High On-Treatment Platelet Reactivity: Aspirin versus Clopidogrel.

BACKGROUND: Antithrombotic regimen in patients on oral anticoagulation (OAC) post-percutaneous coronary intervention (PCI) is challenging. At least, one antiplatelet agent in combination with OAC is recommended after PCI for 6-12 months. Clopidogrel is used most frequently in this setting. However, data comparing P2Y12 inhibition with clopidogrel versus cyclooxygenase inhibition by acetylsalicylic acid (ASA, aspirin) is missing. It is well known that the antiplatelet effects of ASA and clopidogrel are frequently impaired (high on-treatment platelet reactivity [HTPR]). In this pilot investigation, we compared the antiplatelet effects of clopidogrel versus ASA. METHODS: In this retrospective single-center database analysis, we investigated platelet reactivity by light transmission aggregometry in patients under different antiplatelet regimes. Results were presented as maximum of aggregation (MoA). HTPR to ASA and to clopidogrel were assessed. RESULTS: 755 patients were enrolled. 677 were on ASA, 521 were on clopidogrel, and 198 had OAC. Overall mean age was 73 ± 13.4 years, and 458 (60.7%) were male. HTPR to ASA occurred in 94/677 patients (13.9%), and mean arachidonic acid-induced MoA was 14.15 ± 19.04%. HTPR to clopidogrel occurred in 241/521 patients (46.3%), and mean adenosine diphosphate-induced MoA was 50.06 ± 20.42%. HTPR to clopidogrel was significantly more frequent than HTPR to ASA; single antiplatelet therapy (SAPT)-mono ASA: 27/199 (13.6%) versus mono clopidogrel: 6/18 (33.3%); p = 0.037; SAPT with OAC-OAC with ASA: 8/35 (22.9%) versus OAC with clopidogrel: 27/60 (45%); p = 0.046. Same difference in HTPR contingency could be shown in subgroups of dual antiplatelet therapy and ASA + clopidogrel + OAC therapy. CONCLUSION: Impaired pharmacodynamic response to clopidogrel was more frequent as HTPR to ASA. Hence, ASA should be tested in combination with OAC post-PCI.

Left ventricular-aortic angle is associated with platelet reactivity in patients with aortic stenosis.

The impact of aortic stenosis on platelet reactivity is unclear. Previous studies reported contradicting results. The reason for this is unknown. It is known that flow alterations enhance platelet reactivity. A steep left ventricular-aortic angle (LV-AO-angle) is associated with turbulent flow in the aorta ascendens. Therefore, in this study, we hypothesized that LV-AO-angle is associated with platelet reactivity in patients with severe aortic stenosis. We included 289 patients with severe aortic stenosis and performed cardiac computertomography to assess the LV-AO-angle. Platelet function was evaluated by light transmission aggregometry. Platelet reactivity was higher in patients with a steep LV-AO-angle (ADP: <160°: 66.99% ±â€Š20.72% vs. ≥160°: 60.66% ±â€Š19.85%, P  = 0.009; collagen: <160°: 78.67% ±â€Š13.19% vs. ≥160°: 73.85% ±â€Š14.44%, P  = 0.003). Using Spearman correlation, ADP and collagen-induced aggregation was associated with LV-AO-angle (ADP: r  = -0.19, P  = 0.0009, R2  = 0.022; collagen: r  = -0.21, P  = 0.0004, R2  = 0.027). Apart from platelet reactivity, body weight, history of myocardial infarction and other factors were associated with steep LV-AO-angle. However, multivariate cox-regression (including body weight, comorbidities, history of MI and cardiac surgery, kidney function and laboratory parameters) revealed that LV-AO angle was a robust predictor of ADP and collagen-induced platelet aggregation. Steep LV-AO-angle is associated with enhanced platelet reactivity in patients with aortic stenosis. This could be the reason of contradicting results regarding platelet function in patients with aortic stenosis in previous studies. In addition, enhanced platelet reactivity in steep LV-AO-angle aortic stenosis patients might be a promising target in pathogenesis of aortic stenosis.

