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Zusammenfassung Hintergrund Eine verminderte antithrombozytäre Prophylaxe („Low-Response [LR]“/„high on-treatment platelet reactivity [HPR]“) mit Acetylsalicylsäure (ASS) ist mit einem erhöhten Risiko für thrombembolische Ereignisse assoziiert. Die Prävalenz einer Low-Response ist mit ca. 20 % häufig und ein Therapieregime wurde bisher noch nicht etabliert. Das Ziel dieser prospektiven Studie war es, die Effektivität eines Therapieschemas zur Therapieanpassung bei detektierter LR/HPR bei gefäßchirurgischen Patienten zu evaluieren. Methodik Insgesamt wurden 36 gefäßchirurgischen Patienten mit einer antithrombozytären Dauermedikation mit ASS 100 mg/Tag und einer nachgewiesenen ASS-Low-Response (ALR) in die Studie eingeschlossen. Entsprechend dem festgelegten Therapieplan wurde bei diesen Patienten eine Therapieanpassung durchgeführt und eine Kontrollaggregometrie zur Erfolgskontrolle durchgeführt. Das verwendete Therapieschema folgte dem Test-and-treat-Prinzip. Zur Beurteilung der Wirkung von ASS diente die Impedanzaggregometrie mittels Mehrelektrodenaggregometer (Multiplate). Ergebnisse Insgesamt konnten alle 36 Patienten erfolgreich in eine Response überführt werden. Bei 32 (88,89 %) Patienten erfolgte eine Dosiserhöhung auf 300 mg ASS, 2 (5,56 %) Patienten wurden von ASS auf Clopidogrel umgestellt. Bei weiteren 2 (5,56 %) Patienten wurde auf eine orale Antikoagulation mit Phenprocoumon aufgrund anderer Indikationen umgestellt. Blutungskomplikationen oder Nebenwirkungen traten nicht auf. Schlussfolgerung Das gewählte Therapieschema zur Behandlung einer Low-Response erwies sich als effektiv und sicher bei gefäßchirurgischen Patienten. Überwiegend führte eine leitliniengerechte Dosiserhöhung der Prophylaxe von 100 mg auf 300 mg ASS zu einer effektiven Thrombozytenaggregationshemmung in der Aggregometrie.

Background The prevalence of patients with implanted cardioverter defibrillators (ICDs) and the frequency of surgery on these patients are steadily on the rise. Guidelines recommend preoperative ICD reprogramming, although this is sometimes difficult in clinical practice. Placing a magnet on the ICD is a practical alternative and even no inactivation is possible in selected cases. Methods In this prospective observational study, we compared different perioperative ICD management strategies depending on the location of the surgery and the type of electrocautery used. Patients undergoing surgery above the umbilicus with monopolar electrocautery had their ICD therapy inactivated by reprogramming. When surgery below the navel or surgery above the navel with bipolar electrocautery was completed, ICD inactivation was performed using a magnet. No inactivation was performed on patients undergoing lower extremity surgery with bipolar electrocautery. Only ICD patients who were not pacemaker dependent were enrolled. After surgery, the ICDs were assessed regarding documented arrhythmias and parameters. Results Out of 101 patients included in this study, the ICD was preoperatively reprogrammed in 42 patients (41.6%), a magnet was used on 45 patients (44.5%), and ICDs were not deactivated at all in 14 patients (13.9%). No intraoperative electromagnetic interference was detected. Postoperative ICD analysis demonstrated no changes of preset parameters. Conclusions All three tested ICD management strategies were proved safe in this study. Keeping the location of surgery and the type of electrocautery in mind, an intraoperative magnet or even no ICD deactivation at all could be feasible alternatives in surgery on patients with ICDs.

A decreased antiplatelet prophylaxis (low response, LR/high on-treatment platelet reactivity, HPR) with acetylsalicylic acid (ASA) is associated with an increased risk of thromboembolic events. The prevalence of a LR is frequent with about 20% and a therapeutic regimen is not yet established. The aim of this prospective study was to evaluate the effectiveness of a therapeutic regimen for treatment adaptation when LR/HPR is detected in vascular surgery patients.Overall, 36 patients under long-term antiplatelet treatment with 100 mg/day ASA and a detected ASA low response (ALR) were included in the study. In this patient group a modification of the prophylactic medication was carried out according to the established treatment plan and a control aggregometry was performed. The therapeutic regimen followed the test and treat principle. To evaluate the effect of ASA impedance, aggregometry with multiple electrodes was used (multiplate).All 36 patients were successfully transferred to response status with the treatment scheme. In 32 (88.89%) patients an increased dose of 300 mg/day ASA was carried out and in 2 (5.56%) patients the medication was changed from ASA to clopidogrel. A further 2 (5.56%) patients were switched to oral anticoagulation with phenprocoumon, due to other indications. Bleeding complications or other side effects did not occur.The chosen treatment regime for a low response proved to be effective and safe in vascular surgery patients. A guideline-compliant increase of the ASA dose from 100 mg to 300 mg/day predominantly led to an effective inhibition of platelet aggregation in the aggregometry.HINTERGRUND: Eine verminderte antithrombozytäre Prophylaxe („Low-Response [LR]“/„high on-treatment platelet reactivity [HPR]“) mit Acetylsalicylsäure (ASS) ist mit einem erhöhten Risiko für thrombembolische Ereignisse assoziiert. Die Prävalenz einer Low-Response ist mit ca. 20 % häufig und ein Therapieregime wurde bisher noch nicht etabliert. Das Ziel dieser prospektiven Studie war es, die Effektivität eines Therapieschemas zur Therapieanpassung bei detektierter LR/HPR bei gefäßchirurgischen Patienten zu evaluieren.Insgesamt wurden 36 gefäßchirurgischen Patienten mit einer antithrombozytären Dauermedikation mit ASS 100 mg/Tag und einer nachgewiesenen ASS-Low-Response (ALR) in die Studie eingeschlossen. Entsprechend dem festgelegten Therapieplan wurde bei diesen Patienten eine Therapieanpassung durchgeführt und eine Kontrollaggregometrie zur Erfolgskontrolle durchgeführt. Das verwendete Therapieschema folgte dem Test-and-treat-Prinzip. Zur Beurteilung der Wirkung von ASS diente die Impedanzaggregometrie mittels Mehrelektrodenaggregometer (Multiplate).Insgesamt konnten alle 36 Patienten erfolgreich in eine Response überführt werden. Bei 32 (88,89 %) Patienten erfolgte eine Dosiserhöhung auf 300 mg ASS, 2 (5,56 %) Patienten wurden von ASS auf Clopidogrel umgestellt. Bei weiteren 2 (5,56 %) Patienten wurde auf eine orale Antikoagulation mit Phenprocoumon aufgrund anderer Indikationen umgestellt. Blutungskomplikationen oder Nebenwirkungen traten nicht auf.Das gewählte Therapieschema zur Behandlung einer Low-Response erwies sich als effektiv und sicher bei gefäßchirurgischen Patienten. Überwiegend führte eine leitliniengerechte Dosiserhöhung der Prophylaxe von 100 mg auf 300 mg ASS zu einer effektiven Thrombozytenaggregationshemmung in der Aggregometrie.

