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Platelet inhibition by IV glyceryl trinitrate in patients with stable coronary artery disease on dual antiplatelet therapy subjected to PCI
Letters to the Editor in aorto-ostial stenting: angiographic and procedural results. EuroIntervention 2010;5:801–8. [9] Tsuchida K, Daemen J, Tanimoto S, et al. Two-year outcome of the use of paclitaxeleluting stents in aorto-ostial lesions. Int J Cardiol 2008;129:348–53.
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[10] Moreno R, Fernandez C, Hernandez R, et al. Drug-eluting stent thrombosis: results from a pooled analysis including 10 randomized studies. J Am Coll Cardiol 2005;45:954–9.
0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.04.093
Platelet inhibition by IV glyceryl trinitrate in patients with stable coronary artery disease on dual antiplatelet therapy subjected to PCI☆ Periklis Davlouros ⁎, Eleni Mavronasiou, Anastasia Damelou, Ioanna Xanthopoulou, Vassileios Gizas, Georgios Raptis, George Hahalis, Dimitrios Alexopoulos Department of Cardiology, Patras University Hospital, Rion, Patras, Greece
a r t i c l e
i n f o
Article history: Received 26 March 2013 Accepted 6 April 2013 Available online 30 April 2013 Keywords: Glyceryl trinitrate Nitrates Platelet reactivity Clopidogrel PCI Stable coronary artery disease
Organic nitrates administered intravenously (I.V.), per os, sublingually, and/or transcutaneously, are used for relief of symptoms in patients with stable coronary artery disease (SCAD) [1]. Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel, is considered mandatory for patients with SCAD following coronary angioplasty with stenting (PCI) [2]. Many patients may demonstrate increased residual platelet reactivity (PR) while on clopidogrel treatment, attributed to genetic, clinical, and drug–drug interactions [3]. A cross-sectional study of residual PR using a point of care assay in 377 patients with SCAD on maintenance clopidogrel therapy, suggested that chronic nitrate therapy may be associated with higher residual PR compared to patients not on nitrates [4]. On the other hand, there is evidence that these drugs may exert antiplatelet and antithrombotic effects, by nonselectively inhibiting platelet aggregation induced by multiple stimuli [5]. Whether the antiplatelet effects of nitrates are still evident, and/or have any additional clinical importance on the therapy of SCAD, in the contemporary era of routine administration of antiplatelet agents such as aspirin, thienopyridines, or ticagrelor, is unclear [6]. In this prospective, randomized, single-center, single-blind, placebo controlled pharmacodynamic study, we aimed to examine the effect of a short I.V. glyceryl trinitrate (GTN), infusion on residual PR, in patients with SCAD subjected to PCI while on maintenance DAPT with aspirin (100 mg o.d.), and clopidogrel (75 mg o.d.) for at least 7 days. Patients were randomized 24 hours post-PCI in a 1:1 fashion, to receive a continuous I.V. infusion of either GTN (0.01–0.2 mg/min), or placebo
(normal saline 0.9%) for 1 hour. Hemodynamic parameters were continuously monitored to ensure adequate GTN dose titration (a blood pressure decrease ≥ 10 mmHg being the target), and safety (blood pressure decrease ≥ 20 mmHg, and/or significant patient's discomfort). Peripheral venous blood samples were drawn and PR, was assessed with the VerifyNow (Accumetrics Inc., San Diego, CA, USA) point-of-care P2Y12 function assay before any I.V. infusion (Baseline), immediately following cessation of I.V. infusion (Hour 1), and 24 hours later (Hour 24), and was expressed in P2Y12 reaction units (PRU). The baseline value (BASE) of platelet function was also recorded. The percentage inhibition index of the P2Y12 receptor pathway (%inhibition), was calculated as [(1– PRU/BASE) x 100]. High on treatment PR (HPR) was defined as PR ≥208 PRU [7]. The study protocol was approved by the ethics committee of the hospital. All patients provided written informed consent before participation in the study. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institution's human research committee. All statistical analyses were performed using SPSS for Windows (version 16.0 SPSS Inc. Chicago II USA). A total of 40 patients (9 women 22.5% and 31 men 77.5%), were included. Out of them, 20 patients were randomized to receive nitroglycerin and 20 to placebo arm. Baseline characteristics, including
Table 1 Platelet reactivity (VerifyNow PRU, BASE and % inhibition) at 1 and 24 hours post IV nitroglycerin infusion. Time post randomization Hour1 PRU BASE % inhibition
Hour24 PRU BASE % inhibition
☆ All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. ⁎ Corresponding author at: Cardiology Department, Patras University Hospital, Rion 26500, Patras, Greece. Tel./fax: +30 2610992941. E-mail address: [email protected] (P. Davlouros).
