Elod Papp

The genetics of antiplatelet drug resistance

Platelets have a central role in the development of arterial thrombosis and subsequent cardiovascular events. An appreciation of this complex process has made antiplatelet therapy the cornerstone of cardiovascular disease management. However, numerous patients will experience a recurrent atherothrombotic vascular event despite adequate antiplatelet therapy. Individual differences in the rate of platelet activation and reactivity markedly influence normal hemostasis and the pathological outcome of thrombosis. Such an individual variability is largely determined by environmental and genetic factors. These are known to either hamper platelets’ response to agonists, and thereby mimic the pharmacological modulation of platelet function or mask therapy effect and sensitize platelets. In this article, we reviewed the antiplatelet mechanisms of aspirin and clopidogrel and the possible role of different polymorphisms, which may affect the efficacy of antiplatelet therapy. Heterogeneity in the way patients respond to aspirin and clopidogrel may in part reflect variation in cyclooxygenase (COX)‐1, COX‐2, glycoprotein (GP) Ib alpha, GP Ia/IIa, GP IIb/IIIa, UGT1A6*2, P2Y1, P2Y12, CYP2C9, CYP3A4 and CYP3A5 genotypes.

Glycoprotein IIIA Gene (PIA) Polymorphism and Aspirin Resistance: Is There Any Correlation?

BACKGROUND: Platelet glycoprotein (GP) IIb/IIIa receptors play an inevitable role in platelet aggregation. The GP IIIa gene is polymorphic (PIA1/PIA2) and the presence of a PIA2 allele might be associated with an increased risk for acute coronary syndrome (ACS). OBJECTIVE: To examine the prevalence of the PIA2 allele in patients with ACS and in subjects with or without aspirin resistance. METHODS: The prevalence of the PIA2 allele was assessed in 158 patients with ACS and PIA2 compared with its prevalence in 199 healthy volunteers. The antiplatelet efficacy of aspirin was examined in all patients with ACS, as well as in 69 individuals who had suffered ischemic stroke and in 58 high-risk subjects without any known ischemic vascular events. RESULTS: PIA2 prevalence was significantly higher in patients with ACS (59/158) than in the control group (51/199; p < 0.05). Carriers of the PIA2 allele had a significantly higher risk of developing ACS, even after an adjustment to the risk factors (OR 5.74; 95% CI 1.75 to 18.8; p = 0.004). The occurrence of the PIA2 allele was significantly higher among patients with aspirin resistance than in subjects who demonstrated an appropriate response to the drug (allele frequencies, 0.21 vs 0.14; p < 0.05). All patients homozygous for the PIA2 allele had an inadequate platelet response to aspirin. CONCLUSIONS: Our results support the hypothesis that carriers of the PIA2 allele might have an increased risk for ACS. PIA2 homozygosity was associated with an inadequate response to aspirin therapy. Our data further suggest that patients with PIA2 allele homozygosity might benefit from antiplatelet therapy based on adenosine diphosphate antagonists throughout secondary treatment for prevention of ACS.

Aspirin resistance: possible roles of cardiovascular risk factors, previous disease history, concomitant medications and haemorrheological variables.

Background and objectiveRecent studies have described the incidence (approximately one in eight high-risk patients will experience a further atherothrombotic event over a 2-year period) of aspirin (acetylsalicylic acid) resistance and its possible background. The aim of this study was to compare the characteristics (risk profile, previous diseases, medications and haemorrheological variables) of patients in whom aspirin provided effective platelet inhibition with those in whom aspirin was not effective in providing platelet inhibition.Methods599 patients with chronic cardio- and cerebrovascular diseases (355 men, mean age 64 ±11 years; 244 women, mean age 63 ± 10 years) taking aspirin 100–325 mg/day were included in the study. Blood was collected between 8:00am and 9:00am from these patients after an overnight fast. The cardiovascular risk profiles, history of previous diseases, medication history and haemorrheological parameters of patients who responded to aspirin and those who did not were compared. Platelet and red blood cell (RBC) aggregation were measured by aggregometry, haematocrit by a microhaematocrit centrifuge, and plasma fibrinogen by Clauss’ method. Plasma and whole blood viscosities were measured using a capillary viscosimeter.ResultsCompared with aspirin-resistant patients, patients who demonstrated effective aspirin inhibition had a significantly lower plasma fibrinogen level (3.3 g/L vs 3.8 g/L; p < 0.05) and significantly lower RBC aggregation values (24.3 vs 28.2; p < 0.01). In addition, significantly more patients with effective aspirin inhibition were hypertensive (80% vs 62%; p < 0.05). Patients who had effective platelet aggregation were significantly more likely to be taking β-adrenoceptor antagonists (75% vs 55%; p < 0.05) and ACE inhibitors (70% vs 50%; p < 0.05), whereas patients with ineffective platelet aggregation were significantly more likely to be taking HMG-CoA reducíase inhibitors (statins) [52% vs 38%; p < 0.05]. Use of statins remained an independent predictor of aspirin resistance even after adjustment for risk factors and medication use (odds ratio 5.92; 95% CI 1.83, 16.9; p < 0.001).ConclusionsThe mechanisms underlying aspirin resistance are multifactorial. Higher fibrinogen concentrations increase RBC aggregation and can also result in increased platelet aggregation. The higher rate of hypertension in patients with effective platelet aggregation on aspirin could explain the differences in β-adrenoceptor antagonist and ACE inhibitor use between these patients and aspirin-resistant patients. Furthermore, an additive effect of these drugs may contribute to effective antiplatelet therapy. It is also possible that drug interactions with statins might reduce aspirin bioavailability and/or activity, thereby reducing platelet inhibition in aspirin-resistant patients.

