Horst Neubauer

Pantoprazole Does Not Influence the Antiplatelet Effect of Clopidogrel-A Whole Blood Aggregometry Study After Coronary Stenting

Recent attention has been drawn to a potential drug-drug interaction observed between clopidogrel and proton pump inhibitors (PPIs). However, this potential interaction may not be a class effect of PPIs. We investigated if pantoprazole, which has a different metabolism than omeprazole, diminishes the effectiveness of clopidogrel. Our study included 336 patients (mean age 64.6 years; 106 women) 48 hours after percutaneous coronary stent implantation with a loading dose of 600 mg clopidogrel hydrogensulfate and 500 mg aspirin, followed by 75 mg clopidogrel and 100 mg aspirin daily. Whereas 188 patients (59 women) were not given any PPI comedication, 122 patients received pantoprazole and 26 either omeprazole or esomeprazole. The platelet aggregation followed by impedance aggregometry (in Ohm) was induced by 5 μmol/L adenosine diphosphate. The percentage of clopidogrel low-response (CLR) was similar between the non-PPI group [2.75 Ohm (confidence interval, CI: 2.25-3.26); 21.9% CLR] and the pantoprazole group [2.33 Ohm (CI: 1.79-2.87); 16.4% CLR] but higher in patients treated with omeprazole/esomeprazole (3.00 Ohm (CI: 1.49-4.51); 30.8% CLR). Multivariate regression analysis reveals that the risk of CLR in the pantoprazole comedication group was not increased compared with the group without any PPI [odds ratio 0.59 (CI: 0.31-1.13) 0.11]. Our data suggest that pantoprazole does not diminish the antiplatelet effectiveness of clopidogrel early after coronary stenting. Therefore, the use of pantoprazole seems preferable in patients treated with clopidogrel when a concomitant medication with a PPI is indicated.

How to optimise clopidogrel therapy? Reducing the low-response incidence by aggregometry-guided therapy modification

The inhibitory platelet effect of clopidogrel is insufficient in approximately 5 to 30% of patients. These low responders (LR) face a significantly higher risk of cardiovascular complications. The therapeutic management of LR is still undefined. In the present study, we evaluate a novel therapeutic algorithm to reduce the incidence of clopidogrel resistance. One hundred sixty-one patients on 100 mg of aspirin co-medication underwent elective coronary stenting and were given an initial dosage of 600 mg clopidogrel, followed by 75 mg clopidogrel daily. 48 h later, the platelet responsiveness was tested with ADP (5-20 microM) stimulation by impedance aggregometry (Chronolog 590). A significant rise in impedance (>5 Omega after 6 minutes, aggregation index >65%) was defined as LR. In this subgroup, platelets were stimulated with the selective P2Y(12)-ADP receptor antagonist 2-MeS-AMP. One hundred twenty-three patients were clopidogrel-responders (76.4%) and 38 patients were LR (23.6%). A defect of the ADP-receptor P2Y(12) was found in three out of 38 LR (7.9%). Inhibition of platelet aggregation indicating clopidogrel-responsiveness was achieved with either a clopidogrel high-dose regimen (22/38, 57.9%); a repeat loading dose, doubling the maintenance dose) or with an alternative therapy with ticlopidine (8/38 (21.1%); 250 mg twice daily). Thus the incidence of LR was reduced from 23.6% to 5.0%. Our aggregometer-guided therapeutic algorithm reduced the relative percentage of clopidogrel LR by 78.9%. This approach could prove to be helpful in achieving a further decrease in the incidence of clopidogrel resistance.

Which is the best anticoagulant for whole blood aggregometry platelet function testing? Comparison of six anticoagulants and diverse storage conditions.

Major hindrances of impedance aggregometry are caused by limited storage time and the requirement of ex vivo anticoagulation. Data on the influence of different anticoagulants and storage conditions are rare and incomplete. This study has systematically examined the influence of six different anticoagulants (sodium and lithium heparin, 20 µg/mL and 45 µg/mL r-hirudin, benzylsulfonyl-D-Arg-Pro-4-amidinobenzylamide (BAPA), and citrate) on the results of Adenosine 5′-diphosphate (ADP) and arachidonic acid (AA) induced measurements using multiple-electrode impedance aggregometer (MEA). Measurements were carried out in a time frame of 0 min up to 48 h after blood withdrawal. In addition, the influence of storage temperatures of 4°C and 37°C was evaluated. Results of ADP-induced tests significantly varied within the first 30 min in all tested anticoagulants, in citrated blood even within the first 60 min. They remained stable up to 2 h in 20 µg/mL r-hirudin and BAPA, 4 h in citrate, 8 h in 45 µg/mL r-hirudin, and lithium heparin and up to a maximum of 12 h in sodium heparin anticoagulated blood. The analysis of AA-induced tests revealed no significantly different results up to 6 h when BAPA was used, 8 h in lithium heparin, 20 µg/mL r-hirudin and citrate, 12 h in 45 µg/mL r-hirudin, and even 24 h in sodium heparin-anticoagulated samples. A storage temperature of either 4°C or 37°C in contrast to room temperature had a negative influence on the stability of results. In conclusion, sodium heparin and 45 µg/mL r-hirudin as anticoagulants guarantee the longest storage time for impedance aggregometry.