Staphylococcus aureus increases platelet reactivity in patients with infective endocarditis.

Thromboembolism is frequent in infective endocarditis (IE). However, the optimal antithrombotic regimen in IE is unknown. Staphylococcus aureus (SA) is the leading cause of IE. First studies emphasize increased platelet reactivity by SA. In this pilot study, we hypothesized that platelet reactivity is increased in patients with SA- IE, which could be abrogated by antiplatelet medication. We conducted a prospective, observatory, single-center cohort study in 114 patients with IE, with four cohorts: (1) SA coagulase positive IE without aspirin (ASA) medication, (2) coagulase negative IE without ASA, (3) SA coagulase positive IE with ASA, (4) coagulase negative IE with ASA. Platelet function was measured by Multiplate electrode aggregometry, blood clotting by ROTEM thromboelastometry. Bleeding events were assessed according to TIMI classification. In ASA-naïve patients, aggregation with ADP was increased with coag. pos. IE (coagulase negative: 39.47 ± 4.13 AUC vs. coagulase positive: 59.46 ± 8.19 AUC, p = 0.0219). This was abrogated with ASA medication (coagulase negative: 42.4 ± 4.67 AUC vs. coagulase positive: 45.11 ± 6.063 AUC p = 0.7824). Aspirin did not increase bleeding in SA positive patients. However, in SA negative patients with aspirin, red blood cell transfusions were enhanced. SA coagulase positive IE is associated with increased platelet reactivity. This could be abrogated by aspirin without increased bleeding risk. The results of this pilot study suggest that ASA might be beneficial in SA coagulase positive IE. This needs to be confirmed in clinical trials.

Excess Mortality in Aspirin and Dipyrone (Metamizole) Co-Medicated in Patients With Cardiovascular Disease: A Nationwide Study.

Background Pain is a major issue in our aging society. Dipyrone (metamizole) is one of the most frequently used analgesics. Additionally, it has been shown to impair pharmacodynamic response to aspirin as measured by platelet function tests. However, it is not known how this laboratory effect translates to clinical outcome. Methods and Results We conducted a nationwide analysis of a health insurance database in Germany comprising 9.2 million patients. All patients with a cardiovascular event in 2014 and subsequent secondary prevention with aspirin were followed up for 36 months. Inverse probability of treatment weighting analysis was conducted to investigate the rate of mortality, myocardial infarction, and stroke/transient ischemic attack between patients on aspirin-dipyrone co-medication compared with aspirin-alone medication. Permanent aspirin-alone medication was given to 26,200 patients, and 5946 patients received aspirin-dipyrone co-medication. In the inverse probability of treatment weighted sample, excess mortality in aspirin-dipyrone co-medicated patients was observed (15.6% in aspirin-only group versus 24.4% in the co-medicated group, hazard ratio [HR], 1.66 [95% CI, 1.56-1.76], P<0.0001). Myocardial infarction and stroke/transient ischemic attack were increased as well (myocardial infarction: 1370 [5.2%] versus 355 [5.9%] in aspirin-only and co-medicated groups, respectively; HR, 1.18 [95% CI, 1.05-1.32]; P=0.0066, relative risk [RR], 1.14; number needed to harm, 140. Stroke/transient ischemic attack, 1901 [7.3%] versus 506 [8.5%] in aspirin-only and co-medicated groups, respectively; HR, 1.22 [95% CI, 1.11-1.35]; P<0.0001, RR, 1.17, number needed to harm, 82). Conclusions In this observational, nationwide analysis, aspirin and dipyrone co-medication was associated with excess mortality. This was in part driven by ischemic events (myocardial infarction and stroke), which occurred more frequently in co-medicated patients as well. Hence, dipyrone should be used with caution in aspirin-treated patients for secondary prevention.

