Potent Platelet Inhibition Research Articles

Combined and independent impact of diabetes mellitus and chronic kidney disease on residual platelet reactivity

Patients with both chronic kidney disease (CKD) and diabetes mellitus (DM) are at increased risk for thrombotic events compared to those with one abnormality alone. Whether this can be attributed to changes in platelet reactivity among those with both CKD and DM is unknown. We prospectively studied 438 clopidogrel-naïve patients undergoing percutaneous coronary intervention (PCI). Platelet function tests were performed 4-6 hours after loading with 600 mg of clopidogrel. Platelet reactivity was assessed using the VerifyNow system and expressed as P2Y12 reaction units (PRU). High residual platelet reactivity (HRPR) was defined as PRU > 230. Patients were categorised into four groups by the presence or absence of CKD and DM. Among those without CKD or DM (n=166), DM alone (n=150), CKD alone (n=60) and both CKD and DM (n=62) the mean PRU levels were 201.6 ± 96.3, 220.5 ± 101.1, 254.9 ± 106.7 and 275.0 ± 94.5, respectively (p<0.001). Analogously, the prevalence of HRPR was 42.3%, 50.7%, 63.3% and 75.8%, respectively (p< 0.001). Associations between either CKD or DM alone and HRPR were attenuated after multivariable adjustment while the odds for HRPR associated with both CKD and DM remained significant (OR [95% CI]: 2.61 [1.16 - 5.86]). In conclusion, the presence of both CKD and DM confers a synergistic impact on residual platelet reactivity when compared to either condition alone. Whether more potent platelet inhibitors may improve outcomes among patients with both abnormalities warrants investigation.

Prominent features of management strategies in acute coronary syndromes with the new oral antiplatelet agents

The novel oral P2Y12 inhibitors (prasugrel and ticagrelor) have been incorporated into the recently updated acute coronary syndrome (ACS) guidelines, as an adjunct antiplatelet treatment to aspirin. The studies involving the use of new oral antiplatelet agents that are more potent, predictable and faster platelet inhibitors than clopidogrel have demonstrated superiority with respect to the primary composite endpoint (cardiovascular death, non-lethal myocardial infarction, stroke) for both prasugrel and ticagrelor compared to clopidogrel. The subgroup analysis of the relevant studies showed that these new agents differ in their level of efficacy in different ACS patient subgroups: (1) Mortality was reduced with ticagrelor; (2) Ticagrelor is especially more effective in intermediate-and high-risk non-ST elevation ACS patients in whom early invasive strategy is selected; (3) Prasugrel should be especially preferred in patients with acute ST elevation myocardial infarction undergoing percutaneous coronary intervention (PCI) after diagnostic angiography; and (4) Prasugrel is more effective in diabetic patients. While clopidogrel is recommended for ACS patients who are followed with a non-invasive strategy or who have not undergone percutaneous revascularization, it is the last line choice or an alternative to the P2Y12 inhibitor therapy for patients undergoing invasive strategy.

Potent P2Y12 receptor inhibitors in patients with acute coronary syndrome

SummaryBlood platelets are highly activated in the setting of an acute coronary syndrome (ACS). This fact mandates the need for potent platelet inhibition in ACS patients and especially in patients undergoing a percutaneous coronary intervention (PCI). The 2nd generation thienopyridine clopidogrel has been the standard of treatment in the past. Due to its pharmacological properties including a delayed onset of action, a large response variability and an insufficient antiplatelet action in some patients (low responsiveness or high on-treatment platelet reactivity), there was a need to develop, to study and to introduce more potent agents with a fast, reliable and potent antiplatelet action. With the 3rd generation thienopyridine prasugrel and with ticagrelor two potent agents for antiplatelet treatment of ACS patients are available now. Both drugs have demonstrated their superiority compared to clopidogrel in terms of thrombotic risk reduction in large-scale randomized trials. However, for these agents and in line with the expectations towards a more potent anti platelet treatment regimen, a higher risk for bleeding was observed for prasugrel and ticagrelor. Further on, the new anti platelet agents have their own and characteristic contraindications and numerous issues to be considered in clinical practice.This review aims to provide an overview on the state of the art P2Y12 receptor directed inhibition in ACS patients with a focus on patients undergoing a coronary stenting procedure.

Comparison of antiplatelet effects of prasugrel and ticagrelor in cynomolgus monkeys by an ELISA-based VASP phosphorylation assay and platelet aggregation

