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Müller: prevalence of clopidogrel non-responders among patients with stable angina pectoris …

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Prevalence of clopidogrel non-responders among patientswith stable angina pectoris scheduled for elective coronarystent placement Iris Müller, Felicitas Besta, Christian Schulz, Steffen Massberg, Albert Schönig, Meinrad GawazDeutsches Herzzentrum und 1. Medizinische Klinik, Klinikum rechts der Isar,Technische Universität München, Munich, Germany Summary
Dual antiplatelet therapy with aspirin and clopidogrel decreas-
tion that was less than 10% when compared to baseline values es the rate of stent thrombosis in patients undergoing percu- 4 h after clopidogrel intake. Semi-responders were identified by taneous coronary intervention (PCI). However, despite intensi- an inhibition of 10 to 29%. Patients with an inhibition over 30% fied antiplatelet treatment, up to 4.7% of the patients undergo- were regarded as responders.We found that 5 (ADP 5 ␮Mol/L) ing coronary stenting develop thrombotic stent occlusion, sug- to 11% (ADP 20 ␮Mol/L) of the patients were non-responders gesting incomplete platelet inhibition due to clopidogrel re- and 9 to 26% were semi-responders. Among the group of non- sistance. We evaluated the percentage of clopidogrel non- responders there were two incidents of subacute stent throm- responders among 105 patients with coronary artery disease bosis after PCI. We conclude that a subgroup of patients (CAD) undergoing elective PCI.All patients were treated regu- undergoing PCI does not adequately respond to clopidogrel, larly with aspirin 100 mg/d and received a loading dose of 600 which may correspond to the occurrence of thromboischemic mg clopidogrel followed by a maintenance dose of 75 mg/d complications. Point-of-care testing may help to identify these before PCI. Clopidogrel non-responders were defined by an patients who may then benefit from an alternative antiplatelet inhibition of ADP (5 and 20 ␮Mol/L) induced platelet aggrega- Keywords
Platelets, clopidogrel, non-responders, stenting, coronary artery
Thromb Haemost 2003; 89: 783 –7
Intracoronary stents are effective in the treatment of abrupt ves- considerably lowered the rates of stent thrombosis (2-4). A sel occlusion and improvement of suboptimal angioplasty major clinical goal of antithrombotic therapy in patients under- results. In contrast, subacute stent thrombosis is associated with going coronary stent implantation is to be effective as soon as a substantial increase in periprocedural morbidity and mortality possible to prevent early stent thrombosis. Recently we found (1). The introduction of dual antiplatelet therapy with a combi- that increasing the loading dose of clopidogrel up to 600 mg nation of aspirin and a thienopyridine (ticlopidine, clopidogrel) results in rapid and pronounced inhibition of ADP-induced Accepted after revision February 26, 2003 Deutsches Herzzentrum und 1. Medizinische KlinikKlinikum rechts der Isar, Technische Universität München Financial support:This work was supported by a grant from the Deutsche Forschungsgemeinschaft (Ga 381/4-1) and by the Graduate Program 438 Vascular Biology in Medicine.
Tel.: +49-89-1218-4012, Fax: +49-89-1218-4003E-mail: platelet aggregation with maximal inhibition four hours after Platelet aggregation and definition of clopido-
first administration (5, 6). The purpose of the present study was grel non-responders
to evaluate the consistency and inter-individual variability of The effect of clopidogrel on platelet function was evaluated ex platelet inhibition after clopidogrel administration in patients vivo with platelet-rich plasma (PRP) by optical aggregometry as with stable coronary artery disease scheduled for coronary described (7). ADP (5 and 20 ␮Mol/L) was used to induce plate- let aggregation. Inhibition of aggregation was calculated in % asthe absolute reduction in maximum aggregation achieved by ADP (5 and 20 ␮Mol/L) 4 h after clopidogrel administrationcompared to baseline aggregation values before clopidogrelintake. Patients were considered responsive to clopidogrel if Patients
inhibition of aggregation was higher than 30%. Non-responders We studied 105 patients with stable coronary artery disease. All were defined by a platelet inhibition of less than 10% and semi- patients received regular aspirin therapy with a daily dose of responders were characterized by an inhibition of platelet aggre- 100 mg. The study was performed according to the Declaration of Helsinki and after approval by the Institutional EthicsCommittee of the Technische Universität München. All patients Statistical analysis
were extensively informed and provided written consent before Continuous variables are reported as mean ± standard deviation the following treatment. Before coronary angiography they (SD) and categorical variables are presented as frequencies and were given an initial dose of 600 mg clopidogrel. Prior to, 4 and percentages. Continuous variables were tested for intra-individ- 24 h after clopidogrel administration, whole blood was collect- ual differences by using Wilcoxon signed rank test and inter- ed using citrate as anticoagulant. At some patients, blood was individual differences were identified using the Kruskal-Wallis test. Categorical variables were compared using chi-square Table 1: Demographic and clinical character-
istics of patients (n = 105)
Clopidogrel non-responders and coronary stenting Table 2: Mean percentage of aggregation in non-responders,
semi-responders, and responders prior to and 4 h after clopido-
grel administration.
tests. Correlations were calculated by Pearson. P < 0.05 wasconsidered statistically significant. To adjust for multiple com-parisons, a significant level of 0.0125 was used.
