By Renee DiIulio

Cardiovascular disease is the leading cause of death in the United States, costing not only lives but also billions of dollars per year. Fast, accurate testing can help doctors make an earlier diagnosis for patients presenting in the emergency room with chest pain. The result: more lives saved, better care for the sick patient, and less cost for the well patient and the hospital. Guidelines published in the past few years have recognized this and modified recommendations accordingly, encouraging the use of troponin tests that deliver results in under an hour.

Knowing this, i-STAT Corp of East Windsor, NJ developed a point-of-care test that avoids existing compromises in the market. The i-STAT 10-Minute Cardiac Troponin I (cTnI) Test, which delivers specific, sensitive results within 10 minutes, received FDA approval in the fall and is now available to hospitals and other facilities where patients present with chest pain. Though studies are still under way, Gregory W. Shipp, MD, i-STAT’s vice president of Medical Affairs, says that data are expected to indicate trending and significant results in improved patient outcomes. Other studies have already shown a cost savings to hospitals.

The i-STAT Analyzer (left) is small enough to be brought bedside.

Cardiovascular Disease: The Stats
In 2001, heart disease killed more than 700,000 people in the United States, accounting for 29% of all deaths.¹ This was down from 1999, when it killed more than 725,000 Americans and accounted for 30.3% of all deaths.² Yet, despite the decline, heart disease remains the nation’s leading cause of death.

Cerebrovascular disease, whose major event is usually a stroke, is the third-leading killer, responsible for more than 160,000 deaths in the United States in 2001, or 6.8%.¹ Together, these two diseases, which make up the principal components of cardiovascular disease, account for roughly one third of all deaths in the United States.

Of course, not all those suffering from cardiovascular disease will die immediately. According to the Centers for Disease Control and Prevention (CDC), approximately 61 million Americans, nearly a quarter of the population, live with the effects of stroke or heart disease. Information from the CDC and the National Center for Chronic Disease Prevention and Health Promotion indicates that 10 million people are disabled as a result.

The new i-STAT 10-Minute Cardiac Troponin I (cTnI) Test cartridge (below) is designed to run with the company’s portable analyzer and deliver test results in under 30 minutes.

Some of this is preventable. The CDC notes, “Much of the burden of heart disease and stroke could be eliminated by reducing their major risk factors: high blood pressure, high blood cholesterol, tobacco use, diabetes, physical inactivity, and poor nutrition.” Patients may be able to control these factors with diet and behavior, or they may require medical aid. Some of these will likely be one of the almost 6 million annual hospitalizations resulting from cardiovascular disease.³

The High Costs of  Cardiovascular Disease
Much of this is expensive. The American Heart Association estimates the cost of cardiovascular diseases in the United States for 2004 at $368.4 billion.⁴ The CDC and National Center for Chronic Disease Prevention and Health Promotion reported that in 2003, the cost of heart disease and stroke in the United States was projected to be $351 billion: $209 billion for health care expenditures and $142 billion for lost productivity from death and disability. In 1999, the cost of hospitalization for cardiovascular problems among Medicare beneficiaries totaled $26.3 billion.³

Hospital expenses, however, are not the only costs incurred. High, unnecessary costs result from the admission of patients with a low probability of acute coronary artery disease, as well as from releasing patients with a missed acute myocardial infarction (AMI), which can result in a decrease in the patient’s quality of life or even death and, subsequently, medical malpractice claims. Physicians have increased vigilance to exclude myocardial infarction (MI), but despite high admission rates, the rate of missed MI continues to hover at 1.5% to 2%.⁵

Identifying patients experiencing an AMI is not the only distinction physicians need to make. They must also identify those AMI patients who should receive thrombolytic therapy. Greater benefits result the earlier the therapy is initiated.

Because of the costs related to error, particularly human life, physicians will wait to diagnose a patient until they have all of the necessary information. This includes the patient’s history, a physical examination, an electrocardiograph, and initial cardiac biomarker tests.

