American Association for Clinical Chemistry
Better health through laboratory medicine
April 2007 Clinical Laboratory News: New NACB Guidelines Emphasize Cardiac Troponin for ACS

April 2007: Volume 33, Number 4

New NACB Guidelines Emphasize Cardiac Troponin for ACS
Single Cutpoint, Quick Turnaround, and POCT Top Recommendations
By Deborah Levenson


Today, a myocardial infarction (MI) isn’t necessarily a fatal event, thanks to advances in technology that allow for earlier diagnosis and more effective care. In laboratory medicine, much of the credit goes to cardiac troponin (cTn), a biochemical marker of myocardial cell death that has revolutionized the care of patients with acute coronary syndromes (ACS). In its 1999 guidelines on laboratory testing for ACS, the National Academy of Clinical Biochemistry (NACB) first recognized cTn testing as the definitive laboratory standard for the diagnosis of MI. Recommendations from the American Heart Association (AHA) and a new definition of MI issued jointly by the American College of Cardiology (ACC) and the European Society of Cardiology (ESC) have also made cTn the cornerstone of the definition of MI and cemented its position as the eminent biomarker of myocardial cell death. But in the last eight years, studies on the utility of cTn in diagnosis of ACS have exploded. Now, updated NACB guidelines, published in part in this month’s issues of Clinical Chemistry and Circulation, reflect the most important research findings and give laboratorians a much needed source of information to institute practices that will further improve care of ACS patients.

The updated guidelines leave no room for doubt: all patients with suspected ACS should have cTn tests. “The three most important things to remember about the updated guidelines are troponin, troponin, and troponin,” advised Robert Christenson, chair of the NACB committee that developed the guidelines and Director, Clinical Chemistry, Toxicology, and Rapid Response Laboratories at University of Maryland Medical Center, Baltimore, Md. The guidelines also emphasize finding out why cTn is elevated, stress the need for rapid turnaround of test results, and discuss the biomarker’s role as segue to a future panel of molecular assays that may someday improve screening and better tailor interventions to individual patients. In addition, analytical guidelines (See Sidebar, below) issued jointly with the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC), list specifications for cTn testing and reiterate the need for a single cutpoint for both diagnosis of MI and risk stratification.

Key Points of the Biomarkers of ACS Analytical Guidelines

Simultaneously published this month in Clinical Chemistry and Circulation, NACB’s Laboratory Medicine Practice Guidelines for Biomarkers of Acute Coronary Syndrome and Heart Failure represents the product of more than three years’ work by expert laboratorians, cardiologists, and emergency medicine physicians, with input from 25 organizations. Summarized here are the analytical guidelines for labs. The complete guidelines, including recommendations on heart failure, will be published later this spring on the NACB Web site.

  • One decision limit, the 99th percentile, is the optimum cutoff for cardiac troponin I (cTnI), cardiac troponin T (cTnT), and creatine kinase MB (CK-MB) mass. ACS patients with cTnI and cTnT results above the decision limit should be labeled as having myocardial injury and a high-risk profile.
  • Labs should establish decision limits for each cardiac biomarker based on a reference population of normal, healthy individuals, without a known history of heart disease. For cTnI, cTnT and CK-MB mass, the 99th percentile of the reference population should be the decision limit for myocardial injury. The Clinical Laboratory Standards Institute recommends a minimum of 120 individuals per group of healthy individuals be included for appropriate statistical determination of a normal reference cutoff.
  • Assays for cardiac biomarkers should strive for a total imprecision (% CV) of ≤10% at the 99th percentile reference limit. Prior to clinical use, labs should characterize cardiac biomarker assays with respect to potential interferences and preanalytical and analytical assay characteristics, such as stability over time and across temperature ranges, for each acceptable specimen type.
  • Serum, plasma, and anticoagulated whole blood are acceptable specimens for analysis of cardiac biomarkers.

All of these recommendations are designated Class I, meaning they are supported by at least one randomized, controlled trial.

Clinical Chemistry (2007;53:547–551).
Circulation, April 3, 2007 (Citation not available at press time)

Analytical Guidelines: One Cutpoint

Since cTn was first introduced, laboratorians have questioned which cutpoint is the best. In the 1999 analytical guidelines, the NACB recommended separate cutpoints for diagnosis of MI and risk stratification. The updated guidelines, however, put an end to the confusion by setting the 99th percentile of a normal reference population as the optimum cutoff for both purposes.