Nitroglycerin N = 20
Placebo N = 20
LS mean difference (95%CI)
p-value
155.1 (145.4–164.7) 239.5 (221.8–257.3) 31.0 (4.0–49.0)
205.3 (195.7–214.9) 271.6 (254.3–288.8) 33.5 (14.3–36.8)
− 50.3 (− 63.9 to − 36.6) −32.0 (− 57.0 to − 7.0)
b0.001
191.1 (178.4–203.9) 252.8 (233.9–271.6) 18 (3–39)
205.4 (192.6–218.1) 261.1 (242.3–279.9) 25 (4.0–40.0)
− 14.2 (− 32.2 to 3.8) − 8.3 (− 35.3 to 18.7)
0.01 0.5
0.1 0.5 0.7
Platelet reactivity in PRU and BASE were analyzed with mixed effects models with treatment as fixed effect, patient as a random intercept and platelet reactivity in PRU and BASE at baseline respectively as a covariate and is presented as LS estimates (95% CIs) and LS mean difference (95% CIs). % inhibition was analyzed with Mann– Whitney test and is presented as medians (first to third quartile). PRU indicates platelet reactivity unit; LS indicates least squares; CI indicates confidence intervals.
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Fig. 1. Individual values of platelet reactivity at 0, 1 and 24 hours post IV infusion of study drug, as assessed with the VerifyNow assay in PRU. Lines represent medians and error bars interquartile range. A dotted line represents the high on-treatment platelet reactivity threshold of 208 PRU. High on-treatment platelet reactivity rates are shown at the top of each column. PRU indicates platelet reactivity units.
PRU, BASE, and %inhibition, did not differ between the two groups. Systolic blood pressure was reduced significantly from baseline at Hour 1 in the GTN group (125.5 ± 11.9 vs. 112.2 ± 12.2 mmHg, p = 0.023), but not in the placebo group (121.7 ± 11.2 vs. 120.5 ± 9.5 mmHg, p = 0.3). As shown in the Table 1, immediately post-infusion (Hour 1), BASE and PRU were reduced significantly in the GTN group compared to placebo, while the %inhibition did not differ between the 2 groups. At Hour 24 there was no significant difference in any of the above parameters between the 2 groups. Patients' individual PR values along with the corresponding HPR rates are shown in the Fig. 1. HPR rate did not differ significantly between groups at any of the study's time points. No major side effects of GTN infusion were noted, and all patients had an eventful course during hospital stay, without thrombotic or bleeding effects. Our pharmacodynamic study in patients with SCAD subjected to PCI while on maintenance DAPT with aspirin and clopidogrel, showed that a short duration (1 hour) infusion of GTN 24 hours following PCI, was associated with further reversible inhibition of platelet aggregation compared to placebo. The significant and reversible decrease of both BASE and PRU values, but not of %inhibition, suggests that GTN infusion affects generalized platelet aggregation via the thrombin receptor activating peptide, independently of the P2Y12 activation pathway. Nitrates added to platelet suspensions inhibit platelet aggregation and lead to de-aggregation in a dose dependent manner by virtually all known stimuli [5]. Similar to their presumed mechanism of hemodynamic action, it is believed that nitrates exert their antiplatelet action by activation of platelet soluble guanylate cyclase, with consequent increase of platelet cGMP, leading to inhibition of agonist-mediated calcium flux, and reduction of fibrinogen binding to the glycoprotein IIb/IIIa receptor [8]. Our observations are in accord with this P2Y12 receptor independent mechanism of antiplatelet action. It is tempting to speculate that further platelet inhibition by I.V. GTN might be of
0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.04.092
clinical relevance in patients with increased PR immediately post-PCI in both stable and even more importantly in unstable patients (e.g. STEMI patients), who may demonstrate a heightened PR following DAPT loading [9]. However this needs further studying. Additionally, it might be important to know that GTN infusion may potentiate PRU reduction, which might predispose to bleeding, especially in patients treated with potent new antiplatelet agents like prasugrel or ticagrelor.
