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Archives of cardiovascular diseases
Volume 110, n° 11
pages 626-633 (novembre 2017)
Doi : 10.1016/j.acvd.2016.12.017
Received : 2 October 2016 ;  accepted : 22 December 2016
Impact of platelet inhibition level on subsequent no-reflow in patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction
Impact du niveau d’inhibition plaquettaire sur la survenue du no-reflow chez les patients admis pour syndrome coronaire aigu avec sus-décalage du segment ST qui vont bénéficier d’un traitement par angioplastie primaire

Omar Aitmokhtar a, b, , Franck Paganelli c, Saida Benamara a, Adel Azaza a, Laurent Bonello b, c, Ouafa Hamza a, Saber Seddiki a, Tayeb Benathmane b, Mourad Saidane a, Ahmed Bouzid a, Maamar Kara a, Arezki Sik a, Abdelmalek Azzouz a, Faiza Harbi a, Jean-Jacques Monsuez d, Salim Benkhedda a, b
a Department of cardiology, Mustapha Hospital university, 1, place du 1er-Mai, 16001 Algiers, Algeria 
b Cardiology Oncology Research Collaborative Group (CORCG), University of Medicine of Algiers Benyoucef Benkhedda, Algiers, Algeria 
c Department of cardiology, Nord Hospital university, 13015 Marseille, France 
d Cardiology, AP–HP, Hospital René Muret, University of Paris Seine-Saint-Denis, Paris, France 

Corresponding author. Department of cardiology, Mustapha Hospital University, 1, place du 1er-Mai, 16001 Algiers, Algeria.

High P2Y12 platelet reactivity (PR) level after primary percutaneous coronary intervention (PPCI) for ST-segment elevation myocardial infarction (STEMI) affects prognosis and may induce the no-reflow phenomenon.


To investigate the role of PR in the genesis of microvascular obstruction.


Patients with STEMI undergoing PPCI within 12hours of symptoms onset were included prospectively. All patients received a 600mg clopidogrel-loading dose before PPCI and 250mg aspirin. PR was measured thereafter during PPCI while wiring the culprit lesion and before coronary dilatation, using the P2Y12 VerifyNow® assay. No-reflow was defined as ST-segment regression<50% observed 90minutes after PPCI.


Between January 2014 and November 2015, 140 STEMI patients were included, and divided into two groups: a low PR group (LPR) defined as PR<209P2Y12 reaction units (PRU); and a high PR group (HPR) defined as PR209PRU. There were no differences in baseline characteristics between LPR and HPR groups, including age (57.8±11.9 vs. 59.4±13.2 years, respectively; P =0.44) and weight (76.1±15.1 vs. 74.8±10.9kg, respectively; P =0.55). Delay to revascularization was 270.1±175.5 vs. 295.6±206.2minutes (P =0.49) and time between clopidogrel-loading and PR measurement was 53±37 vs 65±54minutes (P =0.29) in the LPR and HPR groups, respectively. No-reflow was more frequent in the HPR group (44 [47.3%] vs. 9 [19.1%]; P =0.0012). Mean PR was higher in patients with no-reflow: 268.3±53 vs. 223.8±50.1 PRU (P =0.002). In multivariable analysis, HPR was an independent predictor of no-reflow. Area under the receiver operating characteristic curve was 0.745 (0.654, 0.835); the cut-off value predicting no-reflow was 254PRU.


High PR level measured at PPCI is independently associated with no-reflow.

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Une réactivité plaquettaire (RP) P2Y12 élevée mesurée après une angioplastie primaire (AP) est associée à un mauvais pronostic et une fréquence plus élevée de no reflow. La prédiction du no-reflow par des tests réalisés au lit du malade avant la réalisation de l’AP pourrait avoir des implications thérapeutiques.


Nous avons voulu étudier la relation entre le niveau de RP mesure avant l’AP et la survenue du no reflow.


Les patients admis pour syndrome coronaire aigu avec sus-décalage du segment ST (SCA sus ST) de moins de 12heures du début des symptômes et qui vont bénéficier d’une AP ont été inclus, ils ont reçu une dose de charge de 600mg de clopidogrel et 250mg d’aspirine dès l’admission. La RP a été mesurée par le VerifyNow P2Y12 (Acumetrics®) au moment de l’AP. Le no-reflow a été défini par une régression de moins de 50 % du segment ST 90mn après l’AP.


