Platelet Inhibitory Effects Research Articles

Platelet inhibitory effects of the NO independent sGC stimulator riociguat (Bay 63-2561)

Background Nitric oxide (NO) is a potent biological mediator and plays an important role in cardiovascular homeostasis. Here it activates the soluble guanylyl cyclase (sGC) that synthesizes cGMP. The intracellular second messenger cGMP regulates vascular tone, vascular permeability, modulates inflammation and platelet reactivity. In platelets cGMP activates platelet inhibitory pathways via PKG and thereby inhibits platelet activation. Many cardiovascular diseases e.g. pulmonary arterial hypertension (PAH), are associated to a defective NO signalling. Therefore agents that stimulate the sGC are interesting therapeutic tools for the treatment of several cardiovascular diseases. Riociguat (Bay 63-2561) stimulates the sGC NOindependently without the risk of nitrate tolerance. Clinical Phase II and III studies determined the efficacy and tolerability in pulmonary hypertension patients. Riociguat was well tolerated and also significantly improved exercise capacity and hemodynamic parameters. To further analyse the effects of riociguat on platelet activation we tested the inhibitory effects on functions in isolated platelets and whole blood to elucidate additional applications of riociguat and to estimate adverse effects such as increased bleeding tendencies.

Amino acid sequence and biological characterization of BlatPLA2, a non-toxic acidic phospholipase A2 from the venom of the arboreal snake Bothriechis lateralis from Costa Rica

Bothriechis is considered a monophyletic, basal genus of arboreal Neotropical pitvipers distributed across Middle America. The four species found in Costa Rica (B. lateralis, B. schlegeli, B. nigroviridis, B. supraciliaris) differ in their venom proteomic profiles, suggesting that different Bothriechis taxa have evolved diverse trophic strategies. In this study, we isolated a phospholipase A2 (PLA2) from B. lateralis venom, aiming at increasing our knowledge on the structural and functional characteristics of group II acidic PLA2s, whose toxic actions are generally more restricted than those displayed by basic PLA2s. The new acidic enzyme, BlatPLA2, occurs as a monomer of 13,917 Da, in contrast to many basic group II PLA2s which associate into dimers and often display myotoxicity and/or neurotoxicity. Its amino acid sequence of 122 residues predicts an isoelectric point of 4.7, and displays significant differences with previously characterized acidic PLA2s, with which it shows a maximum sequence identity of 78%. BlatPLA2 is catalytically active but appears to be devoid of major toxic activities, lacking intravenous or intracerebroventricular lethality, myotoxicity, in vitro anticoagulant activity, and platelet aggregation or inhibition effects. Phylogenetic relationships with similar group II enzymes suggest that BlatPLA2 may represent a basal sequence to other acidic PLA2s. Due to the metabolic cost of venom protein synthesis, the presence of a relatively abundant (9%) but non-toxic component is somewhat puzzling. Nevertheless, we hypothesize that BlatPLA2 could have a role in the pre-digestion of prey, possibly having retained characteristics of ancestral PLA2s without evolving towards potent toxicity.

Cangrelor reduced ischemic PCI complications more than clopidogrel without increasing severe bleeding

Source Citation Bhatt DL, Stone GW, Mahaffey KW, et al; CHAMPION PHOENIX Investigators. Effect of platelet inhibition with cangrelor during PCI on ischemic events. N Engl J Med. 2013;368:1303-13. 23473369

Effect of platelet inhibition on bleeding complications in trauma patients on preinjury clopidogrel

