Expanded role for diagnostic testing in cardiology improves patient management

ACC/AHA guidelines point to new approaches for MI diagnosis and treatment

New guidelines for the management of patients with acute myocardial infarction were published last month by a joint task force of the American College of Cardiology (Bethesda, Maryland) and the American Heart Association (AHA; Dallas, Texas), and also were the subject of considerable discussion at the 69th Scientific Sessions of the AHA, held in New Orleans, Louisiana. The guidelines contain important changes in the recommended approach to patient management, many of which will have significant impacts on the markets for products used in the diagnosis and treatment of heart patients.

Key new recommendations include:

* Classification of myocardial infarction (MI) as ST elevated versus non-ST elevated.

* Use of laboratory tests including Troponin T, Troponin I, and CK-MB isoforms both in the initial diagnosis of MI and for assigning patients to risk and therapeutic categories.

* Prescription of therapies intended to lower the cholesterol level of all patients, including the use of lipid-lowering therapy.

* Expanded availability of automatic external defibrillators (in commercial aircraft, for example).

* Prompt restoration of blood flow following MI, including a "door to needle time" of 30 minutes or less and 60 to 90 minutes for reperfusion using percutaneous transluminal coronary angioplasty (PTCA).

* More discretionary use of calcium channel blockers, since these drugs have not been shown to reduce mortality after acute MI, and in certain patients with cardiovascular disease, there are data to suggest they are harmful.

Although the electrocardiogram (ECG) and a history of ischemic-type chest discomfort remain the primary methods for screening patients for MI, in particular the observation of ST-segment elevation and/or Q waves in the ECG, about 50% of patients with MI display non-diagnostic ECG changes. As a result, for the majority of patients the laboratory plays an essential role in establishing the diagnosis of MI.

Accurate diagnosis of MI remains a major problem. It is estimated that more than 5 million persons a year in the U.S. have episodes of chest pain and present themselves to a hospital emergency room. Half of these individuals are admitted to the hospital, but most are found not to have had a heart attack, resulting in a needless hospital stay. Of the 5 million who [TABULAR DATA FOR TABLE 1 OMITTED] present to the emergency room, only about 500,000 are subsequently diagnosed as having suffered an MI. Misdiagnosis of heart attacks in the number one cause of malpractice litigation in the U.S.

Newer cardiac markers such as the troponins and certain well-known tests, particularly CK-MB isoforms, have proven effective in improving MI diagnosis, and also show promise for triage of MI patients. CK-MB isoforms appear to have the greatest overall sensitivity, but the addition of Troponin T and I to the test panel considerably enhances sensitivity. Myoglobin also has been shown to have a role in early MI diagnosis, since its sensitivity peaks at six hours post-MI. Table 1 describes cardiac markers in use and under evaluation.

Early-stage studies are exploring the utility of both brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) as markers for congestive heart failure, a disease responsible for about 880,000 hospitalizations each year in the U.S., and a contributing cause in an estimated 250,000 deaths per year. Scios Inc. (Mountain View, California) recently obtained approval to market a BNP immunoassay in Japan, and is searching for a major partner prior to beginning clinical trials in the U.S. Other markers under investigation that show promise in prognosis and early diagnosis include fibrinogen and heart fatty acid-binding protein.

Numerous studies have been performed to assess the utility of markers such as the troponins, myoglobin, and CK-MB isoforms, particularly for early diagnosis of MI and for prognosis post-therapy. In a presentation during last month's AHA meeting, Dr. Robert Roberts of Baylor College of Medicine (Houston, Texas) said only CK-MB isoforms are suitable for use as a single marker. If one wishes to employ a combination of markers for diagnosis, either CK-MB isoforms or myoglobin in combination with Troponin T or I appear suitable. No major differences in sensitivity and specificity for detection of MI have been observed thus far between Troponin T and I, but Troponin I is more frequently elevated in unstable angina and Troponin I is more sensitive than T in the [TABULAR DATA FOR TABLE 2 OMITTED] first six hours post-MI. However, certain Troponin I assays are subject to false positive results in patients suffering from renal failure. Troponin T also has been shown to have possible applications in predicting heart attack risk in patients with unstable angina.

The potential market for rapid MI diagnostic markers could well be more than $90 million in the U.S., assuming a $10 cost per test and 5 million patients per year for initial diagnosis, plus three to four follow-up tests on each of the 900,000 patients who suffer a heart attack each year. Based on the estimated number of patients who visit emergency departments worldwide for heart attack symptoms, the global market for such tests may be in excess of $200 million.

Non-invasive technologies promise savings

In addition to advances in laboratory methods for cardiac diagnosis, non-invasive hemodynamic monitoring techniques also are attracting increased attention. Interest has been heightened by a recent study published in the Journal of the American Medical Association (JAMA 1996;889-894) indicating excess mortality and increased cost per stay for patients subject to invasive hemodynamic monitoring with right heart catheters, a longtime standard of treatment.

Table 2 describes non-invasive and minimally invasive hemodynamic monitoring products available in the U.S. market. CardioDynamics International (San Diego, California) is one of the leaders in the field. The CDM 3000/4000 monitor, shown at AHA, employs thoracic electrical bioimpedance measurement and is based on patented technologies developed by BoMed Medical Manufacturing in the 1980s. BoMed's success in commercializing bioimpedance technology was limited, due to insufficient capabilities of early generation microprocessors, inaccurate physiologic assumptions, and a lack of experienced management in medical sales, marketing and distribution. BoMed entered Chapter 11 bankruptcy in March 1992 and re-emerged in 1993 as CardioDynamics. A complete upgrade of the BoMed technology was begun in June 1995, addressing improvements in accuracy from about 65% to 90%, improved detection and rejection of bad beats and noise artifact, digital waveform sampling rates 16 times faster than the old technology, and the use of digital signal processing.

