Original Article
Efficacy of Change to New P2Y12 Receptor Antagonists in Patients High on Treatment Platelet Reactivity Undergoing Percutaneous Coronary Intervention
Clinical and Applied Thrombosis/Hemostasis 2015, Vol. 21(7) 619-625 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1076029614564208 cat.sagepub.com
Rogelio Robledo-Nolasco, MD1, A. Godı´nez-Montes de Oca, MD1, J. F. Zaballa-Contreras, MD1, J. A. Sua´rez-Cuenca, MD, PhD2,3, P. Mondrago´n-Tera´n, PhD2, A. F. Rubio-Guerra, MD, PhD3, and M. A. Mele´ndez-Alca´ntara, MD1
Abstract Selective intensification of platelet inhibition may improve high on treatment platelet reactivity (HPR). We evaluated the efficacy of dual-antiplatelet therapy, including clopidogrel (CPG), compared to new P2Y12-receptor antagonists in patients with HPR undergoing percutaneous coronary intervention, regarding the outcome of composite major adverse cardiac events (MACEs, including death, acute coronary syndrome [ACS], and stent restenosis). The presence of HPR (71 of 181 patients) almost doubled the risk of MACEs. The new antiplatelet agent reduced MACEs (45.8%, 26%, and 16.7% for CPG, prasugrel, and ticagrelor [TGL]; RR 0.36; 0.13-0.98, P ¼ .03, TGL), specifically in patients with ACS. Failure to reduce HPR after the antiplatelet change and diabetes were independent predictors for MACEs. The HPR was early and effectively reduced after changing the antiplatelet therapy, but the intensity of this reduction did not significantly decrease the risk of MACEs. These findings support the benefit of HPR-guided intensification of platelet inhibition. Whether the intensity of this reduction improves the patient’s clinical outcomes deserves further investigation. Keywords acute coronary syndromes, antiplatelet drugs, in vitro platelet function, platelet function, platelet inhibitors, thrombosis prophylaxis
Introduction Clopidogrel (CPG) is widely used in the management of coronary artery disease, as part of a dual antiplatelet therapy either in the setting of acute coronary syndrome (ACS) or for the treatment of stable angina. Additionally, CPG is frequently used in the settings of percutaneous coronary intervention (PCI) to prevent stent thrombosis and ACS. However, many patients still experience recurrent ischemic events, which may be due in part to the variability of the response to dual antiplatelet therapy. The so-called high on treatment platelet reactivity (HPR) refers to a poor response to antiplatelet agents, which is consistently associated with the recurrence of ischemic events. The identification of HPR may predict a higher risk of ischemic complications in patients with stable angina who are submitted to PCI; furthermore, therapy with novel P2Y12-receptor antagonists may reduce HPR and provide a greater antiplatelet effect than CPG in patients with ACS, both during the first hours of treatment and during the maintenance therapy.1,2 To overcome HPR, changing from the standard CPG treatment to other P2Y12-receptor antagonists with higher
antiplatelet effects has been investigated. Most of these studies3,4 have demonstrated a decreased ischemic risk associated with a change in antiplatelet therapy and a consequent reduction in HPR. Whether the intensity of platelet inhibition is related to a lower risk is not yet clear, because the results from these studies are not consistent, and these studies are heterogeneous regarding the study design, the
1
Servicio de Hemodinamia, Departamento de Cardiologı´ay, Centro Me´dico Nacional ‘‘20 de Noviembre’’ ISSSTE, Mexico City, Mexico 2 Divisio´n de Investigacio´n Biome´dica y Clı´nica, Centro Me´dico Nacional ‘‘20 de Noviembre’’ ISSSTE, Mexico City, Mexico 3 Clinical Research Unit, Hospital General de Ticoma´n and Mexican Group for Basic and Clinical Research in Internal Medicine, Mexico City, Mexico Corresponding Author: Rogelio Robledo-Nolasco, Servicio de Hemodinamia, Departamento de Cardiologı´a, C.M.N. ‘‘20 de Noviembre’’ ISSSTE, Edificio A, 6 piso, Av. Fe´lix Cuevas No. 540, Colonia Del Valle, Delegacio´n Benito Jua´rez, CP 03229, Mexico City, Mexico. Email: [email protected]
620 trial drug, and/or the cardiovascular risk of the study population.3-5 The present study was designed to explore the effect of HPR in a cohort of patients treated with CPG who were submitted to urgent and elective PCI and to estimate the impact of changing to new P2Y12-receptor antagonists on the clinical outcome of major adverse cardiac events (MACEs) during a 6-month follow-up.