The demographic and clinical details of the 105 patients aregiven in the Table 1. Concomitant medication did not differ sig-nificantly between groups (not shown). Baseline aggregationvalues of all patients in response to 5 and 20 ␮Mol/L ADP were65 ± 21% and 79 ± 19%, respectively. We found that 5 to 11%were clopidogrel non-responders and 9 to 26% were semi-responders, which was dependent on the concentration of ADPused to induce aggregation ex vivo (5 and 20 ␮Mol/L). The distribution of non-responders, semi-responders, and respond-ers to clopidogrel among the 105 evaluated patients is given in Figure 2: Effect of clopidogrel on ADP-induced platelet aggrega-
tion. Depicted are individual values of maximal aggregation prior
figure 1. The mean percentage of aggregation of non-respond- to and 4 h after clopidogrel administration in response to ADP ers, semi-responders, and responders prior to and 4 h after 5 ␮Mol/L (A) and ADP 20 ␮Mol/L (B). Non-responders (trian- clopidogrel administration is given in Table 2. Figure 2 shows gle), semi-responders (open circle), responders (closed circle).
a scatter plot of individual aggregation values prior to and 4 hafter clopidogrel administration. Aggregation values in response administration showed a significant intra-individual correla- to 5 and 20 ␮Mol/L ADP determined 4 h after clopidogrel tion (r = 0.820; p <0.001) (Fig. 3). However, in response to 20 ␮Mol/L, a higher number of non- and semi-responders wasfound (Fig. 2). Platelet aggregation was additionally evaluated 24 h after clopidogrel administration in a subgroup of patients (n = 29). Asdescribed previously (5) and as shown herein, we did not findenhanced platelet inhibition 24 h after clopidogrel administra-tion compared to the 4 h values (Fig. 4). This indicates, thatmaximal platelet inhibition is achieved already after 4 hourswhen clopidogrel is administered at an initial dose of 600 mg. Subacute stent thrombosis occurred in two patients at day 6 and 7, respectively, after intracoronary stent placement.
According to our definition both patients were non-responders(inhibition of platelet aggregation <10% after 4 h). In one of Figure 1: Distribution of clopidogrel non-responders, semi-
these patients platelet aggregation was also assessed 14 days, in the other patient 2 and 3 months after first administration of clo- Figure 3: Correlation of platelet aggregation values in response
Figure 4: Platelet aggregation of patients prior to (n = 105),
to 5 and 20 µMol/L ADP 4 h after administration of 600 mg clo- 4 h (n = 105) and 24 hours (n = 29) after clopidogrel adminis- tration.
Values are shown as mean ± standard deviation. An asterisksindicates a significant decrease in platelet aggregation relative tobaseline values (p <0.05).
pidogrel. In both patients platelet inhibition remained less than ing complication after coronary stent placement and occurs in 15% (patient 1: 0% (4 h) and 6% (14 d); patient 2: 0% (4 h), 9% approximately 1% of the patients according to studies per- (2 months) and 13% (3 months) [% inhibition of platelet aggre- formed in specialized interventional cardiology centers (12, 13).
However, recent data from the Duke Medical Center shows that Retrospectively, we assessed platelet aggregation of 3 fur- the incidence of stent thrombosis is up to approximately 5% in ther patients, who developed subacute stent thrombosis at day 6, unselected interventional centers (14).
8, and 28 after PCI. Platelet aggregation was assessed in the first The present study shows that a high variability occurs in the patient at day 15, in the second at day 24 and in the third patient platelet inhibitory response to clopidogrel in patients with coro- 9 months after first administration of clopidogrel (patient 1: nary artery disease. Thus, the effectiveness of combined aspi- 100%; patient 2: 100%, patient 3: 83 % [% of maximal possible rin/clopidogrel therapy has to be questioned in a substantial sub- platelet aggregation, ADP 20 ␮Mol/L]). As platelet aggregation group of patients that do not adequately respond to clopidogrel.
in these patients was subsequently assessed, no baseline value Although the present study did not prospectively test the prior to clopidogrel intake was available. Therefore inhibition hypothesis that clopidogrel non-responders have an increased of platelet aggregation could not be calculated. risk for stent thrombosis, our data showed that 5 patients whodeveloped a stent thrombosis were non-responders. This obser- Discussion
vation suggests that clopidogrel resistance has clinical signifi-cance and that patients with a risk for stent thrombosis may be The present study demonstrates, that 5 (ADP 5 ␮Mol/L) to 11% identified by point-of care testing. The number of clopidogrel (ADP 20 ␮Mol/L) of patients with stable coronary artery dis- non-responders depended on the concentration of ADP used to ease do not respond adequately to clopidogrel therapy. An effec- induce aggregation ex vivo. The incidence of stent thrombosis is tive combined antiplatelet therapy consisting of aspirin and clo- between 1 to 5%, which is comparable to the rate of clopidogrel pidogrel is critical to prevent subacute stent thrombosis in non-responders (5%) when 5 ␮Mol/L ADP are used to induce patients undergoing coronary stenting and has become the stan- platelet aggregation. Although further studies are necessary to dard antiplatelet treatment. Thus, clopidogrel non-responders compare the most sensitive platelet function test to identify non- may have an increased risk to develop subacute stent thrombo- responders, we would suggest, based on our present study, that sis. Periinterventional evaluation of platelet inhibition identifies 5 ␮Mol/L instead of 20 ␮Mol/L ADP should be used in order to non-responders and may justify the treatment of these patients not overestimate the rate of non-responders. with an alternative antiplatelet strategy. Antiplatelet drug resistence has been previously described Acknowledgements
for aspirin (8-10) and for clopidogrel (11, 12). However, data on The authors are indebted to Sandra Kerstan and Kirsten Langenbrink forexpert technical assistance. the clinical significance of clopidogrel non-responders is notavailable yet. Subacute stent thrombosis is a major life-threaten- Clopidogrel non-responders and coronary stenting References
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