Impact of Transcatheter Aortic Valve Implantation on Thrombin Generation and Platelet Function.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) is an evolving treatment of severe aortic valve stenosis. However, thromboembolic events such as stroke are common, predominantly early after TAVI. Optimal periprocedural antithrombotic regime is unknown. Especially, as antithrombotic medication enhances bleeding risk, thrombin generation and platelet function are crucial in the pathogenesis of ischemic events. However, the impact of the TAVI procedure on thrombin formation and platelet reactivity is not known by now. METHODS: We evaluated thrombin levels using thrombin-antithrombin (TAT) complexes and prothrombin fragments (PTFs) using enzyme-linked immunosorbent assay. Furthermore, platelet reactivity was measured via light transmission aggregometry before and 2 hours after TAVI in 198 patients. RESULTS: TAT complexes and PTF F1 + 2 substantially increased during TAVI. Postprocedurally, TAT complexes and PTF were significantly higher after TAVI compared with percutaneous coronary intervention due to acute myocardial infarction, while preprocedural TAT complexes and PTF F1 + 2 did not differ. In contrast, platelet reactivity was not altered early after TAVI. Only adenosine diphosphate-induced aggregation was reduced, reflecting preprocedural loading with clopidogrel. CONCLUSION: In this pilot study, we were able to demonstrate that thrombin generation is significantly increased early after TAVI, while platelet function is not affected. Increased thrombin concentrations may contribute to the high risk of postprocedural thromboembolic events. This leads to the hypothesis that extended peri-interventional anticoagulation early after TAVI may be an approach to reduce thromboembolic events.

Noncanonical Effects of Oral Thrombin and Factor Xa Inhibitors in Platelet Activation and Arterial Thrombosis.

Nonvitamin K oral anticoagulants (NOACs) or direct oral anticoagulants comprise inhibitors of factor Xa (rivaroxaban, apixaban, edoxaban) or factor IIa (dabigatran). Both classes efficiently interfere with the final or penultimate step of the coagulation cascade and showed superior net clinical benefit compared with vitamin K antagonists for prevention of thromboembolic events in patients with AF and for prevention and therapy of deep vein thrombosis and pulmonary embolism. None the less, accumulating data suggested, that there may be differences regarding the frequency of atherothrombotic cardiovascular events between NOACs. Thus, the optimal individualized NOAC for each patient remains a matter of debate. Against this background, some basic and translational analyses emphasized NOAC effects that impact on platelet activity and arterial thrombus formation beyond inhibition of plasmatic coagulation. In this review, we will provide an overview of the available clinical and translational evidence for so-called noncanonical NOAC effects on platelet activation and arterial thrombosis.

Lipid lowering therapy in cardiovascular disease: From myth to molecular reality.

Lipid-lowering therapy is one major cornerstone of medical treatment of cardiovascular disease in order to modulate atherosclerosis. Statins, ezetimibe and novel PCSK9-inhibitors are already recommended in current guidelines and were shown to improve lipid profiles and have positive effects on the rate of ischemic events and cardiovascular mortality. Recent studies suggest that the concept of "The lower the better" might be valid at least regarding low density lipoproteins. In addition, lowering lipoprotein (a) still displays a major challenge in lipid therapy. Furthermore, also lowering triglycerides seems to improve cardiovascular outcome. Regarding triglycerides, icosapent ethyl, a polyunsaturated fatty acid recently attracted attention showing cardiovascular risk reduction due to triglyceride lowering. Therefore, new therapeutic strategies and drug classes are eagerly awaited. Targeting LDL, bempedoic acid and the siRNA inclisiran provide promising results. Moreover, regarding TG a monoclonal antibody called evinacumab and an antisense-oligonucleotide against ANGPTL3 showed effective TG-lowering. At least, using antisense-oligonucleotides against ApoC-III and Lp(a) resulted in promising outcomes. In this review, current and future options for lipid management are presented depending on different drug classes.

A novel mechanism of ACE inhibition-associated enhanced platelet reactivity: disproof of the ARB-MI paradox?

