CDU Contributing Editor
New tests used in risk assessment for cardiovascular disease represent one promising area of growth in an otherwise generally stagnant clinical chemistry products sector. Those include emerging markers such as C-reactive protein (CRP) that can be measured on newer chemistry/immunochemistry testing platforms, as well as increases in use of such traditional tests as total LDL and HDL cholesterol, as well as triglycerides. In part, interest in cardiovascular risk assessment testing has increased because of new recommendations for use of an expanded panel of markers for assessing risk and selecting strategies for secondary prevention published by the American Heart Association (AHA; Dallas, Texas) and American College of Cardiology (Bethesda, Maryland) in September 2001.
Another product segment that has helped support the market for clinical chemistry products is lab automation systems used for sample preparation and distribution of samples to analyzers. The market for such systems has expanded as laboratory consolidation has reduced the total number of hospital and reference labs: in the U.S., the number of hospital labs dropped 4.2% between 1996 and 2000, while the number of independent labs dropped by 15.5% over the same period. While total chemistry test volume in the U.S. declined over that period, the consolidation of testing into a smaller number of labs generally resulted in higher volume per lab for the remaining laboratories. That trend, coupled with a worsening shortage of laboratory technologists, has forced labs to adopt more automation in order to keep up with demand, benefiting suppliers of automated lab equipment for clinical chemistry testing.
An emerging segment of the clinical chemistry market is small, easy-to-use analyzers that can allow many chemistry tests to be performed in alternate sites, including ancillary sites outside of the central lab in hospitals, and in physician offices and clinics. Such products can allow some of the testing workload to be shifted out of the central lab, alleviating capacity issues, while also allowing test results to be delivered to physicians more rapidly and efficiently. So far, that segment has developed more slowly than suppliers expected. However, companies marketing alternate-site chemistry/immunochemistry systems also are developing new tests such as high-sensitivity CRP that could help stimulate sales.
Cardiac risk tests stimulate market
The importance of cardiovascular disease management in medicine is fundamentally driven by the fact that cardiovascular disease remains the No. 1 cause of death in the U.S. and other developed countries, with an estimated 61.8 million in the U.S. having one or more forms of the disease, according to the AHA. A key issue in risk assessment has historically been the failure of existing testing methods, including both in vitro tests and physiological exams such as ECG and blood pressure measurement, to identify all those individuals who suffer an acute coronary event. For example, as discussed by Mary Lou Gantzer, PhD, the new president of the American Association for Clinical Chemistry (AACC; Washington) at a recent symposium on cardiovascular disease risk factors, 35% of coronary heart disease occurs in patients having a total cholesterol level of less than 200 mg/dL, the generally accepted threshold for indication of high risk. As a result, other potential markers continue to be evaluated, with high-sensitivity CRP being one of the most promising at the moment.
Suppliers have responded quickly to the growing interest of laboratorians and clinicians in using CRP as a risk assessment tool. As shown in Table 1, there are at least eight high-sensitivity CRP tests on the market in the U.S., with more in development. Listprices for high-sensitivity CRP tests that run on chemistry/immunochemistry analyzers, such as the Synchron and Dimension range from $5 to $8, with actual selling prices about 25% less in low volume. While CRP is typically measured using immunoassay technology, and is in fact classified as an immunology test by the FDA, it has become widely available on new combined chemistry/immunochemistry analyzers that have entered the market within the past few years, such as the Dade Behring (Deerfield, Illinois) Dimension RxL, the Roche Diagnostics (Mannheim, Germany)/Hitachi 900 Series systems, and Beckman Coulter's (Brea, California) Synchron LX20 PRO, with a test also in development for the Olympus AU Series analyzers. Such systems incorporate multiple analytical technologies, such as absorption spectroscopy for measurement of conventional chemistry analytes, plus nephelometric or turbidimetric analysis modules to perform immunoassays. For example, the Dimension RxL employs a photometric technology called Particle Enhanced Turbidimetric Immunoassay (PETIA) to obtain high sensitivity detection on a high-throughput chemistry/immunochemistry platform. Likewise, Beckman Coulter's Synchron LX20 PRO uses a new near-infrared detection module that measures at 940 nanometers to detect CRP levels as low as 0.02 mg/dL, in a system that is capable of performing up to 1,440 tests per hour. Such systems are helping to drive integration of the chemistry and immunochemistry markets, and improving operational efficiency in the laboratory while allowing suppliers in the chemistry segment to expand their served market to include higher-growth opportunities.
