Monitoring antiplatelet therapy: where are we now? : Journal of Cardiovascular Medicine

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Monitoring antiplatelet therapy: where are we now?

Marcucci, Rossellaa; Berteotti, Martinaa; Gragnano, Feliceb,c; Galli, Mattiad,e; Cavallari, Ilariaf; Renda, Giuliag; Capranzano, Pierah; Santilli, Francescai; Capodanno, Davideh; Angiolillo, Dominick J.j; Cirillo, Pliniok; Calabrò, Paolob,c; Patti, Giuseppel; De Caterina, Raffaelem,n,o

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Journal of Cardiovascular Medicine ():10.2459/JCM.0000000000001406, December 15, 2022. | DOI: 10.2459/JCM.0000000000001406
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Abstract

Introduction

Since its first introduction into cardiovascular prevention in the 1980s, aspirin has become an essential pharmacological compound in this setting.1 The subsequent introduction of clopidogrel, and, more recently, of prasugrel and ticagrelor, offered the potential to enhance platelet inhibition through the blockade of the P2Y12 receptor.2,3 However, the evidence of a substantial proportion of patients who experience subsequent ischemic events while on antiplatelet therapy have suggested the possibility of having ‘drug resistance’.4 Thus, platelet function tests (PFTs) have been adopted in order to assess residual platelet reactivity (RPR). On the other hand, since the efficacy of clopidogrel relies on its activation by the hepatic cytochrome P450 (CYP) 2C19 for its two-step oxidation process, the search for genetic variants affecting the function of this enzyme has also been proposed.5 In the past few years, several studies have addressed this topic, trying to answer two main questions: is laboratory evidence of insufficient platelet inhibition associated with more frequent major ischemic events and does a strategy of tailored antiplatelet prescription guided by these tests lead to a significant clinical benefit?

In the present article, we aim at reviewing the existing evidence surrounding the application of PFTs in patients with coronary, cerebrovascular or peripheral atherosclerosis.

Acute coronary syndromes

Aspirin resistance

Antiplatelet therapy with aspirin is the cornerstone of secondary prevention in patients with coronary artery disease (CAD).6 Historical trials have provided evidence of the efficacy of aspirin to mitigate the risk of thrombotic events in patients with chronic coronary syndromes or acute coronary syndrome (ACS), either in combination with a P2Y12 inhibitor or as monotherapy.6,7 Despite the benefit of aspirin in secondary prevention being indisputable, a substantial proportion of patients with recent or remote ACS still experience recurrent atherothrombotic events while on chronic aspirin therapy.8–10 This observation prompted the idea that aspirin may, in some cases, fail to prevent cardiovascular events, thus setting the stage for the concept of aspirin resistance or poor responsiveness.11,12

Aspirin exerts its antiplatelet effect by reducing the production of thromboxane (TX) A2 through the inhibition of cyclooxygenase-1 (COX-1) in platelets.12 Of note, in the presence of COX-1 inhibition, platelets can still be activated by other agonists (i.e. thrombin, ADP, and collagen), thus bypassing the COX-1 pathway. This concept has relevant therapeutic implications.13

Patients with high-on-aspirin RPR have been reported to have a higher risk of cardiovascular events.11 RPR in patients taking aspirin can be evaluated using laboratory tests dependent on COX-1 activity.11,14–16 Platelet aggregation can be measured ex vivo by light transmission aggregometry or by electrical impedance after adding agonists (i.e. arachidonic acid, collagen), or by automated and semi-automated tests (i.e. Platelet Function Analyzer 100, Multiplate analyzer, VerifyNow), which has simplified the use of PFT, although the reproducibility and correlation across different techniques remain modest.11,14–16 Laboratory tests can be classified as COX-1-specific or nonspecific. In previous reports, COX-1-specific tests have systematically shown a low prevalence of aspirin resistance, and lower compared with nonspecific methods.11,14–16

Poor compliance is probably the most frequent cause of insufficient COX-1 inhibition in aspirin-treated patients and should be taken into account as a primary explanation for the reduced effect of the drug.12 Several studies explored the impact of genetic variability and COX-1 polymorphisms on high-on-aspirin RPR, yielding mixed and inconclusive results.11,17 The degree of on-treatment platelet inhibition may depend on the dosage or daily frequency of aspirin administration or concomitant systemic conditions (i.e. inflammatory disease, diabetes mellitus).18 An increased platelet turnover may also cause high-on-aspirin RPR.11 Drug–drug interactions between aspirin and other pharmacologic agents (i.e. nonsteroidal anti-inflammatory drugs, statins, selective serotonin reuptake inhibitors) have also been reported as possible reasons for poor responsiveness to aspirin.11,19 Particularly, ibuprofen can block the COX-1 active site, thus preventing aspirin-related irreversible acetylation/inactivation of the enzyme and causing aspirin resistance.19

