- Email: [email protected]
Platelet Reactivity: Is There a Role to Switch?
PR O GRE S S I N C ARDI O VAS CU L AR D I S EAS E S 5 8 ( 2 0 15 ) 27 8–2 84
Available online at www.sciencedirect.com
ScienceDirect www.onlinepcd.com
Platelet Reactivity: Is There a Role to Switch? Dániel Aradi a,⁎, Béla Merkely b , András Komócsi c a
Department of Cardiology, Heart Center Balatonfüred, Balatonfüred, Hungary and from Heart and Vascular Center, Semmelweis University, Budapest, Hungary b Heart and Vascular Center, Semmelweis University, Budapest, Hungary c Division of Cardiology, Heart Institute, University of Pécs, Pécs, Hungary
A R T I C LE I N FO
AB S T R A C T
Keywords:
Antiplatelet agents are essential to prevent thrombotic events in patients with coronary artery
Platelet function testing
disease, especially in those with acute coronary syndrome or undergoing percutaneous
High platelet reactivity
coronary intervention (PCI). However, the benefits of antiplatelet therapy always come at a
Low platelet reactivity
price of increased risk for bleeding, and the clinical values of antiplatelet strategies depend on
Stent thrombosis
this characteristic benefit/risk ratio. Platelet function testing aiming at determining an
Bleeding
individual’s response to the administered agent was hoped to help balance bleeding and thrombosis in order to maximize benefit/risk ratio. However, randomized trials failed to demonstrate an improved clinical outcome of a platelet function-based treatment selection and consequently platelet function testing has not become a routine part of the management of antiplatelet therapies. This review aims to discuss results and shortcomings of available trials and registries regarding the potential role of platelet reactivity testing in guiding antiplatelet treatment selection in patients undergoing PCI. © 2015 Elsevier Inc. All rights reserved.
Introduction: theoretical considerations supporting platelet function testing Antiplatelet therapy is the cornerstone of preventing atherothrombotic events in patients with a wide spectrum of vascular diseases.1 Acetyl salicylic acid, commonly referred to as aspirin, is the choice for primary prevention in individuals with high risk for cardiovascular (CV) events2 and means a lifetime treatment for the chronic phase of secondary prevention in patients with established coronary heart disease (CHD), stroke or with peripheral artery disease.1,3 However, in patients after vascular events with very high recurrent thrombotic risk, such as those with acute coronary syndromes (ACS) and/or undergoing percutaneous coronary interventions (PCI), a
combination of antiplatelet agents is necessary to effectively prevent thrombotic complications.1 For that reason, in addition to aspirin, a platelet P2Y12 ADP-receptor inhibitor, such as clopidogrel, prasugrel or ticagrelor is given for a certain timeframe according to the bleeding and thrombotic risk profile of the patient.1 Recently, novel antiplatelets such as vorapaxar, a thrombin protease activated receptor 1 (PAR-1) inhibitor, were also found to be effective in reducing thrombotic complications among patients with high risk for atherothrombotic events, when given in addition to aspirin and clopidogrel.4 All these lines of evidence support that platelet activation plays a major role in the occurrence of thrombotic events in patients with atherosclerotic disease in coronary, carotid or peripheral beds, and the risk of recurrent thrombotic complications can be
Statement of Conflict of Interest: see page 283. ⁎ Address reprint requests to: Daniel Aradi, MD, PhD, Heart Center Balatonfüred and Semmelweis University, Heart and Vascular Center, 2 Gyogy Sq. Balatonfüred, 8230 Hungary. E-mail address: [email protected] (D. Aradi). http://dx.doi.org/10.1016/j.pcad.2015.08.008 0033-0620/© 2015 Elsevier Inc. All rights reserved.
PR O G RE S S I N C ARDI O V A S CU L A R D I S EA S E S 5 8 (2 0 1 5) 27 8–2 8 4
Abbreviations and Acronyms
decreased by increasing the potency of antiACS = acute coronary syndrome platelet agents and/or BRS = bleeding risk score using multiple antiplatelet combinations. CHD = coronary heart disease On the other hand, CV = cardiovascular since the advent of antiplatelet therapies, it DES = drug eluting stent was obvious that the GPI = glycoprotein IIbIIIa inhibitor downside of the more potent agents and mulHPR = high platelet reactivity tiple combinations is LPR = low platelet reactivity the higher risk for bleeding. Therefore, MACE = major adverse cardiac the risks of induced events bleeding should be MI = myocardial infarction weighed against the benefits of preventing OPR = optimal platelet reactivity thrombotic events, and PAR-1 = protease activated the clinical value of receptor 1 an antiplatelet strategy depends on this charPCI = percutaneous coronary acteristic benefit/risk intervention ratio.5 Clinical studies PR = platelet reactivity have shown that both bleeding and recurrent STEMI = ST-segment elevation myocardial infarction thrombotic events are independent correlates of overall patient survival, supporting that major bleeding should be recognized as an equally important prognostic factor as thrombotic CV events.5 However, in recent years, due to the effective triage of ACS and due to the use of evidence-based medical therapy, the absolute risk of thrombotic events has been decreasing to the magnitude of the major bleeding induced, suggesting a potential situation when both prevented and induced complications may become similar, leading to lack of clinical usefulness. This paradigm may not only be applicable to the type of antiplatelet agent used, but also relates to the duration of treatment: longer antiplatelet exposure is more effective in preventing thrombotic events; however, it is associated with a higher risk for bleeding.6 Recent data from trials found that the optimal length and intensity may be individually different and while longer intensive treatment may be beneficial in some high-risk cases the risk of bleeding may compromise the benefits of such a strategy if routinely applied in unselected patients.6 Keeping the above considerations in mind, one way to maximize the benefit/risk ratio of antiplatelet regimes and durations may be to adequately estimate the risk of bleeding and thrombosis in the patients treated and to achieve an individually-targeted level of platelet inhibition with the drugs administered. Therefore, platelet function testing could help to determine the achieved level of residual platelet reactivity (PR) and to use this information to select the most appropriate agent and dose for the patient. Importantly, although baseline PR shows some degree of inter-patient variation, the real value of PR testing may be observed with agents of variable on-treatment effect; platelet function testing lacks importance in agents with reliable, uniform antiplatelet action.7 With this
279
respect, the group of P2Y12-inhibitors may be of highest interest, because cyclo-oxigenase-1 inhibition by aspirin is highly uniform8 and evidence is lacking on the variability of PAR-1 inhibitors.7 In contrast to aspirin, the level of PR after using fixed-dose clopidogrel therapy varies largely between individuals,8 and there is also a smaller but relevant variability in cases of prasugrel and ticagrelor.9 It is important to re-emphasize that a successful tailored antiplatelet treatment strategy requires careful assessment of thrombotic and bleeding risks of the patient (based on clinical and procedural characteristics) and should not only focus on platelet function testing alone, because the clinical relevance of post-treatment PR largely depends on disease activity, patient comorbidities and procedural features.10