PURPOSE: ACE inhibitors (ACEI) and angiotensin II receptor blockers (ARB) are important drugs in cardiovascular disease. However, little is known about which of these drug class is to be preferred. First analyses show that the blockade of the renin-angiotensin-aldosterone system (RAAS) influences platelet reactivity. Therefore, we evaluated the effects of ACEI and ARB on platelet reactivity and thrombin generation. METHODS: We conducted a time series analysis in 34 patients. We performed light transmission aggregometry (LTA) to evaluate platelet reactivity. Results are given as maximum of aggregation (MoA). Thrombin generation was measured as endogenous thrombin potential (ETP) via calibrated automated thrombogram. Flow cytometry was used to analyze protease-activated receptor (PAR)-1 expression. RESULTS: ACEI treatment significantly increased platelet reactivity already 4 h after initiation of treatment (prior vs. 4 h post ACEI: MoA 41.9 ± 16.2% vs. 55.2 ± 16.7%; p = 0.003). After switching from ACEI to ARB treatment, platelet reactivity decreased significantly (3 months after switching: MoA 34.7 ± 20.9%; p = 0.03). ACEI reduced endogenous thrombin potential significantly from before to 3 months after ACEI (ETP 1527 ± 437 nM × min vs. 1088 ± 631 nM × min; p = 0.025). Platelet thrombin receptor (PAR1) expression increased from 37.38 ± 10.97% before to 49.53 ± 6.04% after ACEI treatment (p = 0.036). CONCLUSION: ACEI enhanced platelet reactivity. This can be reversed by changing to ARB. The mechanism behind RAAS influencing platelet function seems to be associated with PAR-1 expression.

Enhanced Platelet Reactivity under Aspirin Medication and Major Adverse Cardiac and Cerebrovascular Events in Patients with Coronary Artery Disease.

Aspirin is indispensable in secondary prevention of ischemic events in patients with coronary artery disease (CAD). However, insufficient platelet inhibition despite aspirin medication is frequent. This is referred to as high on-treatment platelet reactivity (HTPR). Nevertheless, if this is associated with clinical outcome instead of only laboratory phenomenon remains unclear so far. In this study, we test whether patients with ischemic events have higher platelet reactivity despite aspirin medication than patients without ischemic events. In this prospective study of 72 CAD patients, we determined pharmacodynamic response to aspirin by arachidonic acid induced aggregation via light-transmission aggregometry and expressed as maximum of aggregation (MoA). During a mean follow-up duration of 3.2 years, major adverse cardiac and cerebrovascular events (MACCE), mortality, non-ST-elevation myocardial infarction (NSTEMI), and stroke were assessed as endpoints via yearly telephone interviews with the treating physician of the patients. Patients who suffered from MACCE, death, and NSTEMI had a significantly higher MoA than those without (MACCE: 5.4 vs. 16.4%, p < 0.05; death: 5.6 vs. 16.8%, p < 0.05; NSTEMI: 1.8 vs. 21%, p < 0.001). MoA did not differ with regard to the occurrence of stroke (10.1 vs. 14.9%, p = 0.59). Patients with MACCE, death, and NSTEMI show enhanced platelet reactivity despite aspirin medication as compared to patients without ischemic events. Hence, insufficient response to aspirin medication should be regarded as risk factor for ischemic events in CAD patients. Further trials are needed to assess options to overcome HTPR to aspirin.

Aspirin antiplatelet effects are associated with body weight.

BACKGROUND: Aspirin is indispensable in secondary prevention of ischemic events. Recently, it was reported that clinical aspirin effects are hampered in patients above 70 kg body weight. It is well known that a plethora of reasons beside obesity is associated with increased platelet reactivity and insufficient aspirin effects (HTPR). However, data regarding an association between pharmacodynamic response to aspirin and body weight are missing. METHODS: In this pilot study, we included 59 patients from University Hospital Duesseldorf. Impedance aggregometry was used to assess pharmacodynamic response to aspirin. RESULTS: AA-induced platelet reactivity was significantly higher in patients above 70 kg (<70 kg: 28.27 ± 26.33 vs. >70 kg: 45.93 ± 27.1, p = .035) and correlated well with the bodyweight of patients in this study (r = 0.33, R2 = 0.09, p = .016). According to this, insufficient pharmacodynamic response (HTPR) to aspirin was significantly more frequent in patients over 70 kg (<70 kg: 25% vs. >70 kg: 43%, p = .035). CONCLUSION: Insufficient pharmacodynamic response to aspirin is associated with body weight. This finding may play a role in the impaired clinical efficacy of aspirin in patients >70 kg. An optimal aspirin regime in these patients needs to be evaluated in large scale trials.