The practical implications of high-on-aspirin RPR remain controversial.11 Given the absence of robust evidence, current guidelines do not recommend the routine use of PFT in patients taking aspirin.6 Importantly, a universally accepted definition of ‘aspirin resistance’ is currently lacking. This term should be reserved for situations in which aspirin fails to hit its pharmacological target (documented by COX-1-specific laboratory tests).11,13 Ideally, aspirin response should be evaluated and monitored by addressing its biochemical drug target, platelet COX-1, as reflected by serum TXB2 levels, that is uniformly and persistently suppressed by aspirin treatment in most conditions.17 The term ‘clinical aspirin resistance’ might be misleading and should not be adopted to define patients experiencing recurrent cardiovascular events while on aspirin.12 The term might however also apply to prothrombotic situations in which the relative role of the COX-1 pathway and of other pathways of platelet activation is tilted in favor of the latter, thus limiting the efficacy of aspirin on PFTs.

Collectively, available evidence indicates that the identification of patients with CAD at high risk of recurrent ischemic events despite optimization of antiplatelet therapy is a key, yet unsolved, issue in practice and it has to be addressed by future research.

Resistance to oral P2Y12 inhibitors

Adding an oral P2Y12 platelet receptor inhibitor (clopidogrel, prasugrel or ticagrelor) on top of aspirin, the so-called dual antiplatelet therapy (DAPT), is now the standard of care for patients with ACS or undergoing percutaneous coronary intervention (PCI).20 Because large randomized clinical trials (RCTs) have shown prasugrel and ticagrelor to reduce major adverse cardiovascular events compared with clopidogrel at the relatively acceptable cost of increased bleeding, these two more recent P2Y12 inhibitors are recommended in patients with ACS.2,3,20,21 The different clinical results of P2Y12 inhibitors are the consequence of their different pharmacokinetic (PK) and pharmacodynamic (PD) profiles. In fact, clopidogrel, but not prasugrel and ticagrelor, is subject to a large interindividual variability in PK and PD effects resulting in high RPR, a modifiable marker of thrombotic risk, in 20 to 40% of treated patients (‘clopidogrel poor or nonresponders’).22,23 Indeed, clopidogrel is a pro-drug that requires a two-step oxidation process by CYP2C19 to be activated, and carriers of genetic variants [∗2 and ∗3, the so-called ‘loss-of-function’ (LoF) alleles] affecting the function of this enzyme are associated with reduced levels of the clopidogrel active metabolite (intermediate or poor metabolizer), leading to a higher risk of ischemic events (Fig. 1).23–26

F1
Fig. 1:
Clinical outcomes and main strengths and limitations of tools for a guided selection of P2Y12 inhibiting therapy in patients with acute coronary syndrome or undergoing percutaneous coronary intervention. ACS, acute coronary syndrome; LTA, light transmission aggregometry; TEG, thromboelastography; VASP, vasodilator-stimulated phosphoprotein.

Furthermore, prasugrel and ticagrelor appear to be associated with enhanced platelet inhibition compared with clopidogrel also among patients without impaired production of clopidogrel active metabolite (‘clopidogrel responders’), which in turn is associated with a higher risk of bleeding without any reduction in ischemic events,22,27,28 a finding still needing a clear explanation. With the aim of reducing bleeding among ACS patients, PFT and genetic testing have been proposed as tools to perform a guided de-escalation of P2Y12 inhibiting therapy, thanks to the identification of patients responding to clopidogrel and the selective use of the more potent and predictable drugs ticagrelor or prasugrel among clopidogrel nonresponders.23,28 Indeed, PFT allows a direct measure of platelet reactivity, while genetic testing allows the identification of patients carrying LoF alleles of the CYP2C19 gene who are at risk of being clopidogrel nonresponders (Fig. 1). Despite the strong rationale for such a guided de-escalation of P2Y12 inhibiting therapy, RCTs testing this hypothesis have not yielded consistent results, largely driven by the pitfalls of early trials (inadequate selection of target populations and strategies to identify and overcome poor responsivity to clopidogrel) and the limited sample sizes of recent trials.29 Indeed, even the more recent TROPICAL-ACS trial, comparing standard versus PFT-guided de-escalation among 2610 patients with non-ST-elevation myocardial infarction, and the POPular Genetics trial, comparing standard versus genotype-guided de-escalation in 2488 patients with ST-elevation myocardial infarction,30,31 were burdened by noninferiority designs and the use of a composite end point including both ischemic and bleeding outcomes leading to relatively low statistical power with respect to hard ischemic events (i.e. cardiovascular death, myocardial infarction, stent thrombosis), resulting in weak guideline recommendations in clinical practice (Class IIb, level of evidence A).23,30,31 To this extent, by increasing statistical power for hard individual end points, a recent meta-analysis has shown that a strategy of guided de-escalation is associated with a 19% reduction in bleeding without any trade-off in ischemic events among more than 20 000 PCI patients randomized to either standard or test-guided antiplatelet therapy.28 Furthermore, a recent network meta-analysis comparing guided de-escalation versus prasugrel or ticagrelor in ACS patients has shown that a guided de-escalation is associated with a favorable balance between safety and efficacy.32 The main published RCT escalation and de-escalation strategies after PCI are listed in Table 1.