Use of antiplatelet medications for acute coronary syndromes and stroke prevention continues to rise as the population ages, although their effects on trauma outcomes remain unclear. This study sought to determine if trauma patients on preinjury clopidogrel with a higher degree of platelet inhibition (PI), as determined by the VerifyNow P2Y12 Test, experienced bleeding complications more frequently than did patients with a lower degree of PI. Retrospective, cohort study of adult trauma patients admitted to a Level 1 trauma center between October 1, 2009, and August 31, 2011, with documentation of clopidogrel as a home medication. Patients were excluded if they did not receive the P2Y12 assay, had a platelet count at the time of assay less than 100 × 10/L, or had warfarin, dabigatran, or other thienopyridine therapy documented as a concomitant home medication. The primary outcome compared a composite of bleeding complications between patients with 20% PI or greater and those with less than 20% PI. Bleeding complications were defined as the progression of neurologic insult, postoperative hemorrhage or initiation of the institutional massive blood transfusion protocol. Baseline characteristics were similar between groups. The incidence of bleeding complications was not different between study groups (24.2% vs. 27.6%, p = 0.78). No difference in the secondary outcomes of length of stay, in-hospital mortality, and red blood cell transfusion were observed. Patients with 20% PI or greater received platelet transfusion more frequently than did patients with less than 20% PI (51.5% vs. 10.3%, p = 0.0008). The VerifyNow P2Y12 Test may be a tool to stratify trauma patients at a higher risk of bleeding and who subsequently may benefit from transfusion. More frequent platelet transfusion in patients with 20% PI or greater may have resulted in fewer bleeding complications, although confirmation in a prospective, randomized trial is warranted. Prognostic study, level III.

Platelet Inhibitory Effect of Clopidogrel in Patients Treated With Omeprazole, Pantoprazole, and Famotidine: A Prospective, Randomized, Crossover Study

Concerns about an inhibitory effect of proton pump inhibitors (PPIs) on clopidogrel metabolism have been raised. Because the pharmacological effect of clopidogrel is dependent on genetically determined activity of the hepatic cytochrome P450 isoenzymes system, it is important to examine the interaction between different PPIs and high on-treatment platelet reactivity (HPR) after controlling for genetic variability. The aim of the study was to assess the effect of 2 PPIs and a histamine-2 (H2) receptor-blocker on platelet reactivity in a crossover trial where each patient was alternately treated with each drug. Omeprazole reduces HPR more than other PPI or H2 blockers. Patients treated with aspirin and clopidogrel for at least 1 month were assigned to 3 consecutive 1-month treatment periods during which they were treated with each of the 3 study medications twice daily: omeprazole 20 mg, famotidine 40 mg, and pantoprazole 20 mg. At the end of each treatment phase, platelet function was evaluated with the Verify Now system using 2 cutoff values (>208 P2Y12 reaction units [PRUs] and >230 PRUs) for the definition of HPR. Patients with HPR were older than those without HPR (62 ± 10 vs 55 ± 8 years, respectively, P = 0.03). HPR was more prevalent during omeprazole therapy compared to famotidine or pantoprazole (48%, 33%, and 31%, respectively, for the 208 PRU cutoff, P= 0.04; and 37%, 17%, and 23%, respectively, for the 230 PRU cutoff, P= 0.003). After eliminating the effects of interindividual variability in clopidogrel metabolism, omeprazole therapy was associated with substantially more HPR than famotidine or pantoprazole.

Effect of Platelet Inhibition with Cangrelor during PCI on Ischemic Events

BackgroundThe intensity of antiplatelet therapy during percutaneous coronary intervention (PCI) is an important determinant of PCI-related ischemic complications. Cangrelor is a potent intravenous adenosine diphosphate (ADP)–receptor antagonist that acts rapidly and has quickly reversible effects.MethodsIn a double-blind, placebo-controlled trial, we randomly assigned 11,145 patients who were undergoing either urgent or elective PCI and were receiving guideline-recommended therapy to receive a bolus and infusion of cangrelor or to receive a loading dose of 600 mg or 300 mg of clopidogrel. The primary efficacy end point was a composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 hours after randomization; the key secondary end point was stent thrombosis at 48 hours. The primary safety end point was severe bleeding at 48 hours.ResultsThe rate of the primary efficacy end point was 4.7% in the cangrelor group and 5.9% in the clopidogrel group (adjusted odds ratio with cangrelor, 0.78; 95% confidence interval [CI], 0.66 to 0.93; P=0.005). The rate of the primary safety end point was 0.16% in the cangrelor group and 0.11% in the clopidogrel group (odds ratio, 1.50; 95% CI, 0.53 to 4.22; P=0.44). Stent thrombosis developed in 0.8% of the patients in the cangrelor group and in 1.4% in the clopidogrel group (odds ratio, 0.62; 95% CI, 0.43 to 0.90; P=0.01). The rates of adverse events related to the study treatment were low in both groups, though transient dyspnea occurred significantly more frequently with cangrelor than with clopidogrel (1.2% vs. 0.3%). The benefit from cangrelor with respect to the primary end point was consistent across multiple prespecified subgroups.ConclusionsCangrelor significantly reduced the rate of ischemic events, including stent thrombosis, during PCI, with no significant increase in severe bleeding. (Funded by the Medicines Company; CHAMPION PHOENIX ClinicalTrials.gov number, NCT01156571.)

