Pharmacodynamic profiles of dual-pathway inhibition with or without clopidogrel vs dual antiplatelet therapy in patients with atherosclerotic disease

Mattia Galli ◽  
Francesco Franchi ◽  
Fabiana Rollini ◽  
Latonya Been ◽  
Patrick Abou Jaoude ◽  

Aim: Inhibition of thrombin-mediated signaling processes using a vascular dose of rivaroxaban in adjunct to antiplatelet therapy, known as dual-pathway inhibition (DPI), reduces atherothrombotic events in patients with stable atherosclerotic disease. However, there are limited data on the pharmacodynamic (PD) effects of this strategy. Methods and Results: This investigation was conducted in selected cohorts of patients (n=40) with stable atherosclerotic disease enrolled within a larger prospective PD study who were treated with either aspirin plus clopidogrel (DAPT), aspirin plus rivaroxaban 2.5 mg/bid (DPI) or DAPT plus rivaroxaban 2.5 mg/bid. Multiple PD assays assessing of markers of thrombosis were used. PD endpoints included platelet-mediated global thrombogenicity measured by light transmittance aggregometry (LTA) following stimuli with CATF [collagen‐related peptide +adenosine diphosphate (ADP) +tissue factor (TF)], markers of P2Y12 reactivity, markers of platelet aggregation using LTA following several stimuli (arachidonic acid, ADP, collagen, TF, and TRAP), thrombin generation and thrombus formation. There was no difference in platelet-mediated global thrombogenicity between groups. Rivaroxaban significantly reduced thrombin generation and was associated with a trend towards reduced TF-induced platelet aggregation. Clopidogrel-based treatments reduced markers of P2Y12 signaling and TRAP‐induced platelet aggregation. There were no differences between groups on markers of cyclooxygenase‐1 mediated activity. Conclusions: Compared with DAPT, DPI does not result in any differences in platelet-mediated global thrombogenicity, but reduces thrombin generation. These PD observations support that modulating thrombin generation by means of factor Xa inhibition in adjunct to antiplatelet therapy provides effective antithrombotic effects, supporting the efficacy and safety findings of DPI observed in clinical

2021 ◽  
Vol 23 (Supplement_G) ◽  
Mattia Galli ◽  
Francesco Franchi ◽  
Fabiana Rollini ◽  
Latonya Been ◽  
Patrick Jaoude ◽  

Abstract Aims Inhibition of thrombin-mediated signalling processes using a vascular dose of rivaroxaban in adjunct to single antiplatelet therapy, known as dual-pathway inhibition (DPI), reduces atherothrombotic events in patients with stable atherosclerotic disease. However, there is limited data on the pharmacodynamic (PD) effects of this strategy. Methods This investigation was conducted in selected cohorts of patients (n = 40) with stable atherosclerotic disease enrolled from a larger prospective, open-label, parallel-group PD study who were treated with either aspirin, aspirin plus rivaroxaban 2.5 mg/bid or clopidogrel plus rivaroxaban 2.5 mg/bid. Multiple PD assays providing a comprehensive assessment of markers of thrombosis were used. The primary endpoint was the comparison between groups of platelet-mediated global thrombogenicity by light transmittance aggregometry (LTA) following stimuli with collagen-related peptide + adenosine diphosphate + tissue factor (CATF). Results There were no differences in the primary endpoint between aspirin vs. aspirin plus rivaroxaban 2.5 mg/bid (P = 0.110), aspirin vs. clopidogrel plus rivaroxaban 2.5 mg/bid (P = 0.611) or aspirin plus rivaroxaban 2.5 mg/bid vs. clopidogrel plus rivaroxaban 2.5 mg/bid (P = 0.315). Rivaroxaban-based treatments significantly reduced markers of thrombin generation (peak thrombin and thrombin velocity index). Clopidogrel-based treatments reduced markers of P2Y12 signalling (LTA ADP 20 max and VerifyNow). Aspirin-based treatments reduced markers of markers of cyclooxygenase-1 activity (LTA collagen). Conclusions Compared with aspirin alone, DPI with either aspirin or clopidogrel might provide superior ischaemic protection by targeting pathways alternative to those affected by antiplatelet agents with only a moderate trade-off in bleeding as supported by similar platelet-mediated global thrombogenicity between treatments.