Table 1 - Studies assessing the effectiveness of platelet function-guided therapy with P2Y12 inhibitors after percutaneous coronary intervention
Study name Number of patients in each arm Clinical presentation, percentage Type of test and targets or cut-offs Follow-up duration (months) Main results in terms of efficacy (guided versus standard arm) Main results in terms of safety (guided versus standard arm)
Escalation strategy
 TAILOR PCI Pereira et al. 2020 33 2641/2635 STEMI 22%, NSTEMI 29%, UA 18%, CCS 31% Genotype-guidedCYP2C19∗2 or ∗3 LoF alleles 12 CV death, MI, ST, stroke, severe recurrent ischemia: 4.0% versus 5.9%; HR 0.66; 95% CI 0.43–1.02; P = 0.06 Major or minor bleeding: 1.9% versus 1.6%; HR 1.22; 95% CI 0.60–2.51; P = 0.58
 Tuteja et al. 2020 34 249/255 STEMI 14%, NSTEMI 21%, UA 15%, CCS 50% Genotype-guidedCYP2C19∗2 ∗3 and ∗17 alleles 16 CV death, MI, ST, stroke, urgent revascularization: 13.7% versus 10.2%; P = 0.27 BARC bleeding 2, 3, 5: 2% versus 3.1%, P = 0.87
 PHARMCLO Notarangelo et al. 2018 35 448/440 STEMI 28%, NSTEMI 68%, UA 2%, CCS 2% Genotype-guidedABCB1 3435, CYP2C19∗2 and ∗17 12 CV death, MI, stroke: 13% versus 21.4%; HR 0.57; 95% CI 0.41–0.8; P < 0.001 All bleeding events: 4.2% versus 6.8%; HR 0.62; 95% CI 0.35–1.1; P = 0.1
 Lee et al. 2018 36 683/248 NA Genotype-guidedCYP2C19∗2, ∗3, and ∗17 12 All-cause death, MI, stroke, TVR: 3.6% versus 9.4%; P = 0.038 TIMI major bleeding: 0.5% versus 0.5%; P = 0.999
 Sánchez-Ramos et al. 2016 37 317/402 STEMI 42%, NSTEMI 27%, UA 20%, CCS 11% Genotype-guidedCYP2C19∗2 and ∗3 and ABCB1 12 CV death, ACS, stroke: 10.1% versus 14.1%; HR 0.63, 95% CI 0.41–0.97; P = 0.037 TIMI major and minor bleeding: 4.1% versus 4.7%, HR 0.80, 95% CI 0.39–1.63; P = 0.55)
 Shen et al. 2016 38 309/319 NA Genotype-guidedCYP2C19∗2 and ∗3 12 All-cause death, MI, TVR: 4.2% versus 9.4%; P = 0.010 Bleeding events: 8.1% versus 6%; P = 0.29
 IAC-PCI Xie et al. 2013 39 301/299 NA Genotype-guidedCYP2C19∗2 or ∗3 6 All-cause death, MI, stroke, TVR: 2.6% versus 9.03%; P = 0.001 All bleeding events: 1.3% versus 3.7%, P = 0.073
 PATH-PCI Zheng et al. 2020 40 1146/1139 CCS 100% PFT(PL-12)HPR: MAR > 55% 6 Cardiac death, MI, ST, stroke, urgent revascularization: diabetes 6.8% versus 11.3%; HR 0.59, 95% CI 0.34–0.99; P = 0.049; no diabetes 1.8% versus 4.2%; HR 0.43, 95% CI 0.23–0.76; P = 0.006 Major bleeding: diabetes 3.5% versus 3.3%, HR1.07, 95% CI 0.46–2.46, P = 0.882; no diabetes 1.6% versus 0.9%, HR 1.8, 95% CI 0.72–4.52; P = 0.209
 Zhu et al. 41 2015 154/151 NA PFT(PACKS-4 Aggregometer)Low clopidogrel response: < 10% IPA 12 CV death, MI, stroke: 5.8% versus 9.3%; P = 0.257 No major bleeding. Minor bleeding events: 0.6% versus 0%; P = 1.0
 ARCTIC Collet et al. 2012 42 1213/1227 CCS 73%, NSTEMI 27% PFT(Verify Now)HPR if PRU ≥235, ≤15% inhibition, or both 12 All-cause death, MI, ST, stroke, urgent revascularization: 34.6% versus 31.1%; HR 1.13; 95% CI 0.98–1.29; P = 0.10 Major or minor bleeding: 3.1% versus 4.5%; HR, 0.69; 95% CI 0.46–1.05; P = 0.08
 Hazarbasanov et al. 2012 43 97/95 STEMI 24%, NSTEMI 33%, CCS 43% PFT(Multiplate analyzer)HPR if ≥46 U by ADPtest 6 Cardiac death, MI, ST, stroke: 0% versus 5.3%; P = 0.03 TIMI major bleeding: 1 versus 0
De-escalation strategy
 POPular Genetic Claassens et al. 2019 31 1242/1246 STEMI (100%) Genotype-guidedCYP2C19∗2 or ∗3 LoF alleles 12 CV death, MI, ST, stroke: 2.7% versus 3.3%; HR 0.83; 95% CI 0.53–1.31 PLATO major and minor bleeding: 9.8% versus 12.5%; HR 0.78; 95% CI 0.61–0.98; P = 0.04
 TROPICAL-ACSSibbing et al. 2017 30 1304/1306 STEMI 55%, NSTEMI45% PFT(Multiplate analyzer)HPR if ≥46 U by ADPtest 12 CV death, MI, stroke: 3% versus 3%; HR 0.77, 95% CI 0.48–1.21; pnon-inf = 0.0115 BARC bleeding ≥2: 6% versus 5%; HR 0.82, 95% CI 0.59–1.13; P = 0.23
 ANTARCTICCayla et al. 2016 44 435/442 STEMI 35%NSTEMI 48%UA 18% PFT(Verify Now)HPR if PRU ≥208LPR if PRU ≤85 12 CV death, MI, ST, urgent revascularization: 10% versus 9%; HR 1.06; 95% CI 0.69–1.62; P = 0.8 BARC total bleeding events: 38% versus 39%; HR 0.98; 95% CI 0.79–1.22; P = 0.87
CCS, chronic coronary syndromes; CI, confidence interval; CV, cardiovascular; CYP, cytochrome P450; HPR, high platelet reactivity; HR, hazard ratio; IPA, inhibition of platelet aggregation; LoF, loss-of-function; LPR, low platelet reactivity; MI, myocardial infarction; NSTEMI, non-ST-elevation myocardial infarction; ST, stent thrombosis; STEMI, ST-elevation myocardial infarction; TVR, target vessel revascularization; UA, unstable angina.