PR for risk stratification to predict bleeding and stent thrombosis Before the clinical value of platelet function testing in adjusting treatment may be evaluated, it is important to determine which assays and specific test kits are able to provide results that are predictive for bleeding and thrombosis. Such associations between assay results and outcomes are essential for potential treatment guidance; lack of association suggests that the biomarker is not useful for potential treatment adjustment. 11 In this regard, it is important to emphasize that not all platelet function tests are equal. In the largest head-to-head comparison between platelet assays in the setting of a prospective clinical registry, 1069 subjects undergoing elective coronary stent placement were recruited in the POPULAR study to determine the prognostic utility of test results on major adverse cardiac events (MACE). 12 From the five different platelet function assays, only light transmittance aggregometry (LTA), VerifyNow and Plateletworks were associated with the occurrence of thrombotic events, while the results of IMPACT-R and PFA-100 assays were not related to MACE.12 In addition to the above-mentioned valuable assays, Multiplate analyzer and the VASP assay were shown in other studies to predict the occurrence of bleeding and stent thrombosis in clopidogrel-treated patients after PCI.7,13 These results confirm that differences in measurement principles between assays may have serious consequences on the measured level of PR inhibition, leading to only poor-to-fair correlation between assays and lack of potential to substitute one assay for the other. Therefore, clinical studies with a dedicated device may be attributable to that specific device only, not generalizable for all platelet function assays as a class-effect. In addition to the type of the device, the type of platelet stimulation agonist is also important (i.e. the test kit). In the largest prospective, multinational, multicenter registry exploring the clinical value of platelet function testing, the VerifyNow P2Y12 kit with ADP (and PGE1) stimulation showed a significant association with one-year occurrence of stent thrombosis, mortality and major/clinically important bleeding among 8500 patients after PCI.14 However, in the same cohort, results obtained with the VerifyNow ASPIRIN test kit
280
PR O GRE S S I N C ARDI O VAS CU L AR D I S EAS E S 5 8 ( 2 0 15 ) 27 8–2 84
using an arachidonic acid agonist were not associated with thrombotic complications.14 Up to now, the role of platelet function assays for predicting bleeding and thrombosis and to stratify patients into categories of risk after PCI was best evaluated in a recent collaborative analysis including 17 studies of 20,839 patients.15 In this dedicated analysis, only standardized platelet function assays were included (VerifyNow, Multipalte and VASP) and patients were categorized into three groups according to the level of PR: high (HPR), optimal (OPR) or low (LPR).15 Of note, in this analysis, uniform cutoff values were used for the selected platelet function categories (VerifyNow: 95 and 208 PRU, VASP: 16 and 50% PRI, Multiplate: 19 and 46 U) in all of the included studies. As a result, patients in the HPR group had a 2.7-fold higher risk for definite or probable stent thrombosis, while those with LPR had a 1.7-fold higher risk for bleeding in contrast to the OPR group.15 These results suggest that in PCI-treated patients, PR on clopidogrel, measured by VerifyNow, Multiplate or VASP, predicts both thrombotic and bleeding events; therefore, platelet reactivity may be a valuable biomarker for risk stratification.7,13 The low positive predictive value for stent thrombosis (approximately less than 5%) mostly relates to the low prevalence of the event, not poor performance of the assays.11 Further supporting the role of platelet reactivity for risk stratification after PCI, Mangiacapra and colleagues recently published a comparison of a validated clinical risk score for bleeding and PR.16 As a result, LPR was as good as the bleeding risk score (BRS) to predict bleeding events; however, the highest area under the curve could be achieved when the two independent markers were joined for a novel BRS.16 Understanding potential failures of prior randomized trials on platelet function-guided antiplatelet therapies requires careful consideration of another important factor: the impact of baseline risk on the predictive capability of PR on clinical outcomes. The interplay between baseline risk and platelet reactivity was elegantly demonstrated by the study of Palmerini and colleagues. 10 The authors analyzed the prognostic impact of PR measured by the VASP assay in 1053 clopidogrel-treated patients with a non ST-segment elevation-ACS undergoing PCI. As a result, HPR (VASP-PRI > 50%) was associated with a significant increase in CV mortality, myocardial infarction (MI) and stent thrombosis, while LPR (VASP-PRI < 50%) was linked to higher risk for bleeding. 5 However, the extent of coronary atherosclerosis, evaluated by the SYNTAX Score, was also an independent predictor of MACE. When the interaction between PR and SYNTAX Score was evaluated, HPR remained an independent predictor of MACE in patients with a SYNTAX Score > 15, but not in others with less extensive coronary artery disease and a SYNTAX Score < 15. 14 In summary, PR measured by validated, standardized assays is associated with the risk of stent thrombosis and bleeding in patients on clopidogrel after PCI.15 However, the predictive value also depends on the baseline risk for thrombotic events; therefore, the clinical information provided by PR may be additive to clinical and procedural factors and should not be interpreted without the patientrelated information. 10,16
Randomized clinical trials on guided treatment based on platelet function testing The first randomized trial comparing platelet function-guided antiplatelet treatment in patients undergoing PCI was the GRAVITAS study.17 The main aim of the multicenter, randomized, double-blind, active-control trial was to compare elevated (150 mg) and standard (75 mg) maintenance doses of clopidogrel in patients with HPR defined as a VerifyNow P2Y12 result greater than 230 PRU after PCI. Altogether, 2214 patients were enrolled into the study: the majority (60%) was low-risk elective patients undergoing PCI, 40% had ACS on admission and only 10% were included due to acute MI; patients with ST-segment elevation MI (STEMI) were excluded. The primary endpoint was the 6-month incidence of death from CV causes, nonfatal MI or stent thrombosis. The study was empowered to a primary endpoint rate of 5% in patients with HPR on standard 75 mg clopidogrel, and anticipated a 50% reduction in the primary endpoint. At six months of follow-up, there was no difference in the risk of the primary endpoint in the two groups: 150 mg clopidogrel did not reduce the risk of CV death, MI or stent thrombosis, corresponding to an HR to a HR of 1.01 (95% CI: 0.58–1.76) and a p value of 0.97.17 Although there were no improvements in clinical efficacy after increasing the dose of clopidogrel based on PR testing, also lack of safety issues should be highlighted: administration of an elevated dose of clopidogrel did not increase the risk of bleeding events.17 Limitations of the study include (i) low-risk patient subset excluding those with STEMI, (ii) 150 mg clopidogrel had only a modest impact on HPR, (iii) the cutoff chosen (230 PRU) for VerifyNow may have been too high, currently a lower cutoff (208 PRU) is recommended7 and (iv) lack of power due to inappropriately estimated primary event rate (anticipated: 5% vs. observed: 2.3%) decreases the statistical validity of results. A fair conclusion from the study may be that in low-risk patients undergoing PCI, increasing the dose of clopidogrel to 150 mg based on the VerifyNow assay does not reduce the risk of MACE, however, at least the strategy is not harmful and did not expose patients to a higher risk for bleeding. Since patients in GRAVITAS were not randomized to platelet function testing but to an elevated or standard dose of clopidogrel, results of GRAVITAS should reflect lack of benefit of the 150 mg clopidogrel, not the clinical failure of platelet function testing (Table 1). The second randomized clinical trial, ARCTIC randomized patients for guided or conventional antiplatelet strategies.18 In this open-label study, investigators recruited patients who were scheduled to undergo drug-eluting stent (DES) implantation at 38 centers in France. Exclusion criteria also included STEMI on admission. Altogether, 2440 patients were randomized either to a platelet function-guided treatment strategy of antiplatelet treatment or to conventional care without platelet function results. The primary end point was the composite of death, MI, stent thrombosis, stroke, or urgent revascularization 1 year after DES implantation. In contrast to current recommendations, patients requiring adjusted treatment comprised a heterogeneous group of patients with HPR on clopidogrel (>235 PRU on VerifyNow P2Y12 test), inappropriate platelet inhibition to clopidogrel (<15% inhibition on VerifyNow P2Y12 test) and HPR
Table 1 – Randomized trials and registries evaluating the clinical impact of adjusting treatment based on platelet function testing.