Entre janvier 2014 et novembre 2015, 140 patients admis pour SCA sus ST ont été inclus. On a individualisé 2 groupes : un groupe avec RP basse (RPB) défini par une RP<209 PRU et un groupe avec RP élevée (RPE) défini par une RP>209PRU. Il n’y avait pas de différences significatives entre les caractéristiques de base entre le groupe RPB et le groupe RPE, incluant l’âge : 57,8±11,9 ans vs. 59,4±13,2 ans (p =0,44) et le poids 76,1±15,1 kg vs. 74,8±10,9 kg (p =0,55) respectivement. Le délai de revascularisation moyen était de 270,1±175,5 vs 295,6±206,2min (p =0,49), le temps entre l’administration du clopidogrel et la mesure de la RP était 53±37mn vs. 65±54min (p =0,29) dans les groupes RPB et RPE respectivement. La survenue du no-reflow était significativement plus fréquente dans le groupe RPE 44 (47,3 %) vs. 9 (19,1 %) p =0,0012. La RP moyenne était plus élevée dans le groupe avec no-reflow comparée au groupe avec reflow 268,3±53 PRU vs 223,8±50,1 PRU, p =0,002. En analyse multivariée, un niveau élevé de RP était un facteur prédictif indépendant de survenue de no-reflow . L’aire sous la courbe (ROC) était 0,745 (0,654, 0,835) pour une valeur seuil de 254 PRU.


Une RP élevée mesurée au moment de l’AP est un facteur indépendant associe à la survenue du no-reflow .

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

Keywords : Primary PCI, ST-segment resolution, No-reflow, Platelet reactivity

Mots clés : Angioplastie primaire, Résolution du segment ST, No reflow, Réactivité plaquettaire

Abbreviations : CI, OR, PPCI, PR, PRU, ROC, STEMI, TIMI


Platelet reactivity (PR) is believed to play a key role in the pathogenesis of acute coronary syndromes and ST-segment elevation myocardial infarction (STEMI) [1, 2]. Potent and rapid-onset platelet inhibition is also important during primary percutaneous coronary intervention (PPCI) in STEMI, a setting with a high degree of platelet activation and risk of periprocedural thrombotic complications [3, 4]. Previous studies have shown that enhanced PR is predictive of the extent of myocardial necrosis in STEMI [5]. Furthermore, the process of thrombus formation, rather than being limited to the culprit lesion, has been shown to spread downwards to the distal microcirculation instead [6, 7].

In patients with STEMI undergoing PPCI, impaired pharmacokinetics response with adenosine diphosphate antagonists has been described after a 600mg clopidogrel-loading dose [8]. Although the P2Y12 inhibitors prasugrel and ticagrelor result in faster antiplatelet action, suboptimal early platelet inhibition has been reported by Valgimigli et al. [9], while clinical studies failed to demonstrate any substantial benefit from the prehospital administration of either prasugrel or ticagrelor to patients with acute coronary syndromes undergoing subsequent PPCI [10, 11]. Thus, in many instances, PPCI is performed with P2Y12 inhibition that may be inadequate [12]. In a recent study of patients treated with the fast-acting antiplatelet agents prasugrel or ticagrelor, as recommended by the European Society of Cardiology guidelines on STEMI [13], up to 40% of patients had high on-treatment PR during PCI [14]. Whereas subsequent studies focused on developing strategies to overcome this initial gap in the early course of STEMI [12, 15, 16], none has been clearly effective. Because of this high on-treatment PR, distal microcirculation injury and the related no-reflow phenomenon may occur in many instances [14, 17, 18]. No-reflow, defined as low or no distal perfusion despite removal of epicardial occlusion, can be detected by angiographic flow, myocardial blush grade, cardiac magnetic resonance imaging and contrast echocardiography, and, in daily practice, by a final thrombolysis in myocardial infarction (TIMI) flow<grade 3 seen with angiography. While also depending on myocardial damage and reperfusion injury, the absence of ST-segment elevation resolution is linked to no-reflow [19, 20].

The present study aimed to evaluate the impact of PR level measured at the bedside at the time of PPCI after a 600mg clopidogrel-loading dose on the no-reflow phenomenon.


