The importance of platelets and thrombosis in the pathophysiology of acute coronary syndromes

By John Young of Accumetrics

The importance of platelets and thrombosis in the pathophysiology of acute coronary syndromes (ACS) has been well demonstrated. This information has formed the backbone of current medical guidelines for patients suffering a myocardial infarction (MI) or anginal symptoms from underlying coronary artery disease (CAD).

Introduction

Aspirin has been a mainstay of treatment for patients with CAD, secondary to data demonstrating a beneficial effect in the prevention of adverse ischemic events. Despite this benefit in the overall CAD population as a whole, there is still ongoing debate as to the correct dosage and timing of aspirin administration, and whether all patients respond equally.

Catheter-based revascularization (percutaneous coronary intervention or PCI) for patients with underlying CAD has risen dramatically over the last decade. Nearly 1 million PCI procedures are performed annually within the U.S. alone, primarily driven by the successful utilization of coronary artery stents. With the relatively recent advent of drug-eluting stents (DES) for CAD, the issue of platelet function and thrombosis has become even more complicated. Concern for delayed or late stent thrombosis with DES technology has limited its current application in all patient subsets. [1] Additionally, antiplatelet therapy (i.e. clopidogrel or Plavix®) mandated for patients with DES has highlighted the link between hyporesponsiveness to this agent and potential serious adverse complications (i.e. stent thrombosis,MI, stroke and/or death). [2-7] With increasing concern for late and very late stent thrombosis, recommendations now suggest that antiplatelet therapy be prolonged in patients with DES, and that adding a third antiplatelet agent may be beneficial. [8,9] This not only increases the cost to manage patients with DES, but also increases the difficulty to ensure patient compliance.

Challenges

Over the past 2-3 years, there has been increasing interest in the concept of ‘platelet resistance’ or platelet hyporesponsiveness to antiplatelet therapies such as aspirin and clopidogrel. Currently, there is general agreement that certain patients with “high platelet reactivity” following an acute event (ACS or stroke), or even at baseline, represent a high risk subgroup for subsequent events. Observational clinical studies have demonstrated a correlation between high platelet reactivity and subsequent adverse ischemic outcomes based on a threshold to classify patients as responders versus non-responders. [10-14]

Despite this link – several questions remain:
1. What is the definition of platelet hyporesponsiveness?
2. How is platelet hyporesponsiveness measured?
3. When should platelet response be measured and in whom?
4. What is the definitive link between platelet response, physiologic event, and alternative therapeutic strategies?

Potential Solution

As mentioned above, the goal of antiplatelet therapy is to prevent ischemic events in patients being treated with one or more agents. And, because individual variability has been found in patients’ response to both aspirin and clopidogrel therapy, the availability of a laboratory test to measure platelet function and guide antiplatelet strategies in an individual patient would be highly valuable. Ideally, such a test could be utilized to determine the agent and dose that would provide the greatest reduction in risk for the patient without increasing the risk of bleeding.

Since the 1960s, several methods of platelet function testing have been used to diagnose a variety of acquired and inherited platelet defects. Most of these diagnostic tests (assays) are based on the ability of platelets to aggregate (form a blood clot) after a specific stimulus (agonist) is given. Determination of the effect of various drugs that inhibit platelet aggregation can then be assessed. Limitations to this technology have been large sample volume of blood needed, complexity of the sample preparation, high level of technical expertise required, and time consuming protocols to generate results.

The VerifyNow System (Accumetrics, Inc., San Diego, CA; formerly known as Ultegra® RPFA) was developed as an easy-to-use, rapid, point-of-care (POC) platelet function test to determine an individual patient’s response to antiplatelet agents. The VerifyNow System measures agglutination of fibrinogen-coated beads by platelets stimulated by an agonist in a small sample of whole blood, easily performed at the bedside with results in approximately 5 minutes. Recent data has demonstrated good correlation between flow cytometry and light transmission aggregometry (LTA; historical measurement standard) and the VerifyNow System, with the ease-of-use of a POC testing device. [15]
 
The VerifyNow System has been used to measure platelet reactivity in a variety of clinical studies. Thienopyridines (i. e. clopidogrel) block platelet activation via the P2Y12 ADP receptor. Percent platelet inhibition as well as PRU (P2Y12 receptor Reaction Units) values are calculated based on the extent of this blockade. Observational data have demonstrated a strong correlation between platelet hyporesponsiveness to antiplatelet therapy and an increase risk for adverse ischemic events following PCI. [4,5,7,11-17] In addition, the risk for stent thrombosis after DES implantation has been demonstrated to be higher in the hyporesponders / nonresponders patient groups. [6,7,10,14] These studies have  recommended a clinically-driven threshold value PRU that has a good positive predictive value for major adverse events.

Future Approach

As outlined in the questions above – monitoring of antiplatelet response in an individual patient would be valuable if the biological response to therapy could subsequently be modified (change of dose or alternative agent) that ultimately results in an improved clinical outcome. Already, the VerifyNow System is being used in various clinical settings around the world to help guide physicians in making treatment decisions, and is also being used to assess platelet function in important ongoing clinical trials addressing this question.

The GRAVITAS (Gauging Responsiveness with A VerifyNow Assay: Impact on Thrombosis and Safety) trial recently began enrolling patients at over 60 clinical sites in the U.S. and Canada. The objective of the study is to determine whether tailored antiplatelet treatment using the VerifyNow assay reduces major adverse cardiovascular events (MACE) after DES implantation. This is the first randomized, controlled trial to utilize the VerifyNow System in this manner, and will provide important information regarding event rates based on platelet function testing-driven changes in drug therapy (i.e. tailored therapy).

The ADAPT-DES (Assessment of Dual Antiplatelet Therapy with Drug-Eluting Stents) study is a very large trial (> 10,000 patients) that will also utilize the VerifyNow system to assess platelet responsiveness following DES implantation. The primary objective of this trial is the incidence, timing and correlates of DES thrombosis out to 5 years of follow-up. Being able to predict which patients may be at an increased risk of DES thrombosis, based on platelet function testing, would be clinically invaluable in the treatment algorithm of these patients. Other large scale studies of DES may afford the opportunity to incorporate the VerifyNow System into their trial design to add to the growing database of knowledge in this important area.

Other areas outside CAD where platelet function testing may prove to be valuable is in stroke prevention, and reduction in bleeding events in patients scheduled for surgery currently taking antiplatelet therapies. It may also serve a role in therapeutic approaches to migranuers, and for oncologic therapy. The inter-individual variability in response to antiplatelet agents may explain the differences in recurrent events in susceptible patients. The ability to tailor therapy based on an individual’s own response truly ushers in the era of ‘personalized medicine’ which will undoubtedly be the future of medicine.

Contact details:
John Young, MD, Chief Medical Officer of Accumetrics
E: medaffairs@accumetrics.com
www.accumetrics.com

References:
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