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January 2022 Supplement
Sponsored by Silk Road Medical
Platelet Function Testing and TCAR
With Edgar Guzman, MD, FACS; Katherine Teter, MD; Tom Hawken, MD; Hernan Bazan, MD, DFSVS, FACS; and Angela Martin, MD
Preoperative confirmation of dual antiplatelet therapy (DAPT) compliance is essential to transcarotid artery revascularization (TCAR) practitioners. Unfortunately, even with this emphasis, a recent analysis of the Vascular Quality Initiative (VQI) data set reports that only 79% of patients received DAPT.1 With > 40,000 cases performed to date worldwide, breaches in DAPT compliance have been implicated as the single most important factor in perioperative stroke events.
Given that the incidence of TCAR-related stroke is very low at 1.4%,1 it is difficult for a single practitioner or institution to discern meaningful trends in their negative outcomes. It is in assessing the totality of data that actionable patterns emerge as we strive toward a zero-stroke therapy for carotid stenosis. From this vantage point, testing for clopidogrel resistance and first-line use of more reliable (albeit more expensive) antiplatelet agents emerge as the main strategies with the potential to improve outcomes in this population.
In this collection of articles the authors present their perspectives on the magnitude of the clopidogrel resistance problem and awareness among practitioners, primers on testing protocols available, and pointers on incorporating platelet function testing in a TCAR practice.
The authors recognize there are currently no data proving the superiority of platelet function testing-guided clopidogrel therapy over blind therapy in improving TCAR outcomes; nor are there specific data supporting the use of ticagrelor to the same end. Given the low frequency of stroke events with TCAR, it will take very large numbers to demonstrate either hypothesis. And yet, there are presently two reliable, affordable, and widely available methods to estimate the effectiveness of DAPT as well as pharmacologic alternatives to clopidogrel. With these options, accepting a therapy that is at best 80% effective is no longer necessary or, for that matter, justifiable. We hope that, over time, efforts to optimize DAPT will prove beneficial not only in further improving TCAR outcomes but in bettering the care of vascular patients at large.
THROMBOELASTOGRAPHY
Thromboelastography (TEG) is a whole blood assay that records the kinetics of the coagulation process from initial activation to clot lysis. It does so by tracking the viscoelastic changes of blood as it transitions from a liquid to a gel. These changes are reflective of the functional contributions of the various hemostatic components.
In its original form, TEG assessed global platelet function via determination of the peak viscosity of the sample, expressed by the maximum amplitude (MA) in the tracing. This result is representative of platelets binding to the developing fibrin mesh and is therefore affected by both platelets and fibrin with an 80%/20% contribution between the two. However, in its basic form, the test is unable to determine whether variations in MA are due to changes in platelet number or function and does not offer therapeutic ranges to guide antiplatelet therapy. Furthermore, full activation of the platelets in the sample by the addition of kaolin and calcium chloride overshadows the effect of platelet inhibitors.2
To address this, TEG with platelet mapping (TEG-PM) was developed. This assay consists of four parallel TEG tests carried out with different agonists. Maximum platelet function is determined in one channel with kaolin and calcium chloride, as described previously, for standard TEG.3
The contribution of fibrin to MA is determined in a second channel by the addition of activator F. This activator is a combination of reptilase (which has a thrombin-like effect transforming fibrinogen to fibrin) and factor XIIIa (which crosslinks fibrin). In effect, these two agonists bypass the coagulation cascade and elicit fibrin formation and crosslinking from the sample without directly activating platelets. The addition of abciximab (IIb/IIIa receptor blocker) inhibits platelet activation.
The P2Y12 receptor binds adenosine diphosphate (ADP) on the platelet surface and activates them. Estimation of the effect of P2Y12 inhibitors, such as clopidogrel, is determined by the addition of activator F and ADP to the sample. Comparison to the activator F channel allows the estimation of the incremental contribution of platelets activated by ADP to the MA. Comparison to the standard TEG channel may identify a deficit in MA amplitude attributable to the presence of a P2Y12 inhibitor.