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 500mg 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 100mg 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 100mg and of 2.97 (95% CI 1.58-5.60) when 200mg ASA was taken compared to a dose of 500mg. 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.

Platelet Function Testing and Tailored Antiplatelet Therapy

Dual antiplatelet therapy, consisting of aspirin and a P2Y12 receptor inhibitor, has dramatically reduced the incidence of atherothrombotic events for patients with acute coronary syndrome and those undergoing a percutaneous coronary intervention (PCI). However, the platelet inhibitory effect of clopidogrel, the most commonly used P2Y12 inhibitor, is variable between patients. Patients exhibiting high platelet reactivity (HPR) despite clopidogrel treatment are at higher risk of recurrent atherothrombotic events after PCI. In order to reduce the incidence of HPR, the more potent P2Y12 receptor inhibitors prasugrel and ticagrelor are used. However, these drugs increase the risk of bleeding. As there is evidence of a therapeutic window for platelet inhibition, platelet function tests could be helpful for tailoring antiplatelet therapy based on the patient's thrombotic and bleeding risk. In the present article, we review the most commonly used platelet function tests and the current evidence for tailoring of antiplatelet therapy in PCI patients.

Temporal and pharmacological characterization of angiostatin release and generation by human platelets: implications for endothelial cell migration.

Platelets play an important role in thrombosis and in neo-vascularisation as they release and produce factors that both promote and suppress angiogenesis. Amongst these factors is the angiogenesis inhibitor angiostatin, which is released during thrombus formation. The impact of anti-thrombotic agents and the kinetics of platelet angiostatin release are unknown. Hence, our objectives were to characterize platelet angiostatin release temporally and pharmacologically and to determine how angiostatin release influences endothelial cell migration, an early stage of angiogenesis. We hypothesized anti-platelet agents would suppress angiostatin release but not generation by platelets. Human platelets were aggregated and temporal angiostatin release was compared to vascular endothelial growth factor (VEGF). Immuno-gold electron microscopy and immunofluorescence microscopy identified α-granules as storage organelles of platelet angiostatin. Acetylsalicylic acid, MRS2395, GPIIb/IIIa blocking peptide, and aprotinin were used to characterize platelet angiostatin release and generation. An endothelial cell migration assay was performed under hypoxic conditions to determine the effects of pharmacological platelet and angiostatin inhibition. Compared to VEGF, angiostatin generation and release from α-granules occurred later temporally during platelet aggregation. Consequently, collagen-activated platelet releasates stimulated endothelial cell migration more potently than maximally-aggregated platelets. Platelet inhibitors prostacyclin, S-nitroso-glutathione, acetylsalicylic acid, and GPIIb/IIIa blocking peptide, but not a P2Y12 inhibitor, suppressed angiostatin release but not generation. Suppression of angiostatin generation in the presence of acetylsalicylic acid enhanced platelet-stimulated endothelial migration. Hence, the temporal and pharmacological modulation of platelet angiostatin release may have significant consequences for neo-vascularization following thrombus formation.

Circulation: Clinical Summaries

<i>Circulation:</i> Clinical Summaries

Friend or Foe? Discussion about Dual Platelet Inhibition as a Salvage Procedure from Imminent Flap Failure