Prasugrel is the third generation thienopyridine prodrug, and ticagrelor is a non-competitive direct acting P2Y12 antagonist. In phase 3 studies, both agents reduced ischaemic event rates compared to clopidogrel. The present in vitro human and monkey studies showed that ticagrelor's active metabolite (AM) was more potent than ticagrelor and prasugrel's AM on inhibition of ADP-induced platelet aggregation by light transmission aggregometry and ELISA-based vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay. In contrast, on an oral dosage basis (mg/kg), prasugrel showed more potent platelet inhibition compared to ticagrelor on ex vivo aggregation and VASP phosphorylation assays in monkeys. Single oral doses of prasugrel (0.3 and 1 mg/kg) resulted in robust antiplatelet effects, which were sustained up to 24 hours after administration. Ticagrelor (3 and 10 mg/kg, p.o.) also showed significant antiplatelet effects but its effects were diminished at 24 hours after the dosing. Repeat administration of prasugrel (1.8 mg/kg loading dose [LD], 0.3 mg/kg once daily maintenance dose [MD]) showed more rapid antiplatelet effects and longer duration of action throughout the entire day. Twice a day repeat administration of ticagrelor (10 mg/kg bid MD following a single 20 mg/kg LD) also showed significant antiplatelet effects but with more intra-day variability compared to prasugrel. The in vitro and ex vivo studies showed strong correlations between platelet aggregation and VASP phosphorylation for prasugrel, ticagrelor and their AMs. These strong correlations between platelet aggregation and VASP phosphorylation in non-human primates also suggest that ELISA-based human VASP assay can be utilised for non-human primate platelet studies.

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.

Abstract 19144: New Ischemic Stroke and Outcomes with Vorapaxar vs. Placebo: Results from TRA 2°P-TIMI 50 Trial

Vorapaxar is a potent platelet inhibitor that reduces thrombotic events in stable patients with a history of myocardial infarction (MI) or peripheral artery disease (PAD); however, this benefit is offset by increased bleeding including intracranial hemorrhage particularly in patients with established cerebrovascular disease (CVD). We investigated the outcomes in patients with MI or PAD experiencing a first ischemic stroke on vorapaxar. METHODS: The TRA2P-TIMI 50 trial was a randomized, double-blind, placebo controlled trial of vorapaxar 2.5 mg daily in 26,449 patients with established atherosclerotic vascular disease. Patients were stratified at randomization by their qualifying atherosclerotic condition (MI, PAD, or CVD). After two years, the Data and Safety Monitoring Board recommended discontinuation of study treatment in those with prior stroke or incident stroke. We evaluated the risk of new ischemic stroke outcomes with vorapaxar in 20,170 patients with MI or PAD but no history of CVD. RESULTS: In patients with MI or PAD and no history of CVD, vorapaxar significantly reduced ischemic stroke (HR 0.57, 95% CI 0.43 - 0.75, p&lt;0.001)(Figure A). Overall there were numerically fewer hemorrhagic conversions in patients treated with vorapaxar who suffered a first ischemic stroke. The risk of hemorrhagic conversion (HR 1.19, 95% CI 0.49 - 2.91, p=0.70) or death (HR 1.09, 95% CI 0.57 - 2.07, p=0.79) during follow up was not significantly increased with vorapaxar. Although hemorrohagic stroke was increased (HR 2.78, 95% CI 1.00- 7.73, p=0.049) overall stroke was significantly reduced (HR 0.68, 95% CI 0.52 - 0.8, p=0.005) with vorapaxar (Figure B). CONCLUSIONS: Vorapaxar reduces thrombotic events including ischemic stroke in stable patients with MI or PAD. There is no significant increase in the risk of hemorrhagic conversion or death in MI or PAD patients who experience a first ischemic stroke on vorapaxar. Hemorrhagic stroke is increased but all stroke is reduced.

Approaches to Diagnosing and Managing Anticoagulant-Related Bleeding

Anticoagulant therapy reduces deaths and disability in patients with or at risk of both arterial and venous thromboembolism. Highly effective antithrombotic therapies now exist that reduce the risk of both arterial thrombosis and venous thrombosis. Anticoagulant strategies include platelet inhibition, using a variety of potent platelet inhibitors, and antithrombotic therapy, designed to interfere with thrombosis by blocking activation of the coagulation cascade. All anticoagulants increase the risk of bleeding. Older antithrombotic agents have, in most cases, effective antidotes and well-developed (although perhaps not very evidence-based) treatment strategies. Newer anticoagulants, and most antiplatelet drugs, do not have effective antidotes or well-tested reversal strategies. This narrative review will provide advice on the diagnosis and management of anticoagulant bleeding with a particular focus on the antithrombotic drugs, including warfarin, heparin, and the novel agents.

Clinical Use of Clopidogrel

In patients with stable and unstable coronary disease and those undergoing coronary stenting, the activation of platelets plays a central role in the occurrence of major thrombotic events such as death, myocardial infarction and stent thrombosis. Antiplatelet therapy for primary and secondary prevention of thromboembolic events is a cornerstone for the management of these patients and for many years the cyclooxygenase-1 (COX-1) inhibitor aspirin and the second generation thienopyridine clopidogrel which targets the ADP P2Y12 receptor on platelets served as the main antiplatelet agents for these indications. Clopidogrel in particular is very efficient in reducing ischemic cardiovascular events but exposes patients to an increased risk of bleeding. Therefore the optimal dosage and duration of clopidogrel therapy is of utmost importance. Furthermore, platelet function studies have revealed that responsiveness to clopidogrel is not uniform and that a low response is linked to a higher incidence of thrombotic events. Causes are multifactorial and several genetic and non-genetic factors including patients' co-morbidities and co-medications have been identified. As a result clopidogrel's long lasting monopole as the only antiplatelet agent in patients undergoing coronary stenting is currently challenged by the newer P2Y12 blockers such as prasugrel and ticagrelor, which provide a stronger and more consistent inhibition of platelets. In the setting of acute coronary syndromes, this more potent platelet inhibition led to less thrombotic events with these newer agents, but at the cost of a higher bleeding risk. This review provides an overview of the indication, dosage and duration of clopidogrel therapy and discusses its role in light of the recent introduction of newer P2Y12 receptor antagonists, the combination with newer oral anticoagulants such as dabigatran, apixaban and rivaroxaban as well as the emerging use of platelet function testing in clinical practice.