In the 2007 guidelines, the authors state that ACS patients with test results above this cutoff have myocardial injury and a high-risk profile. “The ninety-ninth percentile is the new line in the sand” dividing normal from abnormal results, asserted Fred Apple, PhD, a member of the guidelines writing committee. Apple is Professor of Laboratory Medicine and Pathology at University of Minnesota School of Medicine in Minneapolis, Medical Director of Clinical Laboratories at Hennepin County Medical Center in Minneapolis, and Chair of the IFCC Committee on Standardization of Markers of Cardiac Damage.

But the use of a single cutpoint for cTn raises several issues for laboratorians to consider, Apple pointed out. First, although experts from the NACB and IFCC, as well as cardiologists, agree that the 99th percentile is the best cutoff, “not all Food and Drug Administration (FDA) package inserts are reporting results that way,” he noted. “FDA is just starting to understand that the ninety-ninth percentile is the appropriate cutoff.”

Labs will also see substantially more patients with positive troponin results if they switch from a higher ROC curve cutoff to the 99th percentile. Sensitivity will still be very high, about 95% to 100%, but the specificity will decline from about 90% to about 80%, Apple added.

At the same time, while labs will see an increase in the number of true positives for cTn, they will not necessarily result from MIs. “In the non-ischemic clinical settings, there are other pathologies that clinicians must chase down with increased cTn,” Apple noted, emphasizing the importance of EKG and clinical exam results.

A cardiologist from the NACB committee also stressed this point. “The NACB guidelines emphasize finding out why troponin is elevated,” explained Robert Jesse, MD, PhD, National Program Director for Cardiology at Veterans Health Administration in Washington, D.C. and Professor of Medicine, Virginia Commonwealth University in Richmond, Va. Noting that the 2000 consensus statement issued by ACC and ESC redefined MI presence of myocardial necrosis due to ischemia, using a troponin standard, he added, “Too many people see troponin elevation and associate it with an acute coronary event. Other things besides a blocked artery could result in cell damage. These may include hypertensive urgencies, congestive heart failure, viral infections, chemotherapy agents, and chest trauma, to name a few.”

While the new NACB guidelines may result in more positive cTn tests overall, laboratorians should be aware that first-generation assays using the 99th percentile will not detect as many true positive samples as the newer second-, third-, or fourth-generation assays at the 99th percentile cutoff. Because older assays have lower analytical sensitivity, they may miss MIs in some patients, Apple explained. “You have to know your assay,” he emphasized.

Quick Turnaround: Time for POCT

Rapid turnaround for cTn testing—within 60 minutes—is another hallmark of the updated guidelines, agreed members of the NACB guideline committee. “The new guidelines emphasize in a much stronger way the need for rapid turnaround and suggest consideration of POCT testing. That’s a big change for emergency medicine,” said Alan Storrow, MD, Associate Professor of Emergency Medicine at Vanderbilt University, Nashville, Tenn. However, the suggested turnaround time may present a challenge for many small hospitals, especially if their labs are closed at night or operate without sufficient staff.

For these hospitals, POCT for cTn may be a worthwhile consideration. Laboratorians should work with clinicians to implement POCT if their institutions’ central labs can’t provide results within the suggested timeline and if practice patterns and triage management will make the required investment worthwhile, Apple suggested.

Hennepin’s emergency and cardiology departments both perform POC cTn testing, with a turnaround time of 20 minutes. But even a fast cTn result that is available so rapidly “makes no difference if a physician doesn’t act on it,” Apple emphasized. Because of established triage and critical-care pathways at Hennepin, physicians can get ACS patients to the appropriate level of care quickly and send low-risk patients home. For this reason, POCT, while it carries a substantial up-front cost to implement, can provide “several levels of appropriate cost savings,” Apple noted.

Another reason that labs should consider POCT is that POC instruments have become more accurate in the last several years, Storrow noted. He predicts that POC tests will burgeon, especially if costs decrease. But clinical evidence for POCT is limited. “While POCT has been shown to improve patient satisfaction, in part because patients get admitted or sent home faster, no study has actually proven it improves clinical outcomes.”

