Interaction between clopidogrel and proton-pump inhibitors and management strategies in patients with cardiovascular diseases

Dual antiplatelet therapy (DAPT) with clopidogrel and aspirin has been successful in reducing ischemic events in a wide range of patients with cardiovascular diseases. However, the anti-ischemic effects of DAPT may also be associated with gastrointestinal (GI) complications including ulceration and bleeding particularly in ‘high risk’ and elderly patients. Current guidelines recommend the use of proton-pump inhibitors (PPIs) to reduce the risk of GI bleeding in patients treated with DAPT. However, pharmacodynamic studies suggest an effect of PPIs on clopidogrel metabolism with a resultant reduction in platelet inhibitory effects. Similarly, several observational studies have demonstrated reduced clopidogrel benefit in patients who coadministered PPIs. Although recent US Food and Drug Administration and European Medicines Agency statements discourage PPI (particularly omeprazole) and clopidogrel coadministration, the 2009 AHA/ACC/SCAI PCI guidelines do not support a change in current practice in the absence of adequately powered prospective randomized clinical trial data. The data regarding pharmacologic and clinical interactions between PPI and clopidogrel therapies are herein examined and treatment strategies are provided

What is the Optimal Duration of Dual Antiplatelet Therapy After Stenting?

The optimal duration of dual antiplatelet therapy (DAPT) of aspirin and a P2Y12 receptor blocker after stenting is still being debated. The current recommendations for DAPT duration are significantly focused on reducing stent thrombosis; a less frequent event with later than earlier generation drug eluting stents (DES). A persistent occurrence of late and very late stent thrombosis with first generation DES supported extended use of DAPT beyond one year. However, recent studies have demonstrated that extended duration DAPT is associated with increased bleeding; an independent predictor for poor outcomes, including long-term mortality. Second-generation DES are associated with less late and very late stent thrombosis. Some recent studies have supported a shorter duration of DAPT for second generation DES. However, these studies were inadequately powered to assess significant differences in stent thrombosis. Furthermore, extended duration DAPT has been associated with a reduced risk of thrombotic events in non-culprit vessels in addition to stent thrombosis in patients with acute coronary syndromes (ACS). The higher risk of bleeding associated with extended DAPT therapy provides a strong rationale for personalized DAPT based on patient risk factors (e.g. ACS vs. non-ACS), type of stents, and cost-benefit analyses

Acetylsalicylic acid and clopidogrel hyporesponsiveness following acute coronary syndromes

This review discusses the response variability to acetylsalicylic acid (ASA) and particularly to clopidogrel, and their relation to adverse recurrent ischaemic events in patients with arterial diseases. The higher rate of ASA resistance reported in the literature may be mainly due to the cyclooxygenase-1 non-specific assays, non-compliance, and underdosing. Clopidogrel response variability and non-responsiveness are established concepts. Moreover, high platelet reactivity (HPR) to adenosine diphosphate during clopidogrel therapy is now a known risk factor for recurrent ischaemic events in high-risk percutaneous coronary intervention/acute coronary syndrome patients. Variable active metabolite generation is the primary explanation for clopidogrel response variability and non-responsivenes. Variable levels of active metabolite generation following clopidogrel administration could be mainly explained by functional variability in hepatic cytochrome (CYP)P450 isoenzyme activity that is influenced by drug–drug interactions and single nucleotide polymorphisms of specific genes encoding CYP450 isoenzymes. Treatment with more potent P2Y12 receptor blockers, such as prasugrel and ticagrelor are credible alternative strategies to overcome HPR during clopidogrel therapy

Increased Risk in Patients With High Platelet Aggregation Receiving Chronic Clopidogrel Therapy Undergoing Percutaneous Coronary Intervention Is the Current Antiplatelet Therapy Adequate?

ObjectivesWe sought to determine whether patients receiving chronic clopidogrel therapy undergoing nonemergent stenting who display high on-treatment preprocedural platelet aggregation measured by standard light transmittance aggregometry and thrombelastography (TEG) will be at increased risk for poststenting ischemic events.BackgroundPatients exhibiting heightened platelet reactivity to adenosine diphosphate (ADP) might be at increased risk for recurrent ischemic events after coronary stenting.MethodsA total of 100 consecutive patients receiving chronic antiplatelet therapy consisting of aspirin (325 mg qd) and clopidogrel (75 mg qd) were studied before undergoing nonemergent stenting. Patients were followed for 1 year after coronary stenting for the occurrence of death, myocardial infarction, stent thrombosis, stroke, or ischemia requiring a hospital stay.ResultsAll patients were aspirin responsive. Patients with ischemic events (23 of 100, 23%) within 1 year had greater on-treatment prestent ADP-induced platelet aggregation than patients without ischemic events by aggregometry and TEG (p < 0.001 for both measurements). Of patients with an ischemic event, 70% and 87% displayed high on-treatment platelet reactivity at baseline by aggregometry and TEG, respectively. High on-treatment platelet reactivity as measured by aggregometry and TEG were the only variables significantly related to ischemic events (p < 0.001 for both assays). The administration of eptifibatide reduced periprocedural elevation in platelet reactivity, with no significant differences in bleeding events.ConclusionsPatients receiving chronic clopidogrel therapy undergoing nonemergent percutaneous coronary intervention who exhibit high on-treatment ADP-induced platelet aggregation are at increased risk for postprocedural ischemic events. These findings might have implications for the alteration in clopidogrel maintenance dose and use of glycoprotein IIb/IIIa inhibitors in selected patients

Updated evidence on intracoronary abciximab in ST-elevation myocardial infarction: A systematic review and meta-analysis of randomized clinical trials