Cyclooxygenase in platelets converts arachidonic acid (AA) into thromboxane, which in turn promotes platelet activation. Assessment of the inhibitory effect of aspirin on this enzyme is estimated similarly by the addition of activator F and arachidonic acid to the sample. In parallel to what has been described previously; comparison to the activator F channel allows the estimation of the incremental contribution of platelets activated by AA to the MA. Comparison to the standard TEG channel may identify a deficit in MA amplitude attributable to the presence of a cyclooxygenase inhibitor. In either case, the degree of inhibition can be expressed as an absolute MA in millimeters or as a percentage of the MA in relation to the maximally activated sample.
Until relatively recently, TEG-PM measurements were carried out in a moving cuvette system in which a filament immersed in the sample recorded varying degrees of resistance as the cuvette moved and the sample shifted phases. This process was labor-intensive and required four parallel tests to be performed, as described previously. This has been improved upon by the introduction of an automated cartridge-based system that replaces the moving cuvette and filament method by observations of the oscillations in the sample as it is subjected to vibrations across a frequency spectrum. Generally speaking, as the sample shifts from liquid to gel the resonant frequency increases as does the amplitude of oscillations.4
From a pragmatic approach, interpretation of a TEG-PM result for TCAR need only focus on two reported values.
- A maximum amplitude induced by ADP (MA-ADP) of ≤ 47 mm
- A percent inhibition of platelet function by AA (AA%) of ≥ 50%
In my experience, the use of these two values has proven enough to adjudicate most cases, with further analysis needed sporadically in equivocal scenarios; mostly when there is a poor correlation between expected and actual results.
Implementation of TEG testing into a TCAR practice can be very straightforward if the technology is already available at the organization. This is often the case in centers that practice trauma surgery and cardiac surgery. However, some barriers I have encountered at different institutions include the availability of TEG but not TEG-PM and the competing use of resources with other service lines that may have “blocked time” on the analyzer.
TEG-PM is affordable at a laboratory cost of $250 per study. Full results are available in approximately an hour, but real-time reporting yields MA data in 20 to 30 minutes. The test is usually available to order directly by the physician through the electronic medical record and I would advise colleagues to do just that. Administrative discussions can be had in the future if objections arise.
Performing TEG-PM the day of surgery versus during presurgery testing is a logistical decision heavily influenced by local practice and resource availability. The advantage of the former is that it provides the most up-to-date information possible and may identify intervening factors beyond resistance; the latter minimizes disruptions in scheduling due to unexpected results.
TEG-PM can be very useful in the management of bleeding complications within the 30 days of recommended DAPT after TCAR. I have observed a few cases of gastrointestinal bleeding and found that these patients had very intense platelet inhibition by both aspirin and clopidogrel. Using TEG-PM, we were able to safely hold both drugs until values returned to the low end of the therapeutic range, at which point patients would often settle into alternating day aspirin and clopidogrel dosing.
In closing, I believe present-day TEG-PM represents a very elegant implementation of a complex testing algorithm that nonetheless yields results that are broad in scope, reproducible, and easy to interpret having the potential to modify day-to-day clinical practice.
1. Liang P, O’Donnell TFX, Cronenwett JL, et al. Vascular Quality Initiative risk score for 30-day stroke or death following transcarotid artery revascularization. J Vasc Surg. 2021;73:1665-1674. doi: 10.1016/j.jvs.2020.10.023
2. Thakur M, Ahmed AB. A review of thromboelastography. Int J Periop Ultrasound Appl Technol. 2012;1:25-29.
3. Dias JD, Haney EI, Mathew BA, et al. New-generation thromboelastography: comprehensive evaluation of citrated and heparinized blood sample storage effect on clot-forming variables. Arch Pathol Lab Med. 2017;141:569-577. doi: 10.5858/arpa.2016-0088-OA
4. Coramed Technologies LLC. 501(k) substantial equivalence determination decision memorandum – coagulation resonance analysis system with platelet mapping assay. Available from https://www.accessdata.fda.gov/cdrh_docs/reviews/K140893.pdf. Accessed on September 24, 2021.