When considering POCT for cTn, labs must also take into account that neither central lab nor POC cTn assays are calibrated with the same reference materials. Therefore, results from different manufacturers may not correlate. “Don’t mix and match assays unless you know how they correlate,” Apple warned. “Not all cTn assays are created equal. You have to understand your assay before you implement it.”

Recognizing this problem, the NACB guidelines have called upon manufacturers to work toward standardization. The only way to achieve complete standardization, they assert, “would be for all manufacturers to agree on using the same antibody pairs for all commercial assays, as well as a common reference material for calibration.” IFCC’s committee on standardization is exploring development of a serum-based secondary reference material, the guidelines also note, while suggesting that manufacturers need to use methods to determine detection limit, functional sensitivity, and total imprecision suggested by the Clinical and Laboratory Standards Institute.

For Some, Quick Results Remain Elusive

While the ACS guidelines emphasize the need for quick turnaround of cTn results, research has shown that a large proportion of hospitals can’t produce them within an hour. The largest study of turnaround time to date, with data from cTn and creatine kinase MB (CK MB) tests in 159 mostly North American hospitals, reported a median and 90th percentile troponin times of 82 and 131 minutes, respectively. In fact, fewer than 25% of hospitals were able to meet the 60-minute turnaround, defined as order-to-report time, for both tests.

But at Department of Veterans Affairs (VA) medical centers, turnaround of troponin results in 60 minutes is a performance measure backed up by emergency department POCT in facilities that can’t meet this standard in their central labs, noted Jesse. “At VA, rapid troponin is not only important for clinical care, but also is a systems measure reflecting the front end of acute cardiac care,” he explained. “Among MIs, you need to differentiate risk. For example, ST-elevation myocardial infarction (STEMI) carries the highest risk among the MIs, and there’s an absolute time stamp for treatment, but absent that, troponin identifies an additional higher-risk cohort.”

This performance measure helps get patients the appropriate care quickly, a crucial goal in any hospital. “In the U.S., ERs and ICUs are crowded. The sooner you know where to send the patient, the better,” Jesse emphasized. For all suspected MIs, the VA facilities perform an initial EKG within 10 minutes of a patient’s arrival. “The EKG tells who has a STEMI and facilitates rapid treatment for that group of patients,” Jesse explained. “But a relatively small proportion of patients will have a diagnostic ECG at presentation. Many of the other high-risk patients will be troponin positive, so that’s an argument to identify them early and initiate the appropriate treatment as rapidly as possible.”

Other Markers on the Horizon

The revised guidelines give lesser recommendations to other biochemical markers, including the CK-MB. Although no longer the gold standard, some labs will be pleased to learn that the NACB committee found that CK-MB by mass assay is an acceptable alternative when cardiac troponin is not available.

The committee also gave a IIa recommendation, which represents divergence of committee opinion in the absence of at least one large, randomized, controlled trial, to use high-sensitivity CRP (hs-CRP) for risk stratification in conjunction with cTn. Measurement of hs-CRP may be useful in addition to cTn for risk stratification, but benefits remain uncertain. “Consistent and compelling evidence for interactions between other available biomarkers (e.g. BNP and hs-CRP) and specific treatment strategies in ACS are not yet available,” note the guidelines’ authors.

Turning its attention towards the future, the NACB committee cited several cardiac biomarkers that could someday be part of a multi-marker strategy. Along with cTn, these markers could identify events on the continuum of ACS, including inflammation, plaque buildup and rupture, ischemia, and decreased blood flow. This strategy would enable clinicians to tailor individual treatment for patients and avert cell death, myocardial dysfunction, and heart failure, Apple explained. Recent AHA guidelines on preventing cardiovascular disease (CVD) in women and stroke newly embrace this concept of CVD as a condition that develops on a continuum over time, rather than one a patient does or doesn’t have (See Sidebar, below).

Guidelines for Women’s Heart Health Focus on Individual Risk

Updated guidelines on acute coronary syndromes from the National Association of Clinical Biochemistry are not the only recommendations that discuss how to stem cardiovascular disease (CVD). Updated American Heart Association (AHA) CVD and stroke prevention guidelines for women, just released in February, aim to stem CVD’s development and advancement to the point where hospital care is necessary. AHA recommendations emphasize individuals’ cardiovascular health in an era when improved technology for identifying CVD has blurred the distinction between primary and secondary prevention.