2020 ◽  
Vol 120 (08) ◽  
pp. 1147-1158 ◽  
Jeffrey Ian Weitz ◽  
Dominick J. Angiolillo ◽  
Tobias Geisler ◽  
Stefan Heitmeier

AbstractDespite advances in secondary prevention strategies in patients with cardiovascular disease, the residual risk of recurrent atherothrombotic events remains high. Dual-antiplatelet therapy is the standard of care for secondary prevention in patients with acute coronary syndrome (ACS), whereas single antiplatelet therapy, generally with aspirin, is the standard of care for secondary prevention in stable patients with coronary artery disease (CAD), peripheral artery disease (PAD), or cerebrovascular disease. However, atherosclerotic plaque disruption not only triggers platelet activation but also results in thrombin generation because of tissue factor exposure. Therefore, blocking both pathways by combining antiplatelet therapy with an anticoagulant, or dual pathway inhibition (DPI), has the potential to be more effective than inhibiting either pathway alone. The benefit of DPI has been demonstrated in the ATLAS ACS 2-TIMI 51, COMPASS, and VOYAGER PAD trials, where the combination of rivaroxaban vascular dose (2.5 mg twice daily) plus aspirin significantly reduced the risk of atherothrombotic events compared with aspirin across a broad range of patients, including those with recent ACS, those with chronic CAD and/or PAD, and patients with PAD who have undergone peripheral revascularization. This article provides the rationale for this regimen in more detail, including why the DPI regimen with the rivaroxaban vascular dose was developed for vascular protection in a broad spectrum of patients with atherosclerotic disease.

2020 ◽  
Vol 41 (Supplement_2) ◽  
M.M Engelen ◽  
C Van Laer ◽  
M Jacquemin ◽  
C Vandenbriele ◽  
K Peerlinck ◽  

Abstract Introduction Contact of blood with artificial surfaces such as mechanical support devices, catheters, and mechanical heart valves activates the contact activation (CA) pathway of coagulation. Furthermore, recent animal data and clinical studies suggest a more important contribution of CA in pathological thrombus formation in other cardiovascular diseases. Direct oral anticoagulants (DOACs) are recommended as first-line treatment in most patients who require long-term anticoagulation. However, because DOACs directly inhibit a single downstream coagulation factor (thrombin (fXIIa) or factor Xa (fXa)), it has been suggested that their efficacy could be reduced in the presence of strong activation of the CA pathway as compared to anticoagulants that target multiple, more upstream located coagulation factors. Purpose To compare the efficacy of a DOAC (apixaban) and heparin to suppress thrombin generation in the presence of strong CA pathway activation. Methods Pooled platelet-poor plasma was spiked with either apixaban (dissolved in DMSO and PBS) or unfractionated heparin to achieve therapeutic plasma levels. SynthASil, a commercially available mixture of phospholipids and silica, was used to stimulate the CA pathway in two different dilutions (1–80 and 5–80). Downstream coagulation was accessed by Thrombin Generation Test using Thrombinoscope by Stago and associated Thrombin Calibrator (activity 640 nM). The endogenous thrombin potential (area under the thrombin generation curve; ETP), peak thrombin generation (PTG), time to peak (ttPeak) and time to start (ttStart) were accessed. Results With decreasing concentrations of apixaban, stimulation with the lower dose SynthASil reveals an increasing ETP and PTG. As expected, ttPeak and ttStart decreased. Even supratherapeutic levels of apixaban (i.e. 1120 ng/mL) could not inhibit thrombin from being generated, in striking contrast with UFH where no thrombin was formed. Using a five times higher dose of SynthASil showed comparable ETP for all concentrations of apixaban, allocated around the control value. PTG, however, slightly increased with decreasing concentrations of apixaban. ttPeak and ttStart slightly decreased. Except for the subtherapeutic UFH concentration of 0,114 IU/mL, no thrombin was generated with UFH. Conclusion UFH is more effective in inhibiting downstream thrombin generation compared to apixaban as a response to activation of the CA pathway in vitro. These findings could help explain why direct inhibitors were not able to show non-inferiority in patients with mechanical heart valves and support the development of specific CA pathway inhibitors for patients with conditions that activate the CA pathway. Thrombin generation curves Funding Acknowledgement Type of funding source: None