Cyclooxygenase activity in bradykinin-induced dermal extravasation. A study in mice and humans.

BACKGROUND: Non-allergic angioedema is largely driven by increased plasma levels of bradykinin and over-activation of bradykinin receptor type II (B2), but the specific downstream signalling pathways remain unclear. The aim of this study was to identify signal transduction events involved in bradykinin-induced dermal extravasation. METHODS: Quantification of dermal extravasation was accomplished following intradermal (i.d.) injection of bradykinin or the B2 agonist labradimil in mice with endothelial NO-synthase (eNOS) deficiency and in C57BL/6J mice pre-treated with vehicle, NO-synthase or cyclooxygenase (COX) inhibitors. In the multicentre clinical study ABRASE, 38 healthy volunteers received i.d. bradykinin injections into the ventral forearm before and after oral treatment with the COX inhibitor ibuprofen (600 mg). The primary endpoint of ABRASE was the mean time to complete resolution of wheals (TTCR) and the secondary endpoint was the change of maximal wheal size. RESULTS: Neither NOS inhibitors nor eNOS deficiency altered bradykinin-induced extravasation. In striking contrast, the COX inhibitors ibuprofen, diclofenac, SC560 and celecoxib significantly diminished this extravasation when given before injection. As for diclofenac, a similar but significantly lower effect was observed when given after i.d. injection of bradykinin. Similar results were obtained when bradykinin was replaced by labradimil. In volunteers, ibuprofen significantly reduced TTCR (P < 0.001) and maximal wheal size (P = 0.0044). CONCLUSION: These data suggest that COX activity contributes to bradykinin-induced dermal extravasation in mice and humans. In addition, our findings may open new treatment options and point to a potential activity of drugs interfering with the release of the COX substrate arachidonic acid, e.g. glucocorticoids.

Platelet reactivity in patients with chronic kidney disease and hemodialysis.

End stage renal disease requiring hemodialysis (HD) is frequent and coronary artery disease (CAD) is a common comorbidity. It is associated with bleeding and ischemic events. Platelet reactivity is a well-known determinant of both. However, the impact of HD due to end stage chronic kidney disease (CKD) on platelet reactivity is unknown. Therefore in this study, we evaluated platelet reactivity during hemodialysis in patients with CKD and coronary artery disease. 22 patients with CKD, HD and CAD were included in this study. Light transmission aggregometry (LTA) and flow cytometry were used for evaluating platelet function immediately before and 2 h after initiation of HD. Arachidonic acid-induced maximum of aggregation (MoApre HD: 27.36% ± 25.23% vs. MoAduring HD: 28.05% ± 23.50%, p value = 0.822), adenosine diphosphate (ADP)-induced platelet aggregation (MoApre HD: 65.36% ± 12.88% vs. MoAduring HD: 61.55% ± 17.17%, p-value = 0.09) and collagen-induced platelet aggregation (MoApre HD: 62.18% ± 18.14% vs. MoAduring HD: 64.82% ± 18.31%, p-value = 0.375) were not affected by HD. P-selectin expression was significantly lower after 2 h of HD (pre HD: 31.56% ± 18.99%, during HD: 23.97% ± 15.28%, p = 0.026). In this pilot study, HD did not enhance platelet aggregation. Baseline platelet reactivity was decreased during HD.

Rivaroxaban Reduces Arterial Thrombosis by Inhibition of FXa-Driven Platelet Activation via Protease Activated Receptor-1.