Practical considerations deserve to be made when implementing a guided selection of antiplatelet therapy in patients with ACS. In particular, PFT, but not genetic testing, provides a direct measure of response to therapy, but results may vary over time and require the patient to be on treatment with clopidogrel to assess drug responsiveness. This latter issue is particularly problematic in the setting of ACS, where prasugrel and ticagrelor represent the standard therapy. On the other hand, genetic testing does not require the patient to be on clopidogrel, and a single test is sufficient to assess the genetic profile of the patient. It has to be remarked, however, that the genotype represents only one of the components defining platelet responsivity, and thus genetic testing needs to be integrated with clinical variables to enhance its accuracy in identifying patients at risk of developing adverse outcomes (Fig. 1).45–47 Importantly, the implementation of PFT and genetic testing has been associated with reduced costs due to the larger use of generic P2Y12 inhibitor formulations (now, however, superseded by the decreasing costs of prasugrel and clopidogrel), and the reduced clinical events and hospitalizations.29 Finally, the use of clopidogrel in nonresponders to the compound may be of particular concern among patients for whom clopidogrel is used as monotherapy, such as those dropping aspirin after 1–3 months or 1 week after ACS/PCI in patients with sinus rhythm or concomitant oral anticoagulant therapy.48 Further evidence is warranted to support the implementation of a guided selection of P2Y12 inhibiting therapy in such patients.

Interestingly, an interethnic difference in platelet reactivity exists: Asian patients present a higher prevalence of the CYP2C19 LoF allele carriage as compared with Caucasians, which may explain the higher prevalence of HPR during clopidogrel treatment found in this population.49 Besides, a higher cut-off of high RPR has been suggested in eastern Asians.50,51 Despite that, it has been consistently reported that East Asian patients present a lower risk of stent thrombosis and a higher risk of bleeding compared with Western patients, giving rise to the so-called ‘East Asian paradox’.52,53

Collectively, PFT or genetic testing represents a promising strategy for optimizing the balance between bleeding and ischemic risks in ACS patients and reducing costs. Future recommendations may be influenced by new available evidence supporting the use of a guided selection of P2Y12 inhibiting therapy, also accounting for interethnic variability.

Cerebrovascular disease

Aspirin resistance

Administration of aspirin is recommended in patients with acute ischemic stroke, regardless of the etiology, within 24–48 h after onset.54 A pooled analysis of 15 778 participants from 12 trials of aspirin versus control in secondary prevention, showed that aspirin reduced the 6-week risk of recurrent ischemic stroke by about 60% [hazard ratio (HR) 0.42, 95% confidence interval (CI) 0.32–0.55, P < 0.0001] and disabling or fatal ischemic stroke by about 70% (HR 0.29, 95% CI 0.20–0.42, P < 0.0001), with greatest benefit noted in patients presenting with transient ischemic attack (TIA) or minor stroke.55 However, a proportion of patients have stroke recurrence while they are on treatment with aspirin, due to a number of mechanisms involving different environmental and genetic factors, drug interactions and co-morbid risk factors. Even medication nonadherence has to be considered as a cause of resistance to aspirin because the irregularity of drug intake is estimated to be as high as 40% among subjects with cardiovascular diseases and in stroke populations.56 Even if the frequency of laboratory aspirin resistance depends on the application of a testing method,57 it may result in a worse prognosis and a poor clinical outcome in ischemic stroke, regardless of the etiology.58,59 In a population of patients post ischemic stroke, aspirin resistance, evaluated using a BioData PAPS-4 platelet aggregometer, has been shown to be more prevalent in patients with diabetes and high LDL values, also leading to a greater risk of another stroke, heart attack, peripheral arterial disease, or death from any cause.60