Blood ◽  
1998 ◽  
Vol 91 (11) ◽  
pp. 4197-4205 ◽  
J.M. Herbert ◽  
J.P. Hérault ◽  
A. Bernat ◽  
R.G.M. van Amsterdam ◽  
J.C. Lormeau ◽  

Abstract SANORG 34006 is a new sulfated pentasaccharide obtained by chemical synthesis. It is an analog of the “synthetic pentasaccharide” (SR 90107/ ORG 31540) which represents the antithrombin (AT) binding site of heparin. SANORG 34006 showed a higher affinity to human AT than SR 90107/ORG 31540 (kd = 1.4 ± 0.3 v 48 ± 11 nmol/L), and it is a potent and selective catalyst of the inhibitory effect of AT on factor Xa (1,240 ± 15 anti–factor Xa U/mg v850 ± 27 anti-factor Xa U/mg for SR 90107/ORG 31540). In vitro, SANORG 34006 inhibited thrombin generation occurring via both the extrinsic and intrinsic pathway. After intravenous (IV) or subcutaneous (SC) administration to rabbits, SANORG 34006 displayed a long-lasting anti–factor Xa activity and inhibition of thrombin generation (TG) ex vivo. SANORG 34006 was slowly eliminated after IV or SC administration to rats, rabbits, and baboons, showed exceptionally long half-lives (between 9.2 hours in rats and 61.9 hours in baboons), and revealed an SC bioavailability near 100%. SANORG 34006 displayed antithrombotic activity by virtue of its potentiation of the anti–factor Xa activity of AT. It strongly inhibited thrombus formation in experimental models of thromboplastin/stasis-induced venous thrombosis in rats (IV) and rabbits (SC) (ED50values = 40.0 ± 3.4 and 105.0 ± 9.4 nmol/kg, respectively). The duration of its antithrombotic effects closely paralleled the ex vivo anti–factor Xa activity. SANORG 34006 enhanced rt-PA–induced thrombolysis and inhibited accretion of125I-fibrinogen onto a preformed thrombus in the rabbit jugular vein suggesting that concomitant use of SANORG 34006 during rt-PA therapy might be helpful in facilitating thrombolysis and preventing fibrin accretion onto the thrombus under lysis. Contrary to standard heparin, SANORG 34006 did not enhance bleeding in a rabbit ear incision model at a dose that equals 10 times the antithrombotic ED50 in this species and, therefore, exhibited a favorable therapeutic index. We suggest that SANORG 34006 is a promising compound in the treatment and prevention of various thrombotic diseases.

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Paul Gurbel ◽  
Joseph Dichiara ◽  
Kevin P Bliden ◽  
Mark J Antonino ◽  
Lawal Lookman

