International Journal of Cardiology 178 (2015) 221–222
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Platelet reactivity assessment with VerifyNow®: Substitute or complement for light transmission aggregometry? Ander Regueiro a, Xavier Freixa a,⁎, Diego Fernández-Rodríguez a, Maribel Diaz-Ricart b, Ginés Escolar b, Victoria Martín-Yuste a, Salvatore Brugaletta a, Manel Sabaté a, Mónica Masotti a a b
Cardiology Department, Thorax Institute, Hospital Clínic, IDIBAPS, University of Barcelona Hemotherapy and Hemostasis Department, Biomedical Diagnostic Center, Hospital Clínic, IDIBAPS, University of Barcelona
a r t i c l e
i n f o
Article history: Received 17 October 2014 Accepted 20 October 2014 Available online 22 October 2014 Keywords: Percutaneous coronary intervention Platelet aggregation inhibitors Platelet function test
Platelet aggregation inhibition is mandatory for patients undergoing percutaneous coronary intervention (PCI) [1]. High on-treatment platelet reactivity is an important independent risk factor for the occurrence of thrombotic and ischemic events after PCI [2]. Some point of care platelet aggregation assays are currently used in daily practice as a substitute for more expensive and time consuming complex methods. Despite the wide use of such tests, clinical trials testing the strategy of individual tailoring based on one test result have shown no clinical benefit, being the poor correlation between assays one possible explanation. Several clinical studies with the VerifyNow P2Y12 system have proposed a cut-off value of b 240 platelet reaction unit (PRU) to identify “good responders” [3,4]; however, the reasons for a PRU N 240 after clopidogrel treatment are not clear, and might reflect either false positives in good responders or “true” poor responders [5]. The objective of our study was to evaluate the correlation between light transmission aggregometry (LTA) and VerifyNow P2Y12 test with emphasis on patients with VerifyNow P2Y12 PRU N 240 after clopidogrel treatment. This was a single center, observational study. Subjects with stable coronary artery disease undergoing percutaneous coronary intervention were prospectively included. Platelet responsiveness to ADP was assessed 4 h after 600 mg clopidogrel loading dose using two different tests: ADP-induced platelet aggregation by LTA (turbidimetric) in ⁎ Corresponding author at: Cardiology Department, Thorax Institute, Hospital Clínic, IDIBAPS, University of Barcelona, Spain. E-mail address: [email protected] (X. Freixa).
http://dx.doi.org/10.1016/j.ijcard.2014.10.051 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
response to 4 μmol/l ADP (results are expressed as platelet aggregation percentage), and platelet reactivity assessment with the VerifyNow® P2Y12 test (Accumetrics, San Diego, CA, USA) (results are expressed as P2Y12 platelet reaction unit: PRU, and percentage inhibition index). High on treatment platelet reactivity was defined as a 4 μmol/L ADPinduced LTA N50% [6], and a VerifyNow P2Y12 PRU N240. Statistical analyses were performed at the level of significance b 0.05 using PASW 18 (SPSS Inc, Chicago IL, USA). All patients received a loading dose of 300 mg of AAS before the procedure. Informed consent was obtained from each patient and the study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institution's ethics committee. A total of 115 patients were included in the study. Of them, 81% were males, 17% had a history of diabetes mellitus, and 64% had a history of hypertension. In addition, 81% were previously treated with aspirin, 39% with clopidogrel, and 86% with proton pump inhibitors. Mean VerifyNow P2Y12 PRU was 239.4 ± 91.9, percentage inhibition index 74.8% ± 23.6%, and 4 μmol/L ADP-induced LTA 25.4 ± 14.7. VerifyNow P2Y12 PRU offered a modest correlation with 4 μmol/L ADP-induced LTA (Pearson = 0.539; p b 0.01) but superior to the one provided by the VerifyNow P2Y12 percentage inhibition index (Pearson = 0.437; p b 0.01) (Fig. 1). Receiver-operating characteristic (ROC) curve analysis demonstrated that PRU (cut-off value of N240) distinguished between patients with and without 4 μmol/L ADP-induced platelet reactivity of N 50% with an area under curve [AUC] of 0.82 (p b 0.01; 95% confidence interval (CI) 0.71–0.93) with a sensitivity of 100% (95% CI; 62.9%–100%) and a specificity of 55% (46.1%–65.7%). The negative predictive value of the test was 100% (95% CI; 93.9%–100%), with a positive predictive value of 14.5% (95% CI; 6.51%–26.7%) (Fig. 2). Overall, we found 55 patients (48%) with PRU N240. Of these patients, 28 (51%) had a 4 μmol/L ADP-induced platelet aggregation between 25 and 50% and 19 (34%) between 0 and 25%. It is well known that inhibition of P2Y12-mediated platelet reactivity reduce post-procedural myocardial infarction and stent thrombosis [1]. High on treatment platelet reactivity diagnosis using VerifyNow P2Y12 is a reliable and independent measure of risk for cardiovascular events [7]. However, even in patients with this condition, intensive antiaggregation treatment based on a measure of platelet reactivity has never been successfully proven [8,9]. Using a cut-off value of b240 PRU, VerifyNow P2Y12 was an excellent tool to screen patients as all subjects were correctly anti-aggregated
