College of American Pathologists
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Better cardiac calls

New marker for ischemia helps rule out ACS

Back to POC in motion—the changing face of mobile testing

June 2003
Karen Lusky

As the first biochemical marker that can detect cardiac ischemia

before the heart muscle undergoes necrosis, ischemia modified albumin, or IMA, might be more than just a modest improvement to the mousetrap.

“It’s potentially a fundamentally better mousetrap,” says Kent Lewandrowski, MD, associate chief of pathology and director of the core laboratory at Massachusetts General Hospital, Boston. “If the test performs as billed, it could fundamentally change the way physicians triage and evaluate chest pain.”

The Food and Drug Administration recently approved the albumin cobalt binding, or ACB, test to detect IMA as an aid in ruling out acute coronary syndrome when used with the cardiac necrosis marker troponin and an electrocardiogram. The body produces IMA when blood passes through an ischemic vascular bed, which reduces serum albumin’s ability to bind with metals—in this case, cobalt.

IMA turns positive within six to 10 minutes of an ischemic cardiac event, according to clinical trials that examined ischemia created by percutaneous transluminal coronary angioplasty, or PCTA. Several studies by multiple authors have shown that IMA returns to baseline about six hours after cessation of an ischemic event, as induced by balloon inflation.

IMA can detect the majority of patients with unstable angina and is
negative in less than 20 percent of ACS patients. By contrast, troponin has about 14 percent sensitivity in predicting adverse cardiac outcome in the emergency department observation-unit population, says Frank Peacock, MD, director of clinical operations for the emergency department at the Cleveland Clinic. Electrocardiograms miss about half of patients with ACS on initial presentation.

“Yet the combination of a negative IMA and troponin and a nondiagnostic ECG yields a negative predictive value of 99 percent, meaning the likelihood that the patient has ACS is one percent,” says Robin Daigh, vice president of commercial operations for Denver-based Ischemia Technologies, which developed and is marketing IMA.

Cutting out the chase

Hospitals will pay about $30 per test for IMA, about the same price as other new cardiac blood tests. The ACB test may get a crosswalk CPT code reimbursed 30 to 50 percent higher than that amount, based on similar tests.

So, if IMA performs as expected, the test is managed care’s dream come true: a simple and relatively inexpensive way to determine which patients can safely forego big-ticket testing, which carries its own risks.

“As it stands now, physicians can tell someone with chest pain that they’ve had an MI,” says Dr. Peacock, “but they aren’t very good at telling them they haven’t had one—not without a lot of expensive testing, with a total bill of about $4,500 per episode. And since physicians are wary of malpractice litigation, a patient who presents with chest pain in the ED is usually admitted at least overnight for observation and a cardiac workup.”

As a result, 2.5 million people a year who present to the ED with chest pain receive testing that turns up negative, he says.

IMA is expected to lower that figure significantly. “If IMA allows hospitals to shift the percentage of patients with chest pain who are sent home from the ED by 10 to 15 percent,” says Dr. Lewandrowski, “then the test is extremely valuable, especially when used in a managed care population.” He estimates that most hospitals now release about 20 percent of such patients from the ED.

What a positive means
At this point, the significance of a positive IMA in the setting of acute coronary syndrome is unclear. Other conditions can cause an elevation, such as various cancers and acute infections, end-stage renal disease, liver cirrhosis, and brain ischemia.

In that regard, clinicians will have to consider the population of patients seen in a chest pain clinic, says Stephen Bauer, MD, director of laboratories at Mercy San Juan Hospital, Carmichael, Calif. “If someone presents with some other obvious form of ischemia—for example, an acute abdomen that the physician suspects may be a gangrenous bowel—then IMA is obviously not a good test in that situation,” he says.

“IMA is a better test if one confines its use to that subsegment of patients with chest pain who don’t have other known causes of ischemia,” Dr. Bauer adds. “In that subset, we do think a positive is significant enough to continue to use our more extended evaluation protocols.”

What Dr. Peacock doesn’t want to see happen—and what he believes could even derail the test’s credibility in clinical circles—is for practitioners to start ordering cardiac angiograms based solely on positive IMA results. “The clinical presentation of coronary ischemia does not automatically result in a cardiac catheterization—neither should a positive IMA,” he says.