Control group
Patient number ACS (%) AMI (%) STEMI (%) Shock (%) Mortality (control+adjusted groups) Antiplatelet intervention, if HPR High-dose clopidogrel (guided or HPR group) High-dose ASA Switch to prasugrel PFT Assay Results Comparison
1° Endpoint
1° Results
PECS-HPR REGISTRY22
Single-center registry HPR+prasugrel
Single-center registry HPR+prasugrel/high-dose clopidogrel Patients without HPR
Single-center registry Monitoring and adjustment
741 100% 84% 48% 4.5% 8.2%
1172 0% 0% 0% 0% N/A
GRAVITAS 17
ARCTIC18
RECLOSE-2 ACS21
RCT HPR+150 mg clopidogrel HPR+75 mg clopidogrel
RCT Monitoring and adjustment non-monitored treatment
Single-center registry HPR+high-dose clopidogrel Patients without HPR
2214 40% 10% 0.4% 0% 0.8%
2440 27% N/A 0% 0% 2%
1789 100% N/A 46% 6% 5%
Historical control (HPR+high-dose clopidogrel) 302 42% N/A 5% N/A 6.6%
100%
80%
100%
0%
58%
70% (low risk score)
0% 0% VerifyNow®
45% 12% VerifyNow®
0% 0% LTA
0% 100% LTA
0% 42% Multiplate®
0% 30% (high risk score) VerifyNow®
150 vs. 75 mg clopidogrel in HPR CV death, MI or ST at 6 months
Monitoring vs. conventional therapy CV death, MI, urgent revasc., stroke at 1 year 31.1% vs. 34.6% P=0.10
HPR+high-dose clopidogrel vs. no HPR CV death, MI, urgent revasc., stroke at 2 years 14.6% vs. 8.7% P=0.003
HPR+prasugrel vs. HPR+high-dose clopidogrel Cardiac mortality at 2 years
High-dose clopidogrel vs. prasugrel in HPR
Guided vs. unguided
All-cause death, MI, ST or stroke at 1 year 16.5% vs. 7.1% aP<0.0001
All-cause mortality, MI, ST or stroke at 1 year 8.6% vs. 4.1% P<0.001
2.3% vs. 2.3% P=0.97
9.7% vs. 4.0% P=0.007
Historical control (75 mg clopidogrel)
PR O G RE S S I N C ARDI O V A S CU L A R D I S EA S E S 5 8 (2 0 1 5) 27 8–2 8 4
Patient risk profile Study design Intervention group
POPULAR RISK SCORE REGISTRY (EuroPCR 2015)
RECLOSE-3 ACS (EuroPCR 2015)
Abbreviations: ACS: acute coronary syndrome; AMI: acute myocardial infarction; ASA: acetylic salicylic acid; CV: cardiovascular, HPR: high platelet reactivity; PFT: platelet function test, STEMI: ST-segment elevation myocardial infarction; ST: stent thrombosis. a Comparison between high-dose clopidogrel and prasugrel.
281
282
PR O GRE S S I N C ARDI O VAS CU L AR D I S EAS E S 5 8 ( 2 0 15 ) 27 8–2 84
to aspirin (>550 ARU on VerifyNow ASPIRIN test). antiplatelet interventions to overcome low responsiveness included administering glycoprotein IIbIIIa inhibitors (GPI-s) during PCI, increasing the dose of clopidogrel and increasing the dose of aspirin after PCI. Switching to prasugrel was rarely used in the study (9%). According to the results, guided treatment based on VerifyNowassay did not reduce the risk of the primary endpoint, corresponding to a HR of 1.13 (95% CI: 0.98–1.29) and to a p value of 0.10.18 Limitations of the trial include (i) exclusion of high-risk STEMI patients, (ii) using heterogeneous definitions for low responsiveness not in line with current recommendations, (iii) inappropriate pharmacological interventions including mostly high-dose clopidogrel and high-dose aspirin, (iv) open-label design possibly interfering with data reporting and patient follow-up (Table 1). The third randomized trial comparing intensified antiplatelet therapy in patients with HPR was the TRIGGER PCI study. 19 The study was a randomized, open-label, multicenter trial aiming at comparing standard-dose clopidogrel and prasugrel in stable angina patients with HPR after successful DES implantation. The primary endpoint included CV death or MI at 6 months. Importantly, the study was prematurely stopped for futility due to the lower-than anticipated event rate in study groups. Therefore, no clinical conclusion can be drawn from the first 212 patients randomized in the trial. The only relevant take-home message is that stable angina patients with successful new-generation DES implantation have very low rates of thrombotic complications; therefore, as mentioned before, patients with higher baseline risk should be targeted with platelet functionguided treatment. In summary, randomized controlled trials do not support routine use of platelet function testing to adjust treatment in patients undergoing PCI; however, all three trials have serious limitations regarding designs, pharmacologic interventions, definition of low response to clopidogrel and the targeted patient populations. These results suggest that further research is needed to objectively define the role of platelet function testing. Although none of the trials showed clinical improvement by guided therapy, lack of excess risk for bleeding should also be mentioned. Importantly, all randomized trials were performed with the same platelet function assay (VerifyNow), and the value of other devices requires further clarification.
Registry results regarding guided treatment based on platelet function testing Since randomized trials are considered the highest level of evidence in clinical practice, current European and American guidelines do not recommend routine use of platelet function testing. 1,20 As long as new data from ongoing randomized trials emerge, it may be useful to evaluate results of clinical registries on the value of various platelet function devices and antiplatelet interventions. Targeting a high-risk ACS population, investigators of the RECLOSE-2 ACS registry reported the efficacy of high-dose clopidogrel in 1789 patients with HPR in 2011.21 The authors used LTA to select patients with HPR based on ADP
10 μM stimulation (AGGmax >70%) after PCI and compared outcomes between patients with HPR plus adjusted high-dose clopidogrel and those without HPR on standard 75 mg clopidogrel. As a primary result, despite the platelet function testing-based treatment modifications, patients with HPR persisted with significantly higher risk for CV death, MI, urgent revascularization or stroke at two years in contrast to those without HPR.21 These results show that the risk associated with HPR in ACS patients cannot be overcome effectively by high-dose clopidogrel treatment, suggesting that HPR might be rather a marker of risk, but not a modifiable risk factor. Three years later, in a single-center prospective registry, Aradi and co-workers sought to evaluate the value of treatment intensification based on the Multiplate assay in a single-center, all-comer, high-risk ACS registry.22 In this analysis including 741 patients, with almost 50% STEMI, subjects with HPR (defined as a Multiplate ADP test >46 U) were treated with either high-dose clopidogrel or were switched over to prasugrel. The authors compared one-year event rates of all-cause death, MI, stent thrombosis or stroke between patients with high-dose clopidogrel or switched to prasugrel due to HPR and those without HPR treated with standard 75 mg clopidogrel. According to the results, patients with HPR receiving high-dose clopidogrel had a 2.3-fold higher risk for the primary endpoint compared with those without HPR, showing a similar result as the RECLOSE-2 ACS registry, with no clinical benefit for high-dose clopidogrel among patients with HPR.21,22 However, patients with HPR switched to prasugrel showed a significantly lower risk to MACE, reducing the risk of events to the level of non-HPR subjects. These results suggest that high-risk patients with HPR may benefit from switching to prasugrel and may have comparable event rates as those without HPR, while dose-elevations of clopidogrel seem clinically ineffective. Just recently, at the EuroPCR 2015 meeting (21st of May, 2015, Paris, France), authors led by Antoniucci presented the results of the RECLOSE-3 ACS registry. In RECLOSE-3 ACS 550 patients with HPR were compared after treatment with high-dose clopidogrel (historical control, n = 248) or switching to prasugrel (n = 302). According to the results, switching to prasugrel significantly reduced the risk of MACE, including CV mortality (Table 1). At the same meeting, Janssen presented the results of the POPULAR Risk Score Registry that aimed at following patients after PCI and guided antiplatelet intervention based on a risk score incorporating platelet function testing and genotyping (EuroPCR 2015, 21st of May, 2015, Paris). In this registry, patients with a high risk score who were switched to prasugrel showed a significant reduction in major thrombotic events compared to a historical unguided control cohort, receiving standard clopidogrel treatment (Table 1). In sum, contemporary registries suggest that in high-risk patients undergoing PCI, switching to prasugrel may significantly improve outcomes in contrast to high-dose clopidogrel, further explaining the failures of prior randomized trials using increased doses of clopidogrel. Whether switching to ticagrelor in patients with HPR on clopidogrel would be of similar benefit is unknown, since no data is available investigating this strategy. From a biological point of view, ticagrelor should be as effective as prasugrel in those with HPR, suggesting that these potential benefits may not be limited to the prasugrel switch.9
PR O G RE S S I N C ARDI O V A S CU L A R D I S EA S E S 5 8 (2 0 1 5) 27 8–2 8 4
283
Table 2 – Differences between prior and upcoming randomized clinical trials on platelet function testing.