Sir:FigureAntiplatelet drugs and combination therapies are on the rise because or their proven benefits concerning an antithrombotic effect on coronary vessels. Surgeons fear the side effects, including hemorrhage. Nevertheless, both cardiologists and microsurgeons are involved in the patency of small-caliber vessels. In addition, the mechanism of acute coronary syndrome reminds us of the process in microanastomosed and pedicled flaps; similar to myocardium, microsurgical transposed tissue is subjected to ischemia, thrombosis, and endothelial injury. Therefore, the idea suggests transforming the foe into a friend and making use of antiplatelet drugs in microsurgery. This idea is promoted by data acquired through animal models. In animal models, a potential benefit of antiplatelet therapy has been proved in randomized, controlled, double-blind studies.1 Antiplatelet drugs have been shown to result in a significant increase in arterial and venous patency and a decrease in anastomotic thrombus formation. Therefore, this knowledge could be used in clinical practice. We present the case report of a 53-year-old patient whose right breast was reconstructed using a pedicled transverse rectus abdominis musculocutaneous flap. After an inconspicuous initial course, epitheliolysis manifested on the fifth postoperative day, with a rapidly increasing livid coloration of the whole flap between days 7 and 11, suggestive of a no-reflow phenomenon. Therefore, on day 11, a salvage attempt was made. The patient was submitted to double-platelet inhibition therapy consisting of acetylsalicylic acid and clopidogrel. One hundred milligrams of of acetylsalicylic acid was administered daily and clopidogrel was given with a loading dose of 225 mg on the first day of treatment, changing to a 75-mg daily dose on the following days. This treatment was maintained for 4 weeks. After this regimen, the vascular changes ceased and the flap recovered appreciably, leaving only a marginal necrosis in zone IV behind (Fig. 1). In addition, no signs of bleeding were recorded.Fig. 1: Imminent loss of a transverse rectus abdominis musculocutaneous flap affiliated with a no-reflow phenomenon. (Left) The obvious livid coloration in almost the whole flap on postoperative day 11, when dual platelet inhibition therapy started. (Right) The imminent flap loss stopped, and after 10 days of dual platelet inhibition, most of the flap appeared salvaged.Whereas the available data1 strongly suggest a potential benefit of antiplatelet drugs in the prevention of flap failure, the question arises of whether this benefit is paid for by an increased bleeding risk. With regard to continued clopidogrel monotherapy in coronary artery bypass grafting, a significant increase in perioperative blood loss, excessive postoperative hemorrhage, increase in transfusion rate and amount of administered blood products, high reoperation rate, and even mortality have been noted.2 Also, in dermatologic surgery, clopidogrel intake has been found to be significantly associated with hemorrhagic complications.3 Thus, operations performed under continued antiplatelet therapy may be associated with a considerable risk of bleeding. However, what about making use of the positive effect of platelet inhibition by administering the drugs postoperatively? Thus, the bleeding risk should be low and the positive effect must be maintained. We can make use of the experience of cardiac surgeons who routinely operate on patients under acetylsalicylic acid therapy, which is combined with clopidogrel therapy 24 to 48 hours postoperatively. Despite the obvious invasiveness of cardiac operations, studies have shown that this postoperative dual platelet inhibition does not cause any significant increase in bleeding risk when compared with acetylsalicylic acid monotherapy.4,5 Keeping in mind the obvious bleeding risks when administered preoperatively, we suggest examining its potential benefits in microsurgery rather than just considering antiplatelet therapy as a foe when administered postoperatively. Stefan Riml, M.D. Heinz Wallner, M.D. Peter Kompatscher, M.D. Department for Plastic, Aesthetic, and Reconstructive Surgery, Academic Hospital Feldkirch, Feldkirch, Austria ACKNOWLEDGMENT The authors thank A. Piontke for excellent photodocumentation. DISCLOSURE The authors have no financial interest to declare in relation to the content of this communication.

Reduction in First and Recurrent Cardiovascular Events With Ticagrelor Compared With Clopidogrel in the PLATO Study