Introduction Reduced antiplatelet activity of aspirin (ALR) or clopidogrel (CLR) is associated with an increased risk of thromboembolic events. The reported prevalence data for low-responders vary widely and there have been few investigations in vascular surgery patients even though they are at high risk for thromb-embolic complications. The aim of this prospective observational monocentric study was to elucidate possible changes in ALR or CLR after common vascular procedures. Methods Activity of aspirin and clopidogrel was measured by impedance aggregometry using a multiple electrode aggregometer (Multiplate®). Possible risk factors for ALR or CLR were identified by demographical, clinical data and laboratory parameters. In addition, a follow-up aggregometry was performed after completion of the vascular procedure to identify changes in antiplatelet response. Results A total of 176 patients taking antiplatelet medications aspirin and/or clopidogrel with peripheral artery disease (PAD) and/or carotid stenosis (CS) were included in the study. The prevalence of ALR was 13.1% and the prevalence of CLR was 32% in the aggregometry before vascular treatment. Potential risk factors identified in the aspirin group were concomitant insulin medication (p = 0.0006) and elevated C-reactive protein (CRP) (p = 0.0021). The overall ALR increased significantly postoperatively to 27.5% (p = 0.0006); however, there was no significant change in CLR that was detected. In a subgroup analysis elevation of the platelet count was associated with a post-procedure increase of ALR incidence. Conclusion The incidence of ALR in vascular surgery patients increases after vascular procedures. An elevated platelet count was detected as a risk factor. Further studies are necessary to analyse this potential influence on patency rates of vascular reconstructions.

Untersuchungen zeigen, dass eine verminderte antithrombozytare Wirksamkeit („Low Response [LR]“/„high on-treatment platelet reactivity [HPR]“) von Acetylsalicylsaure (ASS) und Clopidogrel mit einem erhohten Risiko fur thrombembolische Ereignisse assoziiert ist. Die Pravalenzangaben fur Low Responder schwanken stark in der Literatur und es gibt wenige Untersuchungen mit gefaschirurgischen Patienten. Ziel der Studie war es, die Pravalenz von ASS- und Clopidogrel-Low-Respondern (ALR/CLR) und Risikofaktoren fur Low Responder bei gefaschirurgischen Patienten zu ermitteln. In die Studie wurden n = 154 Patienten mit einer antithrombozytaren Dauertherapie eingeschlossen, die aufgrund einer pAVK und/oder Arteria-carotis-interna-Stenose behandelt wurden. Zur Ermittlung einer ASS- oder Clopidogrel-Low-Response wurde Vollblut mittels der Impedanzaggregometrie (ChronoLog® Aggregometer Modell 590) untersucht. Zur Detektion von Risikofaktoren wurden der Schweregrad der Gefaserkrankung, Begleiterkrankungen, Laborparameter und die Begleitmedikation erfasst. Es wurde eine Pravalenz von 19,3 % fur ALR und von 21,1 % fur CLR ermittelt. Als Risikofaktoren fur praoperative ASS-Low-Responder wurde eine hohere Thrombozyten- und Leukozytenanzahl, sowie eine Begleitmedikation mit Pantoprazol identifiziert. Die Auswertung ergab keine signifikante Korrelation der erhobenen Parameter mit Clopidogrel-Low-Respondern. Die Pravalenzen fur die ALR und CLR liegen in den, bei anderen Studien ermittelten Bereichen, die vornehmlich an kardiologischen Patienten vorgenommenen wurden. Weitere Untersuchungen sind notwendig zur Evaluation von Risikofaktoren und zur Entwicklung eines wirksamen Therapieregimes zur Optimierung der Therapie mit Thrombozytenfunktionshemmern bei gefaschirurgischen Patienten.

