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August 2011 Clinical Laboratory News: At the Crossroads of Antiplatelet Therapy and Surgery

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August 2011: Volume 37, Number 8


At the Crossroads of Antiplatelet Therapy and Surgery
What’s the Role of Platelet Function Testing in the Timing of Procedures?

By Genna Rollins

Antiplatelet therapy (APT) has become a mainstay of clinical management for patients with cardiovascular disease, making the thienopyridine clopidogrel (Plavix), one of the top 25 prescribed drugs between 2006–2010. While there is good evidence about the benefit of clopidogrel and other APT medications in decreasing the risk of thrombosis, the picture is much less clear about what to do when patients on APT need surgery. Determining the fine balance between preventing thrombotic events and minimizing the risk of excessive bleeding remains more an art than a science, despite the availability of various tests to assess platelet function in patients taking the drugs. Divergent professional guideline recommendations bear out the lack of hard scientific evidence to guide clinical decision-making. One thing is clear, however: as research on this issue progresses, labs will continue to have an important role in working with surgical teams to optimize the timing of surgery for patients on APT.

“The thing that seems to work best is when a team gets together rather than a few individuals making a decision,” observed Victor Ferraris, MD, PhD, Tyler Gill professor of surgery at the University of Kentucky and section chief of cardiothoracic surgery at the Lexington VA Medical Center. “It’s reasonable to enlist the support of laboratorians, cardiologists, intensivists, perfusionists, anesthesiologists, and surgeons, and take a team approach to managing bleeding and blood transfusions. There’s evidence to support that, and it comes across in our guidelines.” Ferraris chaired the recent update to blood conservation clinical practice guidelines issued by the Society of Thoracic Surgeons (STS), the Society of Cardiovascular Anesthesiologists, and the International Consortium for Evidence Based Perfusion (Ann Thorac Surg 2011:91:944–82).

The Complications of Individual Responses

The challenge surrounding APT and surgery is this: discontinuing APT prior to surgery has been associated with a 20% incidence of ischemic events, while continuing the drugs puts patients at an estimated 35% increased risk of bleeding. Adding a layer of complication to these general statistics, patients have variable responses to APT. For example, about 30% of patients have little or no response to clopidogrel, mostly due to genetic polymorphisms in the CYP2C19 liver enzymes that metabolize the drug. Resistance also has been associated with variable intestinal absorption owing to ABCB1 polymorphisms, drug-drug interactions, and other factors like smoking and diabetes.

Aspirin resistance occurs, too. In some patients, this widely used medication does not adequately inhibit cyclooxygenase-1 (COX-1), the enzyme critical to converting arachidonic acid into agents that either increase or decrease platelet aggregation. In other individuals, even though COX-1 is inhibited, thromboxane production continues, which increases platelet aggregation. Still others experience pseudoresistance resistance, in which aspirin inhibits thromboxane production, but platelet activity still occurs through other pathways.

Prasugrel, a newer thienopyridine, is associated with more rapid and consistent inhibition of platelet aggregation than clopidogrel. However, it is used predominantly in high-risk patients, according to experts.

What the Guidelines Say

At least three clinical practice guidelines have offered direction around the timing of surgery in patients on APT (See Table, below). However, all three recommend different windows for discontinuing APT prior to surgery. The guidelines also offer discordant opinions about the role of pre-operative genetic and platelet function testing in helping determine the timing of surgery. Of note, all three guidelines graded the level of evidence on both the timing of APT discontinuation and use of pre-operative testing as weak.

Divergent Guidance on Pre-Operative Platelet Function Testing

Guidelines from professional associations all recommend different windows for discontinuing antiplatelet therapy prior to surgery. The guidelines also offer disparate guidance around pre-operative testing to determine patients’ level of platelet inhibition.

Guideline
Date
Recommendations
Level of Evidence
American College of Chest Physicians 2008

Stopping aspirin- or clopidogrel-containing drugs 7–10 days before surgery or a procedure preferred over stopping them closer to surgery

Routine use of platelet function assays to monitor the antithrombotic effect of aspirin or clopidogrel not recommended in patients receiving antiplatelet therapy

In patients scheduled for CABG, interrupt clopidogrel at least 5 days, and preferably, 10 days prior to surgery

2C


2C


IC

American College of Cardiology Foundation/
American Heart Association
2011

When the procedure can be delayed, discontinue thienopyridine in patients scheduled for CABG to allow the antiplatelet effect to dissipate

Withdraw clopidogrel at least 5 days prior to CABG; withdraw prasugrel at least 7 days prior to CABG unless need for revascularization/net benefit of thienopyridine outweighs risk of excess bleeding

Platelet function testing may be considered if results may alter management

Genotyping for CYP219 may be considered if results may alter management

B


B

C

C


C

Society for Thoracic Surgeons/
Society for Cardiovascular Anesthesiologists/
International Consortium for Evidence Based Perfusion
2011

Discontinue platelet P2Y12 receptor inhibitors as soon as 3 days prior to coronary revascularization

Consider POCT for platelet ADP responsiveness to identify clopidogrel nonresponders who may not require a pre-operative waiting period

IB 

IIb (C)

Sources: Ann Thorac Surg 2011;91:944–82; Chest 2008;133:71S–105S; JACC 2011;57:1920–59.