Acknowledgment:
I would like to thank Dan Mason, MSN, Medical Science Liaison at Haemonetics Corporation for his unwavering support in promoting a thorough understanding of TEG and assistance in ensuring the technical accuracy of this article.
Clopidogrel Resistance in the Vascular Patient
Although clopidogrel resistance (CR) may be underrecognized in routine vascular practice, our experience with CR and routine testing suggests that patients exist on a spectrum of response to clopidogrel. A level of response below normal is common, although complete nonresponse remains rare. Further study is needed to characterize which patients are at the highest risk of adverse events given the degree of CR and to determine if a quantitative measurement of CR is a sufficient risk measurement tool.
In our subgroup analysis of 300 patients enrolled in the Platelet Activity and Cardiovascular Events (PACE) study, 104 patients taking clopidogrel were identified. Patients were then followed for a median of 18 months to assess for major adverse limb events (MALEs), including major amputation or reoperation and major cardiovascular events. Patients were stratified as poor responders or normal responders for platelet aggregation ≥ 50% or < 50%, respectively (VerifyNow P2Y12, Accumetrics, Inc.). Approximately 25% of patients taking clopidogrel were poor-responders based on platelet aggregation, and this was significantly associated with increased MALEs, suggesting that CR is a key component in the risk of adverse outcomes after lower-extremity revascularization.1
CR was similarly common among patients undergoing TCAR at several data-sharing institutions. Sixty-seven patients who underwent TCAR between January 2018 and January 2021 were identified. Of these, 38% of patients met the criteria for CR based on light transmission aggregometry (VerifyNow P2Y12) and 13% were hyper-responders. No significant differences were identified in postoperative ischemia or hemorrhagic complications between patient groups; however, the overall complication rate of TCAR is exceedingly low. Larger studies will be necessary to assess for a statistically significant difference, although this highlights the frequency of CR in the usual vascular patient.2
These studies illustrate that CR is significantly prevalent in vascular patients being treated for peripheral and cerebrovascular disease, and there is a need for a greater understanding of risk stratification based on the degree of responsiveness, as a poor response may be associated with adverse outcomes. As we know from patients enrolled but excluded from ROADSTER 2 due to procedural violations (largely medication noncompliance), patients who did not take dual antiplatelet/statin therapy as instructed had substantially higher adverse events, particularly symptomatic patients.3 This implies that CR may confer the same substantial risk.
1. Tawil M, Maldonado TS, Xia Y, et al. Increased risk of major limb events in poor clopidogrel responders: Platelet Activity in Vascular Surgery and Cardiovascular Events (PACE) Study subgroup analysis. J Vasc Surg. 2020;5. doi: 10.1016/j.jvs.2020.08.098
2. Rokosh RS, Rockman C, Ehlert BA, et al. Multi-institutional patterns of clopidogrel response among patients undergoing transcarotid artery revascularization. Presented at: Society For Vascular Surgery Annual Meeting, San Diego, CA; August 18-21, 2021.
3. Kashyap VS, Schneider PA, Foteh M, et al, ROADSTER 2 Investigators. Early outcomes in the ROADSTER 2 study of transcarotid artery revascularization in patients with significant carotid artery disease. Stroke. 2020;51:2620-2629.
Platelet Function Testing and TCAR
To better understand how common CR is among a mixed cohort of cardiovascular patients, we identified 3,301 patients who underwent CR testing in our health care system from October 2014 to January 2020.
The test used in our system is the VerifyNow P2Y12 rapid platelet-function assay. Results are expressed in P2Y12 reaction units (PRU). A PRU value ≥ 200 while on clopidogrel suggests an insufficient antiplatelet effect of the drug.