We prospectively evaluated 140 consecutive patients presenting with acute STEMI within 12hours of symptom onset. Diagnosis of STEMI was based on the presence of typical angina pain and ST-segment elevation of1mm in at least two contiguous electrocardiographic leads. All patients were treated with an intravenous 250mg-loading dose of aspirin and a 600mg-loading dose of clopidogrel on arrival at the emergency room or the intensive coronary care unit. Administration of a glycoprotein IIb/IIIa antagonist (tirofiban) at the time of PPCI was left to the discretion of the physician performing the coronary angiography. Patients with cardiogenic shock, contraindication to thienopyridine treatment, left bundle branch block and paced rhythm were excluded.

Analyses of angiograms and ST-segment resolution were performed by two cardiologists blinded to the clinical findings and PR. Assessment of coronary blood flow was performed using the thrombolysis in myocardial infarction (TIMI) grading system. Initial and final TIMI flow grades were recorded. Initial TIMI flow was defined as the flow first seen on the initial cine run and final TIMI flow was defined as the flow seen on the last cine run after PPCI. No-reflow was defined as ST-segment resolution<50%. The highest ST-segment elevation was measured at admission and 90minutes after PPCI in the same lead.

PR measurement

PR was measured at the time of PPCI after clopidogrel-loading and before crossing the culprit coronary lesion. The first 2–4mL of blood were discarded to avoid spontaneous platelet activation and blood samples were collected in 2.7mL BD Vacutainer® plastic whole blood tubes with 3.2% sodium citrate (Becton, Dickinson & Co., Plymouth, UK). Then, a platelet function test was performed immediately, using the VerifyNow® point-of-care P2Y12 function assay (Accumetrics Inc., San Diego, CA, USA). The results are expressed in P2Y12 reaction units (PRU). The VerifyNow® P2Y12 assay correlates strongly with inhibition of P2Y12 function, as measured by the gold standard of light transmission aggregometry in patients treated with clopidogrel [21].

Statistical analysis

Continuous variables with a normal distribution are presented as means±standard deviations and were compared using unpaired and paired t tests. Categorical variables are presented as numbers and percentages and were compared by the χ 2 test or Fisher's exact test, as indicated. A multivariable analysis was used to determine predictors of no-reflow. A receiver operating characteristic curve was used to determine the PR cut-off value predicting no-reflow. All P values were two sided, and those<0.05 were considered as significant. All calculations were performed using SPPS software, version 17.0 (IBM, Armonk, NY, USA).


Between January 2014 and November 2015, 140 patients with STEMI were included and were divided into two groups: a low PR (LPR) group defined as PR<209 PRU (47 patients); and a high PR (HPR) group defined as PR209 PRU (93 patients). There were no major differences between the LPR and HPR groups in terms of baseline characteristics, including mean age (57.8±11.9 vs. 59.4±13.2 years, respectively; P =0.44) and weight (76.1±15.1 vs. 74.8±10.9kg, respectively; P =0.55) (Table 1). The proportion of patients who were treated chronically with aspirin or clopidogrel before the acute phase of STEMI and inclusion was similar in the two groups. Use of morphine was similar in the two groups (Table 1). The delay to revascularization was 270.1±175.5minutes in the LPR group and 295.6±206.2minutes in the HPR group (P =0.49); the time between the clopidogrel-loading dose and measurement of PR was similar in the LPR and HPR groups (53±37 vs. 65±54minutes; P =0.29). At the time of PPCI, 66.4% of patients had a PR value209 PRU. Angiographic characteristics are described in Table 2.

The incidence of no-reflow was significantly more frequent in HPR group than in the LPR group (44 [47.3%] vs. 9 [19.1%]; P =0.0012). Mean PR was higher in patients with no-reflow compared with in patients with reflow: 268.3±53 vs 223.8±50.1 PRU (P =0.002) (Figure 1).

Figure 1

Figure 1. 

Mean platelet reactivity in no-reflow and normal flow groups.


Using univariate analysis, predictive factors for no-reflow were diabetes mellitus (odds ratio [OR] 2.03, 95% confidence interval [CI] 1.01–4.12; P =0.048), HPR (OR 4.73, 95% CI 1.75–12.76; P =0.002), female sex (OR 4.34, 95% CI 1.6–12.5; P =0.005) and TIMI flow<grade 3 after PPCI (OR 3.33, 95% CI 1.42–9.09; P =0.003) (Table 3).

Using multivariable analysis, including sex, diabetes mellitus, thrombus aspiration, delay to revascularization, TIMI flow after PPCI, PR status (HPR) and age, HPR and TIMI flow after PPCI remained independent predictors of no-reflow (Table 4). Interestingly, the area under the receiver operating characteristic curve was 0.745 (0.654, 0.835) and 254 PRU was the cut-off value predicting no-reflow (Figure 2).