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, β-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.

To prospectively assess the safety and efficacy of a novel absorbable vascular closure device (ExoSeal) in patients undergoing cardiac catheterization with femoral access compared to the established collagen-based (Angio-Seal) and suture-mediated (ProGlide) closure devices.This prospective, observational, dual-center, non-randomized, non-blinded study enrolled 1013 patients (65.1 ± 11.8 years) undergoing cardiac catheterization via a common femoral artery access in which hemostasis was achieved using a vascular closure device (255 Angio-Seal, 258 ProGlide, and 500 ExoSeal). In hospital complications (bleeding, hematoma, pseudoaneurysm, vessel occlusion, dissection, and arteriovenous fistula) of the puncture site and device failures (persistent bleeding) were recorded and compared for ExoSeal vs. the established devices (Angio-Seal + ProGlide).There were more complications after utilization of ExoSeal compared to established devices (3.6% vs. 1.2%, p=0.012). No significant difference was observed in the device success rate between the established vascular closure devices (96.3%) and the novel device (94.8%, p=0.28). Considering each closure system, Angio-Seal had the lowest complication rate (0.4%) and the highest efficacy (99.2%); the latter differed significantly from ExoSeal (94.8%, p=0.001). Logistic regression analysis revealed a3-fold odds of complications when using ExoSeal, which remained unchanged in multivariate analysis.Utilization of the novel vascular closure device is associated with a higher complication rate and a similar device failure rate compared to collagen-based and suture-mediated devices, with Angio-Seal having the lowest complication and device failure rates.

Background Inflammation plays a key role in atherosclerotic disease. Up until now only limited evidence exists on the mechanism of cardiovascular complications in patients with depression. In addition depression was also linked to an increase in cardiovascular mortality. The present study was designed to evaluate the extent of platelet activation and platelet-derived markers of atherosclerotic disease in patients with newly diagnosed depression. Methods This study used whole blood aggregometry, flow cytometry and ELISA to investigate platelet CD62P (P-selectin) expression and atherosclerotic markers (CD40, CD40L) as well as serum platelet factor 4 (PF-4) and beta-thromboglobulin (β-TG) levels in 46 participants. Patients with newly diagnosed, but not yet medically treated depression (n = 21) were compared to healthy control patients. Results The platelet activation marker CD62P was significantly higher in patients with depression (2.62% depression versus 1.27% controls; p = 0.006). Further we found basal CD40 (6.7% vs. 4.8%; p = 0.002) and basal CD40L (31.0% vs. 22.0%; p = 0.025) to be elevated in patients with depression as compared to control persons. In addition sCD40L (52.7 vs. 44.4 ng/ml; p = 0.023) and β-TG differed significantly in depressed patients (206.9 vs. 182.8 ng/ml; p = 0.001). However, basal CD41 (97.0% vs. 96.3%; p = 0.57), CD42b (96.7% vs. 94.7%; p = 0.28) and PF-4 (89.61 vs. 81.75 IU/ml; p = 0.10) and the aggregometry results did not differ significantly between the study groups. Conclusions Our findings with elevated CD40 and CD40L as well as CD62P and β-TG in newly diagnosed patients emphasize that depression is linked to a prothrombotic and proinflammatory state and this possibly contributes to accelerated atherosclerosis.

SummaryThe 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 reducedfunction 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.

SummaryAntiplatelet agents are essential in treating patients with acute ischaemic stroke (AIS) to prevent recurrent ischaemic events. The aim of this study was to evaluate the effectiveness of early antiplatelet therapy with different aspirin (ASA) dosages in patients with AIS. This observational study included 454 patients with AIS in whom antiplatelet treatment was initiated. The antiplatelet effect was determined by whole blood aggregometry within 48 hours after antplatelet therapy was initiated. An impedance change exceeding 0 Ω after stimulation with arachidonic acid was defined as ASA low response (ALR) and ≥5 Ω in ADP-stimulated specimen as clopidogrel LR. Of the study group 53.5% patients were treated with 200 mg ASA orally, 27.5% with 500 mg ASA intravenously, 8.6% with 100 mg ASA orally, and 7.7% with 75 mg clopidogrel. A dose-dependent antiplatelet effect of ASA treatment was found: 18.4% of patients with 500 mg ASA intravenously were ALR, in contrast to 32.5% on 200 mg and 35.9% on 100 mg ASA orally. Clopidogrel treatment without a loading dose resulted in a high proportion of LR (45.7%). Using the propensity score method revealed a three times higher risk for ALR for patients treated with ASA 200 mg [odds ratio 2.99 (1.55–5.79)] compared to treatment with ASA 500 mg. In conclusion, initiating antiplatelet therapy in patients with AIS resulted in a dose-dependent insufficient platelet inhibitory effect. Our findings suggest using a loading dose of 500 mg ASA intravenously as this seems to be favourable when a sufficient early platelet inhibitory effect is wanted.ClinicalTrials.gov Identifier: NCT01273935

Impedance aggregometry is mainly limited by the time-dependent instability of platelets in whole blood samples, caused by the influence of ex-vivo anticoagulants. The synthesis of a new anticoagulant, Benzylsulfonyl-D-Arg-Pro-4-amidinobenzylamide (BAPA), has recently been introduced. Data from recent studies suggest stable results for up to 32 h. In view of this data we were interested in the results of ADP- and arachidonic acid (AA)-induced measurements after a prolonged storage time depending on the use of citrate or BAPA. Blood samples from 24 healthy individuals were anticoagulated with either citrate or BAPA. ADP- and AA-induced measurements were carried out between 2 h and up to 48 h after blood samples were taken. Results of ADP-induced measurements remained stable for 8 h in citrated and for a maximum of 12 h in BAPA-anticoagulated samples. AA-induced measurements yielded stable results up to 12 h in citrated and up to 24 h in BAPA anticoagulated blood. These data demonstrate that the storage time for whole blood impedance aggregometry can be prolonged when BAPA is used as an anticoagulant. However, in contrast to previous studies implicating considerably longer potential storage times we could not see a clear overall purpose in using BAPA. Further studies including blood samples of patients and the comparison of BAPA to other anticoagulants are necessary to define the potential role of BAPA anticoagulated samples.