Methods Patients A total of 181 patients with risk factors and/or a previous history of ischemic heart disease were treated for current coronary artery disease (chronic stable angina and ACS, including unstable angina, ST-segment elevation myocardial infarction [STEMI], and non-ST-segment elevation myocardial infarction [NSTEMI]) through coronary stenting with drug-eluting stents according to standard techniques. These patients were followed from March 2012 to February 2013. Patients with active bleeding, hemorrhagic diathesis, aspirin or thienopyridine allergy, history of stroke, weight lower than 60 kg, recent use of prasugrel (PSG) or ticagrelor (TGL), recent use of periprocedural glycoprotein IIb/IIIa inhibitors, or any anticoagulant were excluded from the study. Dual antiplatelet therapy previous to PCI was aspirin 81 to 300 mg/d and CPG 75 mg/d in patients with chronic stable angina. Patients with ACS received an aspirin loading dose (LD) of 300 mg and a CPG LD of 600 mg immediately before PCI. This study was designed and conducted according to the Declaration of Helsinki and was approved by the local ethics committees. All patients signed the written informed consent.
Platelet Function Test and Definition of HPR The platelet reactivity to CPG was assessed at the beginning of the study. The platelet reactivity test was performed with a commercially available ‘‘VerifyNow P2Y12 Test’’ (Accumetrics, San Diego, California) by following the supplier’s recommendations. Briefly, 3 mL of arterial blood was obtained during the PCI procedure, was placed in a tube containing a 3.2% sodium citrate solution (GreinerBioOneVacuette; North America, Inc, Monroe, North Carolina), and was analyzed within the next 15 minutes. The assay is based on adenosine diphosphate (ADP)-stimulated platelet activation and prostaglandin E1-induced increases of intraplatelet cyclic adenosine monophosphate to achieve more specific effects of ADP on the P2Y12 receptor. Platelet function was measured based upon the ability of activated platelets to bind to fibrinogen-coated microparticles and consequent aggregation with an expected reduction in binding after exposure to the P2Y12 inhibitor. The assay reports the extent of platelet aggregation in P2Y12 reaction units (PRUs), which depicts the amount of ADP-mediated aggregation specific to the platelet P2Y12 receptor and is calculated as a function of the rate and extent of platelet aggregation in the ADP
Clinical and Applied Thrombosis/Hemostasis 21(7) channel. In this study, HPR was defined as higher than 208 PRU during CPG treatment as described previously.
Change in Antiplatelet Therapy Patients under dual antiplatelet therapy, including CPG, who were also identified with HPR, were randomly assigned to a newer P2Y12-receptor antagonist, including PSG LD of 60 mg and 10 mg/d or TGL LD 180 mg and 90 mg twice a day. For comparison, a group of patients continued CPG LD of 300 mg and 75 mg/d. The platelet reactivity was measured again after 24 hours from the first determination as well as after 6 months; the persistence of a PRU value higher than 208 at these time points was considered to be an additional variable. The percentage of reduction in platelet reactivity was calculated to perform the quartile-grouped analysis. Patients, attending physicians, and laboratory personnel assessing the platelet reactivity were blinded to the study treatments assigned after detection of HPR, including change to PSG, TGL, or maintenance under CPG therapy.