A prospective observational study in about 800 patients with acute ischemic stroke analyzed whether high-on-aspirin RPR, measured using VerifyNow at different time points after aspirin treatment, was associated with a higher occurrence of subsequent vascular events.61 At the 1-year follow-up, aspirin resistance was associated with an increased risk of a composite of stroke, myocardial infarction and vascular death compared with patients with non-RPR. However, more than half of the patients who initially showed RPR to aspirin responded normally to antiplatelet therapy after 5 days, and serial measurement of platelet reactivity better predicted vascular events. Furthermore, determining platelet function may enable the prediction of early neurological deterioration. A high-on-aspirin RPR, measured using thromboelastography, was independently associated with recurrent ischemic events also in patients with minor stroke or TIA.62 Some authors suggested the use of Multiplate as a PFT to guide the change in antiplatelet therapy from aspirin to clopidogrel, rather than to increase the dose of aspirin.63

On the other hand, a study determining the resistance to aspirin or clopidogrel by optical aggregometry, and accordingly modifying treatment by increasing the dose, switching the drug, or adding another drug, observed that changes in antiplatelet therapy following PFT may be associated with a higher – not lower – incidence of death, bleeding, or ischemic events compared with the group of patients who did not receive modified antiplatelet therapy.64 Based on these results, the authors concluded that the PFT is not helpful in optimizing clinical outcomes.

In a meta-analysis of 52 studies evaluating high-on-treatment RPR in patients with ischemic stroke or TIA,65 the prevalence of antiplatelet resistance was found to be 24% (95% CI 20–27): 23% (95% CI 20–28) in aspirin-treated patients, 27% (95% CI 22–32) in clopidogrel-treated patients and 7% (95% CI 5–10) on DAPT. The overall analysis showed a significantly lower prevalence of high RPR in DAPT and provided a possible explanation for the lower risk of stroke recurrence, giving further support to current stroke guidelines recommending DAPT for patients with an acute high-risk TIA or minor ischemic stroke of noncardioembolic origin, who are not at high bleeding risk, for a duration of 21 days after the event, followed by antiplatelet monotherapy thereafter (Class I, Level of Evidence A), with a preference for clopidogrel over prasugrel (not tested) or ticagrelor.66

The extent to which the above-mentioned studies, relying on PFTs, reflect inadequate response to aspirin is uncertain. In general, the variability of the TX-independent component of the different aggregation signals and the instability of the ‘resistant’ phenotype on repeated measurements due to large within-subject coefficient of variation make PFTs unsuitable markers of aspirin responsiveness, reflecting the best RPR.67

A systematic review and meta-analysis including RCTs and cohort studies where clinical failure, instead of laboratory resistance, was addressed showed that among patients who experience an ischemic stroke or TIA on aspirin monotherapy, the addition of or a switch to another antiplatelet agent, especially in the first days after the index event, was associated with fewer future vascular events, including stroke.68

The international guidelines and clinical practice recommendations do not issue final conclusions on this point. According to the American Heart Association/American Stroke Association guidelines, for patients who have a noncardioembolic acute ischemic stroke while taking aspirin, increasing the dose of aspirin or switching to an alternative antiplatelet agent for additional benefit in secondary stroke prevention is not well established (Class IIb, Level of Evidence B-R).66 The Canadian Stroke best practice recommendations state that for patients who experience a stroke while receiving one antiplatelet agent, stroke etiology should be reassessed and addressed, and all other vascular risk factors aggressively managed. Either continuing the current agent or switching to a different antiplatelet agent are reasonable options. At the present time, evidence is lacking to provide more specific recommendations.69

It appears reasonable, therefore, in the case of recurrent ischemic events while on aspirin, to reconsider the stroke etiology, optimize other cardiovascular risk factors, and consider DAPT for 21 days in minor ischemic stroke or TIA if started within 24 h, according to current guidelines.66