SummaryThe 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 ofAspirin 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 μM) stimulation by impedance aggregometry (Chronolog 590). A significant rise in impedance (> 5 Ω after 6 minutes, aggregation index > 65%) was defined as LR. In this subgroup, platelets were stimulated with the selective P2Y12-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 P2Y12 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.

Aberrant patterns of cortisol secretion and serotonergic dysfunction are important features of major depressive disorder (MDD). A multitude of studies investigated the relationship between cortisol and serotonin. Increased salivary cortisol was found after waking in depressed patients (Bhagwagar et al. 2005, 2003). It is assumed that this cortisol awakening reaction (CAR) may be a more exact marker of depression instead of the general assumption of hypercortisolism (Bhagwagar et al. 2005). The present study aimed at investigating the relationship between cortisol and serotonergic function from a new angle. Loudness dependence of auditory-evoked potentials (LDAEP) indicates the activity of synaptically released serotonin. It measures the amplitude change of the auditoryevoked N1/P2 component in response to different stimulus intensities. A low LDAEP indicates a high serotonergic activity and vice versa (Juckel et al. 1996, 1997, 2004, 2007). After excluding four patients with insufficient cortisol data, 12 non-medicated MDD patients [seven females, mean age 47.9±8.6 years, mean Beck Depression Inventory (BDI-II) score 27.4±7.5, all outpatients] were compared to 16 healthy controls (nine females, mean age 50.1± 7.3 years). Structured clinical interview for DSM-IV and BDI-II were used as diagnostic instruments. Salivary cortisol samples were collected in salivettes. CAR was measured by subtracting the cortisol concentration upon waking from the cortisol concentration 30 min after getting up. A time-resolved immunoassay with fluorescence detection was used for cortisol analysis (Lederbogen et al. 2010). Auditory-evoked potentials were tested using a standard procedure. Three hundred fifty sinus tones of five different intensities (60–100 dB SPL) were presented in a pseudorandomised way using Presentation 11.3® (Neurobehavioral Systems Inc., Albany, CA, USA). Artifact-free stimuli were averaged with BrainVision Analyzer® (Brain Products GmbH, Munich, Germany). The N1 amplitude was regarded as the lowest point between 50 and 150 ms after the stimulus, P2 as the highest point between 100 and 250 ms post-stimulus and the N1/P2 amplitude was calculated as the amplitude difference. The LDAEP was calculated as the median slope of the single loudness levels (for further details see Roser et al. 2009). There were no significant differences between patients and controls regarding CAR levels (patients, 7.06±10.07; controls, 13.19±9.70; t test, p=0.129). There was a nonsignificant tendency towards a decreased LDAEP in depressed patients (0.13±0.18) compared to healthy controls (0.24±0.17; t test, p=0.089). I. Uhl (*) : C. Norra :G. Juckel Department of Psychiatry, Psychotherapy and Preventive Medicine, Ruhr University Bochum, LWL University Hospital Bochum, Alexandrinenstrasse 1-3, 44791 Bochum, Germany e-mail: idun.uhl@wkp-lwl.org

Several platelet function test systems exist for the evaluation of the platelet inhibitory effect in patients on P2Y12 inhibitors and/or acetylsalicylic acid (ASA, aspirin) therapy. Studies comparing different available assays found only a poor correlation. The objective of the present study was to evaluate the correlation and agreement between single electrode (SEA) and multiple electrode (MEA) aggregometry.In whole blood arachidonic acid (AA) and adenosine diphosphate (ADP)-induced platelet aggregation was measured simultaneously using SEA (Chrono-Log) and MEA (Multiplate). We analyzed a total of 226 measurements taken from 58 patients on single ASA therapy or dual antiplatelet therapy with ASA and a thienopyridine. A cut-off value for clopidogrel/prasugrel high on-treatment platelet reactivity (HPR) of47 units (U) was chosen for MEA testing using hirudin and5 Ohm for SEA with citrate anticoagulated blood samples. The respective cut-off values for ASA HPR were30 U for the MEA assay and1 Ohm for SEA testing. There was a good correlation of the prevalence of thienopyridine-HPR in both whole blood assays (Spearman rank correlation coefficient r = 0.698) and a good inter-rate accordance (Cohen's Kappa statistic κ = 0.648). For AA-induced aggregation, the correlation of the results obtained was significant (r = 0.536; p0.001) and detecting ASA-HPR revealed a moderate (κ = 0.482) correlation between both impedance aggregometry assays.Platelet function testing using SEA and MEA provided both good accordance and correlation and therefore study results obtained by these two assays similarly enabled the detection of HPR of thienopyridine (and ASA) therapy.