Statistical Analysis For descriptive statistics, continuous variables are reported as the mean + standard deviation, and categorical variables are reported as frequencies and percentages. The normal distribution of the variables was estimated by the Kolmogorov-Smirnov test. The comparative analysis of the continuous variables was performed with an unpaired t test, Mann-Whitney U test, or analysis of variance; categorical variables were compared with a chi-square or Fisher exact test (applied as appropriate). The association between antiplatelet treatment and primary end points was calculated by the relative risk and 95% confidence intervals (95%CIs) or by a comparison through quartiles based on the percentage of reduction in the PRU value. An independent association of the baseline characteristics through a multivariate analysis was also performed using logistic regression. The statistical analyses were performed using SPSS v19.0 for Windows (SPSS Inc, Chicago, Illinois); P values
Efficacy of Change to New P2Y12 Receptor Antagonists in Patients High on Treatment Platelet Reactivity Undergoing Percutaneous Coronary Intervention
Clinical and Applied Thrombosis/Hemostasis 2015, Vol. 21(7) 619-625 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1076029614564208 cat.sagepub.com
Rogelio Robledo-Nolasco, MD1, A. Godı´nez-Montes de Oca, MD1, J. F. Zaballa-Contreras, MD1, J. A. Sua´rez-Cuenca, MD, PhD2,3, P. Mondrago´n-Tera´n, PhD2, A. F. Rubio-Guerra, MD, PhD3, and M. A. Mele´ndez-Alca´ntara, MD1
Abstract Selective intensification of platelet inhibition may improve high on treatment platelet reactivity (HPR). We evaluated the efficacy of dual-antiplatelet therapy, including clopidogrel (CPG), compared to new P2Y12-receptor antagonists in patients with HPR undergoing percutaneous coronary intervention, regarding the outcome of composite major adverse cardiac events (MACEs, including death, acute coronary syndrome [ACS], and stent restenosis). The presence of HPR (71 of 181 patients) almost doubled the risk of MACEs. The new antiplatelet agent reduced MACEs (45.8%, 26%, and 16.7% for CPG, prasugrel, and ticagrelor [TGL]; RR 0.36; 0.13-0.98, P ¼ .03, TGL), specifically in patients with ACS. Failure to reduce HPR after the antiplatelet change and diabetes were independent predictors for MACEs. The HPR was early and effectively reduced after changing the antiplatelet therapy, but the intensity of this reduction did not significantly decrease the risk of MACEs. These findings support the benefit of HPR-guided intensification of platelet inhibition. Whether the intensity of this reduction improves the patient’s clinical outcomes deserves further investigation. Keywords acute coronary syndromes, antiplatelet drugs, in vitro platelet function, platelet function, platelet inhibitors, thrombosis prophylaxis
Introduction Clopidogrel (CPG) is widely used in the management of coronary artery disease, as part of a dual antiplatelet therapy either in the setting of acute coronary syndrome (ACS) or for the treatment of stable angina. Additionally, CPG is frequently used in the settings of percutaneous coronary intervention (PCI) to prevent stent thrombosis and ACS. However, many patients still experience recurrent ischemic events, which may be due in part to the variability of the response to dual antiplatelet therapy. The so-called high on treatment platelet reactivity (HPR) refers to a poor response to antiplatelet agents, which is consistently associated with the recurrence of ischemic events. The identification of HPR may predict a higher risk of ischemic complications in patients with stable angina who are submitted to PCI; furthermore, therapy with novel P2Y12-receptor antagonists may reduce HPR and provide a greater antiplatelet effect than CPG in patients with ACS, both during the first hours of treatment and during the maintenance therapy.1,2 To overcome HPR, changing from the standard CPG treatment to other P2Y12-receptor antagonists with higher
antiplatelet effects has been investigated. Most of these studies3,4 have demonstrated a decreased ischemic risk associated with a change in antiplatelet therapy and a consequent reduction in HPR. Whether the intensity of platelet inhibition is related to a lower risk is not yet clear, because the results from these studies are not consistent, and these studies are heterogeneous regarding the study design, the
1
Servicio de Hemodinamia, Departamento de Cardiologı´ay, Centro Me´dico Nacional ‘‘20 de Noviembre’’ ISSSTE, Mexico City, Mexico 2 Divisio´n de Investigacio´n Biome´dica y Clı´nica, Centro Me´dico Nacional ‘‘20 de Noviembre’’ ISSSTE, Mexico City, Mexico 3 Clinical Research Unit, Hospital General de Ticoma´n and Mexican Group for Basic and Clinical Research in Internal Medicine, Mexico City, Mexico Corresponding Author: Rogelio Robledo-Nolasco, Servicio de Hemodinamia, Departamento de Cardiologı´a, C.M.N. ‘‘20 de Noviembre’’ ISSSTE, Edificio A, 6 piso, Av. Fe´lix Cuevas No. 540, Colonia Del Valle, Delegacio´n Benito Jua´rez, CP 03229, Mexico City, Mexico. Email: [email protected]
620 trial drug, and/or the cardiovascular risk of the study population.3-5 The present study was designed to explore the effect of HPR in a cohort of patients treated with CPG who were submitted to urgent and elective PCI and to estimate the impact of changing to new P2Y12-receptor antagonists on the clinical outcome of major adverse cardiac events (MACEs) during a 6-month follow-up.