Incidence of Atrial Tachyarrhythmias in Pacemaker Patients: Results from the Balanced Evaluation of Atrial Tachyarrhythmias in Stimulated Patients (BEATS) Study

Objectives: The prospective Balanced Evaluation of Atrial Tachyarrhythmias in Stimulated patients (BEATS) study compared atrial tachyarrhythmia (AT) detection by means of serial ECG recordings versus device detection.

The CYP2J2 G-50T polymorphism and myocardial infarction in patients with cardiovascular risk profile

BackgroundCytochrome P450 (CYP) enzyme 2J2, an epoxygenase predominantly expressed in the heart, metabolises arachidonic acid to biologically active eicosanoids. One of the CYP2J2 products, 11, 12-epoxyeicosatrienoic acid, has several vasoprotective effects. The CYP2J2-G-50T-promotor polymorphism decreases gene expression and is associated with coronary artery disease. This association supports the vascular protective role of CYP-derived eicosanoids in cardiovascular disease. In the present study, we investigated the influence of this polymorphism on survived myocardial infarction in two study groups of patients with on average high cardiovascular risk profile.MethodsThe CYP2J2 polymorphism was genotyped in two groups of patients that were collected with the same method of clinical data collection. Data from 512 patients with sleep apnoea (group: OSA) and on average high cardiovascular risk profile and from another 488 patients who were admitted for coronary angiography (CAR-group) were evaluated for a potential correlation of the CYP2J2 polymorphism G-50T and a history of myocardial infarction. The G-50T polymorphism of the CYP2J2 gene was genotyped by allele specific restriction and light cycler analysis.ResultsThe T-allele of the polymorphism was found in 111 (11.1%; CAR-group: N = 65, 13.3%; OSA: N = 46, 9.0%). 146 patients had a history of myocardial infarction (CAR: N = 120, 24.6%; OSA: N = 26, 5.1%). Cardiovascular risk factors were equally distributed between the different genotypes of the CYP2J2 G-50T polymorphism. In the total group of 1000 individuals, carriers of the T-allele had significantly more myocardial infarctions compared to carriers of the wild type (T/T or G/T: 21.6%; G/G: 13.7%; p = 0.026, odds ratio 1.73, 95%-CI [1.06–2.83]). In the multivariate logistic regression analysis the odds ratio for a history of myocardial infarction in carriers of the T-allele was 1.611, 95%-CI [0.957–2.731] but this trend was not significant (p = 0.073).ConclusionIn presence of other risk factors, the CYP2J2 G-50T failed to show a significant role in the development of myocardial infarction. However, since our result is close to the border of significance, this question should be clarified in larger, prospective studies in the future.

Influence of glycaemic control on platelet bound CD40–CD40L system, P‐selectin and soluble CD40 ligand in Type 2 diabetes

Diabet. Med. 27, 384–390 (2010)

Why did mode switching occur

In a 79-year-old patient with recurrent syncope due to intermittent sinus arrest, a dual chamber pacemaker system with complex programmability and extensive diagnostic functions was implanted (Kappa 700 D, Medtronic Inc., Minneapolis, MN, USA). This system provides several automatic algorithms. A mode switching (MS) function automatically changes the pacing mode from DDD to DDIR if either 4 of 7 atrial events are sensed above a programmable rate (nominal 175 beats/min), or if a Blanked Flutter Search algorithm finds a short PP interval if it increases the postventricular atrial refractory period (PVARP) (full algorithm description in Reference 1). A Sensing Assurance algorithm records sensed P and R wave amplitudes and automatically adjusts atrial and ventricular sensitivity to maintain a sensing safety margin. A Search Atrioventricular (AV) algorithm prolongs the programmed AV delay in an adaptive way for up to 110 ms to facilitate spontaneous AV conduction. In addition, several other algorithms (e.g.. Capture Management, automatic PVARP, rate adaptive AV delay, premature ventricular contraction reaction, pacemaker mediated tachycardia intervention, safety window pacing) automatically try to optimize pacemaker performance.

Upregulation of platelet CD40, CD40 ligand (CD40L) and P-Selectin expression in cigarette smokers: a flow cytometry study.