The use of high-sensitivity CRP tests to assess cardiovascular disease risk is an evolving area, with some physicians already using the test to help risk-stratify patients while others do not yet believe enough data is available to justify its use. The concept of using inflammation (of blood vessels) as a risk factor in cardiovascular disease is relatively new, but studies by Paul Ridker, MD, of Harvard Medical School (Cambridge, Massachusetts), and others show increasingly strong evidence that it is an independent element of risk. When combined with an assessment of lipoprotein levels, blood pressure, presence of diabetes,behavioral factors hemostatic factors and genetic factors, inflammation appears to provide increased power for the detection of individuals who are likely to suffer a major adverse cardiac event. The most powerful combination of in vitro risk markers at present appears to be high-sensitivity CRP coupled with measurement of the total cholesterol/HDL cholesterol ratio. The two parameters together provide almost twofold greater ability to detect individuals who are at high risk as compared to either parameter alone.
The value of CRP testing is further enhanced because certain lipid-lowering agents, namely pravastatin, have been shown to modify risk for patients with inflammation as indicated by CRP levels. Acetaminophen (aspirin) also helps lower CRP, possibly explaining at least part of the observed effect of that drug in reducing the incidence of adverse cardiac events.
The use of CRP as a cardiac risk marker is not straightforward, however. CRP is a highly non-specific, general indicator of inflammation, and can be elevated 1,000-fold in the acute phase of a serious infection. In fact, some physicians advocate using CRP testing as routinely as measurement of body temperature, since it is a highly sensitive indicator that a disease process is present. The degree of elevation that is due to inflammation of the coronary arteries, however, is generally much less than for an infection, so physicians must first rule out the presence of infection or inflammation due to other causes (e.g., rheumatoid arthritis) before concluding that an elevated CRP indicates that a patient is at high risk for an adverse cardiovascular event. Typically, measurements are repeated after three to six weeks if an elevated CRP is observed and there are no clear-cut signs of infection or inflammation due to other disease processes, since the elevation will usually subside if due to an infection.
Some physicians are beginning to evaluate the use of high-sensitivity CRP as a prognostic marker in patients who have suffered an acute coronary event. In a patient with angina, for example, a high CRP level might indicate that the atherosclerotic process is in an active stage, warranting more intensive monitoring or perhaps early intervention. It is not yet clear if CRP will prove useful in that role, however.
One indicator of the acceptance of high-sensitivity CRP testing by physicians is the fact that a new reimbursement code was implemented by the Center for Medicare and Medicaid Services this year specifically for the high-sensitivity version of the test. High-sensitivity assays are typically priced considerably higher than conventional CRP tests, which list for as little as $1 per test and often sell for considerably less. The implementation of a new reimbursement code indicates recognition by the most important payer in the U.S. health care system of the growing demand for high-sensitivity CRP testing. As shown in Table 2, the number of CRP tests reimbursed under Medicare has grown at a rate of more than 10% per year over the 1993-2000 interval, and considerably more rapidly in the most recent years, while unit volume for other common chemistry tests, such as glucose, have dropped, stabilizing only recently.
One issue for most suppliers of high-sensitivity CRP assays is a patent application that has been filed by Ridker on the use of inflammation markers in cardiovascular disease risk assessment. So far, that has not stopped suppliers from introducing high-sensitivity CRP testing products, but some suppliers are not marketing those tests as indicated for use in cardiovascular risk assessment. Dade Behring has established an agreement with Ridker for commercial use of the technology.
Test volume for other markers such as total cholesterol, HDL and LDL cholesterol, and triglycerides also is expected to increase as more physicians begin performing cardiovascular risk assessment on a routine basis. As the effectiveness of screening tests increases, primarily due to the introduction of additional markers that can help to identify various risk subsets, and new and improved drugs are launched to modify risk, demand for testing is likely to increase. New guidelines place more individuals in the high-risk category, increasing the need to screen the population in order to identify all those who will benefit from treatment.
