Medical Device Daily Contributing Writer

CHICAGO — Compliance with anti-platelet therapy is seen as one of the more important aspects of reducing thrombosis following implantation of a drug-eluting stent (DES). But what of those patients resistant to this protocol?

One of the more perplexing topics of interest this year at the annual meeting of the American College of Cardiology (Washington) was that of platelet inhibition, highlighted yet again after the discovery that the thrombus in late stent thrombosis associated with DES was comprised of platelets. Since then, various papers have shown that platelets are the nasty little secret behind a variety of cardiac events, not just thrombosis following DES placement.

Thus, management of platelet inhibition has become a major issue, complicated by the understanding of the high variability among patients for platelet responsiveness. Studies have found up to 25% of patient populations resistant to antiplatelet therapy, whether Plavix from Bristol-Myers Squibb/Sanofi Pharmaceuticals (New York), currently the only drug FDA-cleared for platelet inhibition; or aspirin, the long-standing tool for decreasing platelet reactivity.

Since platelets have more than 100 pathways to activation, it is unlikely that any of the several new platelet inhibitors currently in the pipeline — such as Prasugrel by Eli Lilly and Company (Indianapolis) — will be able to provide 100% protection.

And with the high variability of responsiveness among patients, it is possible to unknowingly under- or over-inhibit platelet response, leading to a thrombogenic event if under-inhibited, and bleeding if over-inhibited, both potentially leading to mortality.

Thus, the key issue: Which patients will respond to which drug?

Unlike other cardiac risk factors routinely and easily measured — blood pressure, cholesterol and anticoagulants — there have been no tests that measure platelet reactivity in order to monitor the therapy, at least none able to do it simply and quickly at the point of care. The primary testing for this is done by hospital labs or large reference labs, using laborious systems such as light transmission aggregometry and flow cytometry, taking hours or even days for results.

While the pharmas are busy developing drugs that address the need to inhibit platelets, device companies are busy attempting to develop panels of tests that can give a rapid measurement of platelet reactivity in order to monitor this type of drug therapy.

Dade-Behring, recently purchased by Siemens Healthcare Diagnostics (Deerfield, Illinois), has introduced the first commercially available system that quickly diagnosed primary hemostasis, although this system still requires being operated by a qualified technician in a hospital setting.

And at least three private device companies are addressing this need for a simple point-of-care, CLIA-waived, rapid test for measuring platelet reactivity.

Accumetrics (San Diego) introduced the first simple system for measuring individual response to multiple anti-platelet agents, including aspirin, Plavix, ReoPro and Integrilin. It has the only FDA-cleared, CLIA -waived, point-of-care test that measures whether a drug has blocked a specific pathway to platelet activation by using a specific cartridge for each drug tested. And ThromboVision (Houston) is currently in the developmental stage of its T-Guide that utilizes light-scattering technology to determine platelet aggregation. Once FDA-cleared and commercially available, the T-Guide is positioned to be a CLIA-waived POC device for this type of measurement.

However, one question apparently yet to be answered for both of these devices is that — although they can determine if a specific pathway has been blocked — can they be sure that the platelet does not have residual reactivity through another pathway?

A third company, Placor (Plymouth, Minnesota), believes that it has the answer to this dilemma by testing the platelet reactivity using shear force, mimicking a stenotic artery, rather than using a specific agonist that tests for a certain pathway of inactivation. The company's theory is that it is testing the actual ability of the platelet to aggregate, regardless of whether anti-platelet drugs are on board, eliminating the need to test for each drug prescribed to the patient.

Placor's testing system requires only a fingerstick rather than a venipuncture, and the company anticipates FDA clearance and initial commercialization this quarter, followed by application for CLIA waiver. Since its test takes no more than 10 minutes, it has the potential of fitting into an interventional cardiologist's schedule as practiced today.

The second issue plaguing the development this market is that, until this meeting, there have been no studies conclusively tying high platelet reactivity to adverse outcomes.

Accumetrics recently raised $28.8 million to do just this, conduct an outcomes study that determines the various doses of anti-platelet therapy and associated adverse events.

Placor also currently is raising funds to perform a study demonstrating that outcomes are improved when anti-platelet therapies are guided by platelet reactivity testing.

Laurent Bonello, MD, of Hopital Universitaire Nord (Marseille, France), presented this type of study at the ACC meeting, saying "Clopidogrel (Plavix) resistance plays a key role in ischemic recurrence after PCI [percutaneous coronary intervention]. Tests of clopidogrel resistance have demonstrated their accuracy to predict major adverse cardiovascular events after PCI."

In this study, 164 patients whose platelet reactivity test showed Plavix resistance were randomized into two groups. The doses of Plavix until the platelets were non-responsive were adjusted in one group; the standard dose of Plavix was maintained in the control group.

Study data showed a significantly higher number of adverse events in the group that did not adjust the dose of Plavix. Bonello concluded that the study is the first "demonstrating that adjusted loading doses of clopidogrel, according to platelet monitoring, is safe and significantly improves clinical outcome after PCI in patients with clopidogrel resistance."

Thus, until we see the availability and widespread use of easy-to-use platelet monitoring devices, platelet inhibition therapies will continue to be a shot in the dark.