Background During the first days following an acute ischemic stroke, a consistently good antiplatelet effect of clopidogrel is important due to the increased risk of recurrent ischemia. However, the platelet inhibitory effectiveness of clopidogrel is variable for multifactorial reasons. We investigated the prevalence and risk factors for clopidogrel high-on-treatment platelet reactivity (clopidogrel-HTPR) in acute ischemic stroke patients. Methods Using multiple-electrode impedance aggregometry (MEA), the antiplatelet effectiveness of clopidogrel in patients with acute ischemic stroke was prospectively evaluated. Measurements were performed 48 h after therapy was either initiated or continued after hospital admission. Clopidogrel-HTPR was defined as ADP-induced values > 47 U. Results A total of 159 patients (71.8 ± 9.8 years, 69 female) were enrolled and 44% (n = 70) patients were clopidogrel-HTPR. 35 of the clopidogrel-HTPR were retested within one week and 57.1% (n = 20) showed a good clopidogrel response during subsequent testing. We identified diabetes mellitus (36.3% vs. 54.4%, p-value = 0.003) and higher HbA1c values (6.3% vs. 6.8%, p = 0.007) as risk factors for clopidogrel-HTPR. Multivariate regression analysis revealed that diabetes mellitus more than doubled the risk of clopidogrel-HTPR (OR 2.41; 95%-CI 1.19-4.88; p = 0.015). Conclusions Clopidogrel-HTPR was found in 44% of the patients with acute ischemic stroke. Besides time-dependency of the clopidogrel effect, major risk factors for clopidogrel-HTPR were diabetes mellitus and higher HbA1c values. Further investigations are required to analyse if a function test guided strategy has the potential to optimize the antiplatelet therapy of acute stroke patients.

Although acetylsalicylic acid (ASA, aspirin) reduces the risk of ischemic events in patients with atherosclerosis, a substantial number of incidents continue to occur. As only limited data exist we evaluated the antiplatelet effectiveness of ASA in patients with different manifestations of atherosclerosis as in cerebrovascular, coronary artery and peripheral arterial disease (CVD, CAD, PAD). For the evaluation of the antiplatelet effectiveness of ASA we used whole blood aggregometry (Chrono-log Model 590). The patients in the different subgroups received ASA 100, 200 or 500 mg daily. We analysed 737 consecutive patients: 47.5 % with CVD, 33.6 % with CAD, and 18.9 % with PAD. We identified 28.0 % of the CVD, 18.1 % of the CAD and 21.6 % of the PAD patients to be ASA low-responder (ALR). Comparing subgroups treated with 100 mg ASA, 36.4 % were ALR in the CVD group as were 13.1 % of the CAD and 21.6 % of the PAD patients. Multivariate regression analysis revealed an odds ratio for being ALR of 4.50 (95 % confidence interval (CI) 1.70–11.9) when 100 mg and of 2.97 (95 % CI 1.58–5.60) when 200 mg ASA was taken compared to a dose of 500 mg. Despite the proven benefits of antiplatelet therapy in the secondary prevention of atherosclerotic disease, current antiplatelet management is suboptimal as up to 36 % of patients failed to achieve an adequate platelet inhibitory effect. Our findings may explain, at least in part, the high rates of cardiovascular events observed in the course of atherothrombotic disease and support the need to improve antiplatelet therapy.

Depta et al1 reported that platelet function-guided modification of antiplatelet therapy in patients with stroke may be associated with higher rates of adverse clinical outcomes. Platelet function testing was performed by using optical platelet aggregometry. The definition of antiplatelet modification was any increase of the current antiplatelet dosage, the addition of another antiplatelet agent, or the switch to another antiplatelet agent. There are some remarks concerning the methodology and data of the presented study. At first, aspirin low response was defined as altered aggregation after stimulation with arachidonic acid and with adenosine diphosphate. Unfortunately, adenosine diphosphate is unspecific in regard to the aspirin pathway and is not recommended for measuring platelet inhibitory effects of aspirin.2 Therefore, a distinction should have been drawn …

Background An elevation of inflammatory markers such as high-sensitivity C-reactive protein (hs-CRP) can be found in patients with depressive disorders. Inflammatory processes are known to influence atherosclerosis and might also mediate the link between depression and diabetes. The present study aimed at comparing hs-CRP and its relationship with atherogenic platelet markers in patients with type 2 diabetes (TD2) and/or newly diagnosed major depression (MD). Methods Hs-CRP concentrations in 24 patients with TD2, 21 patients with MD (diagnosed according to ICD-10 and DSM-IV), 19 patients with TD2 and comorbid MD, and 25 healthy controls were compared using analysis of variance. The relationship of hs-CRP with atherogenic platelet markers (CD40, CD40 ligand, soluble CD40L) were examined for the different samples using Pearson's correlations and regression analyses. Results Hs-CRP levels were not associated with depression (F(1, 80)=0.56, p=.814). There was a trend for higher hs-CRP in diabetes patients (p=.095), but not after adjustment for BMI. CD40 or sCD40L were not related to hs-CRP. For CD40L, regression analysis revealed a significant interaction between hs-CRP and subgroup: Hs-CRP was positively associated with CD40L only in depressed patients without diabetes (B=.334, p Limitations Causal inferences are limited because of the cross-sectional design and the small sample size. Conclusions Our results demonstrate preliminary evidence that hs-CRP might contribute to the risk of cardiovascular disease in depressed patients without somatic diseases via its association with platelet expression of CD40L. Further studies are necessary to confirm these findings.

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.