“The concept of CVD as a ‘have-or-have-not’ condition has been replaced with the idea that CVD develops over time and every woman is somewhere in the continuum,” explained Lori Mosca, MD, PhD, chair of the committee that wrote the guidelines and Director of Preventive Cardiology at New York (N.Y.)-Presbyterian Hospital/Columbia University Medical Center. The recommendations, published in Circulation (2004; 109: 672-693), update earlier guidelines released in 2004.

The 2007 guidelines recommend linking treatment to an individual’s risk of having a heart attack in the next 10 years. A standardized scoring method developed by the Framingham Heart Study helps physicians determine whether a woman’s risk is low, medium, or high.

New recommendations in the guidelines include:

  • More moderate-intensity physical activity, totaling 60 to 90 minutes on most, but preferably all, days of the week;
  • Counseling, nicotine replacement, and other therapy to quit smoking;
  • Saturated fat intake of less than 7% of all calorie intake for all women;
  • Eating oily fish at least twice a week and capsule supplements of 850–1000 mg of eicosapentaenoic acid (EA) and docosalhexaeonic acid (DA) for women with CVD, and 2 to 4 grams of DA and EA for women with high triglycerides;
  • Considering routine low dose aspirin therapy for women age 65 or older regardless of CVD risk status and increased aspirin doses for high-risk women; and
  • Thinking about reduction of LDL cholesterol to less than 70 mg/dL in very high-risk women with CVD.

The guidelines no longer recommend:

  • Hormone replacement therapy and selective estrogen receptor modulators;
  • Antioxidant supplements for primary or secondary prevention of CVD; and
  • Folic acid to prevent CVD.

Overall, the NACB guidelines discuss about 25 potential candidates for inclusion in a multi-marker strategy that could, in addition to cTn and an ECG, help identify the approximately 40% to 60% of ACS patients who present with an initial cTn concentration below the clinical decision limit. If research identifies drugs that can stem damage and decrease MI in particular populations, the potential for better patient outcomes and cost savings “would be huge”, Apple predicted. Storrow agreed. “It would be a grand slam for us in the ED to have a marker for ischemia,” he asserted.

Among the other markers described as part of a multimarker strategy in the guidelines, natriuretic peptides and CRP both receive a IIb recommendation. Currently BNP and CRP levels say that a patient “is definitely at higher risk, but there just isn’t any research out that tells clinicians what to do with this information,” Christenson explained. Apple added that the IIb designation, however, means the committee is excited about these markers and believes they “will be important when we know how to use them correctly and there are FDA-cleared assays for them.”

Of the newer markers, ischemia-modified albumin (IMA) and myeloproxidase (MPO) were the focus of the most discussion during the formation of the guidelines. Much has been published on both markers, which have FDA-cleared assays. But according to Christenson, use of the tests remains limited. The MPO test appears to reflect plaque instability; however, the assay is based on enzyme-linked immunosorbent assay (ELISA) technology and is therefore rather time consuming. IMA was “one the hottest areas of contention” among the NACB committee members, according to Christenson. The IMA test rules out ischemia well, as shown in a recent meta-analysis, but the meaning of a positive value is less certain.

More information on the use of this marker should be available soon, as Storrow and other Vanderbilt researchers are investigating IMA as part of the multicenter IMAGINE (Ischemia Modified Albumin in Diagnosing Ischemic New Events) trial. The study will enroll 1,500 patients at Vanderbilt, Massachusetts General Hospital in Boston, Dartmouth Hitchcock Medical Center in Hanover, N.H., and the Cleveland Clinic, Ohio.

Jesse also noted some attention given to whole-blood choline, a marker that has shown promise as an indicator of 30-day mortality in patients presenting with chest pain, and to CD 40 ligand, which has shown some potential as an early marker of ACS.

But the bottom line is that research hasn’t elevated any of these biomarkers to a status akin to troponin’s. “We recognize and make a strong recommendation that cardiac troponin should prompt application of treatment guidelines. The evidence is less robust for other markers,” Storrow emphasized. Added Jesse, “Despite the promise of a number of emerging cardiac markers, troponin remains the most powerful, providing both diagnostic and prognostic information that can positively influence the delivery of cute cardiac care.”