Clinical Science (2015) 128, 121–130 (Printed in Great Britain) doi: 10.1042/CS20140310
The net clinical benefit of personalized antiplatelet therapy in patients undergoing percutaneous coronary intervention
Clinical Science
www.clinsci.org
Jolanta M. Siller-Matula∗ , Carina Gruber†, Marcel Francesconi†, Cornelia Dechant†, Bernd Jilma‡, Georg Delle-Karth∗ , Katharina Grohs§, Andrea Podczeck-Schweighofer† and G¨unter Christ† ∗ Department of Cardiology, Medical University of Vienna, Austria †5th Medical Department of Cardiology, Kaiser Franz Josef Hospital, Vienna, Austria ‡Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria §Clinical Institute for Laboratory Medicine, Kaiser Franz Josef Hospital, Vienna, Austria
Abstract This was a prospective study comparing two groups: personalized and non-personalized treatment with P2Y12 receptor blockers during a 12-month follow-up. We aimed to investigate whether personalized antiplatelet treatment in patients with high on-treatment platelet reactivity (HTPR) improves clinical outcome. Platelet reactivity was assessed by adenosine diphosphate induced aggregation using a multiple electrode aggregometry (MEA) in 798 patients with coronary artery disease undergoing percutaneous coronary intervention (PCI). Patients with HTPR received up to four repeated loading doses of clopidogrel or prasugrel in the personalized treatment group (n = 403), whereas no change in the treatment strategy was undertaken in patients with HTPR in the non-personalized treatment group (n = 395). There were fewer major adverse cardiac events (MACE) in the personalized treatment group than in the non-personalized treatment group (7.4 % compared with 15.3 % respectively; P < 0.001). The multivariate Cox regression analysis showed that the relative risk to develop MACE was 51 % lower in the personalized treatment group as compared with the non-personalized treatment group [hazard ratio (HR) = 0.49; 95 % confidence interval (CI): 0.31–0.77; P < 0.001]. Similarly, there was a clear net benefit of the personalized antiplatelet treatment over the non-personalized treatment (ischemic and bleedings events: 8.2 % versus 18.7 % respectively; HR = 0.46; 95%CI: 0.29–0.70; P < 0.001). Further analysis indicated that patients with aggregation values within the therapeutic window (21–49 units) experienced the lowest event rates (stent thrombosis and major bleeding: 2.5 %) as compared with poor responders (50 units: 5.4 %) or ultra-responders (0–20 units: 5.2 %). In conclusion, personalized antiplatelet treatment might improve patients’ outcome without increasing bleeding complications compared with the non-personalized treatment during a 12-month follow-up. Key words: acute coronary syndrome, blood platelet, clopidogrel, haemorrhage, thrombosis
INTRODUCTION The accumulating body of evidence underlines a considerable concern regarding the one-size-fits-all strategy with use of P2Y12 receptor inhibitors, especially of clopidogrel [1]. More than 40 studies in over 20 000 patients linked high on treatment platelet reactivity (HTPR) to cardiac adverse events [2]. Hence, these intriguing observations led to the suggestion that the level of platelet inhibition by clopidogrel can be measured and individually adjusted [3]. Indeed, the majority of published studies have
demonstrated that HTPR can be overcome in most patients with higher loading or maintenance doses of clopidogrel, or by switching to more potent P2Y12 receptor inhibitors prasugrel, ticagrelor or cangrelor [4–12]. The next logical question which was addressed was whether the reduction in platelet reactivity by tailored antiplatelet treatment would improve clinical outcome. Interestingly, a considerable variability exists in the results of published studies. An improved clinical outcome with individualized antiplatelet therapy resulted in a reduction in major adverse cardiac events without an increase in major bleeding complications in
Abbreviations: AUC, area under the curve; CHAID, χ 2 automatic interaction detection; CI, confidence interval; HR, hazard ratio; HTPR, high on-treatment platelet reactivity; IQR, interquartile range; MACE, major adverse cardiac events; MADONNA, Multiple electrode Aggregometry in patients receiving Dual antiplatelet therapy to guide treatment with Novel platelet Antagonists; MEA, multiple electrode aggregometry; PCI, percutaneous coronary intervention; PPI, proton pump inhibitor; ROC, receiver operating characteristic; TIMI, thrombolysis in myocardial infarction. Correspondence: Dr Jolanta Siller-Matula (email [email protected]) or Professor G¨unter Christ (email [email protected])
C The Authors Journal compilation C 2015 Biochemical Society
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some smaller studies [7,8,13]. In contrast, larger trials have so far failed to demonstrate benefit of individually tailored anti-platelet therapy, although design issues may have contributed to these results, as recently discussed [14]. We have already presented the short-term results of the Multiple electrode Aggregometry in patients receiving Dual antiplatelet therapy to guide treatment with Novel platelet Antagonists (MADONNA) study, which has shown that personalized antiplatelet treatment according to the platelet function testing resulted in an improved efficacy with an equal safety compared with the standard treatment during 1month follow-up [13]. In the present paper, we present 1-year clinical outcome data of the MADONNA study with the focus on the net clinical benefit.
