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Archives of cardiovascular diseases
Volume 106, n° 11
pages 593-600 (novembre 2013)
Doi : 10.1016/j.acvd.2013.06.050
Received : 22 January 2013 ;  accepted : 11 June 2013
Impact of initial clinical presentation on clopidogrel low response
Impact de la présentation clinique initiale sur la réponse au clopidogrel
 

Jean-Baptiste Landel a, Anne Bauters b, Cédric Delhaye a, Laurent Bonello c, Arnaud Sudre a, Sophie Susen b, Christophe Bauters a, Jean-Marc Lablanche a, Gilles Lemesle a,
a Unité des soins intensifs de cardiologie, centre hémodynamique, clinique de cardiologie, hôpital cardiologique, centre hospitalier régional et universitaire de Lille, boulevard du Pr-Jules-Leclercq, 59037 Lille cedex, France 
b Laboratoire d’hématologie, centre hospitalier régional et universitaire de Lille, 59037 Lille cedex, France 
c Service de cardiologie, hôpital Nord de Marseille, Assistance publique des Hôpitaux de Marseille, 13000 Marseille, France 

Corresponding author. Fax: +33 3 20 44 48 98.
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 18–24h after a 600mg 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±5.6kg/m2 in the ACS group and 27.9±5.9kg/m2 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.

The full text of this article is available in PDF format.
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 24heures après une dose de charge de 600mg 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±12ans 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±5,9kg/m2 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.

The full text of this article is available in PDF format.

Keywords : VerifyNow-P2Y12, Clopidogrel response, Antiplatelet therapy, Percutaneous coronary intervention, Acute coronary syndromes

Mots clés : VerifyNow-P2Y12, Réponse au clopidogrel, Antiagrégant plaquettaire, Angioplastie coronaire percutanée, Syndrome coronaire aigu

Abbreviations : ACS, ADP, BMI, PCI, PRU


Background

Large interindividual variability exists in response to clopidogrel [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11]. In 2002, Jaremo et al. were the first to report interindividual variability in clopidogrel response after a 300mg loading dose and by using a flow cytometry technique with adenosine diphosphate (ADP) as agonist [8]. Since then, these results have largely been confirmed by numerous studies using either light transmission aggregometry [5, 6, 7], the vasodilator-stimulated protein test [1, 2, 3, 4, 5] or the VerifyNow-P2Y12® test [10, 11]. 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%) [12]. 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 [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11]. 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” [12].

It is critical, therefore, to identify predictors of clopidogrel low response. Genetic polymorphism (CYP2C19*2, etc.) [13, 14, 15, 16, 17], diabetes [18], obesity [19] and treatment interaction (e.g. with proton pump inhibitors) [14, 20] 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±1kg/m2) 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 18–24hours after a 600mg loading dose of clopidogrel using the VerifyNow-P2Y12® test (Accumetrics, San Diego, CA, USA). The study flow chart is displayed in Figure 1.



Figure 1


Figure 1. 

Study design. ACS: acute coronary syndromes; BMI: body mass index.

Zoom

Power calculation

After a 600mg 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 [21]. Similarly, Price et al. found a mean PRU value of 184±85 in stable patients [11]. By contrast, Patti et al. reported higher PRU values (258±53) in a population of patients of whom 60% had ACS [10]. 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 18–24h after a 600mg loading dose of clopidogrel using the VerifyNow-P2Y12® test [22]. 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 20μmol ADP and 22μmol 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 [23].

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) [23], 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±5.6kg/m2 in the ACS group and 27.9±5.9kg/m2 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.

Baseline biological characteristics are summarized in Table 2. Mean haematocrit, platelet count and creatinine levels were similar between the two groups. Mean glycosylated haemoglobin was 6.7±1.5% in the ACS group and 6.8±1.6% in the stable group (p =0.83). There was a trend for higher glycaemia at admission in the ACS group: 1.30±0.42g/L vs. 1.14±0.44g/L (p =0.07). The mean C-reactive protein value was higher in the ACS group: 15.5±3.4mg/L vs. 4.1±3.6mg/L (p =0.05). Total cholesterol (but not low-density lipoprotein cholesterol) was higher in the ACS group, as was triglyceridaemia.

As shown in Table 3, no differences were noted between the two groups in terms of treatment received within the 24h before the VerifyNow-P2Y12® test except for type of heparin. In accordance with the protocol, none of the patients received bivalirudin, thrombolytic and/or glycoprotein IIb/IIIa inhibitor treatment. None of the patients was on chronic clopidogrel treatment before inclusion.

Impact of initial clinical presentation on clopidogrel low response

As shown in Figure 2, there was a significant difference in PRU values between the ACS group and the stable group: 197±81 vs. 159±94, respectively (p =0.03). When the cut-off point of 230 was used to define patients as low responders, there were 19 (38%) low responders in the ACS group and 9 (18%) in the stable group (p =0.04).



