With FDA clearance of diaDexus’s (South San Francisco, Calif.) PLAC test in June, the clinical laboratory community now has the first blood test designed to assess a patient’s risk of ischemic stroke in conjunction with traditional clinical evaluations, such as age, diabetes, and hypertension measures. The PLAC test measures lipoprotein-associated phospholipase (Lp-PLA2), an enzyme found in blood and arterial plaques that has been touted by some researchers as an independent risk factor for stroke and coronary heart disease (CHD). But as with any hype surrounding a new biomarker, the excitement is tempered with caution in some clinical circles, with many insisting that Lp-PLA2 is not able to predict stroke risk on its own. This month, Strategies looks at the role this new marker has in the clinicians’ cache of CHD and stroke assessment tools, as well as another multi-marker stroke assessment test currently under review by the FDA.
Clinicians have traditionally followed guidelines detailed in the National Cholesterol Education Program’s Adult Treatment Panel III (ATPIII) to predict CHD events. Based on data from the Framingham Heart Study, the ATPIII screens patients using a lipid panel along with other risk factors such as hypertension, age, and diabetes to calculate a person’s risk of having a heart attack in the next 10 years. But while ATPIII might help predict a future coronary event, it does not predict the chance of having a stroke in the near future.
“Lipids are a powerful predictor for coronary heart disease events, but they don’t predict stroke,” said Christie M. Ballantyne, MD, Director of the Center for Cardiovascular Disease Prevention at the Baylor College of Medicine and the Methodist DeBakey Heart Center in Houston, Texas. Ballantyne is also is the Core Laboratory Director for the Atherosclerosis Risk in Communities (ARIC) study, which followed over 12,000 healthy middle-aged men and women over approximately 6 years to examine the relationship between stroke, high sensitivity C-reactive protein (hs-CRP), Lp-PLA2, and traditional risk factors.
“After consideration of traditional risk factors such as age, diabetes, hypertension, and tobacco use, there was about a two-fold increase in risk if you had a high level of Lp-PLA2 or if you had a high level of [hs-]CRP using the cut point of 3.0[mg/L], which has been established by the CDC,” said Ballantyne. “Once again, lipids were not a predictor of stroke.” ARIC findings were presented at the American Heart Association Scientific Sessions 2004 last November. Ballantyne used the PLAC test to measure Lp-PLA2 in ARIC and the data was also used to support diaDexus’ FDA application for the PLAC test.
Traveling primarily on small dense LDL particles, Lp-PLA2 appears to enter the blood vessel wall and then catalyzes the hydrolysis of oxidized LDL to generate lysophosphatidyl choline and free fatty acids, which have been shown to trigger an inflammatory response. This is an enzyme that may be a link between lipoproteins and vascular inflammation, which distinguishes it from hs-CRP—an acute phase reactant marking systemic inflammation.
“Although they both are involved with inflammation, it’s not in the same pathways,” explained Ballantyne. “If you include [hs-]CRP in the model, Lp-PLA2 is still predictive.” However, high levels of both [hs-]CRP and Lp-PLA2 predicted the highest risk for ischemic stroke, according to the ARIC data.
FDA Reviewing Stroke Panel
In addition to the PLAC test, another stroke assessment test could hit the market in the near future. In late December, Biosite (San Diego, Calif.) submitted a premarket approval (PMA) to the FDA for its Triage Stroke Panel, which uses a multimarker approach as an aid in the diagnosis of stroke. The FDA is now conducting a thorough review of the submitted data.
Many clinicians view the introduction of both the PLAC and Triage tests as giving the clinical lab a new role in stroke evaluation. “I think this will be the entrée into a very exciting new era, one in which the clinical laboratory will assist in the risk assessment, diagnosis and management of patients in the context of stroke because of these new markers,” said Robert Christenson, PhD, DABCC, FACB, Director, Rapid Response Laboratories, University of Maryland School of Medicine in Baltimore, Md. Ballantyne emphasized, however, that the tests have distinct clinical applications. The Triage test is useful for clinicians in emergency rooms treating patients complaining of stroke symptoms, while the PLAC test is not used to diagnose a stroke, but rather assess risk.
But Christenson has some hesitations about Lp-PLA2’s role as a stroke marker, namely that the PLAC test’s package insert appears to contain little data beyond the ARIC findings. “The ARIC analysis was a case cohort study, and this design is usually used for exploratory or hypothesis generating studies,” he said. “For this reason I find this very interesting, but not terribly compelling at this point.” One case cohort study is not a strong form of evidence—even if it analyzed a large population- and a prospective study of the marker is needed, he added.
In addition, it’s unrealistic to consider that Lp-PLA2 will be for stroke what troponin is for heart disease. This is because Lp-PLA2 may be used for risk assessment, and while it may be plaque specific, Christenson notes that it is not stroke specific, and therefore must be used in concert with traditional and other CHD diagnostic tests. On the other hand, the Triage stroke panel will be used for acute assessment and this is what makes the Triage stroke panel so exciting, he said, because it is employing multiple markers to hit key parts of the physiological cascades that occur with stroke. So while the PLAC test might be another form of traditional risk assessment, the Triage panel will initially be utilized more for acute stroke assessment.
Ballantyne gives no indication that the Lp-PLA2 should be used independently of other diagnostic tests. “I look at this as one more tool in the tool box for clinicians who are trying to assess the risk for heart attack and stroke in their patients,” he said. The real importance of the test is identifying the high risk patients, because it appears that interventions such as statin therapy, as well as diet and exercise regimens, are most beneficial in preventing coronary events in these patients.
“The concept of a panel of markers that we can measure in plasma or serum is going to continue to advance, and some of this might also be tied in to imaging tests, but I think we’re going to end up seeing a tool box with a lot of good tools in there,” said Ballantyne. “It’s going to get better and better.”