We sought to evaluate the effect of potent platelet inhibition after acute coronary syndrome on total (ie, first and recurrent) occurrences of any of the primary outcome events (e.g., cardiovascular death, myocardial infarction, and stroke) as well as on other ischemic events, such as urgent revascularization, (severe) recurrent ischemia, transient ischemic attacks, and arterial thrombotic events. In the PLATelet inhibition and patient Outcomes (PLATO) study, 18 624 patients presenting with acute coronary syndromes randomly received ticagrelor (n=9333) or clopidogrel (n=9291). Cox proportional hazard models were used to calculate time to first event and hazard ratios. Total events were compared using a Poisson regression model, and time to second event or death was calculated with the Wei Lin Weissfeld method. Patients randomized to ticagrelor had 1057 total primary end point events versus 1225 for patients on clopidogrel (rate ratio, 0.86; 95% confidence interval, 0.79-0.93; P=0.003). The number of additional events was numerically lower for ticagrelor (189 versus 205; P=0.40), resulting in a hazard for time to second event/death of 0.80 (95% confidence interval, 0.70-0.90; P<0.001) and a number needed to treat of 54. For cardiovascular death/myocardial infarction/stroke/(severe) recurrent ischemia/transient ischemic attack/arterial thrombotic events, total events were fewer with ticagrelor (2030 versus 2290; rate ratio, 0.88; 95% confidence interval, 0.82-0.95; P<0.001), with fewer recurrent events with ticagrelor (740 versus 834; P=0.01) and a highly significant concurrent reduction in hazard for time to second event or death of 0.83 (95% confidence interval, 0.75-0.91; P<0.001). Recurrent PLATO major or Thrombolysis in Myocardial Infarction (TIMI) major non-coronary artery bypass graft bleeding events were infrequent and not different between the two therapies (P=0.96 and 0.38, respectively). In PLATO, treatment with ticagrelor compared with clopidogrel resulted in a reduction in total events, including first and subsequent recurrent cardiovascular events, when compared with clopidogrel. These types of analyses demonstrate an even greater absolute benefit of ticagrelor over clopidogrel than previously reported. URL: http://www.clinicaltrials.gov/. Unique identifier: NCT00391872.

Platelet Function Monitoring and Clopidogrel

Antiplatelet therapy with aspirin and a platelet P2Y12 receptor antagonist reduces thrombotic and ischemic events after percutaneous coronary intervention and acute coronary syndrome. The platelet inhibitory effect of the thienopyridine clopidogrel varies widely among individuals, and high on-treatment platelet reactivity has been associated with a substantial hazard for post-PCI cardiovascular events, including stent thrombosis. The clinical availability of ex vivo methods to measure the antiplatelet effect of P2Y12 antagonists raises the possibility that incorporating platelet function testing into clinical practice could facilitate a stratified and efficient approach to antiplatelet therapy following PCI, although data from definitive randomized trials supporting a routine approach are currently lacking.

Switching antiplatelet regimens: Alternatives to clopidogrel in patients with acute coronary syndrome undergoing PCI: A review of the literature and practical considerations for the interventional cardiologist

Dual antiplatelet therapy with aspirin plus a P2Y(12) receptor inhibitor is the cornerstone of treatment for patients with acute coronary syndrome and in those undergoing percutaneous coronary intervention. Clopidogrel is the most widely used P2Y(12) receptor inhibitor. Despite the clinical benefits associated with adjunctive clopidogrel therapy, a considerable number of patients continue to experience recurrent cardiovascular events. Importantly, the interindividual response to clopidogrel is variable and is affected by multiple factors, including genetic polymorphisms and drugs that interfere with the conversion of clopidogrel to its active metabolite. The individual variability to clopidogrel-induced antiplatelet effects has significant clinical implications that can result in an increased risk of atherothrombotic recurrences, including stent thrombosis. The introduction of novel P2Y(12) receptor inhibitors, such as prasugrel or ticagrelor, characterized by more potent and consistent platelet inhibitory effects, represents an opportunity for clinicians to consider these alternative therapies to overcome the limitations of clopidogrel. Understanding the strategies and implications of switching antiplatelet treatment regimens is, therefore, key in the clinical setting. This article provides an overview of the literature on switching antiplatelet treatment strategies and practical considerations for the interventional cardiologist.

Letter by Meves and Neubauer Regarding Article “Clinical Outcomes Using a Platelet Function-Guided Approach for Secondary Prevention in Patients With Ischemic Stroke or Transient Ischemic Attack”

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

Hydrogen Sulfide–Releasing Aspirin Derivative ACS14 Exerts Strong Antithrombotic Effects In Vitro and In Vivo