Cardiologist Robert Jesse, MD, PhD, director of the acute cardiac program at Virginia Commonwealth University, Richmond, agrees. “We don’t yet know what a positive IMA means, but it might mean someone is having ischemia we can’t pick up otherwise.”

Ischemia Technologies is conducting ongoing clinical studies to help define what a positive IMA might mean in terms of guiding therapy and predicting long-term clinical outcomes.

Going with the gestalt
Practitioners must also keep in mind that IMA is just one piece of the gestalt in the art of medicine, says Robert Christenson, PhD, director of clinical chemistry, toxicology, and rapid response laboratories at the University of Maryland Medical Center, Baltimore.

“A clinician would never run an IMA alone,” he says. “They’d run troponin and, in my setting, probably myoglobin as an early marker of necrosis—and in the future, probably B-type natriuretic peptide.” Accumulating evidence shows that elevated BNP can identify high-risk patients and predict the long-term odds of death and subsequent heart failure in patients in the setting of acute coronary syndromes.

And even in cases where clinical laboratory testing and the ECG give an all-clear sign, physicians are not going to ignore a good story. “If someone presents with complaints of chest pain every time he climbs stairs, but the chest pain goes away when he rests, that’s compelling,” Dr. Jesse says. “So even if every test is normal, I’d still stress test that person or take him to the cath lab.”

Dr. Peacock agrees. “If a patient presents in the ED with a high pretest odds of disease and chest pain, I don’t care what any tests show—I will perform serial marker rule-out, then stress test the person.” Thus, as IMA testing moves into the mainstream, ED physicians may release a 35-year-old female with no risk factors and nine minutes of chest pain, a normal EKG, normal troponin, and negative IMA. “But you’re not going to worry about the IMA results for a 67-year-old woman with the same amount of chest pain who’s a smoker with a history of hypercholesterolemia, diabetes, and PCTA. That patient needs the full workup.”

Performing clinical correlations
Even though the FDA has given its blessing to IMA, “and did so quickly because the statistics are robust and promising, hospitals will do a clinical correlation before they change their protocols,” says Sandra Sieck, BBA, RN, director of cardiovascular development for Providence Hospital, Mobile, Ala.

Mercy San Juan Hospital, which participated in the IMA clinical trials and is one of the first hospitals in California to use the new test, won’t change how its ED manages low-risk patients who present with chest pain until it has additional clinical outcome data.

Dr. Bauer, who heads up the hospital’s laboratory, says the hope is that the ED eventually can allow low-risk patients to go home if they aren’t clinically suspicious and have a negative evaluation, including IMA, troponin, and ECG. “That’s ultimately where we’d like to be,” he says, “rather than holding the person for eight hours or more with our current testing protocol.”

In the interim, if clinical outcomes support it, Mercy San Juan may see reductions in the length of time the ED holds patients with chest pain. “The ED may keep them two to four hours and repeat the IMA and other studies,” Dr. Bauer says. “But we are going to need more clinical data before that happens. Testing strategies will evolve just as they did when troponins were introduced.”

In Dr. Bauer’s view, the type of clinical information the hospital is seeking should be relatively easy to obtain. “If we miss patients’ disease with an initial screening, they are going to be showing back up at the ED or elsewhere relatively soon,” he says. “So the clinical outcome is the gold standard in terms of figuring out the effectiveness of the test.”

Yet, as the first cardiac ischemia marker, IMA doesn’t have a gold standard test for comparison. “When troponin first came out,” Dr. Jesse says, “we found a lot of people with positive troponin tests who didn’t have a positive CK-MB, which was the gold standard at the time. But did that mean troponin was a bad test? No, because as it evolved over the next decade, we finally figured out that troponin was more sensitive, more specific, and was simply a much better test. This eventually led to a redefinition of myocardial infarction based on troponin.”

POC testing anticipated in 2004
While IMA is available now on a mainline chemistry platform, Ischemia Technologies hopes to have a point-of-care IMA on the market in 2004. The company sees a potential use for a POC test in the laboratory as a stand-alone station. “It could also be used in the ED, with the cooperation of the laboratory, as a POC test that’s performed as part of the presentation draw for patients with chest pain or symptoms suggestive of ACS,” suggests Donna Edmonds, senior vice president of sales and marketing.