Type 2 diabetes is a potent cardiovascular risk factor, associated with proinflammatory and prothrombotic processes. The purpose of this study was to investigate whether platelet-bound CD40-CD40L signalling, P-selectin expression and soluble CD40L were increased in patients with diabetes mellitus and can be normalized by improving glycaemic control.Soluble (s) CD40L, platelet surface expression of CD40L, CD40 and P-selectin (CD62P) on platelets were measured by flow cytometry in 71 patients with Type 2 diabetes mellitus and 37 healthy volunteers. In addition, the relationship of HbA1c to CD40-CD40L and P-selectin expression was determined in a longitudinal follow-up.In patients with Type 2 diabetes, platelet membrane CD40 expression (Type 2 diabetes 3.1+/-0.61 vs. controls 2.5+/-0.85 mean fluorescence intensity; P=0.001), platelet-bound CD40L (1.2+/-0.32 vs. 1.1+/-0.14; P=0.034) as well as surface expression of CD62P (0.66+/-0.19 vs. 0.57+/-0.12; P=0.007) were higher than in control subjects. Plasma sCD40L values (3.2+/-1.70 vs. 1.8+/-0.50 ng/ml; P0.001) were also significantly increased in Type 2 diabetes. After improving glycaemic control in patients with initial HbA1c8.5% (n=15), platelet P-selectin and CD40-CD40L expression decreased significantly by 54.0%, 36.22% and 16.26%, respectively 1 year later.Type 2 diabetes is associated with up-regulation of the platelet-bound CD40-CD40L system, platelet hyperactivity (enhanced P-selectin expression) and increased sCD40L levels. Improved glycaemic control, however, does help to correct abnormal platelet activation via down-regulation of CD40-CD40L system and P-selectin expression.

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 mmol/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.

Hypertensive urgency/emergency occurs frequently, yet no prospective data on common secondary causes, including sleep apnea (SA), renal artery stenosis (RAS), and hyperaldosteronism, are available.Patients presenting to the emergency room for over 1 year with systolic blood pressureor =180 mmHg and/or diastolic blood pressureor =100 mmHg and typical symptoms were included. RAS was diagnosed by direct duplex/Doppler ultrasound of the renal artery, resistance index, and imaging. The aldosterone/renin ratio (ARR) was determined from morning blood samples taken with the patients supine afteror =2 h of rest. A positive ARR (50) was followed by saline infusion to exclude primary hyperaldosteronism. SA was evaluated by nasal breathing flow screening; when positive [apnea/hypopnea index (AHI)5/h], complete polysomnography was performed.Of 161 patients (age, 66.0 +/- 13.1 years; BMI, 28.6 +/- 5.1 kg), 131 had previously identified hypertension (duration, 12.7 +/- 11.5 years; 1.9 +/- 1.5 antihypertensive medications). SA was found in 114 (70.8%) patients [18% mild (AHI: 5-15/h), 26.8% moderate (15.1-30/h), and 24.2% severe (30/h)]. Aldosterone levels exceeded 160 pg/ml in 22 of 23 patients with hyperaldosteronism; 4 had primary and 12 had secondary hyperaldosteronism. Thirteen (8.1%) patients had RAS. Three secondary causes were found in 1 patient (0.6%),or =2 in 25 (15.5%), andor =1 in 124 patients (77.0%). Of 150 detected secondary causes, only 5 were recognized previously.Secondary causes of hypertension are common and predominantly unrecognized in patients with hypertensive urgency/emergency. Co-prevalence of secondary causes occurs in about 15% and should be considered before therapeutic intervention.

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 micromol/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.

Clopidogrel hydrogensulfate is a thienopyridine acting as an important antiplatelet agent alone or in combination with acetyl salicylic acid to prevent cardiovascular complications. A different clopidogrel salt, clopidogrel besylate, was approved in Germany as a "new drug" in May 2008. Only one study with 46 healthy men compared the plasma concentrations of both clopidogrel formulas. In our crossover study we measured the antiplatelet effect of clopidogrel hydrogensulfate (CHS, clopidogrel bisulfate) and clopidogrel besylate (CB) using two techniques, whole blood impedance aggregometry and flow cytometry in healthy subjects.Twenty-one healthy volunteers (14 male, 7 female, mean age 36.3 years) were treated either with CHS or CB (300 mg loading, followed by 75 mg/day) and after a wash-out period of at least 21 days, the participants were switched to the other clopidogrel salt in a crossover design. Blood samples were drawn before and 2, 4 and 48 h after the initial dose was taken. Flow cytometry measurements of CD62P (P-selectin) expression were done at baseline and 48 h thereafter with three different ADP concentrations (5, 15, 50 micromol/L ADP). Whole blood impedance aggregometry testing (Chrono-log Model 590) was performed at baseline and after 2, 4 and 48 h with two ADP concentrations (5 and 20 micromol/L ADP).Using flow cytometry, the mean inhibitory effect of clopidogrel on the CD62P expression was similar and no significant differences were noted in subjects treated with either of the clopidogrel formulas for hydrogensulfate or besylate salt (5 micromol/L ADP: 8.12 +/- 5.53 CHS vs. 6.48 +/- 5.01 CB; 15 micromol/L ADP: 9.33 +/- 6.44 CHS vs. 8.99 +/- 8.27 CB; 50 micromol/L ADP: 11.17 +/- 6.81 CHS vs. 9.52 +/- 6.17 CB). It is important to note that clopidogrel CB shows similar and conspicuously high interindividual variability as was reported earlier on CHS. We observed both possibilities, subjects responding less to the hydrogensulfate salt, but better to the besylate salt, and vice versa. Using aggregometry, both salt formulas achieved similar inhibitory effects regarding initial platelet function (2 h/5 micromol/L ADP: CHS 4.5 +/- 3.66 Omega; CB 3.89 +/- 3.81 Omega and 4 h/5 micromol/L ADP: CHS 5.78 +/- 3.51 Omega; CB 4.89 +/- 4.03 Omega) as well as during the maintenance phase (48 h/5 micromol/L ADP: CHS 2.86 +/- 2.92 Omega; CB 3.43 +/- 3.06 Omega). Once again the aggregometry results for CB showed a similarly high interindividual variability as also holds true for CHS. Some subjects had a better antiplatelet effect with clopidogrel besylate and vice versa with clopidogrel hydrogensulfate.The crossover study using whole blood aggregometry and flow cytometry shows no overall significant difference in the antiplatelet effect of clopidogrel hydrogensulfate as compared to clopidogrel besylate. However, it is important to note that besides high interindividual there is also high intraindividual variability between the two different clopidogrel formulas. We observed both: subjects responding less to besylate salt, but better to hydrogensulfate salt, and vice versa.

