The Use of Clopidogrel and Pathways of Platelet Function Testing at University Hospitals

Tell us about the cath labs at University Hospital (UH) Case Medical Center and your satellite facilities.

Case Medical Center UH Main has two cath labs and we have just added an eleventh interventionalist. Dr. Marco Costa is the director of the overall interventional program, which includes a vigorous structural heart disease program that includes atrial septal defect closure and aortic valve replacement, among other procedures. We have placed over 30 CoreValves per Medtronic protocol.

In addition to Case, we cover interventions at two cath labs at the VA Medical Center and at the newly opened University Hospitals Health Systems (UHHS) Ahuja Medical Center, where we have a beautiful interventional suite with four labs. One lab is specifically designed for electrophysiology and neuro procedures, another for peripheral procedures, and we have two state-of-the-art cardiac rooms. Finally, we have a no-surgery-on-site interventional program east of Cleveland at our satellite, Geauga Hospital, offering 24/7 percutaneous coronary intervention (PCI) and ST-elevation myocardial infarction (STEMI) coverage.

At UH, we perform between 1,200 and 1,400 PCIs per year. At the VA, we do about 400 interventions per year. We will probably be in the range of 200-300 interventions at Ahuja Medical Center by the end of this year, and have done about 100 interventions, including 35 acute MIs, at Geauga Hospital.

Can you discuss clopidogrel use at your facility?

We have had reservations about clopidogrel due to the relatively high incidence of hyporesponders, or what we call “high on-treatment reactivity.” There are many reasons patients can be hyporesponders to clopidogrel, such as genetic polymorphisms and drug-drug interactions. Simply putting a stent in a coronary artery activates platelets. Heart failure, diabetes, hypertension, complex PCI, obesity, age, sex, ethnicity…they all play a role. Of course, the setting plays a role, too, meaning the vulnerable patient and even the vulnerable vessel — patients with STEMI and acute coronary syndromes (ACS) tend to have higher platelet reactivity. A certain number are going to be hyporesponsive on clopidogrel. Under our chief, Dr. Dan Simon, an interventional cardiologist with a special interest in platelet function and physiology, we have developed a robust platelet function testing program. Although we currently only have platelet function testing on site at the cath labs at UH, we are able to see all patients in the outpatient setting within one to two weeks of their PCIs from any of the other hospitals.

Clopidogrel becoming generic, of course, has become an important issue. We have not seen much financial pressure yet, although there have been isolated incidents where hospital or managed care pharmacy formularies have denied payment for the newer generation agents unless we can show that the patient is a hyporesponder to clopidogrel.  Of course, both we and our patients are interested, in these hard economic times, in the least expensive option. Yet we have to balance financial aspects against what appears to be best for the patient’s needs in the clinical setting.

I have heard of programs providing patients with dual prescriptions. If a patient goes home on a new generation agent in the setting of ACS, for example, they will give the patient a prescription for clopidogrel at 30 days in case the newer generation agent is rejected by their insurance provider, or if the patient is caught in the doughnut hole of part D Medicare. Most patients are left in the cold with some increased expense with the newer agents as compared to generic clopidogrel, which is now about $40/month at Wal-Mart.

Why test for platelet function?

There is a tremendous amount of evidence that can no longer be refuted that high on-treatment reactivity patients have an increased incidence of major adverse cardiac events (MACE). The platelet function testing program is designed to help us determine who these patients are, and then, although it is off-label in the strictest sense, to then be very aggressive about switching agents. Our STEMI and ACS protocols now place clopidogrel lower in the hierarchy for initial clinical use, based on the TRITON and PLATO trials. PLATO found improved outcomes in terms of MI, stent thrombosis, and cardiovascular death for ticagrelor (Brilinta)¹, and the TRITON trials showed reduced stent thrombosis, reduced recurrent MI, reduced enzyme rise at the time of initial procedure, and had an edge for prasugrel (Effient) for diabetics in particular (30-40% of our PCI patients).^2-3 We see an increasingly smaller number of patients coming to our cath labs in the ACS setting on clopidogrel. For these patients, the morning after their procedure, we test to determine if they are a hypo or nonresponder. We are concerned enough about the high incidence of stent thrombosis and thrombotic events in hyporesponders that we will then switch them to a different agent.