MATERIALS AND METHODS Study design The design of the MADONNA study was described previously [13]. Briefly, the MADONNA study was a prospective nonrandomized and non-blinded study comparing two cohorts investigating personalized versus non-personalized antiplatelet therapy. The Ethics Committees approved the study protocol in accordance with the Declaration of Helsinki. Patients gave informed consent prior to inclusion in the present study. Participants were included into the study between March 2007 and November 2010. Inclusion criteria were: stent implantation, percutaneous coronary intervention (PCI) at least 2 h after clopidogrel loading with 600 mg. The only exclusion criterion was participation in interventional trials. Patients in the non-personalized group received only one clopidogrel loading dose (Plavix® 600 mg), patients in the personalized group received an individualized antiplatelet treatment according to the following algorithm: after an initial clopidogrel loading dose of 600 mg on-treatment platelet reactivity was measured the day after PCI and the earliest after 12 h after loading by multiplate electrode aggregometry (MEA). In case of high on-treatment platelet reactivity (HTPR 50 units), patients were reloaded with clopidogrel 600 mg. Subsequently, on-treatment platelet reactivity was measured the day after loading. In case of HTPR after a second or a third clopidogrel loading, patients were re-loaded with clopidogrel 600 mg for a third and fourth time. After prasugrel became available, patients with HTPR were loaded with prasugrel (Efient® 60 mg) except in case of contraindications (history of stroke or intracranial haemorrhage) where a second loading dose of clopidogrel would have been administered. After each re-loading with clopidogrel or switch to prasugrel platelet function was measured 1 day thereafter to ensure that HTPR was overcome. During the maintenance treatment, patients received the antiplatelet therapy matching with the last loading dose they received (clopidogrel responders: clopidogrel 75 mg; clopidogrel non-responders: clopidogrel 75 mg or prasugrel 10 mg). Clinical follow-up information was obtained by contacting all patients by phone at 12 months. Source documents of potential events were obtained. Additionally, information concerning the cause of death was ob-
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tained from national death registry (Statistics Austria). Blood samples from patients were obtained after PCI.
Impedance aggregometry Whole blood aggregation was determined using MEA on a new generation impedance aggregometer (Multiplate Analyzer, Verum Diagnostica). The system detects the electrical impedance change due to the adhesion and aggregation of platelets on two independent electrode-set surfaces in the test cuvette [15]. We used hirudin as anticoagulant, which is recommended by the manufacturer and ADP as agonist [16,17]. A 1:2 dilution of whole blood anticoagulated with hirudin and 0.9 % NaCl was stirred at 37 ◦ C for 3 min in the test cuvettes, ADP: 6.4 μM was added and the increase in electrical impedance was recorded continuously for 6 min [18]. The mean values of the two independent determinations are expressed as the area under the curve (AUC) of the aggregation tracing. We reported AUC in units, as described previously [19]. HTPR cut-off was prespecified and defined as values 50 units (poor responders) [20,21]. Therapeutic window was defined as values: 21–49 units (regular responders). Patients with values of 0–20 units were defined as ultra-responders. Measurements were performed by trained laboratory technicians blinded to the outcomes. We used MEA device due to the reported high effectiveness to predict stent thrombosis [odds ratio (OR) = 9–37; area under the receiver operating characteristic (ROC) curve: 0.78–0.92, sensitivity: 70–90 % and specificity: 84–100%] [20–22] and a satisfied reproducibility (
The net clinical benefit of personalized antiplatelet therapy in patients undergoing percutaneous coronary intervention
Clinical Science
www.clinsci.org
Jolanta M. Siller-Matula∗ , Carina Gruber†, Marcel Francesconi†, Cornelia Dechant†, Bernd Jilma‡, Georg Delle-Karth∗ , Katharina Grohs§, Andrea Podczeck-Schweighofer† and G¨unter Christ† ∗ Department of Cardiology, Medical University of Vienna, Austria †5th Medical Department of Cardiology, Kaiser Franz Josef Hospital, Vienna, Austria ‡Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria §Clinical Institute for Laboratory Medicine, Kaiser Franz Josef Hospital, Vienna, Austria