Background Cytochrome 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. Methods The 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. Results The 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). Conclusion In 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.

The uptake of beta-lactam antibiotics into small intestinal enterocytes occurs by the transport system for small peptides. The role of membrane-bound peptidases in the brush border membrane of enterocytes from rabbit and pig small intestine for the uptake of small peptides and beta-lactam antibiotics was investigated using brush border membrane vesicles. The enzymatic activity of aminopeptidase N was inhibited by beta-lactam antibiotics in a non-competitive manner whereas dipeptidylpeptidase IV was not affected. The peptidase inhibitor bestatin led to a strong competitive inhibition of aminopeptidase N whereas the uptake of cephalexin into brush border membrane vesicles was only slightly inhibited at high bestatin concentrations (greater than 1 mM). Modification of brush border membrane vesicles with the histidine-modifying reagent diethyl pyrocarbonate led to a strong irreversible inhibition of cephalexin uptake whereas the activity of aminopeptidase N remained unchanged. A modification of serine residues with diisopropyl fluorophosphate completely inactivated dipeptidylpeptidase IV whereas the transport activity for cephalexin and the enzymatic activity of aminopeptidase N were not influenced. With polyclonal antibodies raised against aminopeptidase N from pig renal microsomes the aminopeptidase N from solubilized brush border membranes from pig small intestine could be completely precipitated; the binding protein for beta-lactam antibiotics and oligopeptides of apparent Mr 127,000 identified by direct photoaffinity labeling with [3H]benzylpenicillin showed no crossreactivity with the aminopeptidase N anti serum and was not precipitated by the anti serum. These results clearly demonstrate that peptidases of the brush border membrane like aminopeptidase N and dipeptidylpeptidase IV are not directly involved in the intestinal uptake process for small peptides and beta-lactam antibiotics and are not a constituent of this transport system. This suggests that a membrane protein of Mr 127,000 is (a part of) the uptake system for beta-lactam antibiotics and small peptides in the brush border membrane of small intestinal enterocytes.

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. Background: The annual incidence of AT in patients with dual-chamber pacemakers may be significantly underestimated based on ECG and Holter recordings. Methods: A DDD(R) device capable of AT-triggered dual-channel electrogram (EGM) storage was implanted in 254 patients (70 ± 11 years, 159 men) with a class I pacing indication. Patients were seen at 6, 26, and 52 weeks after pacemaker implantation. At all visits, symptoms were checked, surface ECGs were recorded including a 24-hour Holter recording at 6 weeks, and the pacemakers were interrogated. Primary study endpoint was AT documentation by surface ECG/Holter versus stored EGMs. Secondary endpoints consisted of the association between patients' symptoms and AT documentation, and of the AT incidence depending on pacing indication and a history of AT. Results: ATs were documented by ECG/Holter recordings in 37 patients (15%) and by stored EGMs in 137 patients (54%) (P < 0.0001). Symptoms were absent in 108 of 137 patients (79%) with device-documented AT but present in 70 of 117 patients (60%) without AT documentation. AT documentation was more frequent in patients with a history of AT but not in patients with sinus node compared to AV node disease. Conclusion: ATs occur in pacemaker patients significantly more frequently than estimated by ECG/Holter recordings. Only the analysis of device-stored EGMs allows reliable assessment of the AT burden.

Aims Clopidogrel is a pro-drug which is converted to an active, unstable drug by cytochrome P450 (CYP). The active drug irreversibly blocks one specific platelet adenosine 5′-diphosphate (ADP) receptor (P2Y12). It has been recently suggested that the most abundant human CYP isoform, 3A4, activates clopidogrel. Since certain lipophilic statins (i.e. simvastatin, atorvastatin, lovastatin) are a substrate of CYP3A4, we were interested in potential drug interactions between clopidogrel and statins. Methods In patients with coronary artery disease ( n =47) in whom clopidogrel treatment was initiated for balloon angioplasty and stent implantation, blood samples were taken at 0, 5 and 48h after oral administration of clopidogrel (loading dose 300mg, followed by 75mg daily). ADP-stimulated (1, 10, 100μmol/l) expression of P-selectin (CD62P) on platelets was measured by flow cytometry, and used as a marker for the antiplatelet effect of clopidogrel. Results Pre-treatment with statins (atorvastatin, simvastatin) reduced significantly (10μmol/l ADP stimulation) the inhibitory effects of clopidogrel during the loading phase (relative reduction after 5h 29.3%) and, to a lesser extent during the maintenance phase (relative reduction after 48h 16.6%). In addition we found a considerable individual heterogeneity in the response and three patients (6%) were identified in whom clopidogrel exerted almost no effect. Conclusion Certain statins which are substrates of the CYP3A4 isoform competitively inhibit the metabolic activation of clopidogrel. As a result the relative clopidogrel induced platelet inhibition (P-selectin-expression) is diminished—but still there is a relative clopidogrel effect of more than 80% in the maintenance phase. It may be reasonable to test the therapeutic efficacy of clopidogrel in those patients who require long-term treatment.

