CDU Contributing Writer
CHICAGO — During a seminar at the '06 Scientific Sessions of the American Heart Association (Dallas), Renu Virmani, MD, medical director of the International Registry of Pathology (Baltimore), put the case rather directly: She said she has seen up to 31% of patients implanted with drug-eluting stents (DES) experience thrombosis compared to just 12% thrombosis among those implanted with bare metal stents (BMS).
Virmani's data would appear to nail down the current consensus — that the use of DES is associated with a greater risk of thrombosis and at a higher rate than BMS (though whether that difference is significant or not will be the crux of much debate during 2007). Recent studies also indicate a higher propensity of thrombotic events after 90 days (termed "late stent thrombosis") with DES. That constitutes an ironic data reversal of DES superiority over BMS in reducing restenosis, the main benefit pitched for DES by its proponents.
But what's the cause?
One possibility aggressively explored at the Scientific Sessions is platelet reactivity, with the presentations on the subject serving as a backdrop to the heated DES vs. BMS debates in other sessions.
As Ron Waksman, MD, associate director of the Division of Cardiology of Washington Hospital Center (Rockville, Maryland), stated in his presentation of "Clinical Observations" during the Stent Thrombosis seminar, "We have been able to reduce the amount of restenosis with the use of DES but may have increased the incidence of thrombosis." And the recent negative findings that support Waksman's conclusion concerning DES technology served as a springboard at the conference to further explore the causes of thrombosis and the role that platelets play in thrombogenesis.
In a standing-room-only seminar on stent thrombosis, Robert Schwartz, MD, of the Minneapolis Heart Institute (Minneapolis), called stent thrombosis "a significant clinical problem." In what might be considered a clarifying statement, he said: "DES are doing their job" of inhibiting restenosis, but "possibly inhibiting too significantly as the lack of neointima, combined with inflammation, sets the stage for platelet aggregation."
He added: "We need to test to see who has activated platelets."
Paul Gurbel, MD, director of cardiology, Sinai Hospital and associate professor of medicine at John Hopkins University (both Baltimore), said that stent patients are taking anti-platelet drugs, but he warned against using this as a catch-all method of preventing thrombosis, since there is a great variability of responsiveness to anti-platelet drugs, both within the individual and from one person to another. He further proposed that some patients' blood is more vulnerable to platelet reactivity than others and that the intrinsic thromobogeneity of the platelets in the blood is a primary culprit.
"Thrombosis is the leading cause of vascular-related deaths, and we currently do nothing to assess it," he said. "Are patients with non-responsive [very reactive] platelets at risk?" He said he has found that about 20% of patients on aspirin are getting no benefit from it and 10% to15% of patients on Plavix are not responding.
"There is no single pathway that mediates all the thrombolic events in a platelet," he said. This, he said, may suggest "the emergence of a new, quantifiable risk factor/platelet responsiveness that can help predict which patients may be at greater risk for an embolic event."
Although the speakers in this seminar were focused on preventing secondary events — those events following stent placement -- another session of oral presentations titled "Variability in Response to Anti-Platelet Therapy" was focused on primary prevention of adverse cardiovascular events and evaluated several risk factors, one of them once again being platelet reactivity.
Robert McBane, MD, associate professor of medicine at Mayo Clinic (Rochester, Minnesota), presented "The Individual Variability in Platelet Function and Thrombosis." He noted that there is an individual propensity for thrombosis and that this response is persistent. He reported on his study focused on determining if the propensity to develop a clot is in the blood vessel or in the blood. Performing several different tests on pigs, he determined that "the thrombosis propensity lies in the blood [rather than the vessel] and that it can be detected by an in vitro assay."
Alan Michelson, MD, director of the Center for Platelet Function Studies at the University of Massachusetts (Worcester), presented an overview of available test methods for measuring platelet responsiveness. He cited two reasons for testing platelet responsiveness: to monitor drug compliance and to predict outcomes. But he said that collection of data to support in vitro testing for platelet reactivity as it correlates with thrombosis is still in its early stages.
While it was unanimous among the various speakers on the topic that platelet responsiveness is an individual and variable response, it was also unanimous that the need for a quick simple test that could measure platelet reactivity is needed. Most of the tests available currently test for specific drug resistance, or lack of responsiveness by the platelets, also referred to as treatment failure. While the literature states that up to 30% of all patients taking aspirin do not respond to aspirin, unless a test is performed to verify that the patient's platelets are not responding, it remains unknown until the patient has an embolic event. Likewise, when several presenters found up to 25% of their patients not responding to Plavix, they noted that this was only determined by means of a drug-specific platelet responsiveness test.
Industry is trying to catch up to the growing awareness of platelet responsiveness and the need to be able to test for platelet reactivity. Most tests available need to be run by trained personnel in a laboratory setting and can only test for one drug resistance at a time (for instance, aspirin, Plavix).
Accumetrics (San Diego, California) has been the first to address this market need and currently has the leading market share, partially due to its being CLIA-waived; that is, having a test designed and approved to be run by non-technical personnel in an office setting. The company can measure for both aspirin and Plavix resistance, although separate tests using different cartridges are required to do both.
The "new kid" on this particular diagnostic block is Placor (Minneapolis), a privately held start-up company that boasts that it can measure global platelet reactivity, using shear forces rather than a drug-specific chemical that induces platelet aggregation.
This translates into one test that determines the amount of responsiveness the platelets demonstrate, regardless of which drug or combination of drugs the patient is taking. This is also the only test that can be run on a fingerstick sample of blood as opposed to a venipuncture. Placor's initial testing has been done at The Mayo Clinic, the University of Minnesota (Minneapolis) and the Veteran's Hospital (Minneapolis), and they expect FDA clearance in 2007.
If the initial findings presented at this AHA meeting hold true, and platelet reactivity testing becomes a new measurement of cardiovascular disease risk, then the market could be enormous. Current Medicare reimbursement for platelet testing is $30, so, using a minimum of only one test per year, this represents a market potential of well over a billion dollars.