Abstract This was a prospective study comparing two groups: personalized and non-personalized treatment with P2Y12 receptor blockers during a 12-month follow-up. We aimed to investigate whether personalized antiplatelet treatment in patients with high on-treatment platelet reactivity (HTPR) improves clinical outcome. Platelet reactivity was assessed by adenosine diphosphate induced aggregation using a multiple electrode aggregometry (MEA) in 798 patients with coronary artery disease undergoing percutaneous coronary intervention (PCI). Patients with HTPR received up to four repeated loading doses of clopidogrel or prasugrel in the personalized treatment group (n = 403), whereas no change in the treatment strategy was undertaken in patients with HTPR in the non-personalized treatment group (n = 395). There were fewer major adverse cardiac events (MACE) in the personalized treatment group than in the non-personalized treatment group (7.4 % compared with 15.3 % respectively; P < 0.001). The multivariate Cox regression analysis showed that the relative risk to develop MACE was 51 % lower in the personalized treatment group as compared with the non-personalized treatment group [hazard ratio (HR) = 0.49; 95 % confidence interval (CI): 0.31–0.77; P < 0.001]. Similarly, there was a clear net benefit of the personalized antiplatelet treatment over the non-personalized treatment (ischemic and bleedings events: 8.2 % versus 18.7 % respectively; HR = 0.46; 95%CI: 0.29–0.70; P < 0.001). Further analysis indicated that patients with aggregation values within the therapeutic window (21–49 units) experienced the lowest event rates (stent thrombosis and major bleeding: 2.5 %) as compared with poor responders (50 units: 5.4 %) or ultra-responders (0–20 units: 5.2 %). In conclusion, personalized antiplatelet treatment might improve patients’ outcome without increasing bleeding complications compared with the non-personalized treatment during a 12-month follow-up. Key words: acute coronary syndrome, blood platelet, clopidogrel, haemorrhage, thrombosis
INTRODUCTION The accumulating body of evidence underlines a considerable concern regarding the one-size-fits-all strategy with use of P2Y12 receptor inhibitors, especially of clopidogrel [1]. More than 40 studies in over 20 000 patients linked high on treatment platelet reactivity (HTPR) to cardiac adverse events [2]. Hence, these intriguing observations led to the suggestion that the level of platelet inhibition by clopidogrel can be measured and individually adjusted [3]. Indeed, the majority of published studies have
demonstrated that HTPR can be overcome in most patients with higher loading or maintenance doses of clopidogrel, or by switching to more potent P2Y12 receptor inhibitors prasugrel, ticagrelor or cangrelor [4–12]. The next logical question which was addressed was whether the reduction in platelet reactivity by tailored antiplatelet treatment would improve clinical outcome. Interestingly, a considerable variability exists in the results of published studies. An improved clinical outcome with individualized antiplatelet therapy resulted in a reduction in major adverse cardiac events without an increase in major bleeding complications in
Abbreviations: AUC, area under the curve; CHAID, χ 2 automatic interaction detection; CI, confidence interval; HR, hazard ratio; HTPR, high on-treatment platelet reactivity; IQR, interquartile range; MACE, major adverse cardiac events; MADONNA, Multiple electrode Aggregometry in patients receiving Dual antiplatelet therapy to guide treatment with Novel platelet Antagonists; MEA, multiple electrode aggregometry; PCI, percutaneous coronary intervention; PPI, proton pump inhibitor; ROC, receiver operating characteristic; TIMI, thrombolysis in myocardial infarction. Correspondence: Dr Jolanta Siller-Matula (email [email protected]) or Professor G¨unter Christ (email [email protected])
C The Authors Journal compilation C 2015 Biochemical Society
121
J. M. Siller-Matula and others
some smaller studies [7,8,13]. In contrast, larger trials have so far failed to demonstrate benefit of individually tailored anti-platelet therapy, although design issues may have contributed to these results, as recently discussed [14]. We have already presented the short-term results of the Multiple electrode Aggregometry in patients receiving Dual antiplatelet therapy to guide treatment with Novel platelet Antagonists (MADONNA) study, which has shown that personalized antiplatelet treatment according to the platelet function testing resulted in an improved efficacy with an equal safety compared with the standard treatment during 1month follow-up [13]. In the present paper, we present 1-year clinical outcome data of the MADONNA study with the focus on the net clinical benefit.