References [1] Fraker Jr TD, Fihn SD, Gibbons RJ, et al. 2007 chronic angina focused update of the ACC/ AHA 2002 Guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Writing Group to develop the focused update of the 2002 Guidelines for the management of patients with chronic stable angina. Circulation 2007;116:2762–72. [2] Wijns W, Kolh P, Danchin N, et al. Guidelines on myocardial revascularization. Eur Heart J 2010;31:2501–55. [3] Bonello L, Tantry US, Marcucci R, et al. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol 2010;56:919–33. [4] Price MJ, Nayak KR, Barker CM, Kandzari DE, Teirstein PS. Predictors of heightened platelet reactivity despite dual-antiplatelet therapy in patients undergoing percutaneous coronary intervention. Am J Cardiol 2009;103:1339–43. [5] Chirkov YY, Naujalis JI, Barber S, et al. Reversal of human platelet aggregation by low concentrations of nitroglycerin in vitro in normal subjects. Am J Cardiol 1992;70:802–6. [6] Munzel T, Daiber A, Gori T. Nitrate therapy: new aspects concerning molecular action and tolerance. Circulation 2011;123:2132–44. [7] Price MJ, Angiolillo DJ, Teirstein PS, et al. Platelet reactivity and cardiovascular outcomes after percutaneous coronary intervention: a time-dependent analysis of the Gauging Responsiveness with a VerifyNow P2Y12 assay: Impact on Thrombosis and Safety (GRAVITAS) trial. Circulation 2011;124:1132–7. [8] Loscalzo J. Antiplatelet and antithrombotic effects of organic nitrates. Am J Cardiol 1992;70:18B–22B. [9] Alexopoulos D. P2Y12 inhibitors adjunctive to primary PCI therapy in STEMI: Fighting against the activated platelets. Int J Cardiol 2013;163:249–55.
3069
[10] Moreno R, Fernandez C, Hernandez R, et al. Drug-eluting stent thrombosis: results from a pooled analysis including 10 randomized studies. J Am Coll Cardiol 2005;45:954–9.
0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.04.093
Platelet inhibition by IV glyceryl trinitrate in patients with stable coronary artery disease on dual antiplatelet therapy subjected to PCI☆ Periklis Davlouros ⁎, Eleni Mavronasiou, Anastasia Damelou, Ioanna Xanthopoulou, Vassileios Gizas, Georgios Raptis, George Hahalis, Dimitrios Alexopoulos Department of Cardiology, Patras University Hospital, Rion, Patras, Greece
a r t i c l e
i n f o
Article history: Received 26 March 2013 Accepted 6 April 2013 Available online 30 April 2013 Keywords: Glyceryl trinitrate Nitrates Platelet reactivity Clopidogrel PCI Stable coronary artery disease
Organic nitrates administered intravenously (I.V.), per os, sublingually, and/or transcutaneously, are used for relief of symptoms in patients with stable coronary artery disease (SCAD) [1]. Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel, is considered mandatory for patients with SCAD following coronary angioplasty with stenting (PCI) [2]. Many patients may demonstrate increased residual platelet reactivity (PR) while on clopidogrel treatment, attributed to genetic, clinical, and drug–drug interactions [3]. A cross-sectional study of residual PR using a point of care assay in 377 patients with SCAD on maintenance clopidogrel therapy, suggested that chronic nitrate therapy may be associated with higher residual PR compared to patients not on nitrates [4]. On the other hand, there is evidence that these drugs may exert antiplatelet and antithrombotic effects, by nonselectively inhibiting platelet aggregation induced by multiple stimuli [5]. Whether the antiplatelet effects of nitrates are still evident, and/or have any additional clinical importance on the therapy of SCAD, in the contemporary era of routine administration of antiplatelet agents such as aspirin, thienopyridines, or ticagrelor, is unclear [6]. In this prospective, randomized, single-center, single-blind, placebo controlled pharmacodynamic study, we aimed to examine the effect of a short I.V. glyceryl trinitrate (GTN), infusion on residual PR, in patients with SCAD subjected to PCI while on maintenance DAPT with aspirin (100 mg o.d.), and clopidogrel (75 mg o.d.) for at least 7 days. Patients were randomized 24 hours post-PCI in a 1:1 fashion, to receive a continuous I.V. infusion of either GTN (0.01–0.2 mg/min), or placebo
