CASE STUDY: THROMBOSIS AFTER STENTING DESPITE ANTIPLATELET THERAPY
Dr. Deepak Bhatt: We have taken in a wealth of terrific information from the three preceding talks in this symposium. Let’s now share some questions from the audience and explore some of the points raised in the preceding talks in a bit more practical detail for clinicians. Our three prior speakers are joined in this panel discussion by Cleveland Clinic’s Dr. Frank Peacock, who brings an emergency medicine perspective.
Let’s begin with a case-based question supplied from the audience. The patient is a 42-year-old morbidly obese man without diabetes who had a non-ST-elevation myocardial infarction (MI) less than 1 year ago. A drug-eluting stent was placed at the time of his MI, and now restenosis has occurred. He is on aspirin and clopidogrel 75 mg/day. Do you recommend running a vasodilator-stimulated phosphoprotein (VASP) test and possibly increasing the clopidogrel dose to 150 mg/ day, or should the patient just be switched to prasugrel (assuming it is commercially available) without running the VASP test?
I’ll take a quick initial stab at this question. Studies of antiplatelet therapies to prevent instent restenosis have been a mixed bag. Some of the trials with glycoprotein IIb/IIIa inhibitors have shown an effect on restenosis, but most have not. Similarly, some of the analyses of the thienopyridines ticlopodine and clopidogrel have shown an effect on restenosis, but most have not.
For the most part, restenosis does not appear to be heavily mediated by platelets, at least not in a way that we can influence by therapy. On the other hand, stent thrombosis is highly platelet mediated, so I would alter the case to one in which stent thrombosis is the clinical problem. Assuming that the patient has been adherent to his antiplatelet regimen, which tests would you perform, and how would you act on the information from those tests?
Dr. Kandice Kottke-Marchant: The 2007 guidelines on acute coronary syndrome (ACS) management from the American College of Cardiology and American Heart Association (ACC/AHA)1 do not address platelet function testing, and almost none of the clinical trials of antiplatelet agents had an arm that included testing and dose adjustment based on platelet function studies. Platelet testing is available at some centers; at Cleveland Clinic, we use platelet aggregation testing. One can do platelet aggregation testing on a patient-by-patient basis; if inhibition appears to be suboptimal, a treatment decision should be made, but there is little guidance from the literature to steer that decision. I have seen clinicians increase the dose of clopidogrel or aspirin in response to platelet function tests, which occasionally triggers a confirmatory call from the pharmacy department.
Dr. Bhatt: When I was still at Cleveland Clinic, our chief medical resident did an analysis of platelet function testing, and it was remarkable how much testing was performed and how often it changed management, largely in the absence of any outcomes data, as Dr. Kottke-Marchant pointed out. Dr. Alexander, what are your recommendations with respect to platelet function testing today?
Dr. John Alexander: The case you describe is one in which applying evidence is not easy. There are no trials to supply any evidence to change therapy in this patient, a morbidly obese man receiving 75 mg/day of clopidogrel. There is certainly a rationale, however, to believe that a standard “one size fits all” 75-mg daily dose of clopidogrel may not be enough for him. The trade-off with a higher dosage is a higher risk of bleeding, however, so I would first be sure that he has been adherent to his current regimen of clopidogrel and aspirin.
Dr. Bhatt: Is there a role for point-of-care testing to determine whether he is adherent to the medicines?
Dr. Kottke-Marchant: Several of the point-of-care tests, such as the VerifyNow rapid platelet function analyzer, have specific cartridges for aspirin and for clopidogrel. If platelets were not being inhibited, it would suggest that the doses were too low, given the patient’s weight, but you probably would not be able to determine whether he was resistant to clopidogrel.
Dr. W. Frank Peacock: One way to verify that patients are taking their aspirin is to take a small urine sample and squirt in 2 mL of ferric chloride. If the sample turns purple, it means they are taking their aspirin. Once that is established, you can try to determine whether the drug is working on their platelets.
Dr. Alexander: Another potential explanation for stent thrombosis is faulty stent placement. In this case I would consider asking an interventional colleague to perform intravascular ultrasonography to make sure the stent was implanted properly before I changed the patient’s antithrombotic therapy.
Dr. Bhatt: That’s a great technical point. We always want to make sure that a case of stent thrombosis is not due to a mechanical problem. We should be asking: Is the stent properly sized and well opposed? Is there a distal dissection or any other issue that could predispose to stent thrombosis?
Dr. Alexander: This case illustrates a host of other challenges that underscore how much more work we need to do to define optimal antiplatelet therapy. Suppose we perform platelet function testing and find a low level of platelet inhibition in this patient with stent thrombosis, and we change his antiplatelet regimen. When should we test him again? If we retest in 3 months and find that he has a higher than expected level of platelet inhibition on the new antiplatelet regimen, do we dial down the intensity? Once again, there is no evidence to guide these decisions, and levels of platelet inhibition are driven not just by the medications but also by what is going on in the patient’s platelets—it is quite multifactorial.