CardioDynamics is conducting studies with the CDM 3000/4000 at the Mayo Clinic (Rochester, Minnesota), the University of Washington (Seattle, Washington), and Brigham and Women's Hospital (Boston, Massachusetts). Target areas of application include the coronary care unit, nephrology, the pacemaker laboratory, monitoring of high-risk pregnancy, and stress testing. The greatest potential for growth in use of the technology is believed to be with patients who would not typically be candidates for invasive monitoring, but for whom hemodynamic monitoring can prove useful. These include dialysis patients, pre-eclampsia patients, and patients undergoing drug therapy for normalization of blood pressure.

The technology also may prove useful as a supplement to invasive monitoring, allowing a right heart catheter to be removed two to three days earlier, at considerable cost savings. A study is planned to start this month comparing the CDM monitor with Swan-Ganz monitoring, and U.S. product release is targeted for January. CardioDynamics is placing about 21 units a month outside the U.S.

Sorba Medical Systems (Brookfield, Wisconsin) also is stepping up its marketing efforts following publication of the JAMA article. Sorba's CIC-1000 provides a very low-cost alternative to invasive right heart catheterization, with an electrode set costing only $10 per procedure. In the study described in JAMA, the savings of avoiding right heart catheter monitoring in a single patient were $13,600 ($49,300 with monitoring and $35,700 without), almost equal to the list price of the Sorba instrument.

Renaissance Technologies (Newtown, Pennsylvania), a third player in the non-invasive monitoring market, is involved in a 300-patient study of the use of its monitors for congestive heart failure patients, and also is conducting studies in trauma patients and for post-operative monitoring of patients who have undergone coronary artery bypass surgery. Opportunities may expand significantly for the use of monitoring in bypass patients if new minimally invasive surgical techniques are widely adopted, as such monitoring could further reduce the overall invasiveness of bypass therapy.

Advances in coagulation monitoring

Rapid technology-driven change also is transforming the market for products used in monitoring of coagulation status in heart patients and others treated with anti-coagulant therapy. In particular, new systems for monitoring of coagulation status outside of the central laboratory may allow patients to leave the hospital sooner following procedures requiring anticoagulant therapy, with monitoring performed in the home health care setting.

The worldwide market for coagulation monitoring instruments and consumables is estimated at about $415 million this year, with a 3% to 4% annual growth rate. However, point-of-care coagulation monitoring is exhibiting much stronger growth, as shown in Table 3 on page 226. By 2001, the size of this segment is expected to exceed $100 million.

One of the newest products for point-of-care coagulation monitoring is the ProTime Microcoagulation System developed by International Technidyne Corp. (Edison, New Jersey), the market share leader in bedside coagulation testing. Shown at AHA, ProTime provides rapid analysis of International Normalized Ratio using only a fingerstick specimen of whole blood. The 510(k) application for the home-use indication of the ProTime has been granted expedited review by the FDA.

International Technidyne said the system could potentially be used by up to 2 million patients on oral anticoagulant therapy in the home setting, including patients with mechanical heart valves or atrial fibrillation. Recent studies of home anticoagulation monitoring have appeared promising, with no significant bleeding or thromboembolic disorders observed.

Dr. Richard Becker, director of the Cardiovascular Thrombosis Research Center at the University of Massachusetts Medical Center (Worcester, Massachusetts), said 50% of patients who participated in recent studies of coagulation monitoring are candidates for home monitoring, and that percentage could climb to 75% with home health care support.

The patient management approach is similar to that used for glucose monitoring by diabetics, with quality control performed during routine hospital visits. Using a coordinated approach to anticoagulation management, the savings with patient self-testing can reach $1,000 per year per patient due to reduced adverse events and less hospitalization.

Table 3

Point-of-Care Coagulation Testing Products Market (Hospital
Segment)

Year         Total Sales ($M)         Growth

1994          $45.4 million
1995          $50.8 million           11.8%
1996          $56.9 million           12.0%
1997          $63.7 million           12.0%
1998          $71.2 million           11.8%
1999          $79.6 million           11.8%
2000          $89.3 million           12.2%
2001          $100.9 million          13.0%

Compound annual growth rate, 1996-2001 12.1%

Source: The BBI Newsletter

Other important players in the point-of-care coagulation monitoring market include Boehringer Mannheim Diagnostics (Indianapolis, Indiana), with its CoaguChek and CoaguChek Plus monitors; Cardiovascular Diagnostics (Durham, North Carolina), with its Thrombolytic Assessment System; and Medtronic Hemotec Inc. (Englewood, Colorado), with its HemoTec and HepCon systems.

One of the potential limiters of this market, however, is the recent development of improved anticoagulant drugs that may reduce the need for coagulation monitoring. An example is Lovenox (enoxaparin sodium), a new, low-molecular-weight heparin compound developed by Rhone Poulenc Rorer (Collegeville, Pennsylvania). Patients treated with this drug usually do not require routine daily monitoring of coagulation times. That is due in part to the long half-life of the drug, 4.5 hours, four times that of standard heparin. The results of the recent ESSENCE study using Lovenox are quite promising, with only 16.6% of enoxaparin patients experiencing chest pain, heart attack or death, versus 19.8% in the heparin group.

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