Does Baseline Hematocrit Influence Reactivity to Clopidogrel?
Does Baseline Hematocrit Influence Reactivity to Clopidogrel?
The study cohort included patients ≥18 years of age presenting for elective and urgent PCI who were consecutively enrolled in a prospective observational registry from October 2009 to March 2012. Patients who received the glycoprotein IIb/IIIa inhibitor eptifibatide up to 24 hours before platelet reactivity testing were excluded (no patients received abciximab or tirofiban). Similarly, patients on warfarin, nonsteroidal anti-inflammatory drugs, or with a contraindication for aspirin or clopidogrel were excluded. Patients known to be pregnant, with a history of bleeding diathesis, active bleeding, platelet count <100 × 10/L, hematocrit <25%, or who had received a blood transfusion in the preceding 10 days were also excluded. A dedicated data coordinating center performed all data management and analyses. Prespecified clinical and laboratory data during hospitalization periods were obtained from hospital charts reviewed by independent research personnel blinded to the study objectives. The institutional review board at MedStar Washington Hospital Center and the MedStar Research Institute (Washington, DC) approved this study.
All patients received a 600-mg loading dose of clopidogrel ≥6 hours before platelet reactivity testing or a 75-mg maintenance dose for ≥5 days before testing. All patients received aspirin 81 to 325 mg 6 to 24 hours before testing. After the procedure, aspirin was prescribed indefinitely, and clopidogrel was prescribed for a minimum of 1 month in patients receiving bare-metal stents for elective PCI and for 12 months in patients receiving drug-eluting stents and in all acute coronary syndrome patients.
All patients underwent platelet reactivity testing with VN and LTA (Chrono-Log, Havertown, PA). Whole blood samples were drawn 6 to 24 hours post-PCI through an 18-gauge or larger needle into 3.2% sodium citrate tubes, including 1.8-mL Greiner tube for the VN assay. Platelet reactivity testing was performed within 3 hours of blood sampling. The VN assay was performed by the addition of whole blood to dedicated cartridges containing fibrinogen-coated beads. The P2Y12 cartridge consists of 2 channels; in the first, ADP is used as agonist, in combination with prostaglandin E1 to limit the contribution of P2Y1. The increase in light transmittance, proportional to platelet aggregation, is reported as PRU. The second channel contains the thrombin receptor activating agonist (iso-TRAP) as the sole agonist, which provides a base value (iso-TRAP BASE) for platelet function independently of P2Y12 receptor blockade The device also provides an estimated percentage inhibition (percent inhibition) calculated as [(BASE − PRU/BASE) × 100], without preclopidogrel sample by reporting the ratio of the results of the adenosine diphosphate-prostaglandin E1 (ADP-PGE1) and iso-TRAP channels. Light transmission aggregometry was performed at 37°C using platelet-rich plasma. Aggregation parameters were measured with ADP 5 and 20 μM as agonists; these on-treatment platelet reactivity values are reported as percentages of maximum platelet aggregation (MPA).
High on-treatment platelet reactivity (HTPR) was defined as PRU ≥208 for VN P2Y12, MPA ≥46% for LTA with ADP 5 μM, and MPA ≥59% for LTA with ADP 20 μM. The composite end point of major adverse cardiac events (MACEs) included death, nonfatal myocardial infarction, and definite stent thrombosis.
Continuous variables are presented as mean ± SD or median with interquartile range, and categorical variables are presented as percentages. Differences in continuous variables between groups were compared using the Student t test or the Wilcoxon rank sum test as appropriate. Categorical variables were compared using χ test or Fisher exact test. The correlation between continuous variables was established using Pearson correlation coefficient. A receiver operating characteristic curve analysis was used to determine the ability of the assay to distinguish between patients with and without 1-year MACE. Independent correlates of HTPR were identified using multivariable logistic regression. Hematocrit, African American race, gender, age, diabetes mellitus, coronary artery disease, myocardial infarction, coronary artery bypass surgery, creatinine clearance, body mass index, congestive heart failure, hypercholesterolemia, peripheral vascular disease, current smoking, statin use, clopidogrel loading, and clinical presentation of unstable angina and acute myocardial infarction were the variables included in a univariate model. The variables with P < .05 and clinically relevant variables were included in a multivariate analysis using logistic regression in separate models with HTPR by PRU ≥208, LTA ADP 5 μM ≥46%, and LTA ADP 20 μM ≥59% as outcomes. We also assessed the incremental influence of addition of hematocrit, each platelet function assay results, and the interaction between the 2 to a baseline set of clinical variables in predicting the 1-year MACE. The clinical variables included age, history of diabetes mellitus, prior coronary artery disease, prior coronary artery bypass surgery, estimated glomerular filtration rate, body mass index, and unstable angina. The area under the curve (AUC) and 95% CI were calculated for each logistic regression model, and the differences between the AUC for different models were assessed. P < .05 was considered statistically significant. Statistical analyses were performed using SAS 9.3 (SAS Institute, Cary, NC).
No extramural funding was used to support this work. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the manuscript, and its final contents.