Methods Patients A total of 181 patients with risk factors and/or a previous history of ischemic heart disease were treated for current coronary artery disease (chronic stable angina and ACS, including unstable angina, ST-segment elevation myocardial infarction [STEMI], and non-ST-segment elevation myocardial infarction [NSTEMI]) through coronary stenting with drug-eluting stents according to standard techniques. These patients were followed from March 2012 to February 2013. Patients with active bleeding, hemorrhagic diathesis, aspirin or thienopyridine allergy, history of stroke, weight lower than 60 kg, recent use of prasugrel (PSG) or ticagrelor (TGL), recent use of periprocedural glycoprotein IIb/IIIa inhibitors, or any anticoagulant were excluded from the study. Dual antiplatelet therapy previous to PCI was aspirin 81 to 300 mg/d and CPG 75 mg/d in patients with chronic stable angina. Patients with ACS received an aspirin loading dose (LD) of 300 mg and a CPG LD of 600 mg immediately before PCI. This study was designed and conducted according to the Declaration of Helsinki and was approved by the local ethics committees. All patients signed the written informed consent.
Platelet Function Test and Definition of HPR The platelet reactivity to CPG was assessed at the beginning of the study. The platelet reactivity test was performed with a commercially available ‘‘VerifyNow P2Y12 Test’’ (Accumetrics, San Diego, California) by following the supplier’s recommendations. Briefly, 3 mL of arterial blood was obtained during the PCI procedure, was placed in a tube containing a 3.2% sodium citrate solution (GreinerBioOneVacuette; North America, Inc, Monroe, North Carolina), and was analyzed within the next 15 minutes. The assay is based on adenosine diphosphate (ADP)-stimulated platelet activation and prostaglandin E1-induced increases of intraplatelet cyclic adenosine monophosphate to achieve more specific effects of ADP on the P2Y12 receptor. Platelet function was measured based upon the ability of activated platelets to bind to fibrinogen-coated microparticles and consequent aggregation with an expected reduction in binding after exposure to the P2Y12 inhibitor. The assay reports the extent of platelet aggregation in P2Y12 reaction units (PRUs), which depicts the amount of ADP-mediated aggregation specific to the platelet P2Y12 receptor and is calculated as a function of the rate and extent of platelet aggregation in the ADP
Clinical and Applied Thrombosis/Hemostasis 21(7) channel. In this study, HPR was defined as higher than 208 PRU during CPG treatment as described previously.
Change in Antiplatelet Therapy Patients under dual antiplatelet therapy, including CPG, who were also identified with HPR, were randomly assigned to a newer P2Y12-receptor antagonist, including PSG LD of 60 mg and 10 mg/d or TGL LD 180 mg and 90 mg twice a day. For comparison, a group of patients continued CPG LD of 300 mg and 75 mg/d. The platelet reactivity was measured again after 24 hours from the first determination as well as after 6 months; the persistence of a PRU value higher than 208 at these time points was considered to be an additional variable. The percentage of reduction in platelet reactivity was calculated to perform the quartile-grouped analysis. Patients, attending physicians, and laboratory personnel assessing the platelet reactivity were blinded to the study treatments assigned after detection of HPR, including change to PSG, TGL, or maintenance under CPG therapy.
Statistical Analysis For descriptive statistics, continuous variables are reported as the mean + standard deviation, and categorical variables are reported as frequencies and percentages. The normal distribution of the variables was estimated by the Kolmogorov-Smirnov test. The comparative analysis of the continuous variables was performed with an unpaired t test, Mann-Whitney U test, or analysis of variance; categorical variables were compared with a chi-square or Fisher exact test (applied as appropriate). The association between antiplatelet treatment and primary end points was calculated by the relative risk and 95% confidence intervals (95%CIs) or by a comparison through quartiles based on the percentage of reduction in the PRU value. An independent association of the baseline characteristics through a multivariate analysis was also performed using logistic regression. The statistical analyses were performed using SPSS v19.0 for Windows (SPSS Inc, Chicago, Illinois); P values