Cigarette smoking is a well known risk factor for cardiovascular disease with a great impact on mortality. Studies have linked smoking to inflammation, platelet activation and enhanced atherosclerosis. The present study investigated the activation and expression of proinflammatory markers on platelets obtained from smokers. The expression of P-selectin (CD62P) (as a marker of activation) and CD40/CD40L (as a marker for proinflammatory processes) were quantified in platelets by flow cytometry. Platelet-rich plasma was obtained from 34 apparent healthy volunteers (19 cigarette smokers, 15 age-matched control persons). Basal measurements and the response to stimulation with ADP and TRAP (10, 30, 100 μmol/l) were evaluated. Values given (mean fluorescence index, MFI) are mean ± standard deviation. The basal values of platelet bound CD40 (3.20 ± 0.50 vs. 2.71 ± 0.28; P = 0.002), CD40L (1.10 ± 0.12 vs. 0.95 ± 0.12; P = 0.005) and P-selectin (0.70 ± 0.21 vs. 0.55 ± 0.11; P = 0.012) were significantly elevated in smokers as compared to controls. In addition, higher values were noted on stimulation with ADP or TRAP in smokers, although these different values were without statistical significance. According to our data cigarette smoking activates platelets (P-selectin expression) and stimulates the CD40-CD40L-pathway in otherwise healthy volunteers. These findings emphasize that cigarette smoking leads to a proinflammatory and prothrombotic state thus contributing to accelerated atherosclerosis.

Cortisol, platelet serotonin content, and platelet activity in patients with major depression and type 2 diabetes: an exploratory investigation.

Objective Hypothalamic-pituitary-adrenal system dysfunction, serotonergic system alterations, and enhanced platelet activity may contribute to the increased cardiac risk in depression. This exploratory study examined associations between cortisol parameters, platelet serotonin (5-HT) content, and platelet activity markers in patients with newly diagnosed major depression (MD) and/or Type 2 diabetes (T2DM) compared with healthy controls. Methods We compared cortisol awakening response (CAR), diurnal decrease in salivary cortisol concentrations (slope), platelet 5-HT, and platelet markers (CD40, CD40 ligand [CD40L], soluble CD40L, CD62P, &bgr;-thromboglobulin, and platelet factor-4) in 22 T2DM patients, 20 MD patients, 18 T2DM patients with MD, and 24 healthy controls. Results Platelet markers were elevated in MD (F(6,60) = 11.14, p < .001) and T2DM (F(6,60) = 13.07, p < .001). Subgroups did not differ in 5-HT or cortisol slope, whereas T2DM patients without depression had significantly lower CAR than did healthy controls (F(1,61) = 7.46, p = .008). In healthy controls, cortisol slope correlated with platelet activity for CD40 (r = −0.43, p = .048) and 5-HT was correlated with CD40L (r = 0.53, p = .007). In patients with both T2DM and MD, 5-HT and CD62P were correlated (r = 0.52, p = .033). Conclusions Increased platelet activity in T2DM and MD may play a role in the association between diabetes, depression, and coronary artery disease. The present data suggest that group differences in cortisol or 5-HT as well as group-specific associations of cortisol or 5-HT with platelet markers might be of limited importance in the shared pathways of T2DM and depression in the pathophysiology of coronary artery disease.

Cytochrome P450 2B6 and 2C9 genotype polymorphism – a possible cause of prasugrel low responsiveness

The cytochrome P450 (CYP) isoenzymes are essential for the metabolic activation of the prodrug prasugrel. Little is known about the impact of polymorphism of these isoenzymes on the prevalence of prasugrel low responsiveness (PLR) in patients with coronary artery disease. We investigated the frequency of PLR and the question whether PLR is associated with decreased/non-function polymorphisms of the CYP isoenzymes (2C9*2, 2C9*3, 2C19*2, 2C19*3, and 2B6*6). Our study included 355 patients who underwent percutaneous coronary stenting. The patients were initially treated with either prasugrel (n=90; 60/10 mg: loading/daily maintenance dose) or 600/75 mg clopidogrel hydrogensulfate (n=265) in combination with 500/100 mg acetylsalicylic acid (ASA). Platelet function was tested by impedance aggregometry 48 hours after taking the loading dose. Prasugrel achieved on the average significantly higher levels of platelet inhibition as compared to clopidogrel (mean 27.3 U vs 41.2 U). The frequencies of low response for prasugrel, clopidogrel and ASA were 9.8%, 35.1% and 14.9%, respectively. We identified only body mass index to be associated with PLR. PLR was not caused by a loss of ADP P2Y12-receptor function. Half of the patients with PLR were carriers of the reduced-function allele CYP2B6*6, and 41.7% had the genetic variant CYP2C9*2. The allele CYP2C9*3 was detected in three patients with PLR (25%) and two patients with PLR (16.7%) carried the gene variant CYP2C19*2. In conclusion, the rate of low responders was significantly lower among patients treated with prasugrel than with clopidogrel. PLR are more often carriers of CYP2C9*2 (50% in PLR) than when compared to the prevalence described in literature. Also, there is a trend to an increased frequency of CYP2B6*6 in PLR. In conclusion, CYP2B6 and CYP2C9 polymorphisms seem to be associated with prasugrel low-response.