Abstract Background: Intracoronary (IC) abciximab administration remains a promising approach aimed to increase a drug concentration in the target area and possibly improve clinical outcomes in the setting of ST-segment elevation myocardial infarction (STEMI). The goal of this literature review and meta-analysis is to update available knowledge comparing IC and intravenous (IV) abciximab administration in STEMI patients. Methods: A total of 7 randomized clinical trials (RCTs) with a median follow-up of 3 months were included in the meta-analysis (n = 3311). All-cause mortality was selected as the primary end point while recurrent myocardial infarction (re-MI), target vessel revascularization (TVR) and major bleeding complications were the secondary end points. Results: IC abciximab did not provide any benefits in terms of all-cause mortality as compared with IV abciximab (odds ratio [OR] 0.67; 95% confidence interval [CI] 0.34 1.34). However, this neutral effect was driven by the AIDA STEMI trial. The IC route was associated with a reduced rate of re-MI when compared with IV administration (OR 0.61; 95% CI 0.40 0.92) but the difference disappeared after one of the RCTs was excluded from the analysis. Both strategies were equal regarding TVR (OR 0.66; 95% CI 0.40 1.09) and major bleeding complications (OR 1.18; 95% CI 0.76 1.83). Conclusions: Our updated meta-analysis shows that the clinical superiority of IC over IV abciximab administration in STEMI patients is no longer clear after the release of the AIDA STEMI trial results. Further research in high-risk STEMI patients is warranted to finally determine clinical advantages of IC vs IV abciximab administration. (Cardiol J 2012; 19, 3:230 242

Incidence of Dyspnea and Assessment of Cardiac and Pulmonary Function in Patients With Stable Coronary Artery Disease Receiving Ticagrelor, Clopidogrel, or Placebo in the ONSET/OFFSET Study

ObjectivesWe prospectively assessed cardiac and pulmonary function in patients with stable coronary artery disease (CAD) treated with ticagrelor, clopidogrel, or placebo in the ONSET/OFFSET (A Multi-Centre Randomised, Double-Blind, Double-Dummy Parallel Group Study of the Onset and Offset of Antiplatelet Effects of AZD6140 Compared With Clopidogrel and Placebo With Aspirin as Background Therapy in Patients With Stable Coronary Artery Disease) study.BackgroundTicagrelor reduces cardiovascular events more effectively than clopidogrel in patients with acute coronary syndromes. Dyspnea develops in some patients treated with ticagrelor, and it is not known whether this is associated with changes in cardiac or pulmonary function.MethodsIn all, 123 stable aspirin-treated CAD patients randomly received either ticagrelor (180 mg load, then 90 mg twice daily; n = 57), clopidogrel (600 mg load, then 75 mg daily; n = 54), or placebo (n = 12) for 6 weeks in a double-blind, double-dummy design. Electrocardiography, echocardiography, serum N-terminal pro-brain natriuretic peptide, and pulmonary function tests were performed before (baseline) and 6 weeks after drug administration and/or after development of dyspnea.ResultsAfter drug administration, dyspnea was reported by 38.6%, 9.3%, and 8.3% of patients in the ticagrelor, clopidogrel, and placebo groups, respectively (p < 0.001). Most instances were mild and/or lasted <24 h, although 3 patients discontinued ticagrelor because of dyspnea. Eight of 22 and 17 of 22 ticagrelor-treated patients experiencing dyspnea did so within 24 h and 1 week, respectively, after drug administration. In all treatment groups, and in ticagrelor-treated patients with dyspnea, there were no significant changes between baseline and 6 weeks in any of the cardiac or pulmonary function parameters.ConclusionsDyspnea is commonly associated with ticagrelor therapy, but was not associated in this study with any adverse change in cardiac or pulmonary function. (A Multi-Centre Randomised, Double-Blind, Double-Dummy Parallel Group Study of the Onset and Offset of Antiplatelet Effects of AZD6140 Compared With Clopidogrel and Placebo With Aspirin as Background Therapy in Patients With Stable Coronary Artery Disease [ONSET/OFFSET]; NCT00528411

Pharmacosimulation of delays and interruptions during administration of tirofiban: a systematic comparison between EU and US dosage regimens.

Tirofiban is a glycoproteine (GP) IIb/IIIa receptor antagonist, which inhibits platelet-platelet aggregation and is a potential adjunctive antithrombotic treatment in patients with acute coronary syndromes (ACS) or high-risk percutaneous coronary interventions (PCI). It is administered intravenously as a bolus followed by continuous infusion. However, the dosage recommendations in the United States (US) and European Union (EU) differ considerably. Furthermore, in routine clinical practice, deviations from the recommendations may occur. The objective of the present study was to investigate the impact of different alterations on tirofiban plasma concentrations in US and EU administration regimens and to give suggestions for delay management in clinical practice. We therefore mathematically simulated the effects of different bolus-infusion delays and infusion interruptions in different scenarios according to the renal function. Here, we provide a systematic assessment of concentration patterns of tirofiban in the US versus EU dosage regimens. We show that differences between the two regimens have important effects on plasma drug levels. Furthermore, we demonstrate that deviations from the proper administration mode affect the concentration of tirofiban. Additionally, we calculated the optimal dosage of a second bolus to rapidly restore the initial concentration without causing overdosage. In conclusion, differences in tirofiban dosing regimens between the U.S and EU and potential infusion interruptions have important effects on drug levels that may impact on degrees of platelet inhibition and thus antithrombotic effects. Thus, the findings of our modelling studies may help to explain differences in clinical outcomes observed in previous clinical trials on tirofiban