Background: Wide response variability to clopidogrel therapy has been reported. Clopidogrel is a prodrug that requires metabolic activation by hepatic cytochromes (CYP). Cigarette smoking is an inducer of CYP1A2 and may, therefore, enhance the metabolism of clopidogrel. We sought to examine the effect of cigarette smoking on the platelet response to clopidogrel. Methods: Three hundred thirteen consecutive patients undergoing elective coronary stenting were studied. Platelet aggregation (PA) was assessed by light transmittance aggregometry (LTA) stimulated by 5 and 20μ M adenosine diphosphate. One hundred fourteen patients were on chronic clopidogrel therapy, were not reloaded, and had pre-stenting PA measurements. Pre-and post-stenting PA was measured in 199 patients: 60 were loaded with 300mg and 139 were loaded with 600mg. There were 120 current smokers (smoking within 2 weeks of PCI) and 193 non-smokers (no prior history of smoking). Low PA was defined as the lowest two quartiles of 5μM ADP-induced platelet aggregation (≤ 40%). Results: PA was significantly lower (p ≤ 0.008) in smokers on long term chronic clopidogrel treatment (Table ). Relative platelet inhibition (RPI) was higher in smokers treated with either 300mg or 600mg clopidogrel measured by 5 and 20μM ADP-induced PA. In a multivariate analysis, cigarette smoking was an independent predictor of low PA in patients on chronic clopidogrel therapy and in patients loaded with clopidogrel (r=0.3, p=0.0001). Conclusion: Clopidogrel therapy in smokers is associated with increased platelet inhibition and lower aggregation as compared to non-smokers. The mechanism of the smoking effect deserves further study and may be another cause of response variability to clopidogrel. RPI = 100 x ((baseline aggregation-post-treatment aggregation)/(baseline aggregation))

2018 ◽  
Vol 118 (09) ◽  
pp. 1528-1534 ◽  
Uwe Zeymer ◽  
Benedikt Schrage ◽  
Dirk Westermann

AbstractThe optimal anti-thrombotic therapy for secondary prevention after an acute coronary syndrome is still a matter of debate. While current guidelines recommend dual anti-platelet therapy with aspirin and a P2Y12 inhibitor over 12 months especially in patients with stent implantation, the value of prolonged anticoagulation is still controversial. In the ATLAS-TIMI 52 trial, a low-dose direct factor Xa inhibition with rivaroxaban compared with placebo reduced the combined primary endpoint of cardiovascular mortality, myocardial infraction and stroke with an increase in major bleeding complications. This article discusses the value and problems of adding low-dose rivaroxaban to anti-platelet therapy as secondary prevention measure after an acute myocardial infarction. It will describe the pros and cons of intensified anti-platelet therapy versus dual pathway inhibition and give recommendations for different patient groups in clinical practice.

2020 ◽  
Vol 120 (10) ◽  
pp. 1352-1356
Dion Stub ◽  
Himawan Fernando ◽  
James D. McFadyen ◽  
Jathushan Palasubramaniam ◽  
James Shaw ◽  

AbstractThere have been numerous and intriguing advancements in antithrombotic therapy for myocardial infarction since it was described in the earliest issues of Thrombosis and Haemostasis. In this article, we revisit historical breakthroughs and describe the four most challenging contemporary themes relating to antithrombotic therapy in myocardial infarction. In all four, the challenge is to find the best balance of reducing specific levels of ischaemic risks without increasing bleeding risk. The first is the question of the optimal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI). This includes discussion of monotherapy after a period of DAPT. The second relates to the role of genotype and phenotype-guided individualisation of antiplatelet therapy. There is emerging evidence for a role of pheno/genotyping in identifying individuals at high risk for recurrent ischaemic events or in guiding the timing of cardiac surgery for patients on DAPT. The third addresses the increasing evidence for dual pathway inhibition, for example, with rivaroxaban in addition to aspirin in patients where high ischaemic and low bleeding risk is demonstrated. Finally the fourth highlights the challenge of the most appropriate combination of antiplatelet and anticoagulation therapy for patients with known atrial fibrillation after PCI. In most individuals, oral P2Y12 inhibitor therapy combined with a direct acting oral anticoagulant appears to be the best strategy based on the available evidence. Overall, the progress in antithrombotic therapy achieved over the last seven decades is remarkable, however, there are important issues to address and progress still to be made.

