Summary
Background
Large interindividual variability exists in clopidogrel response. Clopidogrel low response correlates with poor prognosis after percutaneous coronary intervention. Some authors also suggest intraindividual variability over time.
Aim
To assess the impact of initial clinical presentation on clopidogrel low response.
Methods
In this prospective study, clopidogrel response was assessed in 100 patients. Fifty patients presenting with acute coronary syndromes (ACS group) were compared with 50 patients with stable coronary artery disease matched 1:1 for age, sex, body mass index and diabetes (stable group). All patients were tested 18–24 h after a 600 mg loading dose of clopidogrel using the VerifyNow-P2Y12 test (results expressed as platelet reaction units [PRUs]). Patients under chronic clopidogrel therapy or treated with glycoprotein IIb/IIIa inhibitors, bivalirudin or thrombolytics were excluded.
Results
Mean age was 61 ± 12 years in each group; 28% of patients in each group were diabetic; mean body mass index was 27.6 ± 5.6 kg/m 2 in the ACS group and 27.9 ± 5.9 kg/m 2 in the stable group ( p = 0.80). Mean PRU values were 197 ± 81 in the ACS group and 159 ± 94 in the stable group ( p = 0.03). By multivariable analysis, the ACS group was significantly associated with a higher PRU value ( p = 0.02). There were significantly more clopidogrel low responders (PRU value > 230) in the ACS group (38% vs. 18%; p = 0.04).
Conclusion
Our study confirms that initial clinical presentation, especially ACS, is a strong predictor of clopidogrel low response; this suggests that the evolution of coronary artery disease for one patient influences the clopidogrel response over time. These results are in accordance with recent trials showing a benefit for more aggressive antiplatelet therapy in ACS patients.
Résumé
Contexte
Une mauvaise réponse biologique au clopidogrel est associée à un pronostic défavorable des patients après angioplastie coronaire percutanée (ACP). Il est clairement démontré qu’il existe une large variabilité interindividuelle dans la réponse au clopidogrel. Certains auteurs suggèrent également la présence d’une variabilité intraindividuelle au cours du temps.
Objectif
Nous avons analysé l’impact de la présentation clinique initiale sur la réponse au clopidogrel.
Méthodes
Dans cette étude prospective, la réponse biologique au clopidogrel a été analysée chez 100 patients. Au total, 50 patients présentant initialement un syndrome coronaire aigu (groupe SCA) ont été appariés 1:1 à 50 patients présentant un angor stable (groupe stable) sur l’âge, le sexe, l’indice de masse corporelle et le diabète. Tous les patients ont été testés par le test du VerifyNow-P2Y12 (résultats exprimés en platelet reaction unit [PRU]) entre 18 et 24 heures après une dose de charge de 600 mg de clopidogrel. Les patients traités au long cours par clopidogrel, ceux ayant reçu un fibrinolytique, de la bivalirudine ou un inhibiteur du récepteur Gp IIb/IIIa ont été systématiquement exclus de cette étude.
Résultats
L’âge moyen était de 61 ± 12 ans dans chaque groupe. Au total, 28% des patients étaient diabétiques dans chaque groupe et l’indice de masse corporelle était de 27,6 ± 5,6 et 27,9 ± 5,9 kg/m 2 dans le groupe « SCA » et dans le groupe « stable », respectivement ( p = ns). Les valeurs de PRU moyennes étaient de 197 ± 80 et 159 ± 94 dans le groupe « SCA » et dans le groupe « stable », respectivement ( p = 0,033). En analyse multivariée, le groupe « SCA » était significativement associé à des valeurs de PRU plus élevées ( p = 0,018). Il y avait significativement plus de « mauvais répondeurs » (définis comme une valeur de PRU > 230) dans le groupe « SCA » (18% vs 38%; p = 0,04).
Conclusion
Cette étude confirme que la présentation clinique initiale, notamment le SCA, est un facteur prédictif puissant de mauvaise réponse au clopidogrel. Elle suggère également que l’évolution de la maladie coronaire pour un patient donné influence la réponse au clopidogrel au cours du temps. Ces résultats sont en accord avec les récents essais montrant un bénéfice à une thérapeutique antiagrégante plaquettaire plus agressive dans le SCA.
