Clopidogrel Responders Research Articles

Randomized Comparison of a High Clopidogrel Maintenance Dose in Patients With Diabetes Mellitus and Coronary Artery Disease

After treatment with clopidogrel, patients with type 2 diabetes mellitus (T2DM) have reduced platelet inhibition compared with patients who are not diabetic. Whether platelet inhibition can be enhanced by increasing clopidogrel maintenance dosage in T2DM patients is unknown. The aim of this pilot study was to assess the functional impact of a high maintenance dose in T2DM patients with suboptimal clopidogrel-induced antiplatelet effects. T2DM patients on chronic dual antiplatelet therapy were screened to identify suboptimal clopidogrel responders. The latter were randomized to 30-day treatment with a standard (75 mg; n=20) or high (150 mg; n=20) daily maintenance dose. Platelet function was assessed at 3 time points: baseline, 30 days after randomization, and 30 days after resuming standard dosing. Platelet function parameters included adenosine diphosphate-induced (20 and 5 micromol/L) maximal and late platelet aggregation, inhibition of platelet aggregation, platelet disaggregation, and P2Y12 reactivity index. A total of 64 T2DM patients were screened to identify 40 suboptimal responders. After randomization, maximal adenosine diphosphate-induced (20 micromol/L) platelet aggregation was significantly reduced in the 150-mg group compared with the 75-mg group (P=0.002; primary end point). However, suboptimal clopidogrel response was still present in 60% of patients on the 150-mg regimen. All other platelet function parameters showed enhanced clopidogrel-induced antiplatelet effects with 150 mg, which returned to baseline values after resumption of standard dosing. A 150-mg maintenance dose of clopidogrel is associated with enhanced antiplatelet effects compared with 75 mg in high-risk T2DM patients. However, enhanced ex vivo platelet reactivity continues to persist, the clinical implications of which are unknown and need to be evaluated in large-scale clinical trials.

Monitoring of Clopidogrel Using Multiple Electrode Aggregometry.

A control of clopidogrel response is one proposed strategy for an improvement of anti-platelet therapy. Different methods have been evaluated for this indication. We assessed ADP induced aggregation in whole blood in healthy blood donors and patients treated with clopidogrel 75 mg qd using a new monitoring method.Methods: Platelet function was determined using multiple electrode aggregometry (MEA) on the Multiplate analyzer (Dynabyte, Munich, Germany). This device uses a single use test cell with two separate impedance sensors, consisting of a total of 4 electrodes and has 5 channels for parallel tests. Aggregation was triggered using ADP (6.4 μM, ADPtest, Dynabyte) and using a combination of ADP (6.4 μM) and prostaglandin E1 (20 nM) (ADPtest high sensitivity = ADPtest HS, Dynabyte). The combination of ADP + prostaglandin E1 (PGE1) is used to enhance sensitivity for the effects of clopidogrel onto ADP induced platelet activation. PGE1 reduces intracellular calcium mobilisation and therefore platelet activation and acts thus synergistical to the effect of clopidogrel. For the analysis 300 μl of blood are analyzed with the addition of 300 μl of saline. Aggregation was quantified by the area under the curve in arbitrary U (1 U corresponds to 10 AU*min). Following IRB approval venous blood was collected from 120 blood donors without anamnestic intake of platelet inhibitors in the 2 weeks before the analysis and 160 patients taking clopidogrel 75 mg qd using the direct thrombin inhibitor Melagatran in a final concentration of 15 μg/ml as the anticoagulant.Results: The distribution of the aggregation values is shown in Fig. 1. The median (min-max) was 83 (36–143) for the blood donors in the ADPtest and 68 (1–130) in the ADPtest HS. In the patient group the median (mix–max) was 30 (2–147) in the ADPtest and 10 (0–108) in the ADPtest HS. If a non-response rate of 25% is assumed, the cut-off between clopidogrel responders and non-responders would be 51 for the ADPtest and 21 for ADPtest HS.Discussion: The comparison of the results of clopidogrel-treated patients and healthy controls (blood donors) reveals a higher sensitivity of ADPtest HS vs. ADPtest for the effects of clopidogrel onto ADP induced aggregation in whole blood. Due to the use of a direct thrombin inhibitor as the anticoagulant in our study platelet function was determined under physiological levels of ionized calcium.For both test methods a significant proportion of patients does not show adequate reductions in their vitro platelet aggregation. Prospective trials are required to show whether a clopidogrel-non-response in this particular method is associated with an increased occurrence of arterial thromboembolism. [Display omitted]