Resistance to oral P2Y12 inhibitors

Despite the widespread use of aspirin for primary and secondary prevention of cardiovascular disease, many patients still experience a first or recurrent ischemic stroke.68 This clinical scenario, so-called ‘aspirin failure’, requires exclusion of alternative causes of stroke, improvement of risk factors control, but also calls into question the best management strategy with regard to antithrombotic therapy. Data from the American Heart Association Get With The Guidelines Stroke Registry reported that nearly half of patients with ischemic stroke while on preventive therapy with aspirin are discharged on aspirin monotherapy, approximately 18% on clopidogrel, 15% on DAPT and the remaining 13% on dipyridamole, oral anticoagulation or no antithrombotic treatment.70 In terms of long-term prevention of stroke recurrence, the first RCTs indicated that DAPT with aspirin and clopidogrel had no clear benefit over single antiplatelet treatment and led to a significant increase in hemorrhagic complications.71–73 Subsequently, two RCTs (CHANCE and POINT) showed that DAPT with aspirin and clopidogrel is beneficial in the short term after TIA and minor ischemic stroke.74,75 The analysis of different time windows in the POINT trial showed that prevention of ischemic events with DAPT was evident at both 7 days and 30 days, whereas major bleeding was not different at 7 days, and significantly increased thereafter.76 Taken together, these studies suggest that DAPT with clopidogrel is likely the best current therapeutic option after a high-risk TIA or minor ischemic stroke, with discontinuation of clopidogrel <21 days after and possibly as early as 10 days after initiation to maximize benefit and minimize harm.77

Regarding the use of other P2Y12 inhibitors, prasugrel is contraindicated in patients with a history of stroke or TIA, because of a higher risk of significant or fatal bleeding. Ticagrelor was tested as an alternative to aspirin in the SOCRATES trial, without reaching superiority, 78 and in combination with aspirin in the THALES trial, with evidence of reduced ischemic end points at the price of increased major bleeding.79 The treatment effect of DAPT with ticagrelor was present from the first week with a possibly favorable net clinical impact that remained constant throughout the 30-day follow-up.80

Building on these findings, current guidelines recommend short-term DAPT – mostly with clopidogrel – followed by long-term single antiplatelet treatment in patients with mild stroke or high-risk TIA.66,81,82 Although the optimal time to switch from dual to single antiplatelet therapy is not entirely clear, in the first 21 days after the event, the benefit of more intensive antiplatelet therapy outweighs the risks, with the bleeding risk prevailing beyond 90 days.

Taking into account that patients with a reduced response to aspirin or clopidogrel may have a greater risk of cardiovascular events, PFT might be helpful to guide antiplatelet strategies with the aim of optimizing protection from first or recurrent cerebrovascular events and limit the bleeding risk.83,84 In the aforementioned meta-analysis on approximately 21 000 patients undergoing PCI, a PFT/genetic testing-guided selection of antiplatelet therapy strategy reduced all the individual components of the outcome, including stroke (risk ratio 0.66, 95% CI 0.48–0.91, P = 0.010).28 Notably, a PFT/genetic testing-guided de-escalation from ticagrelor/prasugrel to clopidogrel after an ACS was inferior in terms of safety compared with an approach of unguided de-escalation.85

Although several data regarding the impact of PFT guiding antiplatelet therapy are available in the setting of CAD, there is a small number of such studies in the setting of ischemic stroke. Table 2 summarizes current evidence on the effectiveness of PFT-guided clopidogrel or ticagrelor therapy in preventing secondary stroke. Depta et al. assessed platelet reactivity in 324 patients with TIA or ischemic stroke with the aim of determining resistance to antiplatelet drugs, such as aspirin or clopidogrel, and modifying treatment by increasing the dose, adding another drug or switching from aspirin to clopidogrel.64 Findings of this study showed that changes in antiplatelet therapy following PFT resulted in a higher incidence of death, bleeding or ischemic events versus a strategy of unmodified treatment. On the other hand, a post-hoc analysis of the CHANCE trial indicated that among 2933 Chinese patients with minor ischemic stroke or TIA, the use of clopidogrel plus aspirin compared with aspirin alone reduced the risk of a new stroke only in the subgroup of patients who were not carriers of the CYP2C19 LoF alleles (P = 0.02 for interaction); this further supports a role for CYP2C19 genotyping in the efficacy of clopidogrel treatment.86 On the same line of evidence, the PRINCE trial showed a reduced proportion of patients with RPR after the addition of ticagrelor on top of aspirin versus clopidogrel at 90 days after an acute cerebrovascular event.87 This trial was not powered for clinical events; however, a lower incidence of stroke and composite outcomes was observed in those treated with DAPT using ticagrelor instead of clopidogrel, without increased risk of major, minor, or intracranial hemorrhages. Recently, the genetic sub-study of the CHANCE-2 trial, including Chinese patients with minor ischemic stroke or TIA carrying CYP2C19 LoF alleles, reported that, with the background of aspirin treatment, the risk of stroke at 90 days was lower with ticagrelor than with clopidogrel, at the cost of a higher risk of total bleeding events, but not of moderate or severe bleeding.88