Background
Large interindividual variability exists in response to clopidogrel . In 2002, Jaremo et al. were the first to report interindividual variability in clopidogrel response after a 300 mg loading dose and by using a flow cytometry technique with adenosine diphosphate (ADP) as agonist . Since then, these results have largely been confirmed by numerous studies using either light transmission aggregometry , the vasodilator-stimulated protein test or the VerifyNow-P2Y12 ® test . However, according to a recent meta-analysis, the rate of “low responders” among patients undergoing percutaneous coronary intervention (PCI) varies greatly from 10% to 50% (average 21%) . Indeed, the methodologies of the different studies sometimes differ widely: loading dose of clopidogrel, type of test used, definition of low response used, type and quantity of agonist used, timing of the test after the loading dose, etc.
Of main importance, clopidogrel low response has been shown to correlate strongly with poor prognosis after PCI. Indeed, many studies have shown an increased risk of death, myocardial infarction and/or major adverse cardiovascular events . The meta-analysis of Snoep et al., which included 25 studies and 3688 patients, reported a pooled odds ratio for major adverse cardiovascular events of 8 (95% confidence interval 3.4–19) in clopidogrel low responders compared with “good responders” .
It is critical, therefore, to identify predictors of clopidogrel low response. Genetic polymorphism (CYP2C19*2, etc.) , diabetes , obesity and treatment interaction (e.g. with proton pump inhibitors) have been shown to significantly impact the clopidogrel response. In addition, some authors also suggest intraindividual variability over time.
This study aims to assess the impact of initial clinical presentation just before stenting (either acute coronary syndromes [ACS] or stable coronary artery disease [CAD]) on clopidogrel low response.
Methods
Study design and population
In this prospective study, clopidogrel response was assessed in 100 patients in our catheter laboratory. All patients were included between November 2010 and August 2011 and gave their informed consent to the study. Fifty patients presenting with ACS (ACS group) were compared with 50 patients with stable CAD, matched 1:1 for age (±3 years), sex, body mass index (BMI ± 1 kg/m 2 ) and diabetes (stable group). All patients in the stable group underwent a coronary angiogram in the context of stable angina and/or documented silent ischaemia. All patients were tested for platelet reactivity and clopidogrel response 18–24 hours after a 600 mg loading dose of clopidogrel using the VerifyNow-P2Y12 ® test (Accumetrics, San Diego, CA, USA). The study flow chart is displayed in Fig. 1 .
Power calculation
After a 600 mg loading dose of clopidogrel, Cuisset et al. reported a mean platelet reaction unit (PRU) value of 199 ± 93 (using the VerifyNow-P2Y12 ® test) in patients with stable CAD . Similarly, Price et al. found a mean PRU value of 184 ± 85 in stable patients . By contrast, Patti et al. reported higher PRU values (258 ± 53) in a population of patients of whom 60% had ACS . Based on these previous results, the expected mean PRU values of 250 in the ACS group and 190 in the stable group and the expected standard deviation of 90, 49 patients were needed in each group to achieve a power of 90% and a significance level (α) of 5%. Altogether, 100 patients were included in the present study: 50 patients in each group.
Exclusion criteria
The exclusion criteria were as followed: patients aged < 18 years; pregnant women; patients who did not consent to the study or who lacked the capacity to consent; patients on chronic clopidogrel treatment (or another ADP receptor antagonist) before the loading dose; patients treated with thrombolytic therapy, bivalirudin and/or glycoprotein IIb/IIIa inhibitors; patients with a platelet count < 100 Giga/L and/or a haematocrit level < 30%; and patients in cardiogenic shock.
Primary endpoint
The aim of the present study was to assess the impact of the initial clinical presentation of patients undergoing PCI on clopidogrel response. The primary endpoint was to compare the mean PRU value (using the VerifyNow-P2Y12 ® test) between the two groups: the ACS group and the stable group.