Figure 2


Figure 2. 

Impact of initial clinical presentation on platelet reaction unit (PRU) values as assessed by the VerifyNow-P2Y12® test. ACS: acute coronary syndromes.

Zoom

When PRU was analysed as a continuous variable, the ACS group was independently associated with higher PRU values by multivariable analysis (p =0.02). BMI was also significantly associated with higher PRU values (p =0.03) and there was a trend for higher PRU values in older patients (p =0.08) (Table 4). When PRU was analysed as a binary variable (low responders if PRU>230), the ACS group was the only independent predictor of low response to clopidogrel by multivariable analysis (p =0.04).

Discussion

The most important finding in our prospective study is that initial clinical presentation seems to play a pivotal role in the response to clopidogrel. Indeed, patients presenting with ACS had significantly higher platelet reactivity after a 600mg loading dose of clopidogrel compared with patients with stable CAD as assessed by the VerifyNow-P2Y12 test: 197 PRUs vs. 159 PRUs, respectively. This difference remained significant when adjusted for previously identified modulators of clopidogrel response and platelet reactivity. In addition, the rate of low responders to clopidogrel (defined as a PRU value>230) [23] was twofold higher in the ACS group compared with in the stable group. Patients of both groups were well matched. This suggests that the evolution of CAD for one patient influences the clopidogrel response over time.

Many studies have reported the presence of a large interindividual variability in clopidogrel response, especially in the context of ACS [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11]. However, the presence of any intraindividual variability over time is still debated. Patients with low response to clopidogrel are at higher risk of severe cardiovascular events, such as death, myocardial infarction and/or stent thrombosis [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11]; it may be critical to perfectly identify such patients. In the literature, many variables have been shown to correlate with low response to clopidogrel. Some of these variables are not modifiable, such as genetic polymorphism (CYP2C19*2, etc.) [13, 14, 15, 16, 17] and the presence of diabetes [18]. Others, however, are clearly not constant over time, such as BMI [19] and, especially, the clinical status of the patients (ACS or stable CAD).

Importantly, some authors have reported that there is particularly high platelet reactivity at baseline in the context of ACS [24, 25, 26, 27] as well as in the settings of infections and/or inflammation. In 1966, Hampton et al. reported that platelets were more activated by ADP and noradrenalin in the context of myocardial infarction [25]. In addition, some authors have suggested a correlation between the level of platelet reactivity at baseline and the response to clopidogrel [24]. Gurbel et al. published data in accordance with such a concept [28]. We subsequently hypothesized the presence of intraindividual variability over time, related to the clinical status of the patient (ACS versus stable CAD). Our results seem to confirm the concept of intraindividual variability to clopidogrel. Indeed, the presence of ACS was independently associated with a lower response to clopidogrel. Just as a reminder, patients in both groups were well matched on age, sex, diabetes and BMI.

Of note, our results are also in accordance with the results of the different randomized trials assessing the benefit of stronger antiplatelet therapies in the context of ACS, even in medically treated patients (no PCI and no stent implantation). Patients with ACS are indeed at high risk of recurrent ischaemic events, potentially related to higher platelet reactivity. In all these trials, authors have subsequently tested stronger antiplatelet therapies without assessing the real response to the standard dose of clopidogrel. The CURE [29], CREDO [30] and CLARITY-TIMI 28 [31] studies showed initially that a standard dose of clopidogrel has significant benefit on top of aspirin in patients with ST-segment elevation or non-ST-segment elevation myocardial infarction, even in the medically treated group. More recently, the CURRENT-OASIS 7 [32], PLATO [33] and TRITON-TIMI 38 [34] studies confirmed the need for higher inhibition of platelet aggregation in STEMI and NSTEMI patients by using higher doses of clopidogrel or more powerful treatments, such as ticagrelor [33] or prasugrel [34, 35]. By contrast, no study has ever shown any benefit for high doses of clopidogrel or other more powerful treatment in stable patients. Together with our results, these observations suggest the presence of intraindividual variability in clopidogrel response over time and the critical impact of ACS in this setting.

If previous studies have suggested large interindividual variability in clopidogrel response: “one size does not fit all”; our study suggests also the presence of intraindividual variability: “one size does not fit the patient throughout life”. The real problem is to know when the low response to clopidogrel related to ACS disappears and when we could decrease antiplatelet therapies after ACS. Indeed, maintaining a high level of platelet inhibition when unnecessary could lead to a high risk of major bleeding [36].

Conclusion

The present study suggests that initial clinical presentation (especially ACS) is a strong predictor of clopidogrel low response; this suggests that the evolution of CAD for one patient influences clopidogrel response over time. These results are in accordance with recent trials showing a benefit for increased antiplatelet therapy in ACS patients.

Disclosure of interest

The authors declare that they have no conflicts of interest concerning this article.

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