Design Target patient population STEMI Platelet function device Reference group Antiplatelet intervention Main aim Mode of adjustment Examples a
Prior Platelet Function Studies
New-Generation Platelet Function Studies
Superiority Low-risk PCI Excluded Only VerifyNow Clopidogrel Mainly increasing the dose of clopidogrel Prevent ischemia (stent thrombosis) Intensification GRAVITAS17, ARCTIC18
Non-inferiority High-risk PCI Included Other devices also, e.g. Multiplate Prasugrel (ticagrelor a) Switching to prasugrel (ticagrelor a) Prevent bleeding, decrease costs De-escalation TROPICAL ACS, ANTARCTIC
Not yet implemented, but theoretically feasible option for the future.
Upcoming randomized trials on platelet function testing Due to several serious limitations related to available randomized trials, the objective role of platelet function testing remains to be established, but it has never been disproved. However, investigators and clinicians need to learn from prior failures and take also results of available registries into account. Of note, that since the initiation of the GRAVITAS trial,17 clinical guidelines have changed regarding the preferred P2Y12-inhibitors in ACS. Currently, novel P2Y12-inhibitors, such as prasugrel and ticagrelor, are the recommended first-line treatments in patients with ACS,1,20 and clopidogrel may only be given to those in whom prasugrel or ticagrelor are not available or contraindicated. Therefore, currently, designing superiority studies of platelet testing with a reference group receiving standard-dose clopidogrel in ACS patients is not possible. Therefore, superiority studies in low-risk patients with reference groups of clopidogrel focusing primarily on thrombotic events may be replaced by non-inferiority studies in high-risk patients with reference groups of prasugrel/ticagrelor and with a primary endpoint consisting of both bleeding and thrombosis (net clinical benefit) (Table 2). Two examples for such ongoing trials are the TROPICAL ACS trial (NCT01959451) and the ANTARCTIC study (NCT01538446). In the ANTARCTIC study, investigators are recruiting patients 75 years or older undergoing PCI and stenting for ACS. The main aim is to compare standard therapy of 5 mg prasugrel with a platelet function-guided therapy of up-titrating treatment in low responders and down-titrating in over responders. The primary endpoint of the study is the composite of CV death, MI, stroke, urgent revascularization, stent thrombosis and bleedings according to the BARC definitions (type 2, 3 or 5) at one year. The other trial, called TROPICAL ACS is comparing a special de-escalation strategy based on the Multiplate analyzer in an all-comer population of biomarker positive ACS patients. In detail, patients in the monitoring arm receive prasugrel for the first week of discharge from hospital after primary PCI, but on the second week, they are switched back to clopidogrel for 7 days. At day 14, platelet function testing is performed to evaluate PR on clopidogrel. Patients having HPR are switched back to prasugrel for one year, while others remain on standard clopidogrel therapy. The primary endpoint is a composite of death from CV causes, MI, stroke and bleeding grade ≥ 2 defined
according to BARC criteria compared in the monitoring and the standard arms, the latter receiving 12-month prasugrel.
Conclusions Antiplatelet therapy is effective in preventing thrombotic complications in a wide spectrum of patients; however, it increases bleeding risk. Due to the large differences in patient characteristics and procedural results, together with large inter-patient variations in platelet inhibition by many antiplatelet agents, individualized antiplatelet therapy seems necessary to maximize the benefit/risk ratio of antiplatelet strategies. Such individualized decision-making should include results of platelet function testing in addition to clinical and procedural features of the patient treated; however, so far evidence only supports the role of platelet function testing in risk stratification for bleeding and thrombosis, not as a routine parameter for treatment adjustment. Failures of prior randomized trials brought important messages for future trials that are essential to objectively clarify the role of PR testing in clinical practice.
Statement of conflict of interest DA: Consulting for Verum Diagnostica, Lecture fees for Roche Diagnostics, Verum Diagnostica, AstraZeneca, DSI/Lilly, Krka. BM: Lecture fees from AstraZeneca, DSI/Lilly, Roche Diagnostics. AK: Lecture fees from DSI/Lilly`.
Acknowledgments The research was supported by the János Bólyai Research Scholarship of the Hungarian Academy of Sciences to DA. REFERENCES
1. Windecker S, Kolh P, Alfonso F, et al. 2014 ESC/EACTS guidelines on myocardial revascularization: the Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) developed with the special contribution of the European
284
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
PR O GRE S S I N C ARDI O VAS CU L AR D I S EAS E S 5 8 ( 2 0 15 ) 27 8–2 84
Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J. 2014;35:2541-2619. Halvorsen S, Andreotti F, ten Berg JM, et al. Aspirin therapy in primary cardiovascular disease prevention: a position paper of the European Society of Cardiology working group on thrombosis. J Am Coll Cardiol. 2014;64:319-327. Antithrombotic Trialists C, Baigent C, Blackwell L, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet. 2009;373:1849-1860. Morrow DA, Braunwald E, Bonaca MP, et al. Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med. 2012;366:1404-1413. Steg PG, Huber K, Andreotti F, et al. Bleeding in acute coronary syndromes and percutaneous coronary interventions: position paper by the Working Group on Thrombosis of the European Society of Cardiology. Eur Heart J. 2011;32:1854-1864. Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med. 2014;371:2155-2166. Aradi D, Storey RF, Komocsi A, et al. Expert position paper on the role of platelet function testing in patients undergoing percutaneous coronary intervention. Eur Heart J. 2014;35:209-215. Kovacs EG, Katona E, Bereczky Z, et al. Evaluation of laboratory methods routinely used to detect the effect of aspirin against new reference methods. Thromb Res. 2014;133:811-816. Alexopoulos D, Galati A, Xanthopoulou I, et al. Ticagrelor versus prasugrel in acute coronary syndrome patients with high on-clopidogrel platelet reactivity following percutaneous coronary intervention: a pharmacodynamic study. J Am Coll Cardiol. 2012;60:193-199. Palmerini T, Calabro P, Piscione F, et al. Impact of gene polymorphisms, platelet reactivity, and the SYNTAX score on 1-year clinical outcomes in patients with non-ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention: the GEPRESS study. JACC Cardiovasc Interv. 2014;7:1117-1127. Dahlen JR, Price MJ, Parise H, Gurbel PA. Evaluating the clinical usefulness of platelet function testing: considerations for the proper application and interpretation of performance measures. Thromb Haemost. 2013;109:808-816. Breet NJ, van Werkum JW, Bouman HJ, et al. Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation. JAMA. 2010;303:754-762.
13. Aradi D, Collet JP, Mair J, et al. Platelet function testing in acute cardiac care — is there a role for prediction or prevention of stent thrombosis and bleeding? Thromb Haemost. 2015;113:221-230. 14. Stone GW, Witzenbichler B, Weisz G, et al. Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study. Lancet. 2013;382:614-623. 15. Aradi D, Kirtane A, Bonello L, et al. Bleeding and stent thrombosis on P2Y12-inhibitors: collaborative analysis on the role of platelet reactivity for risk stratification after percutaneous coronary intervention. Eur Heart J. 2015;36:1762-1771. 16. Mangiacapra F, Ricottini E, Barbato E, et al. Incremental value of platelet reactivity over a risk score of clinical and procedural variables in predicting bleeding after percutaneous coronary intervention via the femoral approach: development and validation of a new bleeding risk score. Circ Cardiovasc Interv. 2015;8. 17. Price MJ, Berger PB, Teirstein PS, et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA. 2011;305:1097-1105. 18. Collet JP, Cuisset T, Range G, et al. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med. 2012;367:2100-2109. 19. Trenk D, Stone GW, Gawaz M, et al. A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the TRIGGER-PCI (Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) study. J Am Coll Cardiol. 2012;59:2159-2164. 20. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;64:e139-e228. 21. Parodi G, Marcucci R, Valenti R, et al. High residual platelet reactivity after clopidogrel loading and long-term cardiovascular events among patients with acute coronary syndromes undergoing PCI. JAMA. 2011;306:1215-1223. 22. Aradi D, Tornyos A, Pinter T, et al. Optimizing P2Y-receptor inhibition in acute coronary syndrome patients based on platelet function testing: impact of prasugrel and high-dose clopidogrel. J Am Coll Cardiol. 2014;63:1061-1070.