Aspirin Resistance : Focus on Clinical Endpoints

Introduction: Via its antiplatelet effect, aspirin reduces the odds of an arterial thrombotic event in high-risk patients by approximately 25%. However, 10% to 20% of patients with an arterial thrombotic event who are treated with aspirin have a recurrent arterial thrombotic event during long-term follow-up. Nevertheless, the effectiveness of aspirin has been questioned by the emergence of the concept of aspirin resistance, which has been introduced as an explanation of the fact that a considerable proportion of patients treated with aspirin exhibit normal platelet function. Objectives and Methods: We systematically reviewed all available evidence till March 2008 on prevalence of aspirin resistance and its association with clinical outcome. We also collected articles showing the possible way of treatment. Conclusion: Analyzing the data of different laboratory methods aspirin resistance seems to be associated with poor clinical outcome, although currently no standardized or widely accepted definition of aspirin resistance exists. The widely used laboratory methods might not be comparable with each other; therefore, specific treatment recommendations for patients who exhibit high platelet reactivity during aspirin therapy or who have poor platelet inhibition by aspirin are not established.

Does glycoprotein IIIa gene (PlA) polymorphism influence clopidogrel resistance? A study in older patients

BackgroundClopidogrel is a potent antiplatelet drug used for secondary prevention after ischaemic cardiovascular or cerebrovascular events. In patients with aspirin (acetylsalicylic acid) intolerance or resistance, it is used as monotherapy. Recent data report that PlA polymorphism of the glycoprotein IIIa gene may account for differences in aspirin-induced antiplatelet effects. An increased degree of platelet reactivity was also reported in PlA2 carriers compared with PlA1/A1 patients after administration of a clopidogrel 300mg loading dose.ObjectivesThe aim of this study was to assess the modulatory effect of the PlA2allele on platelet aggregation in patients taking long-term clopidogrel.MethodsThe prevalence of the PlA2 allele was assessed in 38 (21 males, 17 females; mean age 63 ± 13 years) clopidogrel-resistant and 59 (26 males, 33 females; mean age 63 ± 11 years) clopidogrel-responsive patients. The polymerase chain reaction-restriction fragment length polymorphism method was utilised to evaluate PlA polymorphism. A Carat TX4® optical platelet aggregometer (Carat Diagnostics Ltd, Budapest, Hungary) was used to measure 5 and 10 µmol/L adenosine diphosphate-induced platelet aggregation.ResultsSignificantly more patients were taking combination antiplatelet therapy in the clopidogrel-resistant group than in the clopidogrel-responsive group (50% vs 30%, respectively). The prevalence of the PlA2 allele did not differ significantly between the two groups (0.09 vs 0.13), even after adjustment for combination therapy and various risk factors.ConclusionsOur results show that carriers of the PlA2 allele do not have an increased risk of clopidogrel resistance. These findings and data from our previous studies suggest that patients with a PlA2 allele homozygosity may benefit from antiplatelet therapy based on clopidogrel rather than aspirin.