Of the 3,301 patients identified with a PRU test, 1,789 patients (54%) had a PRU value ≥ 200 while on clopidogrel.
Next, using CPT codes, we identified subgroupings of patients undergoing endovascular peripheral procedures (n = 260) and patients undergoing coronary procedures (n = 935). This comprises a wide mix of endovascular interventions, including carotid/vertebral interventions 55/260 (20.7%), iliac and infrainguinal 117/260 (45%), mesenteric 36/260 (13.9%), intracranial 24/260 (9.2%), and venous intervention 28/260 (10.8%).
In the endovascular cohort, 137 (53%) of 260 patients had a PRU value ≥ 200. In the coronary cohort, 503 (54%) of 935 patients had a PRU value ≥ 200.
In statistical analysis of the groups, patients with a PRU value ≥ 200 were more likely to be older (69.3 vs 66 years; P < .0001), less likely to be male (54.4% vs 64%; P < .0001); more likely to have a history of smoking (76.1% vs 70.1%; P < .0001), diabetes mellitus (54.4% vs 39.9%; P < .0001), have chronic kidney disease (56.4% vs 39.8%; P < .0001), and more likely to be anemic (38.2% vs 25.8%; P < .0001).
The prevalence of inadequate antiplatelet effect of clopidogrel in our cohort of patients undergoing peripheral endovascular and coronary interventions was high (53%-54%). The study did not ascertain whether CR leads to negative clinical effects. Future prospective studies are needed to determine the clinical effect of CR on patients undergoing peripheral intervention.
Understanding P2Y12 Inhibitors, Clopidogrel Resistance, and Alternative Drugs
While aspirin and clopidogrel are the dominant first-line medications to achieve adequate antiplatelet effect in patients undergoing peripheral, coronary, and carotid endovascular interventions, recent literature suggests that CR could be as high as 53% in patients undergoing peripheral endovascular interventions, as highlighted in the previous commentary by Drs. Hawken and Bazan.1
A recent polling of vascular surgeons was conducted regarding their overall understanding of antiplatelet therapies (Macdonald S. Focus group survey. Internal Silk Road Medical Report, unpublished. 2021). They were queried about their practice patterns regarding choice of medication and testing for resistance to these drugs for patients undergoing noncarotid and carotid revascularization procedures. One hundred forty-six surgeons responded across 36 states. The mean years in practice was 15, with an average of 62 carotid revascularization procedures annually. The vast majority (80%) responded that they frequently use clopidogrel, while ticagrelor is less commonly utilized. Prasugrel and intravenous cangrelor were used to a far lesser extent.
The respondents estimated on average that 16% of their vascular patients have resistance to antiplatelet medications. Nineteen percent of surgeons routinely tested for clopidogrel resistance before carotid procedures and slightly fewer tested patients before noncarotid vascular procedures; 43% selectively tested patients receiving carotid revascularizations if they thought their patients were likely resistant to clopidogrel. Characteristics that respondents believed would indicate CR included (in decreasing importance): history of prior stent or graft thrombosis, concurrent medication usage that interferes with clopidogrel metabolism, active smoking, Asian heritage, diabetes, age > 75 years, and having a body mass index > 30.
More than a third of surgeons did not test for CR before carotid procedures and this was not influenced by their years in practice. Of those who did test for CR, 54% utilized the VerifyNow P2Y12 inhibitor assay, whereas 24% used TEG-PM (Haemonetics). Six percent utilized genetic testing while the remaining employed aggregometry, routine clotting labs, or deferred to another specialist.
As evidence mounts that CR is much more common than previously recognized, our testing and understanding of optimal platelet inhibition are evolving. This poll emphasizes the gap between the technical excellence we have achieved with carotid and other major revascularizations and the precise medical management of these patients. Our willingness to adapt with ever-expanding technology will allow our patients to have the best possible outcomes from not only carotid revascularizations but all vascular procedures.
1. Hawken TN. Presented at VAM, San Diego, CA; August 2021.
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