Diagnosing Cardiovascular Disease with Biomarkers
Donald Schreiber, MD, CM, notes in his study, “A recent consensus guideline has redefined AMI and focuses on the central importance of cardiac markers. According to the American College of Cardiology (ACC) (Bethesda, Md) and the European Society of Cardiology (ESC) (Sophia Antipolis, France), AMI is defined as a typical rise and fall of biochemical markers (for example, troponin, creatine kinase [CK-MB]), with at least one of the following: ischemic symptoms; new pathologic Q waves on ECG; ischemic ECG changes (ST-segment elevation or depression); and/or coronary artery intervention.”⁵

Cardiac biomarkers currently used for diagnosis include CK-MB, myoglobin, LDH isoenzymes, and troponin. Though CK-MB has been the gold standard for the past decade, troponin has recently become the preferred marker.

Troponin plays a role in the regulation of both skeletal and cardiac muscle contraction. The troponin complex consists of three polypeptide subunits, troponin I (TnI), troponin T (TnT) and troponin C (TnC). TnT and TnI are found in both types of muscle, though in different forms. Only one tissue-specific isoform of TnI is described for cardiac muscle tissue: cardiac troponin I (cTnI ) is expressed only in myocardium.

Troponin: The New Recommended Cardiac Biomarker
During a heart attack, the heart muscle cells release their contents, which include troponin, myoglobin, and CK. Of these, levels of troponin have demonstrated superior specificity and sensitivity in the detection of myocardial damage. Cardiac troponin I is specific to cardiac injury whereas other markers, such as CK-MB and myoglobin, can be found in low levels within other tissues of the body.

Troponin levels are normally very low, with even slight elevations indicating some damage to the heart.⁶ An elevated troponin level enables risk stratification of patients with acute coronary syndrome (ACS) and identifies patients at high risk of adverse cardiac events (death, MI) up to 6 months after the index event.⁵

Raised cTnI levels may be seen within 3 to 6 hours of cardiac injury and can remain high for as long as two weeks. Troponin’s tendency to remain longer than other biomarkers allows it to be an indicator for patients who have delayed seeing a doctor.

It is also an indicator for patients with unstable angina. Lab Tests Online reports that “studies have shown patients with unstable angina and high troponin, but normal CK, CK-MB, and myoglobin, have a higher risk of having a heart attack or other serious heart problem in the next few months.⁸ Many doctors now check troponin in persons with unstable angina to identify those who may benefit from such treatments as angioplasty (using a balloon to open a blocked heart blood vessel) or heart bypass surgery”.⁶

Because of the more accurate diagnosis, new guidelines have emerged in the past few years detailing the preferred use of troponin as a cardiac biomarker.⁷ “The guidelines by the ACC/ESC, the American Heart Association, and the National Academy of Clinical Biochemistry recommend troponin as the preferred biomarker. The ACC/ESC also suggest that these first results be delivered within 30 minutes, but absolutely no later than 1 hour, after the patient presents for treatment,” says Shipp. He attributes the new guidelines to the number of new therapies that can be administered in the emergency room.

In hospitals where specimens are sent to a central lab for processing, turnaround time can take anywhere from 45 minutes to 1 hour, notes Shipp. Seeing an opportunity to improve patient care, reduce hospital costs, and grow its bottom line, i-STAT set about developing a test that would reduce that turnaround time to within the ACC/ESC recommendations.

Test Results in 10 Minutes
Two years later, the i-STAT 10-Minute Cardiac Troponin I (cTnI) Test is now available in the United States. The cTnI cartridge is designed to work with the current i-STAT Portable Clinical Analyzer, which is easily used in the emergency room, and can produce results within 10 minutes.

Development of the i-STAT cTnI cartridge overcame obstacles related to analyzer compatibility, miniaturization, and whole blood processing. “Most of the 2 years in development was dedicated to miniaturizing the standard ELISA assay. We had to reformat it to fit i-STAT mechanics so that it would run on our standard platform,” says Shipp. The platform is small enough to be brought bedside. The cTnI test is the first micro immunoassay ever done at the company, he adds.

Keeping the guidelines in mind, developers kept a tight balance between sensitivity and speed. “We found that at 10 minutes we could guarantee results under the guidelines’ 30-minute window and still achieve excellent sensitivity,” says Shipp.