Available online at www.sciencedirect.com
ScienceDirect www.onlinepcd.com
Platelet Reactivity: Is There a Role to Switch? Dániel Aradi a,⁎, Béla Merkely b , András Komócsi c a
Department of Cardiology, Heart Center Balatonfüred, Balatonfüred, Hungary and from Heart and Vascular Center, Semmelweis University, Budapest, Hungary b Heart and Vascular Center, Semmelweis University, Budapest, Hungary c Division of Cardiology, Heart Institute, University of Pécs, Pécs, Hungary
A R T I C LE I N FO
AB S T R A C T
Keywords:
Antiplatelet agents are essential to prevent thrombotic events in patients with coronary artery
Platelet function testing
disease, especially in those with acute coronary syndrome or undergoing percutaneous
High platelet reactivity
coronary intervention (PCI). However, the benefits of antiplatelet therapy always come at a
Low platelet reactivity
price of increased risk for bleeding, and the clinical values of antiplatelet strategies depend on
Stent thrombosis
this characteristic benefit/risk ratio. Platelet function testing aiming at determining an
Bleeding
individual’s response to the administered agent was hoped to help balance bleeding and thrombosis in order to maximize benefit/risk ratio. However, randomized trials failed to demonstrate an improved clinical outcome of a platelet function-based treatment selection and consequently platelet function testing has not become a routine part of the management of antiplatelet therapies. This review aims to discuss results and shortcomings of available trials and registries regarding the potential role of platelet reactivity testing in guiding antiplatelet treatment selection in patients undergoing PCI. © 2015 Elsevier Inc. All rights reserved.
Introduction: theoretical considerations supporting platelet function testing Antiplatelet therapy is the cornerstone of preventing atherothrombotic events in patients with a wide spectrum of vascular diseases.1 Acetyl salicylic acid, commonly referred to as aspirin, is the choice for primary prevention in individuals with high risk for cardiovascular (CV) events2 and means a lifetime treatment for the chronic phase of secondary prevention in patients with established coronary heart disease (CHD), stroke or with peripheral artery disease.1,3 However, in patients after vascular events with very high recurrent thrombotic risk, such as those with acute coronary syndromes (ACS) and/or undergoing percutaneous coronary interventions (PCI), a
combination of antiplatelet agents is necessary to effectively prevent thrombotic complications.1 For that reason, in addition to aspirin, a platelet P2Y12 ADP-receptor inhibitor, such as clopidogrel, prasugrel or ticagrelor is given for a certain timeframe according to the bleeding and thrombotic risk profile of the patient.1 Recently, novel antiplatelets such as vorapaxar, a thrombin protease activated receptor 1 (PAR-1) inhibitor, were also found to be effective in reducing thrombotic complications among patients with high risk for atherothrombotic events, when given in addition to aspirin and clopidogrel.4 All these lines of evidence support that platelet activation plays a major role in the occurrence of thrombotic events in patients with atherosclerotic disease in coronary, carotid or peripheral beds, and the risk of recurrent thrombotic complications can be
Statement of Conflict of Interest: see page 283. ⁎ Address reprint requests to: Daniel Aradi, MD, PhD, Heart Center Balatonfüred and Semmelweis University, Heart and Vascular Center, 2 Gyogy Sq. Balatonfüred, 8230 Hungary. E-mail address: [email protected] (D. Aradi). http://dx.doi.org/10.1016/j.pcad.2015.08.008 0033-0620/© 2015 Elsevier Inc. All rights reserved.
PR O G RE S S I N C ARDI O V A S CU L A R D I S EA S E S 5 8 (2 0 1 5) 27 8–2 8 4
Abbreviations and Acronyms
decreased by increasing the potency of antiACS = acute coronary syndrome platelet agents and/or BRS = bleeding risk score using multiple antiplatelet combinations. CHD = coronary heart disease On the other hand, CV = cardiovascular since the advent of antiplatelet therapies, it DES = drug eluting stent was obvious that the GPI = glycoprotein IIbIIIa inhibitor downside of the more potent agents and mulHPR = high platelet reactivity tiple combinations is LPR = low platelet reactivity the higher risk for bleeding. Therefore, MACE = major adverse cardiac the risks of induced events bleeding should be MI = myocardial infarction weighed against the benefits of preventing OPR = optimal platelet reactivity thrombotic events, and PAR-1 = protease activated the clinical value of receptor 1 an antiplatelet strategy depends on this charPCI = percutaneous coronary acteristic benefit/risk intervention ratio.5 Clinical studies PR = platelet reactivity have shown that both bleeding and recurrent STEMI = ST-segment elevation myocardial infarction thrombotic events are independent correlates of overall patient survival, supporting that major bleeding should be recognized as an equally important prognostic factor as thrombotic CV events.5 However, in recent years, due to the effective triage of ACS and due to the use of evidence-based medical therapy, the absolute risk of thrombotic events has been decreasing to the magnitude of the major bleeding induced, suggesting a potential situation when both prevented and induced complications may become similar, leading to lack of clinical usefulness. This paradigm may not only be applicable to the type of antiplatelet agent used, but also relates to the duration of treatment: longer antiplatelet exposure is more effective in preventing thrombotic events; however, it is associated with a higher risk for bleeding.6 Recent data from trials found that the optimal length and intensity may be individually different and while longer intensive treatment may be beneficial in some high-risk cases the risk of bleeding may compromise the benefits of such a strategy if routinely applied in unselected patients.6 Keeping the above considerations in mind, one way to maximize the benefit/risk ratio of antiplatelet regimes and durations may be to adequately estimate the risk of bleeding and thrombosis in the patients treated and to achieve an individually-targeted level of platelet inhibition with the drugs administered. Therefore, platelet function testing could help to determine the achieved level of residual platelet reactivity (PR) and to use this information to select the most appropriate agent and dose for the patient. Importantly, although baseline PR shows some degree of inter-patient variation, the real value of PR testing may be observed with agents of variable on-treatment effect; platelet function testing lacks importance in agents with reliable, uniform antiplatelet action.7 With this
279
respect, the group of P2Y12-inhibitors may be of highest interest, because cyclo-oxigenase-1 inhibition by aspirin is highly uniform8 and evidence is lacking on the variability of PAR-1 inhibitors.7 In contrast to aspirin, the level of PR after using fixed-dose clopidogrel therapy varies largely between individuals,8 and there is also a smaller but relevant variability in cases of prasugrel and ticagrelor.9 It is important to re-emphasize that a successful tailored antiplatelet treatment strategy requires careful assessment of thrombotic and bleeding risks of the patient (based on clinical and procedural characteristics) and should not only focus on platelet function testing alone, because the clinical relevance of post-treatment PR largely depends on disease activity, patient comorbidities and procedural features.10