RATIONALE: A reduced rate of myocardial infarction has been reported in patients with atrial fibrillation treated with FXa (factor Xa) inhibitors including rivaroxaban compared with vitamin K antagonists. At the same time, low-dose rivaroxaban has been shown to reduce mortality and atherothrombotic events in patients with coronary artery disease. Yet, the mechanisms underlying this reduction remain unknown. OBJECTIVE: In this study, we hypothesized that rivaroxaban's antithrombotic potential is linked to a hitherto unknown rivaroxaban effect that impacts on platelet reactivity and arterial thrombosis. METHODS AND RESULTS: In this study, we identified FXa as potent, direct agonist of the PAR-1 (protease-activated receptor 1), leading to platelet activation and thrombus formation, which can be inhibited by rivaroxaban. We found that rivaroxaban reduced arterial thrombus stability in a mouse model of arterial thrombosis using intravital microscopy. For in vitro studies, atrial fibrillation patients on permanent rivaroxaban treatment for stroke prevention, respective controls, and patients with new-onset atrial fibrillation before and after first intake of rivaroxaban (time series analysis) were recruited. Platelet aggregation responses, as well as thrombus formation under arterial flow conditions on collagen and atherosclerotic plaque material, were attenuated by rivaroxaban. We show that rivaroxaban's antiplatelet effect is plasma dependent but independent of thrombin and rivaroxaban's anticoagulatory capacity. CONCLUSIONS: Here, we identified FXa as potent platelet agonist that acts through PAR-1. Therefore, rivaroxaban exerts an antiplatelet effect that together with its well-known potent anticoagulatory capacity might lead to reduced frequency of atherothrombotic events and improved outcome in patients.

Safety and efficacy of Tirofiban in STEMI-patients.

BACKGROUND: Tirofiban is recommended as bail out therapy in patients with ST-elevation myocardial infarction (STEMI). However, evidence regarding safety and efficacy of tirofiban is unclear. Tirofiban has been shown to improve ST-resolution, to decrease infarct size (IS) and to reduce incidence of major adverse cardiac and cerebrovascular events (MACCE). However, bleeding is enhanced in tirofiban treated patients. In this study, we aim to investigate efficacy and safety of Tirofiban in STEMI-patients. METHODS: 610 STEMI patients were analyzed. MACCE (death, myocardial infarction [MI], stroke) and TIMI bleeding events were registered during hospital course and 12 month follow-up. RESULTS: Tirofiban patients were slightly younger (tirofiban 63 ±â€¯13 years vs. control 65 ±â€¯14 years; p = 0.04). They had higher peak-high-sensitive troponin T [Hs-TnT] (tirofiban 6561 ±â€¯11,065 vs. control 4594 ±â€¯11,200, p-value = 0.047) and peak-creatine kinase [CK] (tirofiban 2742 ±â€¯5097 vs. control 1416 ±â€¯2160, p-value < 0.0001). Percutaneous coronary intervention (PCI) was more complex in tirofiban treated patients as radiation time (tirofiban 18 ±â€¯15 vs. control 14 ±â€¯13; p-value = 0.02) and use of contrast agent (tirofiban 240 ±â€¯106 vs. control 209 ±â€¯99; p-value = 0.01) was higher in tirofiban patients. However, there were no differences in MACCE (HR 0.877, 95% CI 0.62-1.25, p = 0.47) and bleeding (major: HR 1.494, 95% CI 0.65-3.44, p = 0.34; minor: HR 1.294, 95% CI 0.67-2.52, p = 0.45). CONCLUSION: MACCE and bleeding events were similar. However, PCI was more complex and infarcts larger in tirofiban treated patients.

Non-vitamin K oral anticoagulants (NOAC) and the risk of myocardial infarction: Differences between factor IIa and factor Xa inhibition?