As a population strategy, clopidogrel has been around for a long time, and for the population at large, it is now an increasingly less expensive, reasonable strategy. For those patients who do come to the cath lab on clopidogrel, we want to weed out hyporesponders and get them on to a newer generation agent. For the occasional patient who cannot take ticagrelor or prasugrel because of a labeled contraindication or cost, we have also had reasonable success adding cilostazol (Pletal), doing what is called “triple” antithrombotic therapy. In other words, the patient would be on aspirin, clopidogrel, and cilostazol. Triple antithrombotic therapy has been pioneered mostly in Asia and seems to be a very effective strategy.⁴ We have been very effective at turning hyporesponders into responders with the addition of 50-100 milligrams twice daily of cilostazol. Unfortunately, cilostazol is contraindicated by heart failure, and many of the patients upon whom we perform interventions have heart failure, even advanced degrees of heart failure, so sometimes we are limited in offering that agent.

While the importance of modifying treatment for high on-treatment reactivity has been in question in the past, most experts, led by Drs. Paul Gurbel and Dominick Angiolillo, generally agree that high on-treatment reactivity can be modified and outcomes can be improved. Our group just presented a well-received abstract at the International Academy of Cardiology 17th World Congress of Cardiology in Toronto. We showed that ACS patients who had high on-treatment reactivity and whose treatment was modified on the basis of their platelet reactivity to a new generation agent or triple Rx such that they became responders, had much lower MACE than predicted by historical controls, and had outcomes similar to elective PCI.⁵

Why do platelet function testing instead of genotyping?

Genetic testing doesn’t give you the option of serially following the patient or titrating or adjusting the therapy. Genotype does not fully correlate with phenotype.  It just tells you if the patient carries one or more loss-of-function alleles. Homozygotes will be essentially non-responders, but reactivity in heterozygotes is variable.  Genotyping can be useful, but at least at the present time, it is expensive, although the cost is coming down. Currently available genetic testing options take about a week to turn around, so in the acute setting, that is not very useful. It might be useful for the elective PCI patient; however, we know that doubling the clopidogrel dose, as shown in GRAVITAS⁶ and a number of other studies, in the much lower risk elective PCI setting, doesn’t change that many hyporesponders to responders. Dr. Jessica Mega’s study, ELEVATE-TIMI 56⁷, increased the clopidogrel dose to 225 mg/day with some success at changing hyporesponders to responders. But such a strategy would probably not be cost effective. The cost of 225 mg of generic clopidogrel would certainly exceed new generation drug therapy. It is an interesting finding, but probably not a clinically useful strategy.

There may be some occasions when the genotyping and the platelet function testing are complementary. But, in general, genotyping doesn’t offer you the option to modify or titrate therapy. The holy grail, of course, is finding the sweet spot for platelet inhibition, with the lowest risk of bleeding and the greatest clinical effect. It may have to be sufficient that we put up with some increased risk of bleeding and be happy with getting the patients into the responder range, the low platelet reactivity unit (PRU) range, whereby they have the lowest likelihood of clinical events like stent thrombosis and recurrent MI.

There are a significant number of patients that have just one loss-of-function allele. Coupled with the other clinical modifiers that I mentioned earlier, including white paper letters the FDA sent out about interactions with proton pump inhibitors, then there will be a much larger number of patients who turn out to be clopidogrel hyporesponders. We use the Accumetrics VerifyNow platelet function test, which correlates extremely well with the more sophisticated in vitro tests such as light transmission aggregometry.

Published statistics show approximately 30% of Caucasians, 40-50% of African-Americans, and up to two-thirds of Asians are hyporesponders or have high on-treatment reactivity. In our own experience, we have found 39% of our overall patient population to be hyporesponders to clopidogrel.

That’s a huge amount.

Very recently, in Circulation⁸, Paul Gurbel pointed out that the cardiology community has been sticking its head in the sand on this issue. To roughly quote him: When you treat high cholesterol, you start the patient on a statin and treat to target. When you start a patient on a hypoglycemic agent for diabetes, you follow their blood sugars. When you want to prevent a stent thrombosis in a patient that had an acute coronary syndrome and a PCI, you start them on clopidogrel…and then forget about them. Again, as an overall population strategy, clopidogrel has been pretty good, but at this point, we think we can do better by measuring platelet function and treating to target.

How long have you been testing patients?