2019 ◽  
Vol 47 (4) ◽  
pp. 1731-1739 ◽  
Jun Lu ◽  
Peng Hu ◽  
Guangyu Wei ◽  
Qi Luo ◽  
Jianlin Qiao ◽  

Objective To investigate the role of alteplase, a widely-used thrombolytic drug, in platelet function. Methods Human platelets were incubated with different concentrations of alteplase followed by analysis of platelet aggregation in response to adenosine diphosphate (ADP), collagen, ristocetin, arachidonic acid or epinephrine using light transmittance aggregometry. Platelet activation and surface levels of platelet receptors GPIbα, GPVI and αIIbβ3 were analysed using flow cytometry. The effect of alteplase on clot retraction was also examined. Results This study demonstrated that alteplase significantly inhibited platelet aggregation in response to ADP, collagen and epinephrine in a dose-dependent manner, but it did not affect ristocetin- or arachidonic acid-induced platelet aggregation. Alteplase did not affect platelet activation as demonstrated by no differences in P-selectin levels and PAC-1 binding being observed in collagen-stimulated platelets after alteplase treatment compared with vehicle. There were no changes in the surface levels of the platelet receptors GPIbα, GPVI and αIIbβ3 in alteplase-treated platelets. Alteplase treatment reduced thrombin-mediated clot retraction. Conclusions Alteplase inhibits platelet aggregation and clot retraction without affecting platelet activation and surface receptor levels.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3943-3943 ◽  
Zuzana Motovska ◽  
Zdenka Sujanova ◽  
Sona Wimmerova ◽  
Jan Ardo ◽  
Marcela Skrakova ◽  

Abstract Background. The goal of our interest is to bring attention to standardisation of the aspirin effectiveness examination in patients profiting from (life)long antithrombotic terapy. Optical platelet aggregation tests have been most widely used. Examination with endogenous inductors of platelet aggregation - thrombin, colagen, arachidonic acid, adenosine diphosphate (ADP) has a low specificity and reproducibility. Aim. To compare a newer inductor of platelets aggregation cationic propyl gallate (CPG) with ADP for the examination of aspirin (ASA) efffectivity with optical aggregometry. Methods. We prospectively enrolled 116 consecutive patiens with a stable cardiovascular disease on ASA 100mg/day for ≥ 1 month. The controll group was formed from 62 healthy volunteers, without antithrombotic treatment. Analysis. We investigated platelet aggregation by optical aggregometry (aggregometer LASER 4x, BIOART). CPG and ADP were added as aggregating agents. The measured parameter were: CPG-slope (this parameter expresses steepness of the aggregation curve and also the speed of aggregation (%/minutes)) and ADP-max (the maximum percent change in light transmittance from baseline). Results. Definition. First, we determined the CPG-slope cut-off value for the definition of ASA-non-effective treated patient. We established it on the ground of CPG-slope values in the control group. The values from controll group followed a normal distribution (test Shapiro - Wilk). We calculated the cut-off value using the 95% - confidence interval. The CPG-slope cut-off value was 79 %/min for ASA-effective treated patient. We marked the patients as ASA-non efffective treated when the CPG-slope was ≥ 79%/min. The same way we used to define the cut-off value for ADP-max. We identified the aspirin treatment as uneffective when the value of ADP-max had been > 62%. Comparison. The values of CPG-slope and ADP-max were in a close correlation in the group of patients treated with aspirin. The correlation index (r = 0,671) was highly significant. By CPG-induced optical aggregation were 33,6% ASA-non-effective treated patients. While using both inductors (CPG, ADP) were the proportion of ASA-non-effective treated patients 25%. By both tests (CPG, ADP) were equally divided 71,6% patients. ASA-non-effective treated patients were more commonly obese (46,2%) with hypertension (94,9%) and hypercholesterolemia (73,7%) and were less commonly treated with statins (30,8%) as the aspirin effective treated patients (42,%, 88,2%, 59,2% resp.42,1%). Conclusion. Meassurement of a platelet aggregation by CPG is reproducible with high sensitivity and specificity. The study has also brought attention to the importance of control the cardiovascular risk factors. Figure. Statistical parameters Figure. Statistical parameters

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