Guidelines already recommend non-vitamin K oral anticoagulants (NOAC) over vitamin-K antagonists (VKA) for stroke prevention in patients with atrial fibrillation. However, recommendations are lacking with respect to which NOAC to use. At the moment, NOACs may employ two different molecular mechanisms: Factor IIa inhibition (dabigatran) and factor Xa inhibition (apixaban, edoxaban, rivaroxaban). The focus of this review is to compare and contrast potential differences between factor IIa- and factor Xa inhibition with respect to risk of myocardial infarction and to detail underlying mechanisms.

Dose reduction, oral application, and order of intake to preserve aspirin antiplatelet effects in dipyrone co-medicated chronic artery disease patients.

BACKGROUND: Dipyrone comedication in aspirin-treated patients is associated with impaired pharmacodynamic response to aspirin (high on-treatment platelet reactivity [HTPR]). Additionally, in small observational studies, an association with impaired outcome has been described. In this uncontrolled, hypothesis-generating study, we aimed to investigate strategies to prevent this drug-drug interaction in patients with coronary artery disease (CAD). METHODS: We analyzed pharmacodynamic response to aspirin in 80 dipyrone co-medicated CAD patients. Aspirin antiplatelet effects were measured using arachidonic acid (AA)-induced light-transmission aggregometry (LTA). Platelet reactivity was associated with daily dose, administration form, and frequency. Additionally, we conducted a time-series analysis in patients with HTPR to aspirin with re-evaluation of pharmacodynamic response to aspirin after 5 days. RESULTS: Patients' mean age was 75.5 ± 9.8 years. Forty-three (54%) were male, 22 (27.5%) obese, and 38 (47.5%) diabetics. Baseline characteristics, cardiovascular risk factors, comorbidities, comedication, or laboratory parameters did not differ between patients with or without HTPR. HTPR to aspirin occurred in 34 out of 80 patients (42.5%). The incidence of HTPR was associated with dipyrone daily dose (< 1 g/day: HTPR 20% vs. > 3 g/day: HTPR 50%, p > 0.0001) and form of administration (i.v. 87.5% vs. oral 37.5%; p < 0.0001). A strict order of intake (aspirin 30 min prior to dipyrone) restored aspirin antiplatelet effects in all patients (HTPR before 100% vs. HTPR after 0%, p = 0.0002). CONCLUSION: This study shows that dipyrone should be used with caution in aspirin-treated patients. If dipyrone seems indispensable, the lowest effective dose and a strict order of intake seem favorable.

Antiplatelet effects of aspirin and clopidogrel after left atrial appendage (LAA) occluder implantation.

BACKGROUND: The optimal antithrombotic strategy after interventional left atrial appendage closure (LAAC) is controversial. Dual antiplatelet therapy with aspirin and clopidogrel is the most frequently used regiment. However, pharmacodynamic response to antiplatelet medication differs significantly between individuals. Therefore, we aimed to analyse pharmacodynamic response to aspirin and clopidogrel after LAAC. METHODS: In this study, we included 129 patients undergoing interventional LAAC. Primary end point was pharmacodynamic response to antiplatelet medication. Platelet reactivity was measured by light transmittance aggregometry and vasodilator stimulated protein phosphorylation assay. Secondary endpoints were TIMI bleeding events and MACCE during hospital course and one-year follow-up. RESULTS: Insufficient pharmacodynamic response (high on-treatment platelet reactivity - HTPR) to clopidogrel occurred in 67 patients (52%); HTPR to aspirin in 15 patients (12%); low on-treatment platelet reactivity - LTPR - to clopidogrel in 13 patients (10%). No occluder thrombosis or stroke occurred during one year follow-up. Pharmacodynamic response to antiplatelet medication was not associated with MACCE. However, the incidence of TIMI minor bleeding was increased in patients with LTPR to clopidogrel. CONCLUSIONS: Impaired clopidogrel antiplatelet effects were very frequent in patients after LAAC. No stroke or occluder thrombosis occurred. Patients with LTPR to clopidogrel showed more minor bleeding events. Therefore, this hypothesis generating pilot study raises the question if clopidogrel early after LAAC is needed. This question should be addressed in large scale trials.