The program has been in place for about a year and a half. We started a pilot run-in phase in December of 2010 to January 2011. We learned to meticulously obtain the blood draws through straight stick 21-gauge needles, not drawing, if you can avoid it, through butterfly or scalp vein IV set ups, Swans, or central lines; however, drawing through larger vascular sheaths is acceptable. Quality control was important from the start, because we did not want to be adjusting patient therapy on the basis of numbers that were suspect or had a wide variability. As a result, we did duplication studies and implemented quality control measures to make sure we were doing things the right way before we started managing patients on the basis of platelet function.

You only test patients who come in to the cath lab on clopidogrel?

We don’t test everybody. We are sort of at a nadir of testing now, because use of clopidogrel in our system has dropped precipitously, and is confined mostly to elective patients or out-of-system transfers. For these patients, we will obtain a VerifyNow test prior to the intervention. If the patient is a clopidogrel hyporesponder, we will probably load them with a new generation agent right in the lab. ACS patients comprise about 75% of our interventional practice. Patients who have an abnormal stress test, get a cath and have an elective PCI, or patients where someone sends you a film and asks you to do an elective PCI, have really become a minority in our practice. For the acute patients, the majority are treated initially with a new generation agent. We have found so little hyporesponsiveness with new generation agents that it is a poor economic strategy to test everyone. Truly, the only patients we test are elective patients who are sent in on clopidogrel or the patient who comes in an acute setting and someone has elected to place or keep them on clopidogrel. We will then test on the morning after the procedure to see if the patient is a hyporesponder. If they are, we usually switch them. If the referring physician for some reason wants the patient to remain on and modify their clopidogrel therapy, or if the patient has some contraindication to being on a new generation agent, we will increase the clopidogrel dose and retest two weeks later. We have been following the CURRENT OASIS-7 protocol9 for the relatively few patients who now go home on clopidogrel. Patients at low risk for bleeding go home on 150 mg clopidogrel/day for a week, and then their dose is stepped down to 75 mg/day. We let them equilibrate for 4-5 days, and then we test them. OASIS-7 showed a 30-50% reduction in thrombotic events and stent thrombosis in the first 30 days after PCI if the clopidogrel dose is doubled through the first week. We try to get platelet function testing and dose adjustment done within the first two weeks after PCI, because that first 30 days is the most vulnerable period of time for a patient with a new stent.

Our surgeons, especially the cardiothoracic surgeons, are using the Verify- Now platelet inhibition level of 20-30% as a green light to take patients to the OR for urgent surgery (obviously if emergent, they just go to OR) for patients just given or chronically on P2Y12 inhibitors. This strategy can allow for earlier surgery than the 5 to 7 days washout recommended on labels and therefore, save expensive days (often ICU days) in the hospital by shortening the interval before we can take a patient to the OR.

Can you share more about the workflow and who is involved in the testing?

For those patients done in our cath lab, either the interventional fellows, cath lab physician assistants or nurse practitioners will obtain the blood. If it is a patient actually on the table in the lab, we will just draw the blood off the sheath and run the test on the spot, so we will have the results “online” while we are doing the procedure. I staff and manage our platelet function clinic, and we have a technician and clinical nurse who obtain the blood and run the tests while the patient is still there. We review medications and then, on the basis of the VerifyNow platelet function test result, will make a recommendation to the patient and his or her cardiologist as to what should be done with their antiplatelet medications. When we started the program, many of my colleagues and some of the referring cardiologists were skeptical, but mostly because the new generation agents were so new and physicians weren’t yet comfortable with their use. We always call the referring cardiologist and ask how they would like us to handle the test results. Now that our referring physicians are comfortable with our program and everyone is much more familiar with ticagrelor and prasugrel, most cardiologists are happy for us to not only make a recommendation, but to go ahead and institute the change if we think it is appropriate.

To run the test, we draw three tubes of blood. The first is a waste or discard tube, because simply performing a venipuncture, drawing blood into a vaccutainer, will activate platelets at the needle tip, and can cause false results. We then obtain two samples (the second sample is just in case we have some questions about the initial result). The blood is agitated very gently, tipped over about five times. It sits for ten minutes, is placed in the Accumetrics VerifyNow machine, and the machine generates a number within three minutes. That number is the platelet reactivity unit, or PRU, that we use for clinical decision-making. The VerifyNow is a very quick point-of-care test.

Are we transitioning away from clopidogrel completely?