Dual Antiplatelet Therapy for Coronary Stenting

It was an important and indeed remarkable observation when several trials reported the consistent finding that dual antiplatelet therapy with aspirin and a thienopyridine was superior to aspirin and oral anticoagulation for prevention of major adverse cardiac events after deployment of a stent in a coronary artery.1 A major benefit of dual antiplatelet therapy was a lower rate of stent thrombosis. The incidence of coronary stent thrombosis in the modern era is reported to be approximately 1%, with an increased likelihood of occurrence in high-risk patient or lesion subsets. Although this rate may seem relatively low, stent thrombosis is associated with major myocardial infarction (MI) in 60% to 70% of cases, resulting in an early mortality rate of 20% to 25%. With increased use of percutaneous coronary intervention (PCI) as a revascularization strategy and implantation of stents in coronary arteries with a small diameter, it is anticipated that the number of patients at risk for stent thrombosis may increase. It therefore continues to be important to construct pharmacological regimens that minimize its occurrence. Several risk factors for stent thrombosis have been identified, including patient- and/or lesion-specific characteristics, procedure-related factors, and inherent stent thrombogenicity.2 These risk factors, in turn, contribute to a state of enhanced platelet reactivity and thrombus formation, which promotes abrupt vessel closure. See p 1153 Although initial studies highlighting the benefits of dual antiplatelet therapy used aspirin and ticlopidine, clopidogrel is the thienopyridine of choice today because it is associated with a lower rate of intolerable side effects. It is noteworthy that clopidogrel as part of the dual antiplatelet regimen to support PCI has not undergone the type of extensive evaluation demanded of ACE inhibitors, angiotensin receptor blockers, or such devices as implantable cardioverter-defibrillators before they were recommended in practice guidelines for management of patients with …

High clopidogrel loading dose during coronary stenting: effects on drug response and interindividual variability

To assess platelet inhibitory effects, interindividual variability in platelet inhibition as well as response to a 600 mg, compared to a standard 300 mg, clopidogrel loading dose (LD) after coronary stenting Platelet function profiles were assessed in 50 patients undergoing coronary stenting receiving either a 300 mg (n=27) or 600 mg clopidogrel LD. ADP (6 microM) and collagen (6 microg/mL) induced platelet aggregation, as well as ADP (2 microM) induced glycoprotein (GP) IIb/IIIa activation and P-selectin expression were assessed at baseline and 4, 24, and 48 h following clopidogrel front-loading. A more intense and rapid inhibition of platelet activation (both GP IIb/IIIa activation and P-selectin expression) were achieved using a 600 mg, compared to a 300 mg, LD throughout the entire 48 hours (p<0.001). Although there were no differences in platelet aggregation, overall a 600 mg LD increased the number of clopidogrel responders and this was also achieved earlier compared to a 300 mg LD. A 600 mg LD did not reduce interindividual variability of platelet response. The use of a 600 mg clopidogrel LD in patients undergoing coronary stenting optimises platelet inhibitory effects early after intervention and may provide a more effective protection against early thrombotic complications.

Identification of low responders to a 300-mg clopidogrel loading dose in patients undergoing coronary stenting

Background Although patients undergoing coronary stenting routinely receive dual antiplatelet treatment to reduce the risk of stent thrombosis, this undesired event still occurs. A suboptimal response to clopidogrel treatment (low responders) has been suggested to contribute to stent thrombosis. In the present study, platelet function profiles were assessed in patients undergoing coronary stenting receiving a standard 300-mg clopidogrel loading dose with the aim to identify low clopidogrel responders. Materials and methods Platelet aggregation was assessed by light transmittance aggregometry following 6 μM ADP stimuli in 48 patients before and 10 min, 4 and 24 h after receiving clopidogrel front-loading. Patients having ≥40% inhibition of platelet aggregation 24 h after clopidogrel administration were defined as normal responders, whereas those having <40% inhibition were low responders. Glycoprotein (GP) IIb/IIIa activation and P-selectin expression were assessed by whole blood flow cytometry following 2 μM ADP stimuli at the same time points. Platelet function profiles were compared between normal and low clopidogrel responders. Results Twenty-seven patients (56%) were normal responders and 21 (44%) low responders. Baseline GP IIb/IIIa activation was higher in low responders (74.6±16.6% vs. 58.2±24.5%, p=0.03). Although GP IIb/IIIa activation reduced following clopidogrel front-loading in both groups, it remained increased among low responders at 24 h (58.6±21.3% vs. 40.2±28.7%, p=0.05) and during the overall study time course ( p=0.02). There were no differences in P-selectin expression. Conclusions A considerable proportion of patients have an early suboptimal response to a 300-mg clopidogrel loading dose. An increased GP IIb/IIIa activation before intervention may identify this group of patients suggesting the use of a more aggressive antithrombotic treatment in these individuals.