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A. Regueiro et al. / International Journal of Cardiology 178 (2015) 221–222
(4 μmol/L ADP-induced platelet aggregation b 50%). Conversely, in patients with PRU N240 an additional test to confirm the high on treatment platelet reactivity should be recommended as only 14.5% of those patients had a “true” poor response to clopidogrel treatment. In our study, the percentage of patients with a high on treatment platelet reactivity defined by VerifyNow P2Y12 was 48%. Of those, more than 85% had a 4 μmol/L ADP-induced platelet aggregation b 50%, highlighting the lack of accuracy of VerifyNow P2Y12 in patients with PRU N 240. In conclusion, VerifyNow is an excellent tool to identify patients who are properly treated with P2Y12 receptor inhibitors; however, high on treatment platelet reactivity defined by a VerifyNow P2Y12 N 240 should be confirmed with the golden standard ADP-induced light transmission aggregometry before suggesting any treatment modification. The authors report no relationships that could be construed as a conflict of interest. Conflict of interest None to declare. Fig. 1. Correlation between 4 μmol/l ADP-induced platelet aggregation by LTA and PRUs measured by the VerifyNow P2Y12 assay. The lines represent the cut-off point for highon treatment platelet aggregation (PRU N240 for VerifyNow and N50% platelet aggregation for LTA). ADP: Adenosine diphosphate. LTA: Light transmission aggregometry. PRU: P2Y12 platelet reaction units.
Fig. 2. Diagnostic test evaluation chart. Gold standard for high on treatment platelet reactivity was defined as 4 μmol/l ADP-induced platelet aggregation N50%. Positive test outcome high on treatment platelet reactivity was defined as VerifyNow P2Y12 N 240 reactivity units. ADP: Adenosine diphosphate. FN: False negative (type II error). FP: False positive (type I error). LTA: Light transmission aggregometry. PRU: P2Y12 platelet reaction units. TN: True negative. TP: True positive.
References [1] S. Windecker, P. Kolh, F. Alfonso, 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), Eur. Heart J. (2014) ehu278. [2] G.W. Stone, B. Witzenbichler, G. Weisz, et al., Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study, Lancet 382 (2013) 614–623. [3] R. Marcucci, A.M. Gori, R. Paniccia, et al., Cardiovascular death and nonfatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting are predicted by residual platelet reactivity to ADP detected by a point-of-care assay: a 12-month follow-up, Circulation 119 (2009) 237–242. [4] F. Mangiacapra, G. Patti, E. Barbato, et al., A therapeutic window for platelet reactivity for patients undergoing elective percutaneous coronary intervention: results of the ARMYDA-PROVE (antiplatelet therapy for reduction of myocardial damage during angioplasty-platelet reactivity for outcome valid), JACC Cardiovasc. Interv. 5 (2012) 281–289. [5] G. Lemesle, J.-B. Landel, A. Bauters, et al., Poor agreement between light transmission aggregometry, Verify Now P2Y12 and vasodilatator-stimulated phosphoprotein for clopidogrel low-response assessment: a potential explanation of negative results of recent randomized trials, Platelets 25 (7) (2014) 499–505. [6] S. Guthikonda, C.L. Alviar, M. Vaduganathan, et al., Role of reticulated platelets and platelet size heterogeneity on platelet activity after dual antiplatelet therapy with aspirin and clopidogrel in patients with stable coronary artery disease, J. Am. Coll. Cardiol. 52 (2008) 743–749. [7] U.S. Tantry, L. Bonello, D. Aradi, et al., Consensus and update on the definition of ontreatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding, J. Am. Coll. Cardiol. 62 (2013) 2261–2273. [8] M.J. Price, P.B. Berger, P.S. Teirstein, et al., Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial, JAMA 305 (2011) 1097–1105. [9] J.-P. Collet, T. Cuisset, G. Rangé, et al., Bedside monitoring to adjust antiplatelet therapy for coronary stenting, N. Engl. J. Med. 367 (2012) 2100–2109.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Platelet reactivity assessment with VerifyNow®: Substitute or complement for light transmission aggregometry? Ander Regueiro a, Xavier Freixa a,⁎, Diego Fernández-Rodríguez a, Maribel Diaz-Ricart b, Ginés Escolar b, Victoria Martín-Yuste a, Salvatore Brugaletta a, Manel Sabaté a, Mónica Masotti a a b