The STS guidelines, published in March 2011, are the most aggressive and suggest that APT may be discontinued as early as 3 days prior to surgery. These guidelines also propose that point-of-care testing (POCT) for platelet adenosine diphosphate (ADP) responsiveness might be reasonable to identify clopidogrel nonresponders who might not require a preoperative waiting period prior to discontinuing this medication. On the other extreme, 2008 guidelines of the American College of Chest Physicians (ACCP)—currently under revision and scheduled for publication in early 2012—recommend interrupting clopidogrel in patients scheduled for coronary artery bypass graft (CABG) procedures at least 5 days, and preferably 10 days, prior to surgery (Chest 2008; 133:71S–105S). This guideline also advises against routine use of platelet function assays to monitor the antithrombotic effect of aspirin or clopidogrel.

In between the STS and ACCP guidelines is an update of guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction issued in May 2011 by the American College of Cardiology Foundation/American Heart Association (JACC 2011;57:1920–59). This document recommends withdrawing clopidogrel for at least 5 days and prasugrel for at least 7 days prior to CABG. The guidelines also suggest that platelet function testing and genotyping for CYP2C19 loss of function variant might be considered if results of testing may alter management.

A Striking Lack of Evidence

The inconsistency among the guidelines reflects the dearth of solid data associating withdrawal of APT and pre-operative platelet function testing with outcomes, according to Linda Shore-Lesserson, MD, professor of clinical anesthesiology at Albert Einstein College of Medicine and director of cardiovascular anesthesiology at Montefiore Medical Center in New York City. “The reason the recommendations are discrepant is because no one has prospectively studied individualized treatment. All of the recommendations have been based on retrospective reviews or pure pharmacokinetics data on the half-life and duration of clopidogrel and other antiplatelet medications.” Shore-Lesserson served on the STS guidelines committee.

Although there is a vast literature on clopidogrel, the paucity of evidence linking use of the drug with surgical outcomes is striking. “The optimal degree of platelet inhibition for the best post-CABG risk/benefit ratio remains entirely unknown … Not a single randomized study has evaluated the safety and efficacy of clopidogrel interruption before CABG surgery,” wrote the authors of a recent editorial (JACC 2010;56:2003–5).

This circumstance is not lost on Paul Gurbel, MD, a leading thrombosis researcher, who was among the first to report on patients’ variable response to clopidogrel. “There have been no definitive prospective studies demonstrating the utility of point-of-care testing to determine the timing of CABG, or any other surgery, for that matter,” he noted. Gurbel is director of the Center for Thrombosis Research at Sinai Hospital in Baltimore and associate professor of medicine at Johns Hopkins University School of Medicine.

Gurbel’s lab recently conducted a prospective pilot study of 200 patients who had platelet function testing by thromboelastography (TEG) prior to CABG. Patients with high platelet reactivity despite being on clopidogrel (non-responders) went to surgery within 24 hours of their last clopidogrel dose, while those with intermediate or low platelet reactivity waited 3 or 5 days, respectively. “We found that people who went to surgery within 24 hours of their last dose had no more bleeding than those who were clopidogrel-naïve,” explained Gurbel. These not-yet-published findings—presented as an abstract at the American Heart Association’s Scientific Sessions 2010—are merely a down payment on the research needed around these issues, he emphasized. “We need a large scale randomized trial.”

Navigating Despite Limited Evidence

With little hard evidence to guide them, many clinicians navigate the APT discontinuation-surgery timing decision by factoring in the average platelet turnover time—10 days—with clopidogrel’s approximate 5-day duration of action to arrive at the 5-day window, at which point presumably enough platelet activity will have been restored to safely take the patient to surgery. However, this one-size-fits-all approach ignores individual response to the drugs and has led to variable practices across the country. As the authors of the editorial noted, “despite many advances, open heart surgery is still associated with the risks of bleeding and thrombotic events. Whether to continue antiplatelet therapy during surgery is often handled differently by different institutions, with little interpatient variability within an institution. This confusion is caused by the lack of scientific evidence, so that decisions are being based on individual or local experience, somewhat oriented by recommendations, but based mainly on expert opinion.”