PR for risk stratification to predict bleeding and stent thrombosis Before the clinical value of platelet function testing in adjusting treatment may be evaluated, it is important to determine which assays and specific test kits are able to provide results that are predictive for bleeding and thrombosis. Such associations between assay results and outcomes are essential for potential treatment guidance; lack of association suggests that the biomarker is not useful for potential treatment adjustment. 11 In this regard, it is important to emphasize that not all platelet function tests are equal. In the largest head-to-head comparison between platelet assays in the setting of a prospective clinical registry, 1069 subjects undergoing elective coronary stent placement were recruited in the POPULAR study to determine the prognostic utility of test results on major adverse cardiac events (MACE). 12 From the five different platelet function assays, only light transmittance aggregometry (LTA), VerifyNow and Plateletworks were associated with the occurrence of thrombotic events, while the results of IMPACT-R and PFA-100 assays were not related to MACE.12 In addition to the above-mentioned valuable assays, Multiplate analyzer and the VASP assay were shown in other studies to predict the occurrence of bleeding and stent thrombosis in clopidogrel-treated patients after PCI.7,13 These results confirm that differences in measurement principles between assays may have serious consequences on the measured level of PR inhibition, leading to only poor-to-fair correlation between assays and lack of potential to substitute one assay for the other. Therefore, clinical studies with a dedicated device may be attributable to that specific device only, not generalizable for all platelet function assays as a class-effect. In addition to the type of the device, the type of platelet stimulation agonist is also important (i.e. the test kit). In the largest prospective, multinational, multicenter registry exploring the clinical value of platelet function testing, the VerifyNow P2Y12 kit with ADP (and PGE1) stimulation showed a significant association with one-year occurrence of stent thrombosis, mortality and major/clinically important bleeding among 8500 patients after PCI.14 However, in the same cohort, results obtained with the VerifyNow ASPIRIN test kit
280
PR O GRE S S I N C ARDI O VAS CU L AR D I S EAS E S 5 8 ( 2 0 15 ) 27 8–2 84
using an arachidonic acid agonist were not associated with thrombotic complications.14 Up to now, the role of platelet function assays for predicting bleeding and thrombosis and to stratify patients into categories of risk after PCI was best evaluated in a recent collaborative analysis including 17 studies of 20,839 patients.15 In this dedicated analysis, only standardized platelet function assays were included (VerifyNow, Multipalte and VASP) and patients were categorized into three groups according to the level of PR: high (HPR), optimal (OPR) or low (LPR).15 Of note, in this analysis, uniform cutoff values were used for the selected platelet function categories (VerifyNow: 95 and 208 PRU, VASP: 16 and 50% PRI, Multiplate: 19 and 46 U) in all of the included studies. As a result, patients in the HPR group had a 2.7-fold higher risk for definite or probable stent thrombosis, while those with LPR had a 1.7-fold higher risk for bleeding in contrast to the OPR group.15 These results suggest that in PCI-treated patients, PR on clopidogrel, measured by VerifyNow, Multiplate or VASP, predicts both thrombotic and bleeding events; therefore, platelet reactivity may be a valuable biomarker for risk stratification.7,13 The low positive predictive value for stent thrombosis (approximately less than 5%) mostly relates to the low prevalence of the event, not poor performance of the assays.11 Further supporting the role of platelet reactivity for risk stratification after PCI, Mangiacapra and colleagues recently published a comparison of a validated clinical risk score for bleeding and PR.16 As a result, LPR was as good as the bleeding risk score (BRS) to predict bleeding events; however, the highest area under the curve could be achieved when the two independent markers were joined for a novel BRS.16 Understanding potential failures of prior randomized trials on platelet function-guided antiplatelet therapies requires careful consideration of another important factor: the impact of baseline risk on the predictive capability of PR on clinical outcomes. The interplay between baseline risk and platelet reactivity was elegantly demonstrated by the study of Palmerini and colleagues. 10 The authors analyzed the prognostic impact of PR measured by the VASP assay in 1053 clopidogrel-treated patients with a non ST-segment elevation-ACS undergoing PCI. As a result, HPR (VASP-PRI > 50%) was associated with a significant increase in CV mortality, myocardial infarction (MI) and stent thrombosis, while LPR (VASP-PRI < 50%) was linked to higher risk for bleeding. 5 However, the extent of coronary atherosclerosis, evaluated by the SYNTAX Score, was also an independent predictor of MACE. When the interaction between PR and SYNTAX Score was evaluated, HPR remained an independent predictor of MACE in patients with a SYNTAX Score > 15, but not in others with less extensive coronary artery disease and a SYNTAX Score < 15. 14 In summary, PR measured by validated, standardized assays is associated with the risk of stent thrombosis and bleeding in patients on clopidogrel after PCI.15 However, the predictive value also depends on the baseline risk for thrombotic events; therefore, the clinical information provided by PR may be additive to clinical and procedural factors and should not be interpreted without the patientrelated information. 10,16
Randomized clinical trials on guided treatment based on platelet function testing The first randomized trial comparing platelet function-guided antiplatelet treatment in patients undergoing PCI was the GRAVITAS study.17 The main aim of the multicenter, randomized, double-blind, active-control trial was to compare elevated (150 mg) and standard (75 mg) maintenance doses of clopidogrel in patients with HPR defined as a VerifyNow P2Y12 result greater than 230 PRU after PCI. Altogether, 2214 patients were enrolled into the study: the majority (60%) was low-risk elective patients undergoing PCI, 40% had ACS on admission and only 10% were included due to acute MI; patients with ST-segment elevation MI (STEMI) were excluded. The primary endpoint was the 6-month incidence of death from CV causes, nonfatal MI or stent thrombosis. The study was empowered to a primary endpoint rate of 5% in patients with HPR on standard 75 mg clopidogrel, and anticipated a 50% reduction in the primary endpoint. At six months of follow-up, there was no difference in the risk of the primary endpoint in the two groups: 150 mg clopidogrel did not reduce the risk of CV death, MI or stent thrombosis, corresponding to an HR to a HR of 1.01 (95% CI: 0.58–1.76) and a p value of 0.97.17 Although there were no improvements in clinical efficacy after increasing the dose of clopidogrel based on PR testing, also lack of safety issues should be highlighted: administration of an elevated dose of clopidogrel did not increase the risk of bleeding events.17 Limitations of the study include (i) low-risk patient subset excluding those with STEMI, (ii) 150 mg clopidogrel had only a modest impact on HPR, (iii) the cutoff chosen (230 PRU) for VerifyNow may have been too high, currently a lower cutoff (208 PRU) is recommended7 and (iv) lack of power due to inappropriately estimated primary event rate (anticipated: 5% vs. observed: 2.3%) decreases the statistical validity of results. A fair conclusion from the study may be that in low-risk patients undergoing PCI, increasing the dose of clopidogrel to 150 mg based on the VerifyNow assay does not reduce the risk of MACE, however, at least the strategy is not harmful and did not expose patients to a higher risk for bleeding. Since patients in GRAVITAS were not randomized to platelet function testing but to an elevated or standard dose of clopidogrel, results of GRAVITAS should reflect lack of benefit of the 150 mg clopidogrel, not the clinical failure of platelet function testing (Table 1). The second randomized clinical trial, ARCTIC randomized patients for guided or conventional antiplatelet strategies.18 In this open-label study, investigators recruited patients who were scheduled to undergo drug-eluting stent (DES) implantation at 38 centers in France. Exclusion criteria also included STEMI on admission. Altogether, 2440 patients were randomized either to a platelet function-guided treatment strategy of antiplatelet treatment or to conventional care without platelet function results. The primary end point was the composite of death, MI, stent thrombosis, stroke, or urgent revascularization 1 year after DES implantation. In contrast to current recommendations, patients requiring adjusted treatment comprised a heterogeneous group of patients with HPR on clopidogrel (>235 PRU on VerifyNow P2Y12 test), inappropriate platelet inhibition to clopidogrel (<15% inhibition on VerifyNow P2Y12 test) and HPR
Table 1 – Randomized trials and registries evaluating the clinical impact of adjusting treatment based on platelet function testing.
