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.

Aspirin I.V. Loading during Elective Percutaneous Coronary Intervention.

Additional loading dose of acetylsalicylic acid (ASA) during percutaneous coronary interventions (PCIs) despite permanent oral ASA medication is frequently applicated. The impact on platelet reactivity and clinical events is not known. In this pilot study, we aimed to analyze high on-treatment platelet reactivity (HTPR) to aspirin in patients undergoing elective PCI. Platelet reactivity was measured using light-transmission aggregometry in 100 patients on permanent low-dose ASA medication undergoing elective PCI. Platelet reactivity measured by arachidonic acid-induced maximum of aggregation (MoA) in patients with versus without additional peri-procedural ASA loading (500 mg i.v.) was compared. HTPR was defined as MoA >20% for ASA. Major adverse cerebro- and cardiovascular events (MACCEs) and bleeding events were evaluated during hospital course. HTPR rate was similar in both groups (HTPR to ASA: loading vs. control 6% vs. 16%, odds ratio [OR] = 0.33, 95% confidence interval [CI] 0.08-1.35, p = 0.12). In-hospital MACCEs were not different between groups (MACCE: loading vs. control: 0 vs. 0 patient, OR = 1.32, 95% CI 0.03-67.95, p = 0.89). Thrombolysis in myocardial infarction minimal bleedings were numerically higher in patients without ASA loading dose. In this pharmacodynamic pilot study, additional ASA loading did not reduce HTPR to ASA. Furthermore, ASA loading did not increase in-hospital MACCE and bleeding complications.

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.

Platelet Reactivity in Patients on Aspirin and Clopidogrel Therapy Measured by a New Bedside Whole-Blood Assay.

Various tests are available for measuring on-treatment platelet reactivity. The pharmacologically most specific assays are time-consuming and elaborate. A highly specific and convenient assay would be desirable for clinical routine. In this pilot study, we aimed to examine the ability of a novel bedside whole-blood assay-ROTEM platelet-to evaluate platelet inhibition compared with established assays. Platelet reactivity was investigated in 93 patients. Forty-Seven patients were on permanent aspirin therapy and 46 on dual antiplatelet therapy (DAPT) with aspirin and clopidogrel. We used ROTEM platelet impedance aggregometry (ROTEM-PTL), light transmission aggregometry (LTA), Multiplate electrode aggregometry (MEA) and vasodilator-stimulated phosphoprotein flow cytometry. Receiver operating characteristic (ROC) analyses showed ROTEM-PTL differentiates well between patients on medication and healthy individuals: aspirin: ROCAUC 0.99 (95% confidence interval, 0.97-1.01); P < 0.0001; DAPT treatment: ROCAUC 0.80 (95% confidence interval, 0.69-0.91); P < 0.001. Pearson regression analyses showed moderate correlations between assays. Aspirin: MEA versus ROTEM-PTL r = 0.435, P ≤ 0.001; LTA versus ROTEM-PTL r = 0.048, P = 0.180. DAPT: MEA versus ROTEM-PTL r = 0.398, P = 0.001; LTA versus ROTEM-PTL r = 0.409, P = 0.001; vasodilator-stimulated phosphoprotein versus ROTEM-PTL r = 0.164, P = 0.055. ROTEM platelet distinguished well between treated and healthy individuals but correlated moderately with other assays. Clinical trials are needed to investigate the ability of this new assay to identify patients at risk of adverse events.

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.

Malondialdehyde Assay in the Evaluation of Aspirin Antiplatelet Effects.

Aspirin is essential in secondary prevention of patients after myocardial infarction and with coronary artery disease. However, impaired pharmacodynamic response to aspirin is frequent (high on-treatment platelet reactivity [HTPR]). This leads to an enhanced prevalence of cardiovascular events and to an impaired clinical outcome. The current specific assays to evaluate aspirin antiplatelet effects are complex, time-consuming and demand for a high laboratory expertise. Therefore, we developed a potentially bedside assay based on the determination of malondialdehyde (MDA). MDA is a by-product of the thromboxane (TX) formation, which is synthesized in equimolar concentrations. In this study, we compared this MDA assay to the conventional assays in determination of pharmacodynamic aspirin response. For this, aspirin antiplatelet effects were measured in 22 healthy individuals and 63 aspirin treated patients using TX B2 formation enzyme-linked antibody assay, arachidonic acid induced light transmission aggregometry (LTA) and the new fluorometric MDA assay. In patients, MDA levels correlated well with TX formation (R = 0.81; 95% CI 0.69-0.88; p < 0.001) and LTA (R = 0.84; CI 0.74-0.91; p < 0.001). Receiver operating characteristic analyses revealed that the MDA assay does detect HTPR to aspirin sufficiently (area under the curve: 0.965; p < 0.001). The optimal cut-off was > 128 nmol/L (sensitivity of 100%, specificity of 91%). The new MDA assay is reliable in detecting HTPR. It is highly specific in the evaluation of antiplatelet effects by aspirin. This promising and potential bedside assay needs to be evaluated in clinical practice.