Der untersuchte MS-Algorithmus zeigte eine rasche Reaktion auf Vorhofflimmern/-flattern auch bei hohem Anteil von Undersensing durch kleine Flimmerpotentiale oder Flatterwellen im Blanking. Der BFS-Algorithmus kann insbesondere bei Sinustachykardie mit intermittierenden SVES oder R-Wellen-Oversensing zu falsch-positivem Mode-Switch fuhren. Um einen unnotigen MS bei kurzen SV-Salven zu vermeiden, sollte bei entsprechenden Patienten eine Verzogerung zwischen Detektion und MS aktiviert werden. Mittels der Schrittmacherspeicher konnten in einem uberraschend hohen Prozentsatz ein falsch-positiver MS-Episoden nachgewiesen werden, die zumeist konventionellen Nachweismethoden (Ekg, 24h-Holter) entgangen waren. Zweikammer-Schrittmacher sollten daher uber derartige Diagnostiken inklusive gespeicherter EGMs verfugen.

Dr. Shechter correctly notes that there exist three different techniques to measure ex vivo the effects of clopidogrel on platelet activity, with the flow cytometry is probably the most sensitive method. Using aggregometry, Lau et al.1 observed a strong and dose-dependent interference between atorvastatin and the inhibitory effect of clopidogrel on platelet function. We measured instead platelet activation by …

Background Dual antiplatelet therapy using acetylsalicylic acid (ASA, aspirin) and clopidogrel is of great importance following coronary stenting. However, the variable platelet inhibitory effectiveness compromises the antithrombotic advantages provided by dual antiplatelet therapy. The aim of this single-center prospective study was to reduce the low response incidence of dual antiplatelet therapy with ASA and clopidogrel according to a prespecified therapy algorithm. Methods Platelet function testing using whole blood aggregometry (Chronolog 590) was performed 48 hours following coronary stenting (for either acute coronary syndromes or stable coronary artery disease) on 504 patients. The antiplatelet therapy included a loading dose of 600 mg clopidogrel and 500 mg ASA, followed by 75 mg clopidogrel and 100 mg ASA once daily. Clopidogrel low responders (CLR: >5 ohm; adenosine diphosphate (ADP) 5 μM) and/or ASA low responders (ALR: >0 ohm; arachidonic acid 10 μM) were treated according to a structured therapy plan: in the case of CLR, the maintenance + dose was doubled (repeated loading dose followed by 150 mg daily), and when still ineffective ticlopidine or prasugrel, if available and not contraindicated, were used. ALR was treated by increasing the dose to 300 mg in a first step or to 500 mg ASA when the first modification did not take effect sufficiently. In addition, ADP receptor antagonist 2-methylthioadenosine 5'-monophosphate triethylammonium salt (MeSAMP) testing and ASA incubation were performed to rule out either a platelet ADP-receptor defect or an ASA pharmacokinetic resistance. Results Of the total cohort of 504 patients, we detected 30.8% clopidogrel low-responders and 19.4% aspirin low-responders. For ALR, with a dose adjustment of 300 mg ASA daily, 94.6% of ALR were effectively treated and the residual 5.4% by administration of daily dosages of 500 mg ASA. This means that after modification of the ASA maintenance dose, all initial ALRs had an adequate antiplatelet response. The results for clopidogrel revealed that 69% of the CLR were treated effectively by increasing the clopidogrel dose to 150 mg daily. When prasugrel was not available or contraindicated, 12.7% of the remaining low responders showed an adequate result after being switched to ticlopidine. Consequently, by applying the therapy algorithm, we were able to reduce the CLR prevalence by 86.6%. On including prasugrel in the therapy plan, we were finally able to eliminate thienopyridine low response. In addition, no ADP receptor defect was found in this study as a potential reason for CLR. We identified the following factors associated with both CLR and ALR status: acute coronary syndromes, positive troponin values as well as diabetes mellitus and elevated HbA1C values and a higher platelet count. Furthermore, our data revealed for CLR elevated C-reactive protein values and a high PREDICT-score (including an age >65 years, acute coronary syndrome, diabetes mellitus, renal failure, and reduced left ventricular function) as risk factors. The following factors correlated with the risk of ASA low response: patients with elevated hemoglobin, serum creatinine and C-reactive protein values. In addition, medication with nitrates reduced the risk of being CLR. As also holds true for CLR, we found the PREDICT-score to be correlated to the risk of being ALR. However, by far the strongest risk factor for CLR or ALR was the fact of dual resistance. Conclusion Following a structured therapy plan based on a "test and treat" strategy, the prevalence of clopidogrel or aspirin low response can be significantly reduced and the risk of inadequate dual antiplatelet therapy minimized. Trial Registration NCT01212302 (Clinicaltrials.gov)