Control group
Patient number ACS (%) AMI (%) STEMI (%) Shock (%) Mortality (control+adjusted groups) Antiplatelet intervention, if HPR High-dose clopidogrel (guided or HPR group) High-dose ASA Switch to prasugrel PFT Assay Results Comparison
1° Endpoint
1° Results
PECS-HPR REGISTRY22
Single-center registry HPR+prasugrel
Single-center registry HPR+prasugrel/high-dose clopidogrel Patients without HPR
Single-center registry Monitoring and adjustment
741 100% 84% 48% 4.5% 8.2%
1172 0% 0% 0% 0% N/A
GRAVITAS 17
ARCTIC18
RECLOSE-2 ACS21
RCT HPR+150 mg clopidogrel HPR+75 mg clopidogrel
RCT Monitoring and adjustment non-monitored treatment
Single-center registry HPR+high-dose clopidogrel Patients without HPR
2214 40% 10% 0.4% 0% 0.8%
2440 27% N/A 0% 0% 2%
1789 100% N/A 46% 6% 5%
Historical control (HPR+high-dose clopidogrel) 302 42% N/A 5% N/A 6.6%
100%
80%
100%
0%
58%
70% (low risk score)
0% 0% VerifyNow®
45% 12% VerifyNow®
0% 0% LTA
0% 100% LTA
0% 42% Multiplate®
0% 30% (high risk score) VerifyNow®
150 vs. 75 mg clopidogrel in HPR CV death, MI or ST at 6 months
Monitoring vs. conventional therapy CV death, MI, urgent revasc., stroke at 1 year 31.1% vs. 34.6% P=0.10
HPR+high-dose clopidogrel vs. no HPR CV death, MI, urgent revasc., stroke at 2 years 14.6% vs. 8.7% P=0.003
HPR+prasugrel vs. HPR+high-dose clopidogrel Cardiac mortality at 2 years
High-dose clopidogrel vs. prasugrel in HPR
Guided vs. unguided
All-cause death, MI, ST or stroke at 1 year 16.5% vs. 7.1% aP<0.0001
All-cause mortality, MI, ST or stroke at 1 year 8.6% vs. 4.1% P<0.001
2.3% vs. 2.3% P=0.97
9.7% vs. 4.0% P=0.007
Historical control (75 mg clopidogrel)
PR O G RE S S I N C ARDI O V A S CU L A R D I S EA S E S 5 8 (2 0 1 5) 27 8–2 8 4
Patient risk profile Study design Intervention group
POPULAR RISK SCORE REGISTRY (EuroPCR 2015)
RECLOSE-3 ACS (EuroPCR 2015)
Abbreviations: ACS: acute coronary syndrome; AMI: acute myocardial infarction; ASA: acetylic salicylic acid; CV: cardiovascular, HPR: high platelet reactivity; PFT: platelet function test, STEMI: ST-segment elevation myocardial infarction; ST: stent thrombosis. a Comparison between high-dose clopidogrel and prasugrel.
281
282
PR O GRE S S I N C ARDI O VAS CU L AR D I S EAS E S 5 8 ( 2 0 15 ) 27 8–2 84
to aspirin (>550 ARU on VerifyNow ASPIRIN test). antiplatelet interventions to overcome low responsiveness included administering glycoprotein IIbIIIa inhibitors (GPI-s) during PCI, increasing the dose of clopidogrel and increasing the dose of aspirin after PCI. Switching to prasugrel was rarely used in the study (9%). According to the results, guided treatment based on VerifyNowassay did not reduce the risk of the primary endpoint, corresponding to a HR of 1.13 (95% CI: 0.98–1.29) and to a p value of 0.10.18 Limitations of the trial include (i) exclusion of high-risk STEMI patients, (ii) using heterogeneous definitions for low responsiveness not in line with current recommendations, (iii) inappropriate pharmacological interventions including mostly high-dose clopidogrel and high-dose aspirin, (iv) open-label design possibly interfering with data reporting and patient follow-up (Table 1). The third randomized trial comparing intensified antiplatelet therapy in patients with HPR was the TRIGGER PCI study. 19 The study was a randomized, open-label, multicenter trial aiming at comparing standard-dose clopidogrel and prasugrel in stable angina patients with HPR after successful DES implantation. The primary endpoint included CV death or MI at 6 months. Importantly, the study was prematurely stopped for futility due to the lower-than anticipated event rate in study groups. Therefore, no clinical conclusion can be drawn from the first 212 patients randomized in the trial. The only relevant take-home message is that stable angina patients with successful new-generation DES implantation have very low rates of thrombotic complications; therefore, as mentioned before, patients with higher baseline risk should be targeted with platelet functionguided treatment. In summary, randomized controlled trials do not support routine use of platelet function testing to adjust treatment in patients undergoing PCI; however, all three trials have serious limitations regarding designs, pharmacologic interventions, definition of low response to clopidogrel and the targeted patient populations. These results suggest that further research is needed to objectively define the role of platelet function testing. Although none of the trials showed clinical improvement by guided therapy, lack of excess risk for bleeding should also be mentioned. Importantly, all randomized trials were performed with the same platelet function assay (VerifyNow), and the value of other devices requires further clarification.
Registry results regarding guided treatment based on platelet function testing Since randomized trials are considered the highest level of evidence in clinical practice, current European and American guidelines do not recommend routine use of platelet function testing. 1,20 As long as new data from ongoing randomized trials emerge, it may be useful to evaluate results of clinical registries on the value of various platelet function devices and antiplatelet interventions. Targeting a high-risk ACS population, investigators of the RECLOSE-2 ACS registry reported the efficacy of high-dose clopidogrel in 1789 patients with HPR in 2011.21 The authors used LTA to select patients with HPR based on ADP
10 μM stimulation (AGGmax >70%) after PCI and compared outcomes between patients with HPR plus adjusted high-dose clopidogrel and those without HPR on standard 75 mg clopidogrel. As a primary result, despite the platelet function testing-based treatment modifications, patients with HPR persisted with significantly higher risk for CV death, MI, urgent revascularization or stroke at two years in contrast to those without HPR.21 These results show that the risk associated with HPR in ACS patients cannot be overcome effectively by high-dose clopidogrel treatment, suggesting that HPR might be rather a marker of risk, but not a modifiable risk factor. Three years later, in a single-center prospective registry, Aradi and co-workers sought to evaluate the value of treatment intensification based on the Multiplate assay in a single-center, all-comer, high-risk ACS registry.22 In this analysis including 741 patients, with almost 50% STEMI, subjects with HPR (defined as a Multiplate ADP test >46 U) were treated with either high-dose clopidogrel or were switched over to prasugrel. The authors compared one-year event rates of all-cause death, MI, stent thrombosis or stroke between patients with high-dose clopidogrel or switched to prasugrel due to HPR and those without HPR treated with standard 75 mg clopidogrel. According to the results, patients with HPR receiving high-dose clopidogrel had a 2.3-fold higher risk for the primary endpoint compared with those without HPR, showing a similar result as the RECLOSE-2 ACS registry, with no clinical benefit for high-dose clopidogrel among patients with HPR.21,22 However, patients with HPR switched to prasugrel showed a significantly lower risk to MACE, reducing the risk of events to the level of non-HPR subjects. These results suggest that high-risk patients with HPR may benefit from switching to prasugrel and may have comparable event rates as those without HPR, while dose-elevations of clopidogrel seem clinically ineffective. Just recently, at the EuroPCR 2015 meeting (21st of May, 2015, Paris, France), authors led by Antoniucci presented the results of the RECLOSE-3 ACS registry. In RECLOSE-3 ACS 550 patients with HPR were compared after treatment with high-dose clopidogrel (historical control, n = 248) or switching to prasugrel (n = 302). According to the results, switching to prasugrel significantly reduced the risk of MACE, including CV mortality (Table 1). At the same meeting, Janssen presented the results of the POPULAR Risk Score Registry that aimed at following patients after PCI and guided antiplatelet intervention based on a risk score incorporating platelet function testing and genotyping (EuroPCR 2015, 21st of May, 2015, Paris). In this registry, patients with a high risk score who were switched to prasugrel showed a significant reduction in major thrombotic events compared to a historical unguided control cohort, receiving standard clopidogrel treatment (Table 1). In sum, contemporary registries suggest that in high-risk patients undergoing PCI, switching to prasugrel may significantly improve outcomes in contrast to high-dose clopidogrel, further explaining the failures of prior randomized trials using increased doses of clopidogrel. Whether switching to ticagrelor in patients with HPR on clopidogrel would be of similar benefit is unknown, since no data is available investigating this strategy. From a biological point of view, ticagrelor should be as effective as prasugrel in those with HPR, suggesting that these potential benefits may not be limited to the prasugrel switch.9
PR O G RE S S I N C ARDI O V A S CU L A R D I S EA S E S 5 8 (2 0 1 5) 27 8–2 8 4
283
Table 2 – Differences between prior and upcoming randomized clinical trials on platelet function testing.