Medica showcases POC offerings
One of the most important new products introduced at the Medica 2001 exhibition for point-of-care testing in the hospital environment was Roche Diagnostics' (Mannheim, Germany) OPTI Plus. The new system combines the original OPTI blood gas/electrolyte technology with the AccuChek Advantage glucose meter and the CoaguChek Pro POC coagulation testing system. The system also will have the capability to interface with the Roche Cardiac Reader, which is now on the market for performing POC cardiac marker testing using the Roche Troponin T and Cardiac M myoglobin assays, as well as the Cardiac D-Dimer assay. In terms of the analytical parameters offered, the system bears some similarity to the MobilCare system that Roche and AVL Medical had under development prior to the acquisition of AVL by Roche in June 2000. However, the new OPTI Plus is considerably more compact and offers features such as the SNAP PAK module, which allows multiple (25) tests to be performed using a single cartridge, and wireless data transmission.
The system will compete with analyzers from suppliers such as i-STAT (Princeton, New Jersey) and Instrumentation Laboratory (Lexington, Massachusetts) that also offer combined blood gas/electrolyte/coagulation/glucose testing at the point of care, with cardiac marker tests planned for addition to the i-STAT menu in the future.
Another new competitor in the cardiac marker segment is Genzyme Diagnostics (Cambridge, Massachusetts). Genzyme is developing a quantitative cardiac marker testing system with a menu that will include Troponin I, CK-MB and myoglobin. The system will consist of a reader and disposable test cartridges, with Troponin I available on one cartridge and a second cartridge offering CK-MB and myoglobin. Kalibrant Ltd. (Loughborough, UK) also is developing a new POC testing system, the Jetstream, that will offer cardiac markers and other tests performed using a new multiplexed fluorescence detection technology and the company's proprietary flow-driven automation technology. The highly compact system will also have applications in central lab testing as well as in drug discovery, proteomics and industrial testing. A high-throughput version of the Jetstream will be capable of performing 200 immunoassay tests per hour. Kalibrant does not plan to market the system directly but is actively seeking commercial partners to bring the product to market.
A number of other new POC testing systems that will likely enter the European market within the next one to two years were described at the Medica exhibition. Additional cardiac marker testing systems for use in the hospital chest pain clinic are under development by the Jaeger (Hoechberg, Germany) unit of Viasys (Conshohocken, Pennsylvania), Cardimac GmbH (Ludersdorf, Germany) and Boditech (Gangwondo, South Korea). The Jaeger system uses technology developed at the Institut fur Chemo- und Biosensorik (Munster, Germany).
While cardiac markers are an important target for the initial system menu for most new POC systems for hospital use, the new systems will also offer POC assays for analytes such as prostate specific antigen (PSA), C-Reactive Protein (CRP) and markers for sepsis such as procalcitonin. Another new marker under development by 8sens.biognostic.AG (Berlin, Germany) is heart-type Fatty Acid Binding Protein (FABP), a low molecular weight marker that appears in the blood up to two hours before markers such as troponin and returns to normal within 24 hours. FABP is believed to be more sensitive than myoglobin, the traditional marker for early myocardial infarct detection, because of its much lower normal levels (20-fold less) and its higher concentration in cardiac muscle (five-fold greater). The company has developed a simple visually read card test using colloidal gold labeled antibodies that requires only two drops of whole blood and that could be used in both the hospital emergency room as well as in alternate sites such as the physician's office. Blood/serum separation is performed on a special membrane included in the card. 8sens.biognostic.AG plans to introduce the test in late 2Q02 in Europe, with a target price of Euro 25 in Germany. The company plans to market the test through pharmacies and other outlets.
Radiometer Medical A/S (Copenhagen, Denmark) introduced the Ultegra POC platelet function testing system in Europe in October 2001, a product added to the company's line via the $10 million acquisition of Accumetrics (San Diego, California), a transaction announced in July 2001. The Ultegra positions Radiometer to enter a new segment of the hospital-based POC testing market in Europe, with products for use in the cardiac catheterization laboratory to monitor patients treated with GPIIb/IIIa inhibitors in combination with an angioplasty or coronary stent procedure.
START Diagnostics (Viernheim, Germany) is developing a new chemistry/immunochemistry analyzer for the physician's office and small specialty laboratories that will provide a highly self-contained format along with a broad menu of about 90 tests including lipid panels with direct LDL, a high-sensitivity CRP assay, procalcitonin, PSA, hemoglobin A1C, CEA and D-Dimer. Development of the system originally began at SCIL Diagnostics (Martinsried, Germany), but the technology has since been acquired by its inventor, the founder of START Diagnostics. The system will offer similar capabilities to those of the CareSide analyzer, marketed in the U.S. by CareSide (Culver City, California), but will offer a broader menu at lower cost per test, according to START. The company plans to launch the product late in 2Q02 in Europe.