Clopidogrel low response assessment
All patients were tested for platelet reactivity and clopidogrel response 18–24 h after a 600 mg loading dose of clopidogrel using the VerifyNow-P2Y12 ® test . The VerifyNow-P2Y12 ® System is an automated point-of-care turbidimetry-based optical detection system that measures platelet-induced aggregation. The system consists of an analyser instrument and a disposable assay device. The instrument controls all assay sequencing, the temperature and reagent sample mixing and performs self-diagnostics. The assay device contains a lyophilized preparation of human fibrinogen-coated beads, platelet activators and buffer. The patient sample is whole blood, automatically dispensed from the blood collection tube into the assay device by the instrument. The VerifyNow-P2Y12 ® assay contains 20 μmol ADP and 22 μmol prostaglandin E1 to reduce the activation contribution from ADP binding to P2Y1 receptors. The VerifyNow-P2Y12 ® instrument measures platelet-induced aggregation as an increase in light transmittance and uses a proprietary algorithm to report values in PRUs and percentage of platelet inhibition. A higher PRU value reflects greater P2Y12-mediated reactivity. According to the literature, clopidogrel low responders are defined as patients with a PRU value > 230 .
Statistical analysis
Continuous variables are expressed as means ± standard deviations. Categorical variables are expressed as absolute numbers and percentages. Baseline characteristics between the two groups were compared using the chi-square test or Fisher’s test for categorical variables and Student’s unpaired t test for continuous variables, as appropriate. Correlations between the clopidogrel response (PRU values assessed as a continuous variable) and the different tested variables were evaluated using Pearson’s correlation test for continuous variables and Student’s t test for categorical variables. A multivariable analysis was then performed using linear regression and including the following variables: age, sex, ACS group, BMI, diabetes, renal failure, proton pump inhibitor use and all variables with a p value < 0.2 in univariate analysis. To identify the predictors of low responders (PRU values assessed as a categorical variable with a cut-off point of 230, according to the literature) , the different variables were tested using the chi-square test. A multivariable analysis was then performed using logistic regression and including the following variables: age, sex, ACS group, BMI, diabetes, renal failure, proton pump inhibitor use and all variables with a p value < 0.2 in univariate analysis. All statistical analyses were performed with SPSS 17.0 for Windows ® software (SPSS Inc., Chicago, IL, USA). Statistical significance was assumed at a p value < 0.05.
Results
Population
Baseline clinical characteristics of the population are summarized in Table 1 . The two groups were well matched for age, sex, diabetes and BMI. The mean age was 61 ± 12 years in each group, 28% of patients in each group were diabetic and the mean BMI was 27.6 ± 5.6 kg/m 2 in the ACS group and 27.9 ± 5.9 kg/m 2 in the stable group ( p = 0.80). No significant differences were noted between the two groups among the other variables. In the ACS group, 26 (52%) patients presented as ST-segment elevation myocardial infarction and 24 (48%) patients as non-ST-segment elevation myocardial infarction.
| ACS group ( n = 50) | Stable group ( n = 50) | p | |
|---|---|---|---|
| Age (years) | 60.9 ± 13.3 | 60.7 ± 11.5 | 0.10 |
| Men | 34 (68) | 34 (68) | 1 |
| BMI (kg/m 2 ) | 27.6 ± 5.6 | 27.9 ± 5.9 | 0.80 |
| Diabetes | 14 (28) | 14 (28) | 1 |
| Tobacco use | 24 (48) | 22 (44) | 0.69 |
| Hypercholesterolaemia | 24 (48) | 30 (60) | 0.23 |
| Hypertension | 24 (48) | 21 (42) | 0.55 |
| Cardiovascular heredity | 16 (32) | 18 (36) | 0.67 |
| Peripheral vascular disease | 4 (8) | 2 (4) | 0.40 |
| History of stroke | 2 (4) | 3 (6) | 0.65 |
| Renal failure (CrCl < 60 mL/min) | 5 (10) | 4 (8) | 0.73 |
| History of coronary artery disease | 8 (16) | 14 (7) | 0.15 |
| LVEF (%) | 54.4 ± 10.8 | 52 ± 13.7 | 0.33 |
| Initial presentation as STEMI | 26 (52) | – | – |
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