Design Target patient population STEMI Platelet function device Reference group Antiplatelet intervention Main aim Mode of adjustment Examples a
Prior Platelet Function Studies
New-Generation Platelet Function Studies
Superiority Low-risk PCI Excluded Only VerifyNow Clopidogrel Mainly increasing the dose of clopidogrel Prevent ischemia (stent thrombosis) Intensification GRAVITAS17, ARCTIC18
Non-inferiority High-risk PCI Included Other devices also, e.g. Multiplate Prasugrel (ticagrelor a) Switching to prasugrel (ticagrelor a) Prevent bleeding, decrease costs De-escalation TROPICAL ACS, ANTARCTIC
Not yet implemented, but theoretically feasible option for the future.
Upcoming randomized trials on platelet function testing Due to several serious limitations related to available randomized trials, the objective role of platelet function testing remains to be established, but it has never been disproved. However, investigators and clinicians need to learn from prior failures and take also results of available registries into account. Of note, that since the initiation of the GRAVITAS trial,17 clinical guidelines have changed regarding the preferred P2Y12-inhibitors in ACS. Currently, novel P2Y12-inhibitors, such as prasugrel and ticagrelor, are the recommended first-line treatments in patients with ACS,1,20 and clopidogrel may only be given to those in whom prasugrel or ticagrelor are not available or contraindicated. Therefore, currently, designing superiority studies of platelet testing with a reference group receiving standard-dose clopidogrel in ACS patients is not possible. Therefore, superiority studies in low-risk patients with reference groups of clopidogrel focusing primarily on thrombotic events may be replaced by non-inferiority studies in high-risk patients with reference groups of prasugrel/ticagrelor and with a primary endpoint consisting of both bleeding and thrombosis (net clinical benefit) (Table 2). Two examples for such ongoing trials are the TROPICAL ACS trial (NCT01959451) and the ANTARCTIC study (NCT01538446). In the ANTARCTIC study, investigators are recruiting patients 75 years or older undergoing PCI and stenting for ACS. The main aim is to compare standard therapy of 5 mg prasugrel with a platelet function-guided therapy of up-titrating treatment in low responders and down-titrating in over responders. The primary endpoint of the study is the composite of CV death, MI, stroke, urgent revascularization, stent thrombosis and bleedings according to the BARC definitions (type 2, 3 or 5) at one year. The other trial, called TROPICAL ACS is comparing a special de-escalation strategy based on the Multiplate analyzer in an all-comer population of biomarker positive ACS patients. In detail, patients in the monitoring arm receive prasugrel for the first week of discharge from hospital after primary PCI, but on the second week, they are switched back to clopidogrel for 7 days. At day 14, platelet function testing is performed to evaluate PR on clopidogrel. Patients having HPR are switched back to prasugrel for one year, while others remain on standard clopidogrel therapy. The primary endpoint is a composite of death from CV causes, MI, stroke and bleeding grade ≥ 2 defined
according to BARC criteria compared in the monitoring and the standard arms, the latter receiving 12-month prasugrel.
Conclusions Antiplatelet therapy is effective in preventing thrombotic complications in a wide spectrum of patients; however, it increases bleeding risk. Due to the large differences in patient characteristics and procedural results, together with large inter-patient variations in platelet inhibition by many antiplatelet agents, individualized antiplatelet therapy seems necessary to maximize the benefit/risk ratio of antiplatelet strategies. Such individualized decision-making should include results of platelet function testing in addition to clinical and procedural features of the patient treated; however, so far evidence only supports the role of platelet function testing in risk stratification for bleeding and thrombosis, not as a routine parameter for treatment adjustment. Failures of prior randomized trials brought important messages for future trials that are essential to objectively clarify the role of PR testing in clinical practice.
Statement of conflict of interest DA: Consulting for Verum Diagnostica, Lecture fees for Roche Diagnostics, Verum Diagnostica, AstraZeneca, DSI/Lilly, Krka. BM: Lecture fees from AstraZeneca, DSI/Lilly, Roche Diagnostics. AK: Lecture fees from DSI/Lilly`.
Acknowledgments The research was supported by the János Bólyai Research Scholarship of the Hungarian Academy of Sciences to DA. REFERENCES
1. Windecker S, Kolh P, Alfonso F, et al. 2014 ESC/EACTS guidelines on myocardial revascularization: the Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) developed with the special contribution of the European
284
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
PR O GRE S S I N C ARDI O VAS CU L AR D I S EAS E S 5 8 ( 2 0 15 ) 27 8–2 84
Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J. 2014;35:2541-2619. Halvorsen S, Andreotti F, ten Berg JM, et al. Aspirin therapy in primary cardiovascular disease prevention: a position paper of the European Society of Cardiology working group on thrombosis. J Am Coll Cardiol. 2014;64:319-327. Antithrombotic Trialists C, Baigent C, Blackwell L, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet. 2009;373:1849-1860. Morrow DA, Braunwald E, Bonaca MP, et al. Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med. 2012;366:1404-1413. Steg PG, Huber K, Andreotti F, et al. Bleeding in acute coronary syndromes and percutaneous coronary interventions: position paper by the Working Group on Thrombosis of the European Society of Cardiology. Eur Heart J. 2011;32:1854-1864. Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med. 2014;371:2155-2166. Aradi D, Storey RF, Komocsi A, et al. Expert position paper on the role of platelet function testing in patients undergoing percutaneous coronary intervention. Eur Heart J. 2014;35:209-215. Kovacs EG, Katona E, Bereczky Z, et al. Evaluation of laboratory methods routinely used to detect the effect of aspirin against new reference methods. Thromb Res. 2014;133:811-816. Alexopoulos D, Galati A, Xanthopoulou I, et al. Ticagrelor versus prasugrel in acute coronary syndrome patients with high on-clopidogrel platelet reactivity following percutaneous coronary intervention: a pharmacodynamic study. J Am Coll Cardiol. 2012;60:193-199. Palmerini T, Calabro P, Piscione F, et al. Impact of gene polymorphisms, platelet reactivity, and the SYNTAX score on 1-year clinical outcomes in patients with non-ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention: the GEPRESS study. JACC Cardiovasc Interv. 2014;7:1117-1127. Dahlen JR, Price MJ, Parise H, Gurbel PA. Evaluating the clinical usefulness of platelet function testing: considerations for the proper application and interpretation of performance measures. Thromb Haemost. 2013;109:808-816. Breet NJ, van Werkum JW, Bouman HJ, et al. Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation. JAMA. 2010;303:754-762.
13. Aradi D, Collet JP, Mair J, et al. Platelet function testing in acute cardiac care — is there a role for prediction or prevention of stent thrombosis and bleeding? Thromb Haemost. 2015;113:221-230. 14. Stone GW, Witzenbichler B, Weisz G, et al. Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study. Lancet. 2013;382:614-623. 15. Aradi D, Kirtane A, Bonello L, et al. Bleeding and stent thrombosis on P2Y12-inhibitors: collaborative analysis on the role of platelet reactivity for risk stratification after percutaneous coronary intervention. Eur Heart J. 2015;36:1762-1771. 16. Mangiacapra F, Ricottini E, Barbato E, et al. Incremental value of platelet reactivity over a risk score of clinical and procedural variables in predicting bleeding after percutaneous coronary intervention via the femoral approach: development and validation of a new bleeding risk score. Circ Cardiovasc Interv. 2015;8. 17. Price MJ, Berger PB, Teirstein PS, et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA. 2011;305:1097-1105. 18. Collet JP, Cuisset T, Range G, et al. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med. 2012;367:2100-2109. 19. Trenk D, Stone GW, Gawaz M, et al. A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the TRIGGER-PCI (Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) study. J Am Coll Cardiol. 2012;59:2159-2164. 20. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;64:e139-e228. 21. Parodi G, Marcucci R, Valenti R, et al. High residual platelet reactivity after clopidogrel loading and long-term cardiovascular events among patients with acute coronary syndromes undergoing PCI. JAMA. 2011;306:1215-1223. 22. Aradi D, Tornyos A, Pinter T, et al. Optimizing P2Y-receptor inhibition in acute coronary syndrome patients based on platelet function testing: impact of prasugrel and high-dose clopidogrel. J Am Coll Cardiol. 2014;63:1061-1070.