Safety and Efficacy in Prasugrel- Versus Ticagrelor-Treated Patients With ST-Elevation Myocardial Infarction.

Prasugrel and ticagrelor are recommended over clopidogrel in patients with ST-elevation myocardial infarction (STEMI). In this registry analysis, we compared efficacy and safety of ticagrelor and prasugrel P2Y12 inhibition in patients with STEMI. We included 318 patients in this single-center analysis. Twelve-month follow-up was conducted during ambulatory care at our department. Patients were on dual antiplatelet therapy with aspirin and ticagrelor or prasugrel during the follow-up period. Prescription of prasugrel or ticagrelor, respectively, was according to the preference of the treating physician. Major adverse cardiac and cerebrovascular events (MACCE) [death, myocardial infarction (MI), stroke, and unplanned reintervention] and thrombolysis in myocardial infarction (TIMI) bleeding (major/minor) were registered during hospitalization and follow-up. TIMI bleeding events were more frequent in ticagrelor-treated patients [17 vs. 5 patients, hazard ratio (HR) 2.85, 95% confidence interval (CI) 1.2-6.6; log-rank P value = 0.01]. Prasugrel-treated patients were significantly younger (ticagrelor 63 ± 12 years vs. prasugrel 57 ± 10; P < 0.0001). Besides that, patients' characteristics were similar in both groups. Multivariate analysis revealed that ticagrelor medication was independently associated with bleeding risk after adjustment for age, percutaneous coronary intervention approach (femoral vs. radial), diabetes mellitus, and kidney function (HR 3.01; 95% CI 1.0-7.4; P = 0.043). In patients treated with ticagrelor, 35 MACCE were detected. There was no difference as compared to prasugrel-treated patients (24 events, HR 1.24, 95% CI 0.79-2.09; log-rank P value = 0.41). TIMI bleeding events were more frequent in ticagrelor-treated patients with STEMI during 12-month follow-up. There were no differences in MACCE between groups in this registry analysis.

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.

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.

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.

Cardioprotection by very mild hypothermia in mice.

Target temperature management is recommended in post-resuscitation care. Additionally, hypothermia is a promising option in adjunctive therapy of acute myocardial infarction (MI). However, first in men data are contradicting. There are still many open questions to identify the optimal regimen and target temperature. In this study, we aimed to investigate the effect of very mild hypothermia on infarct size (IS) in mice. Mice underwent cardiac ischemia by temporary occlusion of the left anterior descending (LAD) artery under conditions of very mild hypothermia (34-36 °C). Hypothermia was reached within the first 5 minutes of ischemia (temperature: 34.6±0.5 vs. 36.8±1.1 °C, P=0.035). Very mild hypothermia reduced IS in mice undergoing 30 minutes ischemia [IS/area at risk (AAR): 45±12% vs. 22±4%, P=0.018] as well as mice undergoing 60 minutes ischemia [IS/AAR: 67±7% vs. 28±2%, P=0.0003]. Very mild hypothermia reduces IS. This new approach in adjunctive therapy of patients with acute MI should be investigated in clinical trials.

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.

Major adverse cardiac events and drug-coated balloon size in coronary interventions.

OBJECTIVE: In-stent restenosis (ISR) is a feared complication after coronary stent implantation. Drug-coated balloon (DCB) is being promoted as a treatment option for ISR. However, the benefit-risk ratio of DCB length has not been investigated. Longer DCBs release more anti-proliferative drug to the vessel wall; however, they are associated with a higher lesion length and vessel injury. HYPOTHESIS: DCB length is associated with clinical outcome. METHODS: We analyzed 286 consecutive Pantera Lux (Biotronik, active component Paclitaxel) DCB-treated patients between April 2009 and June 2012. Of them, 176 patients were treated using a 15-mm DCB and 109 were treated using a 20-mm DCB. Baseline characteristics and major adverse cardiac events (MACE; death, myocardial infarction, and target lesion revascularization) during initial hospital stay and a 2-year follow-up period were obtained. RESULTS: Patients characteristics such as cardiovascular risk factors, prior diseases, co-medication, clinical presentation, target vessel, and left ventricular function did not differ between the groups. MACE during hospital course was similar [1.7% vs. 2.8%, relative risk (RR) 1.6, 95% confidence interval (CI) 0.3-7.9, p=0.554]. Likewise, at 2-year follow-up, MACE did not differ between the groups (23.2% vs. 27.5%, RR 1.2, 95% CI 0.6-1.5, p=0.408). CONCLUSION: DCB length was not associated with clinical outcome during a 2-year follow-up period.