Does Glycoprotein IIIa Gene(PlA) Polymorphism Influence Clopidogrel Resistance

BackgroundClopidogrel is a potent antiplatelet drug used for secondary prevention after ischaemic cardiovascular or cerebrovascular events. In patients with aspirin (acetylsalicylic acid) intolerance or resistance, it is used as monotherapy. Recent data report that PlA polymorphism of the glycoprotein IIIa gene may account for differences in aspirin-induced antiplatelet effects. An increased degree of platelet reactivity was also reported in PlA2 carriers compared with PlA1/A1 patients after administration of a clopidogrel 300mg loading dose.ObjectivesThe aim of this study was to assess the modulatory effect of the PlA2allele on platelet aggregation in patients taking long-term clopidogrel.MethodsThe prevalence of the PlA2 allele was assessed in 38 (21 males, 17 females; mean age 63 ± 13 years) clopidogrel-resistant and 59 (26 males, 33 females; mean age 63 ± 11 years) clopidogrel-responsive patients. The polymerase chain reaction-restriction fragment length polymorphism method was utilised to evaluate PlA polymorphism. A Carat TX4® optical platelet aggregometer (Carat Diagnostics Ltd, Budapest, Hungary) was used to measure 5 and 10 µmol/L adenosine diphosphate-induced platelet aggregation.ResultsSignificantly more patients were taking combination antiplatelet therapy in the clopidogrel-resistant group than in the clopidogrel-responsive group (50% vs 30%, respectively). The prevalence of the PlA2 allele did not differ significantly between the two groups (0.09 vs 0.13), even after adjustment for combination therapy and various risk factors.ConclusionsOur results show that carriers of the PlA2 allele do not have an increased risk of clopidogrel resistance. These findings and data from our previous studies suggest that patients with a PlA2 allele homozygosity may benefit from antiplatelet therapy based on clopidogrel rather than aspirin.

Does Glycoprotein IIIa Gene(Pl A ) Polymorphism Influence Clopidogrel Resistance

BackgroundClopidogrel is a potent antiplatelet drug used for secondary prevention after ischaemic cardiovascular or cerebrovascular events. In patients with aspirin (acetylsalicylic acid) intolerance or resistance, it is used as monotherapy. Recent data report that PlA polymorphism of the glycoprotein IIIa gene may account for differences in aspirin-induced antiplatelet effects. An increased degree of platelet reactivity was also reported in PlA2 carriers compared with PlA1/A1 patients after administration of a clopidogrel 300mg loading dose.ObjectivesThe aim of this study was to assess the modulatory effect of the PlA2allele on platelet aggregation in patients taking long-term clopidogrel.MethodsThe prevalence of the PlA2 allele was assessed in 38 (21 males, 17 females; mean age 63 ± 13 years) clopidogrel-resistant and 59 (26 males, 33 females; mean age 63 ± 11 years) clopidogrel-responsive patients. The polymerase chain reaction-restriction fragment length polymorphism method was utilised to evaluate PlA polymorphism. A Carat TX4® optical platelet aggregometer (Carat Diagnostics Ltd, Budapest, Hungary) was used to measure 5 and 10 µmol/L adenosine diphosphate-induced platelet aggregation.ResultsSignificantly more patients were taking combination antiplatelet therapy in the clopidogrel-resistant group than in the clopidogrel-responsive group (50% vs 30%, respectively). The prevalence of the PlA2 allele did not differ significantly between the two groups (0.09 vs 0.13), even after adjustment for combination therapy and various risk factors.ConclusionsOur results show that carriers of the PlA2 allele do not have an increased risk of clopidogrel resistance. These findings and data from our previous studies suggest that patients with a PlA2 allele homozygosity may benefit from antiplatelet therapy based on clopidogrel rather than aspirin.

Experience with endeavor stent implantations

Restenosis is the most common disadvantage of percutaneous coronary interventions. The incidence of restenosis can be lowered with the use of stents. After the use of stents, ‘in-stent’ restenosis can occur. To avoid it drug-eluting stents were developed, but the occurrence of stent thrombosis is higher than observed in case of bare-metal stents. Endeavor is a new zotarolimus-eluting stent developed to reduce the stent thrombosis. AimsIn a prospective study we aimed to follow-up our patients regarding the incidence of in-stent restenosis, stent thrombosis, and clinical end points after Endeavor stent implantation. Patients and methodsEndeavor stents have been implanted in patients undergoing coronary angiography with the following indications: complex lesions susceptible to restenosis and after recanalization of chronic total occlusions. ResultsEndeavor stent implantations were successfully performed in 99 patients and has been successful in 98% of cases, two stents could not be implanted because of technical difficulties. Significant restenosis was observed in eight patients (8.1%). Subacute stent thrombosis (within 10 days) occurred in two patients (2.0%). Any late stent thrombosis was not observed. ConclusionOur registry affirmed the results of the Endeavor I trial in a population with more severe and longer coronary stenosis. We can conclude that the Endeavor stent is suitable for implantation in complex, longer coronary lesions. Our long-term follow-up data do not prove those opinions which prefer bare-metal stent implantation in all patients because of the late adverse events of the drug-eluting stents.