Table 2 - Studies assessing the effectiveness of platelet function-guided therapy with P2Y12 inhibitors for preventing secondary stroke
Study Type of study Setting N Comparison FUP Main results in terms of efficacy Main results in terms of safety
Depta JP et al. 2012 64 Observational, retrospective Ischemic stroke or TIA 324 ATM versus standard therapy after platelet function testing 4.6 ± 1.1 years Recurrent ischemic stroke: 8% ATM versus 4% standard therapy, P = 0.23 Bleeding: 19% ATM versus 10% standard therapy, P = 0.04
Wang Y et al. 2016 CHANCE 86 RCT Minor stroke or TIA 2933, 59% carriers of CYP2C19 loss-of-function alleles Clopidogrel (300 mg LD followed by 75 mg od for 3 months) plus aspirin for 21 days versus aspirin alone 90 days Stroke:Noncarriers Clopidogrel-aspirin 6.7% versus 12.4% aspirin, HR 0.51, 95% CI 0.35–0.75CarriersClopidogrel-aspirin 9.4% versus 10.8% aspirin, HR 0.93, 95% CI 0.69–1.26 Bleeding:Noncarriers Clopidogrel-aspirin 2.5% versus 1.7% aspirin, HR 1.42, 95% CI 0.64–3.15CarriersClopidogrel-aspirin 2.3% versus 1.4% aspirin, HR 1.65, 95% CI 0.80–3.40
Wang Y et al. 2019 PRINCE 87 RCT Minor stroke or TIA 675, 57% carriers of CYP2C19 loss-of-function alleles Ticagrelor (180 mg LD followed by 90 mg bid through day 90) versus clopidogrel (300 mg LD followed by 75 mg od through day 90) plus aspirin for 21 days 90 days Extensive CYP2C19 metabolizersStroke: ticagrelor 2.9% versus clopidogrel 6.0%, HR 0.48, 95% CI 0.14–1.58 -
Wang Y et al. 2021 CHANCE-2 88 RCT Minor ischemic stroke or TIA in individuals carrying CYP2C19 loss-of-function alleles 6412 Ticagrelor (180 mg LD followed by 90 mg bid through day 90) versus clopidogrel (300 mg LD followed by 75 mg od through day 90) plus aspirin for 21 days 90 days Stroke: 6.0% ticagrelorversus 7.6% clopidogrelHR 0.77, 95% CI 0.64–0.94; P = 0.008 Severe or moderate bleeding: 0.3% ticagrelor, versus 0.3% clopidogrel
ATM, antipletelet therapy modification; LD, loading dose; RCT, randomized controlled trial; TIA, transient ischemic attack.

In conclusion, given the paucity of data supporting the clinical usefulness and cost-effectiveness of PFT in the setting of acute cerebral ischemia, antithrombotic regimens should be here prescribed based on clinical presentation, timing of diagnosis and bleeding risk.

Peripheral arterial disease

Peripheral arterial disease (PAD) is part of the atherosclerotic process with high prevalence, mortality and morbidity in the general population.89–91 The dramatic major complication of PAD is lower extremity amputation, the incidence of which ranges between 120 and 500 per million with very high morbidity, mortality, and healthcare costs.90–94 Thus, optimization of cardiovascular prevention strategies in PAD patients is of great importance and antithrombotic therapy is the cornerstone to prevent other events including major complications.95,96 Available evidence has clearly pointed out that platelets are actively involved in the pathophysiology of thrombotic events observed in PAD patients.97,98 Thus, current indications in the United States are that DAPT with aspirin and clopidogrel as P2Y12 inhibitor should be prescribed in patients with symptomatic PAD who have undergone lower extremity revascularization.99 Similarly, the ESC guidelines indication is to recommend long-term single antiplatelet therapy in patients with symptomatic PAD and DAPT (aspirin plus clopidogrel) for at least 1 month in patients treated with stent placement.99,100 However, several studies have reported that PAD patients treated with DAPT continue to have significant adverse thrombotic cardiovascular events,101,102 suggesting that monitoring of platelet function in response to antiplatelet therapy might be helpful. The evaluation of platelet function should here be strongly considered in this setting under the rationale that several factors may significantly reduce the clinical efficacy of clopidogrel, the P2Y12 inhibitor of choice in PAD patients.103,104

In the clinical context of PAD, five small studies including a total of 473 PAD patients have used light transmission aggregometry to test platelet function in this class of patients on an antiplatelet regimen,105–109 but with controversial results that do not support to date the use of this PFT in the routine evaluation of platelet reactivity in such patients. Two prospective, observational studies using Multiplate Electrode Aggregometry and including 236 PAD patients have been published,110,111 but the small number of patients included, the lack of a standardized protocol and the clinical setting in which this test has been used all contributed to the impossibility to reach a firm conclusion.