(normal saline 0.9%) for 1 hour. Hemodynamic parameters were continuously monitored to ensure adequate GTN dose titration (a blood pressure decrease ≥ 10 mmHg being the target), and safety (blood pressure decrease ≥ 20 mmHg, and/or significant patient's discomfort). Peripheral venous blood samples were drawn and PR, was assessed with the VerifyNow (Accumetrics Inc., San Diego, CA, USA) point-of-care P2Y12 function assay before any I.V. infusion (Baseline), immediately following cessation of I.V. infusion (Hour 1), and 24 hours later (Hour 24), and was expressed in P2Y12 reaction units (PRU). The baseline value (BASE) of platelet function was also recorded. The percentage inhibition index of the P2Y12 receptor pathway (%inhibition), was calculated as [(1– PRU/BASE) x 100]. High on treatment PR (HPR) was defined as PR ≥208 PRU [7]. The study protocol was approved by the ethics committee of the hospital. All patients provided written informed consent before participation in the study. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institution's human research committee. All statistical analyses were performed using SPSS for Windows (version 16.0 SPSS Inc. Chicago II USA). A total of 40 patients (9 women 22.5% and 31 men 77.5%), were included. Out of them, 20 patients were randomized to receive nitroglycerin and 20 to placebo arm. Baseline characteristics, including
Table 1 Platelet reactivity (VerifyNow PRU, BASE and % inhibition) at 1 and 24 hours post IV nitroglycerin infusion. Time post randomization Hour1 PRU BASE % inhibition
Hour24 PRU BASE % inhibition
☆ All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. ⁎ Corresponding author at: Cardiology Department, Patras University Hospital, Rion 26500, Patras, Greece. Tel./fax: +30 2610992941. E-mail address: [email protected] (P. Davlouros).
Nitroglycerin N = 20
Placebo N = 20
LS mean difference (95%CI)
p-value
155.1 (145.4–164.7) 239.5 (221.8–257.3) 31.0 (4.0–49.0)
205.3 (195.7–214.9) 271.6 (254.3–288.8) 33.5 (14.3–36.8)
− 50.3 (− 63.9 to − 36.6) −32.0 (− 57.0 to − 7.0)
b0.001
191.1 (178.4–203.9) 252.8 (233.9–271.6) 18 (3–39)
205.4 (192.6–218.1) 261.1 (242.3–279.9) 25 (4.0–40.0)
− 14.2 (− 32.2 to 3.8) − 8.3 (− 35.3 to 18.7)
0.01 0.5
0.1 0.5 0.7
Platelet reactivity in PRU and BASE were analyzed with mixed effects models with treatment as fixed effect, patient as a random intercept and platelet reactivity in PRU and BASE at baseline respectively as a covariate and is presented as LS estimates (95% CIs) and LS mean difference (95% CIs). % inhibition was analyzed with Mann– Whitney test and is presented as medians (first to third quartile). PRU indicates platelet reactivity unit; LS indicates least squares; CI indicates confidence intervals.
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Letters to the Editor
Fig. 1. Individual values of platelet reactivity at 0, 1 and 24 hours post IV infusion of study drug, as assessed with the VerifyNow assay in PRU. Lines represent medians and error bars interquartile range. A dotted line represents the high on-treatment platelet reactivity threshold of 208 PRU. High on-treatment platelet reactivity rates are shown at the top of each column. PRU indicates platelet reactivity units.
