Perioperative changes of response to antiplatelet medication in vascular surgery patients.

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.

Comparison of perioperative strategies in ICD patients: The perioperative ICD management study (PIM study).

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.

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, ß-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.

Safety and effectiveness of a novel vascular closure device: a prospective study of the ExoSeal compared to the Angio-Seal and ProGlide.

PURPOSE: 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. METHODS: 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). RESULTS: 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 a >3-fold odds of complications when using ExoSeal, which remained unchanged in multivariate analysis. CONCLUSION: 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.

Monitoring ASA and P2Y12-specific platelet inhibition--comparison of conventional (single) and multiple electrode aggregometry.

OBJECTIVE: 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. METHODS AND RESULTS: 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) of > 47 units (U) was chosen for MEA testing using hirudin and > 5 Ohm for SEA with citrate anticoagulated blood samples. The respective cut-off values for ASA HPR were > 30 U for the MEA assay and > 1 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; p < 0.001) and detecting ASA-HPR revealed a moderate (κ = 0.482) correlation between both impedance aggregometry assays. CONCLUSION: 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.

Clopidogrel high-on-treatment platelet reactivity in acute ischemic stroke patients.

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.

Effectiveness of antiplatelet therapy in atherosclerotic disease: comparing the ASA low-response prevalence in CVD, CAD and PAD.

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.

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.

Newly diagnosed depression is associated with increased beta-thromboglobulin levels and increased expression of platelet activation markers and platelet derived CD40-CD40L.

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 (ß-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 ß-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 ß-TG in newly diagnosed patients emphasize that depression is linked to a prothrombotic and proinflammatory state and this possibly contributes to accelerated atherosclerosis.

Ventricular tachycardia during basilar-type migraine attack.

Autonomic dysfunction is a characteristic of migraine attacks, rarely, even cardiac repolarization abnormalities have been associated with migraine. We report a case of documented ventricular tachycardia during basilar-type migraine attack. The therapeutic implications of such a co-occurrence as well as a possible relationship between ventricular tachycardia and the underlying biology of basilar-type migraine are discussed.

New pathways of increased cardiovascular risk in depression: a pilot study on the association of high-sensitivity C-reactive protein with pro-atherosclerotic markers in patients with depression.

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<.05). 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.

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.

Dose-dependent effect of early antiplatelet therapy in acute ischaemic stroke.

Antiplatelet 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 W 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.

Is there an ideal way to initiate antiplatelet therapy with aspirin? A crossover study on healthy volunteers evaluating different dosing schemes with whole blood aggregometry.

BACKGROUND: Guidelines recommend an early initiation of aspirin treatment in patients with acute cerebral ischemia. Comparative studies on the best starting dose for initiating aspirin therapy to achieve a rapid antiplatelet effect do not exist. This study evaluated the platelet inhibitory effect in healthy volunteers by using three different aspirin loading doses to gain a model for initiating antiplatelet treatment in acute strokes patients. METHODS: Using whole blood aggregometry, this study with a prospective, uncontrolled, open, crossover design examined 12 healthy volunteers treated with three different aspirin loading doses: intravenous 500 mg aspirin, oral 500 mg aspirin, and a course of 200 mg aspirin on two subsequent days followed by a five-day course of 100 mg aspirin. Aspirin low response was defined as change of impedance exceeding 0 Ω after stimulation with arachidonic acid. RESULTS: Sufficient antiplatelet effectiveness was gained within 30 seconds when intravenous 500 mg aspirin was used. The mean time until antiplatelet effect was 74 minutes for 500 mg aspirin taken orally and 662 minutes (11.2 hours) for the dose scheme with 200 mg aspirin with a high inter- and intraindividual variability in those two regimes. Platelet aggregation returned to the baseline range during the wash-out phase within 4 days. CONCLUSION: Our study reveals that the antiplatelet effect differs significantly between the three different aspirin starting dosages with a high inter- and intraindividual variability of antiplatelet response in our healthy volunteers. To ensure an early platelet inhibitory effect in acute stroke patients, it could be advantageous to initiate the therapy with an intravenous loading dose of 500 mg aspirin. However, clinical outcome studies must still define the best way to initiate antiplatelet treatment with aspirin.

BAPA, a synthetic dual inhibitor of Factor Xa and Thrombin, extends the storage-time to a maximum of 12 hours in ADP- and 24 hours in arachidonic acid-induced impedance aggregometry.

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.

Tailored antiplatelet therapy can overcome clopidogrel and aspirin resistance--the BOchum CLopidogrel and Aspirin Plan (BOCLA-Plan) to improve antiplatelet therapy.

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.