Dr. Christenson can also see paramedics using a point-of-care IMA test “because if the IMA test is negative, it essentially tells you the answer to the question: Can ACS be ruled out in this patient? And if the answer is no, that is, if the IMA is negative and the EKG is normal in a low-risk patient, then the paramedics might take the patient to a different hospital or triage the person to some other level of care,” he says. “But that’s an important decision, and the paramedics would have to follow exact protocols.”

The POC IMA test may also find a niche in physician offices and clinics, especially those that see a lot of patients with atypical chest pain or chest pain equivalent that mimics common noncardiac conditions. Edmonds reports that pharmaceutical companies have expressed an interest in gaining an understanding of the assay’s application in the community physician setting. “We are in early discussions with them in terms of providing data to show how a positive IMA might be an indication for cardioprotective agents,” she says.

In Dr. Jesse’s view, a POC test may prove to have a “huge value” in the primary care physician’s office, given that studies show more patients with chest pain initially present to such settings than to the hospital ED. “So if the primary care physician could rule out ischemia in the low-risk patient, it would save a lot of resources and the physician could triage the patient more appropriately,” he says.

Dr. Peacock agrees it might be reasonable for a family physician to use a portable IMA to test patients who present with chest pain. “The physician would also have to perform a risk assessment, an EKG, and a troponin, and put the information into context,” he says. “But if a low-risk patient’s IMA and other testing were negative, then the physician could schedule a stress test for the following week on an elective basis, saving the patient a trip to the hospital ED. The physician would, of course, give the patient reasonable instructions to come back if the chest pain returns or go to the ED after hours.”

Yet based on current understanding, IMA testing would not be appropriate as part of a workup to detect coronary artery disease, let alone for routine screening, which could produce a net full of red herrings.

“One has to differentiate between disease state markers for coronary artery disease and event markers for ACS,” Dr. Jesse says. In that regard, “there’s been a lot of interest in C-reactive protein, which does go up in patients who have acute events. But CRP is a much better predictor of the disease state that might predispose someone to an MI by detecting inflammation associated with arterial plaques,” he adds.

By contrast, a patient can have a normal troponin 20 minutes before an MI because it is a marker of acute necrosis, not of the disease coronary atherosclerosis. The IMA test is probably not a marker of a disease state either, however. “It might be, but we don’t fully know what a positive means, so we will have to reserve judgment until that is clarified,” Dr. Jesse adds.

Dr. Lewandrowski does, however, envision physicians eventually using IMA as an adjunct to the stress test and nuclear imaging studies to detect ischemic areas of the heart. “If you did a stress test in conjunction with IMA and an ECG, it might be possible to get a more definitive answer as to whether ischemia exists—and perhaps pass on the nuclear scan.

“Imaging studies are expensive, and patients don’t relish being injected with radionucleotides,” he adds. “So if the IMA test truly has a 98- to 99-percent reliability in ruling out ischemia, then it could become a replacement for some of the more expensive modalities. But it will take time for the market to accept that, once the test’s performance has been proven to be true.”

Potential for savings
IMA and other cardiac ischemia markers in the pipeline have the potential to produce large savings by reducing unnecessary inpatient admissions. In that regard, the test appears to support the direction Medicare is heading in the hospital outpatient arena, notes Providence Hospital’s Sieck.

“The Centers for Medicare and Medicaid Services in April 2002 implemented an outpatient carve-out code, APC 0339, that pays for an observation period separately above and beyond the outpatient fee,” she notes. And this shift in reimbursement will encourage hospital EDs to use best practices, such as IMA, to perform better risk stratification of patients up front before determining who requires inpatient care.

“If IMA is really as robust as some clinical trials say it is, the test will be a financial winner for all involved—at least for everyone except the nuclear cardiologists,” Dr. Lewandrowski says. “But that’s how progress in medicine works. No other industry works so hard to put itself out of business.

Karen Lusky is a writer in Brentwood, Tenn.