Despite the limited evidence, hospitals are implementing pre-operative testing protocols—some more aggressively than others—in a bid to safely narrow the wait time between APT discontinuation and surgery. Huntsville Hospital in Huntsville, Ala. is on the forefront of such initiatives. “Initially our protocols were if a patient was on clopidogrel, to hold them for five days in intensive care waiting to have their CABG,” explained James Fortenberry, MSN, clinical nurse educator for the cardiovascular service line. “Now that we are doing platelet function testing, we’ve dropped the hold time from an average of five days to about two days.”

Huntsville Hospital’s cardiovascular service line originally started using a POCT for platelet inhibition in 2007 as a means of checking patient compliance with APT. As data from this testing mounted, however, it became clear that about 40% of patients were non- or hypo-responders to clopidogrel. That fact, coupled with an institutional interest in blood conservation, led the cardiovascular surgical team to instigate new pre-operative testing protocols. Now, surgeons aim for a cutoff of <20% platelet inhibition before patients discontinued from APT get the green light for surgery. “It’s all individual. Everyone will respond a little differently as to how long it takes to get the thienopyridine out of their system,” said Fortenberry. “If a patient’s baseline is 60 percent inhibition, we know we’ll probably have to wait at least five days prior to going to surgery. If they’re that high, we’ll start testing every 24 hours until they get to less than 20 percent. On the other hand, if their baseline is 28 percent, we’ll test every 12 hours, or even every six hours.”

Although this protocol started in cardiac surgery, it now has spread to other specialties, including neurosurgery, and is becoming the standard of care for all surgical patients, according to Fortenberry. He maintains a database of about 9,800 patients who were taking clopidogrel and about 2,200 on prasugrel, and hopes to publish some of the hospital’s outcomes data.

If Huntsville Hospital is one of the most enthusiastic adopters of platelet function testing to determine the timing of surgery, others, like Brigham and Women’s Hospital in Boston, are not at that point yet. “We have a difference of opinion among our surgical staff in terms of how long they would wait, but it would all be based on clinical experience; not an any assessment of platelet function. I don’t think there’s enough evidence to support solid clinical decision-making in this area at this point,” said Daniel FitzGerald, CCP, LP, chief perfusionist, and a member of the STS guidelines committee. “Occasionally a surgeon will ask why we aren’t testing platelet function. I’m waiting for that to become a consensus of the group before we look into technologies that allow us to assess it.”

Still other labs, like Mount Sinai Hospital in New York City, offer platelet function testing, but without a fixed protocol for surgeons to order the test. “It’s variable depending on the case and how bloody it’s going to be, but we do get requests, particularly from our neurosurgeons, who may be performing an interventional procedure like stenting on patients with stroke,” explained Ellinor Peerschke, PhD, professor of pathology, director of the hematology and coagulation laboratories, and associate director of the center for clinical laboratories.

Which Test to Use?

The choice of platelet function test appears to be as variable as the decision to use it in determining the wait time for surgery. For example, both Huntsville Hospital and Marshfield Labs in Marshfield, Wisc. offer a POCT cartridge-based assay of platelet aggregation, but both perform the test in their central labs. “The instrumentation was developed initially for cardiac cath labs and the operating room, but there’s not always staff there to do it, whereas our lab is staffed around-the-clock,” explained Mike Sanfelippo, MS, MT(ASCP), technical director of the coagulation service at Marshfield Labs. “Also, if you use it as a point-of-care test, you have to train and maintain competency for an array of people with variable backgrounds.”

At Marshfield Labs, the decision to go with the POCT was made at the request of a neurosurgeon who had used the test elsewhere. “We’ve always had platelet function testing available with the gold standard, light transmission aggregometry. Using that method, I can tell if the patient’s inhibited, whether they’re on aspirin, clopidogrel, or prasugrel, but I can’t do it quickly,” said Sanfelippo. “It takes anywhere from an hour-and-a-half to two hours to complete, from the time the blood arrives in the lab.”

Meanwhile, Montefiore Medical Center uses TEG. “We evaluated a point-of-care test, but we were already using TEG for other reasons and it was meeting our needs. For example, we use a pediatric ventricular assist device, and the very comprehensive anticoagulation algorithm that’s used to manage this device uses TEG,” explained Kenneth Shann, CCP, assistant director of perfusion services, senior advisor for cardiac surgery performance improvement, and a member of the STS guidelines committee.

Genetic Testing: Not Ready for Primetime

Whereas surgical teams are all over the map in terms of whether to use platelet function testing to guide timing of surgery as well as which test to use, there generally appears to be less enthusiasm for genetic testing for the CYP2C19 loss of function variant. Fortenberry summed up the sentiments of several observers. “Genetic testing will tell you more specifically why someone isn’t responding to a thienopyridine, but in the big picture, all we want to know is how it’s working. Plus, we can run our point-of-care test for about $52 versus more than $400 for genetic testing, which is a send-out and will take three-to-seven days for a result. But we need results much sooner than that. That’s why we don’t use genetic testing on a routine basis,” he said.