PRU, BASE, and %inhibition, did not differ between the two groups. Systolic blood pressure was reduced significantly from baseline at Hour 1 in the GTN group (125.5 ± 11.9 vs. 112.2 ± 12.2 mmHg, p = 0.023), but not in the placebo group (121.7 ± 11.2 vs. 120.5 ± 9.5 mmHg, p = 0.3). As shown in the Table 1, immediately post-infusion (Hour 1), BASE and PRU were reduced significantly in the GTN group compared to placebo, while the %inhibition did not differ between the 2 groups. At Hour 24 there was no significant difference in any of the above parameters between the 2 groups. Patients' individual PR values along with the corresponding HPR rates are shown in the Fig. 1. HPR rate did not differ significantly between groups at any of the study's time points. No major side effects of GTN infusion were noted, and all patients had an eventful course during hospital stay, without thrombotic or bleeding effects. Our pharmacodynamic study in patients with SCAD subjected to PCI while on maintenance DAPT with aspirin and clopidogrel, showed that a short duration (1 hour) infusion of GTN 24 hours following PCI, was associated with further reversible inhibition of platelet aggregation compared to placebo. The significant and reversible decrease of both BASE and PRU values, but not of %inhibition, suggests that GTN infusion affects generalized platelet aggregation via the thrombin receptor activating peptide, independently of the P2Y12 activation pathway. Nitrates added to platelet suspensions inhibit platelet aggregation and lead to de-aggregation in a dose dependent manner by virtually all known stimuli [5]. Similar to their presumed mechanism of hemodynamic action, it is believed that nitrates exert their antiplatelet action by activation of platelet soluble guanylate cyclase, with consequent increase of platelet cGMP, leading to inhibition of agonist-mediated calcium flux, and reduction of fibrinogen binding to the glycoprotein IIb/IIIa receptor [8]. Our observations are in accord with this P2Y12 receptor independent mechanism of antiplatelet action. It is tempting to speculate that further platelet inhibition by I.V. GTN might be of
0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.04.092
clinical relevance in patients with increased PR immediately post-PCI in both stable and even more importantly in unstable patients (e.g. STEMI patients), who may demonstrate a heightened PR following DAPT loading [9]. However this needs further studying. Additionally, it might be important to know that GTN infusion may potentiate PRU reduction, which might predispose to bleeding, especially in patients treated with potent new antiplatelet agents like prasugrel or ticagrelor.
References [1] Fraker Jr TD, Fihn SD, Gibbons RJ, et al. 2007 chronic angina focused update of the ACC/ AHA 2002 Guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Writing Group to develop the focused update of the 2002 Guidelines for the management of patients with chronic stable angina. Circulation 2007;116:2762–72. [2] Wijns W, Kolh P, Danchin N, et al. Guidelines on myocardial revascularization. Eur Heart J 2010;31:2501–55. [3] Bonello L, Tantry US, Marcucci R, et al. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol 2010;56:919–33. [4] Price MJ, Nayak KR, Barker CM, Kandzari DE, Teirstein PS. Predictors of heightened platelet reactivity despite dual-antiplatelet therapy in patients undergoing percutaneous coronary intervention. Am J Cardiol 2009;103:1339–43. [5] Chirkov YY, Naujalis JI, Barber S, et al. Reversal of human platelet aggregation by low concentrations of nitroglycerin in vitro in normal subjects. Am J Cardiol 1992;70:802–6. [6] Munzel T, Daiber A, Gori T. Nitrate therapy: new aspects concerning molecular action and tolerance. Circulation 2011;123:2132–44. [7] Price MJ, Angiolillo DJ, Teirstein PS, et al. Platelet reactivity and cardiovascular outcomes after percutaneous coronary intervention: a time-dependent analysis of the Gauging Responsiveness with a VerifyNow P2Y12 assay: Impact on Thrombosis and Safety (GRAVITAS) trial. Circulation 2011;124:1132–7. [8] Loscalzo J. Antiplatelet and antithrombotic effects of organic nitrates. Am J Cardiol 1992;70:18B–22B. [9] Alexopoulos D. P2Y12 inhibitors adjunctive to primary PCI therapy in STEMI: Fighting against the activated platelets. Int J Cardiol 2013;163:249–55.