer of the University of Basel (Switzerland). In a typical catheterization laboratory, perhaps two-thirds of patients 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

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42% 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

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BY BRUCE JANCIN

Chest Pain Threefer

raphy myocardial perfusion imaging (SPECT MPI), which were inappropriate indications for SPECT, and which were uncertain 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 reasonable approach in 27 of the clinical scenarios. These included evaluation of asymptomatic patients 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

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CARDIOLOGY NEWS • November 2005

Analysis Raises Muraglitazar CV Safety Concerns BY MIRIAM E. TUCKER

Senior Writer

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oncerns over the cardiovascular safety of muraglitazar have delayed the Food and Drug Administration’s decision about licensure of the investigational diabetes drug. Just two days after the FDA granted an “approval” letter for muraglitazar (Pargluva), the combination peroxisome proliferator-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 cardiovascular event rates among muraglitazar-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 documented 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 Administration’s Web site on Sept. 8 and discussed in detail at a Sept. 9 meeting of the FDA’s Endocrinologic and Metabolic Drugs Advisory 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.

events in the muraglitazar groups was approximately twice that of comparators. However, when broken down by monotherapy (two studies) and combination therapy (three studies), the imbalance of CV adverse events was seen only in the combination studies, and in fact was mostly driven by one study in which muraglitazar 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 placebo subjects, and none of 823 on pioglitazone, 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 incidence 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 impact 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 treatment 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 pioglitazone—a nonsignificant difference, Rene Belder, M.D., vice president for muraglitazar 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 muraglitazar. “By taking into account the difference in patient exposure, the apparent imbalance in cardiovascular death is reversed,” Dr. Belder said. But that analysis was challenged by James M. Brophy, M.D. in an editorial accompanying the JAMA report. He pointed out that the company’s analysis included 495 patients who had received subtherapeutic doses of 2.5 mg or less in whom there were no CV events, thereby diluting the risk estimate. When the rates were recalculated to include just those patients receiving 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 control group, said Dr. Brophy, of McGill University, 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 additional information may be necessary.” ■

when recruiting the 12 members of the technical panel. In addition to specialists in nuclear cardiology, the panel included general cardiologists, experts in echocardiog“These new technologies are terrific,” raphy, an outcomes researcher, and the said Ralph G. Brindis, M.D., chair of the chief medical officer of a health insurance ACCF appropriateness criteria working provider. Although the American College of Ragroup. “They offer new advances in diagnosis and treatment. But we need to be diology (ACR) was invited to send a panable to use them in the appropriate set- elist, they declined, Dr. Brindis said. “The ACR made a vigorous effort to tings, [with] the right patient at the right identify ...a member of the college to reptime and for the right indication.” resent us in this efDr. Brindis, a carfort,” said ACR presdiologist from Oak‘We need to be able to use ident Milton J. land (Calif.) Kaiser [these new technologies] Guiberteau, M.D., in Medical Center, said an interview. “But that the cost of care in the appropriate settings, the timing was such was one of the main [with] the right patient at that we were unable motivations for conto do so in a time sidering appropriatethe right time and for the frame to fit the alness criteria for right indication.’ ready-begun process. SPECT. “I think we ... It certainly wasn’t owe it to our patients and to the cardiovascular community as a a snub of the process, because we applaud whole to better get our hands on the bur- these efforts even though we have some geoning costs of cardiovascular care,” he differences in the way we approach them. said in an interview with this newspaper. ... I think overall it was a well-construct“If we continue to let costs go unchecked ed document.” The ACR has developed appropriateness without doing due diligence about appropriateness and efficiency in the use of criteria for 170 clinical indications since our resources, we’re just going to bust the their first in 1993. Their approach is to take a clinical indication, such as chest pain, and system.” Funded by almost $1 million from rank the available tests in terms of what ACCF, future panels will consider other would be the most appropriate. “When imaging modalities, including CT, MRI, you just do it from a modality approach, ...it doesn’t tell you whether SPECT myoand echocardiography. Dr. Brindis said that he cast a wide net cardial perfusion imaging is preferable to

echocardiography or to a simple stress test, which is a lot cheaper,” Dr. Guiberteau 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 medicine at the University of Virginia, Charlottesville, who was not involved in developing 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 exercise,” he said. “Where I think it might be useful is for reinforcing the clinical practice 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-performance criteria, which are now based exclusively on quality. “I expect over time that pay-for-performance criteria will extend 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 appropriateness criteria have received. “I’ve had nuclear cardiologists tell us this is too restrictive, 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.” ■

For their analysis, Dr. Nissen, Eric J. Topol, M.D., and Kathy Wolski combined the data from five clinical trials and restricted 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 placebo or 30-mg pioglitazone, for a relative risk (RR) of 2.23. Substituting cardiovascular death for allcause mortality, the combined end points occurred in 1.14% (27) of 2,374 muraglitazar-treated patients, versus 0.52% (7) of 1,351 controls (RR 2.21). When heart failure 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 individual components of the primary outcome measure were not statistically significant, the investigator reported. These and other safety data were analyzed 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

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 unreadable ECG. The panel found SPECT to be generally unacceptable and an unreasonable approach in 13 of the scenarios. These included the evaluation of asymptomatic patients with low Framingham risk of CHD and asymptomatic patients with cardiac calcium scores less than 100; it was also unacceptable for preoperative risk assessment 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 asymptomatic patients with moderate Framingham risk of CHD, asymptomatic patients diagnosed with stenosis of unclear significance after CT angiography, and asymptomatic patients for the first 5 years post revascularization. The authors of the criteria recommended that third-party payers should definitely reimburse for the appropriate and uncertain indications, but that reimbursement for indications judged inappropriate should require a documented exception from the physician ordering the study.

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