Cardiology Department, Thorax Institute, Hospital Clínic, IDIBAPS, University of Barcelona Hemotherapy and Hemostasis Department, Biomedical Diagnostic Center, Hospital Clínic, IDIBAPS, University of Barcelona
a r t i c l e
i n f o
Article history: Received 17 October 2014 Accepted 20 October 2014 Available online 22 October 2014 Keywords: Percutaneous coronary intervention Platelet aggregation inhibitors Platelet function test
Platelet aggregation inhibition is mandatory for patients undergoing percutaneous coronary intervention (PCI) [1]. High on-treatment platelet reactivity is an important independent risk factor for the occurrence of thrombotic and ischemic events after PCI [2]. Some point of care platelet aggregation assays are currently used in daily practice as a substitute for more expensive and time consuming complex methods. Despite the wide use of such tests, clinical trials testing the strategy of individual tailoring based on one test result have shown no clinical benefit, being the poor correlation between assays one possible explanation. Several clinical studies with the VerifyNow P2Y12 system have proposed a cut-off value of b 240 platelet reaction unit (PRU) to identify “good responders” [3,4]; however, the reasons for a PRU N 240 after clopidogrel treatment are not clear, and might reflect either false positives in good responders or “true” poor responders [5]. The objective of our study was to evaluate the correlation between light transmission aggregometry (LTA) and VerifyNow P2Y12 test with emphasis on patients with VerifyNow P2Y12 PRU N 240 after clopidogrel treatment. This was a single center, observational study. Subjects with stable coronary artery disease undergoing percutaneous coronary intervention were prospectively included. Platelet responsiveness to ADP was assessed 4 h after 600 mg clopidogrel loading dose using two different tests: ADP-induced platelet aggregation by LTA (turbidimetric) in ⁎ Corresponding author at: Cardiology Department, Thorax Institute, Hospital Clínic, IDIBAPS, University of Barcelona, Spain. E-mail address: [email protected] (X. Freixa).
http://dx.doi.org/10.1016/j.ijcard.2014.10.051 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
response to 4 μmol/l ADP (results are expressed as platelet aggregation percentage), and platelet reactivity assessment with the VerifyNow® P2Y12 test (Accumetrics, San Diego, CA, USA) (results are expressed as P2Y12 platelet reaction unit: PRU, and percentage inhibition index). High on treatment platelet reactivity was defined as a 4 μmol/L ADPinduced LTA N50% [6], and a VerifyNow P2Y12 PRU N240. Statistical analyses were performed at the level of significance b 0.05 using PASW 18 (SPSS Inc, Chicago IL, USA). All patients received a loading dose of 300 mg of AAS before the procedure. Informed consent was obtained from each patient and the study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institution's ethics committee. A total of 115 patients were included in the study. Of them, 81% were males, 17% had a history of diabetes mellitus, and 64% had a history of hypertension. In addition, 81% were previously treated with aspirin, 39% with clopidogrel, and 86% with proton pump inhibitors. Mean VerifyNow P2Y12 PRU was 239.4 ± 91.9, percentage inhibition index 74.8% ± 23.6%, and 4 μmol/L ADP-induced LTA 25.4 ± 14.7. VerifyNow P2Y12 PRU offered a modest correlation with 4 μmol/L ADP-induced LTA (Pearson = 0.539; p b 0.01) but superior to the one provided by the VerifyNow P2Y12 percentage inhibition index (Pearson = 0.437; p b 0.01) (Fig. 1). Receiver-operating characteristic (ROC) curve analysis demonstrated that PRU (cut-off value of N240) distinguished between patients with and without 4 μmol/L ADP-induced platelet reactivity of N 50% with an area under curve [AUC] of 0.82 (p b 0.01; 95% confidence interval (CI) 0.71–0.93) with a sensitivity of 100% (95% CI; 62.9%–100%) and a specificity of 55% (46.1%–65.7%). The negative predictive value of the test was 100% (95% CI; 93.9%–100%), with a positive predictive value of 14.5% (95% CI; 6.51%–26.7%) (Fig. 2). Overall, we found 55 patients (48%) with PRU N240. Of these patients, 28 (51%) had a 4 μmol/L ADP-induced platelet aggregation between 25 and 50% and 19 (34%) between 0 and 25%. It is well known that inhibition of P2Y12-mediated platelet reactivity reduce post-procedural myocardial infarction and stent thrombosis [1]. High on treatment platelet reactivity diagnosis using VerifyNow P2Y12 is a reliable and independent measure of risk for cardiovascular events [7]. However, even in patients with this condition, intensive antiaggregation treatment based on a measure of platelet reactivity has never been successfully proven [8,9]. Using a cut-off value of b240 PRU, VerifyNow P2Y12 was an excellent tool to screen patients as all subjects were correctly anti-aggregated