The PRECLOP was the first study that investigated the possible correlation between platelet reactivity and clinical outcomes in a prospective cohort of 100 PAD patients treated with percutaneous angioplasty or stenting for disease of the femoropopliteal artery.112 Patients received DAPT with clopidogrel 75 mg plus aspirin 100 mg daily for 1 month before the planned procedure and continued this antithrombotic therapy for 6 months thereafter. Platelet reactivity was measured using the VerifyNow test immediately before the procedure. The authors established a P2Y12 reactive unit (PRU) threshold of ≥234 in patients with symptomatic PAD to define clopidogrel resistance, and concluded that higher PRU results were associated with an increased rate of the composite outcome of death, clinically driven target vessel re-intervention (up 95%), major amputation, and bleeding at 1 year. In another study, including 154 patients with angiographically documented carotid artery (up to 40%) or lower extremity PAD (up to one-third presenting with claudication or critical limb ischemia), a PRU value of ≥235 was associated with a higher rate of stroke, myocardial infarction and all-cause death, limb loss, and target vessel revascularization at 1 year.113 A larger cohort of PAD patients (N = 876) receiving DAPT was analyzed in the post-hoc analysis of the ADAPT-DES trial.114 Here, the authors investigated whether patients with PAD were more likely to experience a worse clinical outcome after PCI and whether RPR was more frequent in PAD patients treated with DAPT.115,116 A PRU value of ≥208 was chosen as the cut-off based on prior literature in CAD patients.116 PAD patients with RPR showed a trend toward a higher rate of stent thrombosis, myocardial infarction and all-cause death. Moreover, the presence of PAD did not seem to increase the risk for RPR.

In conclusion, the impact of platelet reactivity and the usefulness of studying it in patients with PAD are not yet completely defined. Although the study of RPR would appear of great importance in PAD patients treated with clopidogrel who are under the ‘sword of Damocles’ of clopidogrel resistance, the studies that have investigated this topic included only a small number of patients and have so far failed to show any benefits in the management of PAD patients.117 Moreover, a major issue is the lack of a well established cut-off value for defining high RPR in PAD patients with the currently available tests.115 Thus, focused clinical trials are still needed to shed brighter light on the use of the platelet functional test in PAD patients.

Conclusions

We have here summarized the current evidence for the use of PFTs and their applicability in different clinical settings. Other ongoing RCTs are further addressing the role of a genotype-guided strategy in the setting of patients with PAD (Genotype-guided Strategy for Antithrombotic Treatment in Peripheral Arterial Disease; GENPAD; NCT04619927) or undergoing coronary stenting (Genotyping Guided Antiplatelet Therapy in Patients Treated With Drug Eluting Stents; GUARANTEE; NCT03783351).

The main considerations that can be drawn from the existing literature on this topic are listed in Fig. 2: while a number of studies have been published so far in support of a guided selection of P2Y12 inhibitors in CAD patients, which may influence future recommendations, the role of PFTs in ischemic stroke and PAD still needs to be further addressed by future research.

F2
Fig. 2:
Suggested indication for PFT in clinical practice. DAPT, dual antiplatelet therapy; PCI, percutaneous coronary intervention; PFT, platelet function test; RPR, residual platelet reactivity.

Acknowledgements

Conflicts of interest

Conflicts of Interest and Source of Funding: Rossella Marcucci: lecture fees from Sanofi; AMGEN; Bayer; Viatris; Werfen; Pfizer; Daiichi Sankyo. Mattia Galli: speaker fee from Terumo. Giulia Renda: speaker/ consultant fee from Astra Zeneca, Bayer, BMS-Pfizer, Boehringer Ingelheim, Daiichi Sankyo. Piera Capranzano: personal fees from Bayer, Daiichi Sankyo, Boehringer Ingelheim and Chiesi, outside the submitted work. Francesca Santilli: speaker/advisory board fee from Bayer. Davide Capodanno: speaker's fee and honoraria from Arena, Daiichi Sankyo, Sanofi, Terumo. Dominick J Angiolillo: consulting fees or honoraria from Abbott, AMGEN, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Daiichi Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, PhaseBio, PLx Pharma, Pfizer, and Sanofi. D.J.A. also declares that his institution has received research grants from AMGEN, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, Osprey Medical, Renal Guard Solutions and Scott R. MacKenzie Foundation. Plinio Cirillo: consultant/advisory board fee from Astra-Zeneca and Chiesi. Giuseppe Patti: speaker/consultant/advisory board fee from Abbott, Astra Zeneca, Sanofi, AMGEN, Menarini, Bayer, Pfizer, BMS, Daiichi Sankyo, Chiesi, MSD, Boehringer Ingelheim, Servier, Guidotti, Medtronic, Biosensors, Terumo. Raffaele De Caterina: Steering Committee member, National Coordinator for Italy, and Co-author of APPRAISE-2, ARISTOTLE, AVERROES, ENGAGE AF-TIMI 38, Re-DUAL PCI; Fees, honoraria and research funding from Sanofi-Aventis, Boehringer Ingelheim, Bayer, BMS/Pfizer, Daiichi Sankyo, Novartis, Merck, Portola, Roche, AstraZeneca, Menarini, Guidotti, Milestone. For the remaining authors none was declared.

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Keywords:

antiplatelet therapy; aspirin; clopidogrel; functional assessment; genetic testing; P2Y12 inhibitors; platelet function tests

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