Hydrogen sulfide (H(2)S)-releasing NSAIDs exert potent anti-inflammatory effects beyond classical cyclooxygenase inhibition. Here, we compared the platelet inhibitory effects of the H(2)S-releasing aspirin derivative ACS14 with its mother compound aspirin to analyze additional effects on platelets. In platelets of mice fed with ACS14 for 6 days (50 mg/kg per day), not only arachidonic acid-induced platelet aggregation but also ADP-dependent aggregation was decreased, an effect that was not observed with an equimolar dose of aspirin (23 mg/kg per day). ACS14 led to a significantly longer arterial occlusion time after light-dye-induced endothelial injury as well as decreased thrombus formation after ferric chloride-induced injury in the carotid artery. Bleeding time was not prolonged compared with animals treated with equimolar doses of aspirin. In vitro, in human whole blood, ACS14 (25-500 µmol/L) inhibited arachidonic acid-induced platelet aggregation, but compared with aspirin additionally reduced thrombin receptor-activating peptide-, ADP-, and collagen-dependent aggregation. In washed human platelets, ACS14 (500 µmol/L) attenuated αIIbβ3 integrin activation and fibrinogen binding and increased intracellular cAMP levels and cAMP-dependent vasodilator-stimulated phosphoprotein (VASP) phosphorylation. The H(2)S-releasing aspirin derivative ACS14 exerts strong antiaggregatory effects by impairing the activation of the fibrinogen receptor by mechanisms involving increased intracellular cyclic nucleotides. These additional antithrombotic properties result in a more efficient inhibition of thrombus formation in vivo as achieved with aspirin alone.

EFFECT OF SARPOGRELATE ON FISTULA PATENCY OF FOREARM ARTERIOVENOUS ANASTOMISIS IN UREMIC PATIENTS

Subcutaneous arteriovenous fistula in the forearm is a common vascular access for hemodialysis. However, primary failure of native fistula occurs because of either thrombosis formation within the first several weeks after surgery or immature vein dilatation. To evaluate the effect of platelet inhibition on fistula thrombosis and maturation failure, we used an antiplatelet agent, sarpogrelate hydrochloride, in our study. The study was designed as an open-label, parallel, prospective, randomized study for 8 weeks, comparing patients receiving sarpogrelate 300 mg/day (sarpogrelate group, n =33) with controls receiving no medication ( n =46). The primary outcome was fistula patency failure determined by pulse Doppler ultrasound examination of the arteriovenous fistula performed 8 weeks after surgery. Pulse wave velocity was also measured to determine the ankle brachial pressure index (ABI). The drug was well-tolerated and did not increase bleeding events during the 8-week study period. In the sarpogrelate group, patency failure occurred in 1 of 33 patients (3.0%), and the occlusion rate was significantly lower ( P =0.001) than that in the control group (3 of 46 patients; 6.5%). Average blood flow rate in the sarpogrelate group was 546±174 mL/min, and was significantly higher ( P =0.036) than 448±183 mL/min in the control group. However, the diameter of the shunt vessel in the sarpogrelate group was 5.2±1.3 mm, which was not different from 5.1±0.6 mm in the control group. The Vmax was not significantly different between two groups (1.01±0.56 m/sec in the sarpogrelate group and 0.89±0.66 m/sec in the control group). In all patients ( n =79), blood flow correlated with ABI ( r =0.34, P =0.045). Our results suggest that sarpogrelate reduces the frequency of fistula patency failure. Sarpogrelate may maintain fistula patency, which is necessary for hemodialysis, by increasing ABI.

Pharmacodynamic effects of cangrelor and clopidogrel: the platelet function substudy from the cangrelor versus standard therapy to achieve optimal management of platelet inhibition (CHAMPION) trials

Cangrelor is an intravenous antagonist of the P2Y(12) receptor characterized by rapid, potent, predictable, and reversible platelet inhibition. However, cangrelor was not superior to clopidogrel in reducing the incidence of ischemic events in the cangrelor versus standard therapy to achieve optimal management of platelet inhibition (CHAMPION) trials. A prospectively designed platelet function substudy was performed in a selected cohort of patients to provide insight into the pharmacodynamic effects of cangrelor, particularly in regard to whether cangrelor therapy may interfere with the inhibitory effects of clopidogrel. This pre-defined substudy was conducted in a subset of patients from the CHAMPION-PCI trial (n = 230) comparing cangrelor with 600 mg of clopidogrel administered before percutaneous coronary intervention (PCI) and from the CHAMPION-PLATFORM trial (n = 4) comparing cangrelor at the time of PCI and 600 mg clopidogrel given after the PCI. Pharmacodynamic measures included P2Y12 reaction units (PRU) assessed by VerifyNow P2Y12 testing (primary endpoint marker), platelet aggregation by light transmittance aggregometry following 5 and 20 μmol/L adenosine diphosphate stimuli, and markers of platelet activation determined by flow cytometry. The primary endpoint was the percentage of patients who achieved <20 % change in PRU between baseline and >10 h after PCI. The main trial was stopped early limiting enrollment in the platelet substudy. A total of 167 patients had valid pharmacodynamic assessments for the primary endpoint. The percent of individuals achieving <20 % change in PRU between baseline and >10 h after PCI was higher with cangrelor + clopidogrel (32/84, 38.1 %) compared with placebo + clopidogrel (21/83, 25.3 %), but this was not statistically significant (difference:12.79 %, 95 % CI: -1.18 %, 26.77 %;p = 0.076). All pharmacodynamic markers as well as the prevalence of patients with high on-treatment platelet reactivity were significantly lower in patients treated with cangrelor. A rapid platelet inhibitory effect was achieved during cangrelor infusion and a rapid offset of action after treatment discontinuation. This CHAMPION platelet function substudy represents the largest pharmacodynamic experience with cangrelor, demonstrating its potent P2Y(12) receptor inhibitory effects, and rapid onset/offset of action. Although there was no significant pharmacodynamic interaction when transitioning to clopidogrel therapy, further studies are warranted given that enrollment in this study was limited due to premature interruption of the main trial.