222
A. Regueiro et al. / International Journal of Cardiology 178 (2015) 221–222
(4 μmol/L ADP-induced platelet aggregation b 50%). Conversely, in patients with PRU N240 an additional test to confirm the high on treatment platelet reactivity should be recommended as only 14.5% of those patients had a “true” poor response to clopidogrel treatment. In our study, the percentage of patients with a high on treatment platelet reactivity defined by VerifyNow P2Y12 was 48%. Of those, more than 85% had a 4 μmol/L ADP-induced platelet aggregation b 50%, highlighting the lack of accuracy of VerifyNow P2Y12 in patients with PRU N 240. In conclusion, VerifyNow is an excellent tool to identify patients who are properly treated with P2Y12 receptor inhibitors; however, high on treatment platelet reactivity defined by a VerifyNow P2Y12 N 240 should be confirmed with the golden standard ADP-induced light transmission aggregometry before suggesting any treatment modification. The authors report no relationships that could be construed as a conflict of interest. Conflict of interest None to declare. Fig. 1. Correlation between 4 μmol/l ADP-induced platelet aggregation by LTA and PRUs measured by the VerifyNow P2Y12 assay. The lines represent the cut-off point for highon treatment platelet aggregation (PRU N240 for VerifyNow and N50% platelet aggregation for LTA). ADP: Adenosine diphosphate. LTA: Light transmission aggregometry. PRU: P2Y12 platelet reaction units.
Fig. 2. Diagnostic test evaluation chart. Gold standard for high on treatment platelet reactivity was defined as 4 μmol/l ADP-induced platelet aggregation N50%. Positive test outcome high on treatment platelet reactivity was defined as VerifyNow P2Y12 N 240 reactivity units. ADP: Adenosine diphosphate. FN: False negative (type II error). FP: False positive (type I error). LTA: Light transmission aggregometry. PRU: P2Y12 platelet reaction units. TN: True negative. TP: True positive.
References [1] S. Windecker, P. Kolh, F. Alfonso, 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), Eur. Heart J. (2014) ehu278. [2] G.W. Stone, B. Witzenbichler, G. Weisz, et al., Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study, Lancet 382 (2013) 614–623. [3] R. Marcucci, A.M. Gori, R. Paniccia, et al., Cardiovascular death and nonfatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting are predicted by residual platelet reactivity to ADP detected by a point-of-care assay: a 12-month follow-up, Circulation 119 (2009) 237–242. [4] F. Mangiacapra, G. Patti, E. Barbato, et al., A therapeutic window for platelet reactivity for patients undergoing elective percutaneous coronary intervention: results of the ARMYDA-PROVE (antiplatelet therapy for reduction of myocardial damage during angioplasty-platelet reactivity for outcome valid), JACC Cardiovasc. Interv. 5 (2012) 281–289. [5] G. Lemesle, J.-B. Landel, A. Bauters, et al., Poor agreement between light transmission aggregometry, Verify Now P2Y12 and vasodilatator-stimulated phosphoprotein for clopidogrel low-response assessment: a potential explanation of negative results of recent randomized trials, Platelets 25 (7) (2014) 499–505. [6] S. Guthikonda, C.L. Alviar, M. Vaduganathan, et al., Role of reticulated platelets and platelet size heterogeneity on platelet activity after dual antiplatelet therapy with aspirin and clopidogrel in patients with stable coronary artery disease, J. Am. Coll. Cardiol. 52 (2008) 743–749. [7] U.S. Tantry, L. Bonello, D. Aradi, et al., Consensus and update on the definition of ontreatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding, J. Am. Coll. Cardiol. 62 (2013) 2261–2273. [8] M.J. Price, P.B. Berger, P.S. Teirstein, et al., Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial, JAMA 305 (2011) 1097–1105. [9] J.-P. Collet, T. Cuisset, G. Rangé, et al., Bedside monitoring to adjust antiplatelet therapy for coronary stenting, N. Engl. J. Med. 367 (2012) 2100–2109.