Methods
Study Population and Data Collection
The study cohort included patients ≥18 years of age presenting for elective and urgent PCI who were consecutively enrolled in a prospective observational registry from October 2009 to March 2012. Patients who received the glycoprotein IIb/IIIa inhibitor eptifibatide up to 24 hours before platelet reactivity testing were excluded (no patients received abciximab or tirofiban). Similarly, patients on warfarin, nonsteroidal anti-inflammatory drugs, or with a contraindication for aspirin or clopidogrel were excluded. Patients known to be pregnant, with a history of bleeding diathesis, active bleeding, platelet count <100 × 10/L, hematocrit <25%, or who had received a blood transfusion in the preceding 10 days were also excluded. A dedicated data coordinating center performed all data management and analyses. Prespecified clinical and laboratory data during hospitalization periods were obtained from hospital charts reviewed by independent research personnel blinded to the study objectives. The institutional review board at MedStar Washington Hospital Center and the MedStar Research Institute (Washington, DC) approved this study.
Procedures and Adjunctive Medical Therapy
All patients received a 600-mg loading dose of clopidogrel ≥6 hours before platelet reactivity testing or a 75-mg maintenance dose for ≥5 days before testing. All patients received aspirin 81 to 325 mg 6 to 24 hours before testing. After the procedure, aspirin was prescribed indefinitely, and clopidogrel was prescribed for a minimum of 1 month in patients receiving bare-metal stents for elective PCI and for 12 months in patients receiving drug-eluting stents and in all acute coronary syndrome patients.
Platelet Function Testing
All patients underwent platelet reactivity testing with VN and LTA (Chrono-Log, Havertown, PA). Whole blood samples were drawn 6 to 24 hours post-PCI through an 18-gauge or larger needle into 3.2% sodium citrate tubes, including 1.8-mL Greiner tube for the VN assay. Platelet reactivity testing was performed within 3 hours of blood sampling. The VN assay was performed by the addition of whole blood to dedicated cartridges containing fibrinogen-coated beads. The P2Y12 cartridge consists of 2 channels; in the first, ADP is used as agonist, in combination with prostaglandin E1 to limit the contribution of P2Y1. The increase in light transmittance, proportional to platelet aggregation, is reported as PRU. The second channel contains the thrombin receptor activating agonist (iso-TRAP) as the sole agonist, which provides a base value (iso-TRAP BASE) for platelet function independently of P2Y12 receptor blockade The device also provides an estimated percentage inhibition (percent inhibition) calculated as [(BASE − PRU/BASE) × 100], without preclopidogrel sample by reporting the ratio of the results of the adenosine diphosphate-prostaglandin E1 (ADP-PGE1) and iso-TRAP channels. Light transmission aggregometry was performed at 37°C using platelet-rich plasma. Aggregation parameters were measured with ADP 5 and 20 μM as agonists; these on-treatment platelet reactivity values are reported as percentages of maximum platelet aggregation (MPA).
Definitions
High on-treatment platelet reactivity (HTPR) was defined as PRU ≥208 for VN P2Y12, MPA ≥46% for LTA with ADP 5 μM, and MPA ≥59% for LTA with ADP 20 μM. The composite end point of major adverse cardiac events (MACEs) included death, nonfatal myocardial infarction, and definite stent thrombosis.
Statistical Analysis
Continuous variables are presented as mean ± SD or median with interquartile range, and categorical variables are presented as percentages. Differences in continuous variables between groups were compared using the Student t test or the Wilcoxon rank sum test as appropriate. Categorical variables were compared using χ test or Fisher exact test. The correlation between continuous variables was established using Pearson correlation coefficient. A receiver operating characteristic curve analysis was used to determine the ability of the assay to distinguish between patients with and without 1-year MACE. Independent correlates of HTPR were identified using multivariable logistic regression. Hematocrit, African American race, gender, age, diabetes mellitus, coronary artery disease, myocardial infarction, coronary artery bypass surgery, creatinine clearance, body mass index, congestive heart failure, hypercholesterolemia, peripheral vascular disease, current smoking, statin use, clopidogrel loading, and clinical presentation of unstable angina and acute myocardial infarction were the variables included in a univariate model. The variables with P < .05 and clinically relevant variables were included in a multivariate analysis using logistic regression in separate models with HTPR by PRU ≥208, LTA ADP 5 μM ≥46%, and LTA ADP 20 μM ≥59% as outcomes. We also assessed the incremental influence of addition of hematocrit, each platelet function assay results, and the interaction between the 2 to a baseline set of clinical variables in predicting the 1-year MACE. The clinical variables included age, history of diabetes mellitus, prior coronary artery disease, prior coronary artery bypass surgery, estimated glomerular filtration rate, body mass index, and unstable angina. The area under the curve (AUC) and 95% CI were calculated for each logistic regression model, and the differences between the AUC for different models were assessed. P < .05 was considered statistically significant. Statistical analyses were performed using SAS 9.3 (SAS Institute, Cary, NC).
No extramural funding was used to support this work. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the manuscript, and its final contents.
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