The structures and inhibitory effects of Buame [N-(3-hydroxy-1,3,5(10)-estratrien-17β-yl)-butylamine] and Diebud [N,N′-bis-(3-hydroxy-1,3,5(10)-estratrien-17β-yl)-1,4-butanediamine] on platelet aggregation

Compounds with estrogenic effects that also inhibit platelet aggregation might be useful in reducing thrombotic events associated with estrogenic therapy. In this study, two aminoestrogens, Buame [N-(3-hydroxy-1,3,5(10)-estratrien-17β-yl)-butylamine] and Diebud [N,N′-bis-(3-hydroxy-1,3,5(10)-estratrien-17β-yl)-1,4-butanediamine], were synthesized and characterized using common analytical methods and spectrophotometric analyses. The location and orientation of these molecules on the estrogenic receptor α (ERα) were also evaluated. Platelet inhibitory effects were elucidated ADP-induced platelet aggregation and ADP- and collagen-induced ATP release. Molecular docking demonstrated that Buame can reach and bind to the ERα in the ligand binding domain (LBD) similar to 17β-estradiol (co-crystallized ligand). On the other hand, Diebud binds only to the surface of ERα due to its high molecular volume compared to 17β-estradiol and Buame.

Antiplatelet Therapy and Proton Pump Inhibition

A 77-year-old man with history of diabetes mellitus and coronary artery disease presented with angina and evidence of ischemia despite maximal medical therapy. He underwent a percutaneous coronary intervention with a drug-eluting stent and was started on long-term dual antiplatelet therapy with aspirin and clopidogrel. His medical history was significant for an episode of gastrointestinal (GI) bleeding in the setting of using nonsteroidal antiinflammatory drugs. Dual antiplatelet therapy, typically the addition of an ADP receptor antagonist to aspirin, has become the cornerstone of management of patients with acute coronary syndromes and after percutaneous coronary intervention. However, along with the reduction of thrombotic outcomes, this therapeutic strategy has the untoward effect of increasing the risk of bleeding events, including GI bleeding.1 The use of gastroprotective strategies, most notably proton pump inhibitors (PPIs), has become a widely adopted and recommended practice in this patient population.2 Currently, the most commonly prescribed ADP receptor antagonist is clopidogrel, a prodrug that undergoes activation by the cytochrome P450 system, in particular CYP2C19. The importance of this reaction on the overall platelet inhibitory effects of clopidogrel is highlighted by the fact that patients with reduced-function CYP2C19 alleles exhibit a reduced response to clopidogrel compared with those with the wild-type alleles. This finding might translate into increased risk of adverse events after acute coronary syndromes and percutaneous coronary intervention. Given that PPIs are inhibitors of CYP2C19, coupled with reports suggesting a clinically significant interaction,3 regulatory agencies issued a cautionary statement advising against the combined use of PPIs (specifically omeprazole and esomeprazole) and clopidogrel.4 Aspirin causes direct damage to the gastric epithelium and inhibits prostaglandin production by the gastric mucosa, leading to ulcerations and an estimated 2-fold increased risk of GI bleeding with low-dose aspirin alone.1 The risk increases with the additional use of …