Peerschke agreed. “I think a functional test, a test of phenotype, is much more immediate than genotype testing and takes into account environmental factors as well as specific genetic factors,” she observed. “The genetic testing we currently run only looks at the metabolism of clopidogrel. It doesn’t look at polymorphisms associated with intestinal absorption or platelet hyper-reactivity. We also don’t have the luxury of waiting for genetic test results.”

What’s the Future?

Gurbel argued that there is insufficient evidence for both platelet function testing and genetic testing in the context of the timing of surgery for patients withdrawn from APT. However, while Shore-Lesserson agreed with the call for more evidence, she emphasized that clinical need inevitably will move the field forward. “One of the reasons we work so closely on this issue is that cardio-pulmonary bypass alone is associated with a bleeding problem. Couple that with preoperative clopidogrel therapy, and they bleed even more. So this is clearly a medical problem that needs to be addressed,” she said.

FitzGerald also suggested the growing interest in blood conservation would be a factor. “Viewing blood as an organ donation is a philosophy that’s growing. There are programs—and we’re one of them—that strive to be bloodless,” he said. “The information is clear about short- and long-term risks of homologous blood transfusions. The evidence for risks is mounting in all populations, but especially in the cardiovascular surgical population.”
Surgical programs that might be considering incorporating pre-operative platelet function testing to determine the timing of surgery for patients on APT will do well to collaborate closely with laboratories, according to Fortenberry. “Nursing and lab have had to collaborate closer than ever before to make this work in our institution,” he said.

Fortenberry emphasized the importance of staff training to achieve consistent blood draws and specimen handling. Even years into the initiative, he still verifies blood draw procedures and specimen handling for any test results indicating <20% platelet inhibition. “We didn’t want to send patients for cardiovascular surgery that we said were good to go, and have the physician have a bleeding issue. We have to give them good data, and good results from the forefront, because if they lose confidence in the beginning, they’ll never go back to the technology,” he argued.

Peerschke stressed that labs need to be informed about the science and keep in touch with clinicians on this issue. “As laboratorians, we need to support the clinical mission, and we can only do that if we know what the clinical needs are and what surgeons are thinking. Then we must be able to recommend the best solution for their problem.”

For Further Information

Bonello L, Tantry US, Marcucci R, Blindt R, et al. Consensus and Future Directions on the Definition of High On-Treatment Platelet Reactivity to Adenosine Diphosphate. JACC 2010;56:919–33.

Cattaneo, M. New P2Y12 Inhibitors. Circulation 2010;121:171–79.

Ferreiro JL, Sibbing D, Angiolillo DJ. Platelet function testing and risk of bleeding complications. Thromb Haemost 2010;103:1128–35.

Gurbel PA, Mahla E, Tantry US. Peri-operative platelet function testing: The potential for reducing ischaemic and bleeding risks. Thromb Haemost 2011;106.1/2011.

Interindividual variability in the response to oral antiplatelet drugs: a position paper of the Working Group on antiplatelet drugs resistance appointed by the Section of Cardiovascular Interventions of the Polish Cardiac Society, endorsed by the Working Group on Thrombosis of the European Society of Cardiology. Eur Heart J 2009;30:426–35.

Kwak YL, Kim JC, Choi YS, Yoo KJ, et al. Clopidogrel Responsiveness Regardless of the Discontinuation Date Predicts Increased Blood Loss and Transfusion Requirement after Off-Pump Coronary Artery Bypass Graft Surgery. JACC 2010;56:1994–2002.

Lordkipanidze M, Pharand C, Nguyen TA, Schampaert E, et al. Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients. Eur Heart J 2008;29:2877–85.

Montalescot G, Hulot, JS, Collet JP. Antiplatelet Therapy and Coronary Artery Bypass Graft Surgery. JACC 2010;56:2003–5.

Madsen EH, Saw J, Kristensen SR, Schmidt EB, et al. Long-term aspirin and clopidogrel response evaluated by light transmission aggregometry, VerifyNow, and thromboelastography in patients undergoing percutaneous coronary intervention. Clin Chem 2010;56:839–47.

Mr. Fortenberry has received honoraria from Daiichi Sankyo, Inc. and Lilly USA. Dr. Gurbel has received research grants/honoraria from Merck, Astra Zeneca, Medtronic, Lilly/Sankyo, Daiichi, Pozen, Sanofi/Aventis, Boston-Scientific, Bayer, Accumetrics, Nanosphere, Novartis, and NIH.