Figure 2

Figure 2. 

Receiver operating characteristic (ROC) analysis determining the VerifyNow® cut-off value predicting no-reflow. AUC: area under the curve.



In the present study, we prospectively evaluated the impact of PR level measured at the time of PPCI after pretreatment with a clopidogrel-loading dose on no-reflow. The major findings were: that a high level of P2Y12 PR measured at the moment of PPCI is independently associated with no-reflow; and that a PR level>254 PRU has a high predictive value for no-reflow.

Campo et al. [22] showed that a high baseline PR measured by PFA-100® (Siemens Heathineers, Erlangen, Germany) before antiplatelet treatment was associated with no-reflow, as assessed by electrocardiography. In their study, mean PFA-100® was 67 vs. 78seconds in patients with and without no-reflow, respectively (P <0.001). Another study showed that a 600 vs. 300mg clopidogrel-loading dose improved microvascular reperfusion evaluated by blush grade in 255 STEMI patients (OR 0.64, 95% CI 0.43–0.96; P =0.03), thereby emphasizing the key role of PR in this setting [23]. Bozbeyoglu et al. [17] studied the impact of P2Y12 PR on no-reflow in 127 patients. PR was measured 6hours after a clopidogrel-loading dose using P2Y12 VerifyNow®. The incidence of no-reflow was higher in patients with HPR defined as PR>235 PRU (57.1% vs 25.3%; P =0.006). These findings agree with our results, which showed that PR>254 PRU was linked to no-reflow. The use of the new-generation thienopyridines prasugrel and ticagrelor is recommended in STEMI patients [13]. While in stable patients their onset of action is faster than clopidogrel [24, 25], their onset of action remains slow in the setting of PPCI. A recent pharmacodynamic study found that PR measured 2hours after conventional loading doses of prasugrel or ticagrelor in the setting of PPCI was higher than 208 PRU in 35% and 42% of patients, respectively [24]. Also, in the ATLANTIC trial, there was no difference in PR 1, 2 and 6hours after admission in patients pretreated prehospitalization compared with those who were given the loading dose in the catheterization laboratory, although there was a relatively short time difference between the two approaches in this study [10]. In our study, adequate platelet inhibition at the time of PPCI was associated with better indexes of myocardial reperfusion, including a significant inverse correlation between PR at the time of PPCI and ST-segment resolution [10]. These findings agree with previous results. Frossard et al. showed that PR is an independent predictor of infarction extent measured by cardiac biomarkers [5]. A substudy of the single high dose bolus tirofiban and sirolimus eluting stent versus abciximab and bare metal stent in myocardial infarction (STRATEGY) trial demonstrated, in a group of 70 patients with STEMI undergoing PPCI, that PR after a glycoprotein IIb/IIIa antagonist bolus was associated with angiographical success, a degree of ST-segment resolution and limited myocardial damage [21]. The present study expands on these data by showing a similar association between platelet response to clopidogrel-loading at the time of PPCI and the results of PPCI in patients with STEMI, because early ST-segment resolution is a reliable marker of myocardial reperfusion [26, 27, 28].

Study limitations

This study has limitations that are mainly inherent to the small sample size. Also, it was performed in a single centre, using a single platelet function assay. The small number of patients warrants cautious interpretation of results and, consequently, this study is not sufficiently powered for clinical outcome reliability. Delay to revascularization in our study was high compared with that observed in large standard-care registries. As this delay has been reported to be a strong predictor of no-reflow, this may partly explain the relatively high incidence of no-reflow in our series [29]. Whether more rapid and profound platelet inhibition could be achieved using alternative strategies, such as novel oral agents or intravenous administration of P2Y12 inhibitors, and thus improve patient outcome, remains to be determined. However, our results support further implications, among which achieving a more potent inhibition of P2Y12 PR before PPCI may be beneficial and may improve subsequent clinical outcome.


Bedside HPR measured at the moment of PPCI is independently associated with ST-segment elevation persistence after revascularization.

Sources of funding

Hikma Laboratory and Vicralys Laboratory, Algeria.

Disclosure of interest

The authors declare that they have no competing interest.


We thank Hikma Laboratory and Vicralys Laboratory, Algeria, for their financial support.


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