To keep specimen processing fast, the analyzer and, therefore the test, process whole blood, eliminating the separation step. This presented challenges to valving and mixing inside the cartridge as well as interaction with the antibodies in the immunoassay. However, the developers were able to meet the challenge and do so requiring only a 16-µL sample. Shipp notes that competitors require anywhere from 500 µL to 4 mL.

The company made note of competitors’ products during development in order to provide a unique test. “We wanted a test that would be conducive to the emergency room and alleviate the standard compromises made with traditional products. For instance, a fast product has typically offered low sensitivity while a precise test has required time,” says Michael F. Corsello, i-STAT’s senior marketing manager.

Developers of the i-STAT 10-Minute Cardiac Troponin I Test wanted a test that could be easily used in the emergency department.

Benefits to Patients and Facilities
A fast, accurate test will play a positive role in improving the ability to accurately diagnose patients presenting with chest pain. It is expected to improve patient care, decrease unnecessary hospital admissions, and efficiently utilize hospital resources. “Time equals muscle,” says Shipp, citing a phrase well known in cardiology. “The faster you can treat someone having a heart attack, the more muscle you will save and the less chance the patient will have for later cardiac arrest.”

To quantify the actual effect faster treatment has on outcome, i-STAT is conducting its own tests. “The clinical trials completed for the FDA approval process showed interference data, specificity, and sensitivity,” says Shipp. Studies under way are more clinically oriented to prove the therapeutic value of a fast turnaround time, defined as starting when the blood is drawn from the vein to when therapy is administered. Patients will be followed for 30 days after treatment. Shipp notes that results are expected to show trends and identify potentially significant results.

Other research has already proven a link between reduced expenses and earlier diagnoses. An analysis, taken after the introduction of troponin testing in one hospital and published this summer in the Irish Medical Journal by McKiernan et al, noted “a highly statistically significant reduction of 354 total bed days utilized due to the increased proportion of patients with the shorter length of stay associated with a diagnosis of noncardiac chest pain.”⁸ This translated into a large cost savings for the hospital. With advantages for both patients and facilities, i-STAT’s new point-of-care test is small in size but big in benefits.

References
1. Arias E, Anderson RN, Kung HC, Murphy SL, Kochanek KD. Deaths: final data for 2001. Nat Vital Stat Rep. 2003;18;52(3):1-115.
2. Centers for Disease Control and Prevention. Declining prevalence of no known major risk factors for heart disease and stroke among adults—United States, 1991–2001. MMWR Morb Mortal Wkly Rep. 2004;53(1):4-7.
3. Centers for Disease Control and Prevention and National Center for Chronic Disease Prevention and Health Promotion. The burden of chronic disease and their risk factors: National and state perspectives 2002. August 30, 2002. Available at http://www.cdc.gov/nccdphp/burdenbook2002. Accessed February 10, 2004.
4. American Heart Association. Heart Disease and Stroke Statistics—2004 Update. Available at http://www.americanheart.org/presenter.jhtml?identifier=3000090. Accessed February 10, 2004.
5. Schreiber D. Use of cardiac markers in the emergency department [eMedicine.com]. February 12, 2002. Available at www.emedicine.com/emerg/topic932.htm. Accessed February 10, 2004.
6. Lab Tests Online. Troponin test. Available at www.labtestsonline.org/understanding/analytes/troponin/test.html. December 21, 2001. Accessed February 10, 2004.
7. Alpert JS, Thygesen K, Antman E, Bassand JP. Myocardial infarction redefined—a consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol. 2000;36(3):959-969.
8. McKiernan P, Buckley A, Pate GE, Quigley C, Reardon M, Toddy D. Research correspondence—troponin. Irish Medical Journal. 2002;95(7). Available at www.imj.ie/news_detail.php?nNewsId=2424&nCatId=8&nVolId=94. Accessed February 10, 2004.

For additional information, contact Michael F. Corsello, senior marketing manager, or Gregory W. Shipp, MD, vice president of medical affairs, i-STAT Corp, 104 Windsor Center Dr, East Windsor, NJ 08520; phone: (609) 443-9300; fax: (609) 443-9310.