Much of that will depend on the economics of pricing, system contracts, managed care, and formularies. As long as there is a cost advantage to using clopidogrel, there are going to be insurers and formularies that will want their physicians and patient panels to be using the cheapest alternative. Many patients are responders to clopidogrel. It isn’t a worthless drug at all. I don’t want anybody to get that impression from my comments. For 60% of patients, it works just fine.

With generic medications, the FDA permits approximately a 15-20% variability in the bioavailability of a generic drug, so the regulatory standards that branded drugs have to meet are not met by generic equivalents. However, we have not had an opportunity yet, to the best of my knowledge, to test somebody who is on generic clopidogrel, so I can’t comment on that aspect.

Any interesting trials coming up?

The CHARISMA trial with Deepak Bhatt out of Boston showed that in a mixed, mostly low-risk population, there is not a distinct, major advantage in continuing clopidogrel beyond 12 months. There is some thought now that a higher risk subset of patients might benefit from more than 12-14 months of dual antiplatelet therapy, using one of the stronger, new generation agents. TRILOGY ACS is looking at using prasugrel for a more extended period of time in the medical management of ACS. PEGASUS, by the TIMI group, will study high-risk patients more than a year out from their event with ticagrelor. TRILOGY and PEGASUS should help answer the question of whether providing longer dual antiplatelet therapy with stronger antiplatelet agents is of benefit to high-risk patients.

Any final thoughts?

Much of the rationale for how robust platelet function testing continues be in the future will depend upon what happens economically, especially with the low cost of generic clopidogrel. In our limited experience, we have already had to write letters and fill out forms for patients who were initially placed on the newer agents, even in the ACS setting, where there definitely is data suggesting that a new generation agent would be better, because insurance companies have denied payment for these drugs. We know what the economics of healthcare are — it is becoming an increasingly dismal situation in this country. I think physicians are going to be under increased pressure to use the cheapest possible drug and that may prove to be generic clopidogrel, which for any given patient, on the basis of their platelet function testing, may not always be the best thing for them.

Dr. Tom Lassar can be contacted at Tom.Lassar@UHhospitals.org. 

References

1. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, et al; PLATO Investigators, Freij A, Thorsén M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009 Sep 10; 361(11): 1045-1057.
2. Wiviott SD, Braunwald E, McCabe CH, et al. for the TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. New Engl J Med 2007; 357: 2001–2015.
3. Wiviott SD, Braunwald E, Angiolillo DJ, et al. TRITON-TIMI 38 Investigators. Greater clinical benefit of more intensive oral antiplatelet therapy with prasugrel in patients with diabetes mellitus in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction 38. Circulation 2008; 118: 1626–1636.
4. Suh JW, Lee SP, Park KW, Lee HY, et al. Multicenter randomized trial evaluating the efficacy of cilostazol on ischemic vascular complications after drug-eluting stent implantation for coronary heart disease: results of the CILON-T (influence of CILostazol-based triple antiplatelet therapy ON ischemic complication after drug-eluting stenT implantation) trial. J Am Coll Cardiol 2011 Jan 18; 57(3): 280-289.
5. Asher E, Lassar T, et al.  Outcomes of antiplatelet therapy directed by post PCI platelet function testing in a real world setting. Proceedings of the International Academy of Cardiology 17th World Congress of Cardiology. July 27-30 2012, Toronto Canada, No. 190, p. 55.
6. Price MJ, Berger PB, Teirstein PS, Tanguay JF, et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA 2011 Mar 16; 305(11): 1097-1105.
7. Mega JL, Hochholzer W, Frelinger AL 3rd, Kluk MJ, et al. Dosing clopidogrel based on CYP2C19 genotype and the effect on platelet reactivity in patients with stable cardiovascular disease. JAMA 2011 Nov 23; 306(20): 2221-2228.
8. Gurbel PA, Tantry US. Platelet function testing and genotyping improve outcome in patients treated with antithrombotic agents. Circulation 2012; 125: 1276-1287.
9. Mehta SR, Tanguay JF, Eikelboom JW, et al. Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): A randomised factorial trial. Lancet 2010 Oct 9; 376(9748): 1233-1243, doi:10.1016/S0140-6736(10)61088-4. 

Suggested Reading

1. Price MJ, Tantry US, Gurbel PA. The influence of CYP2C19 polymorphisms on the pharmacokinetics, pharmacodynamics, and clinical effectiveness of P2Y12 inhibitors. Reviews in Cardiovascular Medicine 2011; 12(1): 1-12.