MATERIALS AND METHODS Study design The design of the MADONNA study was described previously [13]. Briefly, the MADONNA study was a prospective nonrandomized and non-blinded study comparing two cohorts investigating personalized versus non-personalized antiplatelet therapy. The Ethics Committees approved the study protocol in accordance with the Declaration of Helsinki. Patients gave informed consent prior to inclusion in the present study. Participants were included into the study between March 2007 and November 2010. Inclusion criteria were: stent implantation, percutaneous coronary intervention (PCI) at least 2 h after clopidogrel loading with 600 mg. The only exclusion criterion was participation in interventional trials. Patients in the non-personalized group received only one clopidogrel loading dose (Plavix® 600 mg), patients in the personalized group received an individualized antiplatelet treatment according to the following algorithm: after an initial clopidogrel loading dose of 600 mg on-treatment platelet reactivity was measured the day after PCI and the earliest after 12 h after loading by multiplate electrode aggregometry (MEA). In case of high on-treatment platelet reactivity (HTPR 50 units), patients were reloaded with clopidogrel 600 mg. Subsequently, on-treatment platelet reactivity was measured the day after loading. In case of HTPR after a second or a third clopidogrel loading, patients were re-loaded with clopidogrel 600 mg for a third and fourth time. After prasugrel became available, patients with HTPR were loaded with prasugrel (Efient® 60 mg) except in case of contraindications (history of stroke or intracranial haemorrhage) where a second loading dose of clopidogrel would have been administered. After each re-loading with clopidogrel or switch to prasugrel platelet function was measured 1 day thereafter to ensure that HTPR was overcome. During the maintenance treatment, patients received the antiplatelet therapy matching with the last loading dose they received (clopidogrel responders: clopidogrel 75 mg; clopidogrel non-responders: clopidogrel 75 mg or prasugrel 10 mg). Clinical follow-up information was obtained by contacting all patients by phone at 12 months. Source documents of potential events were obtained. Additionally, information concerning the cause of death was ob-
122
C The Authors Journal compilation C 2015 Biochemical Society
tained from national death registry (Statistics Austria). Blood samples from patients were obtained after PCI.
Impedance aggregometry Whole blood aggregation was determined using MEA on a new generation impedance aggregometer (Multiplate Analyzer, Verum Diagnostica). The system detects the electrical impedance change due to the adhesion and aggregation of platelets on two independent electrode-set surfaces in the test cuvette [15]. We used hirudin as anticoagulant, which is recommended by the manufacturer and ADP as agonist [16,17]. A 1:2 dilution of whole blood anticoagulated with hirudin and 0.9 % NaCl was stirred at 37 ◦ C for 3 min in the test cuvettes, ADP: 6.4 μM was added and the increase in electrical impedance was recorded continuously for 6 min [18]. The mean values of the two independent determinations are expressed as the area under the curve (AUC) of the aggregation tracing. We reported AUC in units, as described previously [19]. HTPR cut-off was prespecified and defined as values 50 units (poor responders) [20,21]. Therapeutic window was defined as values: 21–49 units (regular responders). Patients with values of 0–20 units were defined as ultra-responders. Measurements were performed by trained laboratory technicians blinded to the outcomes. We used MEA device due to the reported high effectiveness to predict stent thrombosis [odds ratio (OR) = 9–37; area under the receiver operating characteristic (ROC) curve: 0.78–0.92, sensitivity: 70–90 % and specificity: 84–100%] [20–22] and a satisfied reproducibility (