Rapid P2Y 12 Inhibition

Acute coronary syndrome (ACS) is still a serious condition associated with decreased quality of life, increased healthcare expenditures, and premature death. The prevalence of ACS is expected to increase with aging of the population and with the epidemics of obesity and diabetes. The short- and long-term mortality after an ACS has been dramatically reduced by the development of revascularization techniques and new antithrombotic agents. The past decade has seen many trials evaluating new oral and parenteral antiplatelet agents with greater potency than aspirin and clopidogrel. Several antiplatelet agents have been developed, with the ultimate goal to obtain optimal antiplatelet therapy for both the acute and the chronic phases of disease. Articles see p 336, 347 Ideally, efficiency requires several pharmacodynamic proprieties, such as a fast onset of action (immediate onset for emergency situations), a strong degree of platelet inhibition (at least stronger than the standard of care [aspirin and clopidogrel]), a narrow interindividual variability with no impact of genetic variants and no drug-to-drug interaction, and an easy administration (an oral drug for maintenance therapy and an intravenous formulation for rapid loading). Of course, this drug should also lead to a convincing reduction of recurrent ischemic events in an adequately powered phase 3 trial. With regard to safety, the illusion of having the same dose of a single antiplatelet drug to treat all clinical situations has passed. The degree of platelet activation and aggregation is different across clinical situations (eg, acute ST-segment–elevation myocardial infarction [STEMI] versus secondary prevention) and varies over time in the same patient. Recent large phase 3 trials have confirmed the importance of dosing and the target population treated with the new agents.1–4 From a safety standpoint, an ideal antiplatelet agent would also have an intravenous and oral formulation, with different doses tested in …

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.

Is a higher loading dose of clopidogrel more effective during primary angioplasty for patients with STEMI?

Evaluation of: Patti G, Barczi G, Orlic D et al. Outcome comparison of 600 and 300 mg loading doses of clopidogrel in patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: Results from the ARMYDA-6 MI randomized study. J. Am. Coll. Cardiol. 58, 1592–1599 (2011). Primary angioplasty remains the mainstay of therapy for patients with ST-elevation myocardial infarction. Given the high prothrombotic state and large thrombotic burden in these patients, there is need for more rapid and potent platelet inhibition. To date, there have been several observational studies and one randomized trial supporting the notion that clopidogrel 600 mg compared with 300 mg improves outcomes. The ARMYDA-6 trial is the first randomized trial comparing clopidogrel 600 mg versus 300 mg specifically in a population with ST-elevation myocardial infarction. The authors found that a 600 mg loading dose of clopidogrel was associated with a significant reduction in the infarct size...

Prasugrel

The antithrombotic therapy in patients with atherosclerotic vascular disease is subject of several new therapeutic approaches. Simultaneous treatment with aspirin and a thienopyridin (clopidogrel) represents the standard of care for patients with acute coronary syndrome and following coronary stenting recommended by many guidelines. Without true evidence this drug combination is used for the prevention of arterial thrombosis in many other vascular interventions (e.g. carotid stenting, aortic stenting, peripherial arterial stents). The main problems of dual antiplatelet therapy with aspirin and clopidogrel are the slow onset of action and the high interindividual variation in the degree of platelet inhibition. The thienopyridin prasugrel is a more potent platelet inhibitor with a more rapid onset of action and smaller interindividual variations in platelet inhibition. The therapeutic superiority of prasugrel with respect to coronary events and stent thromboses was proven in patients with acute coronary syndrome undergoing coronary interventions. Specifically patients with Diabetes mellitus and patients with ST-elevation myocardial infarction seemed to benefit most due to the improved inhibition of platelet activity. A higher rate of bleeding complications was seen in those over the age of 75 years and a body weight below 60 kg for which a daily dose of 5mg/day was approved. Further clinical studies with prasugrel in patients with non-invasively treated acute coronary syndromes are ongoing.

Inter-patient variability and impact of proton pump inhibitors on platelet reactivity after prasugrel

Although there is considerable variability of platelet reactivity among patients treated with clopidogrel, little is known about inter-individual differences and possible role of proton pump inhibitors (PPIs) after prasugrel. We defined the extent of inter-patient variability, and evaluated the impact of PPI interaction in prasugrel-treated patients with acute coronary syndrome (ACS). Between January 2010 and May 2011, 104 prospective, high-risk patients with ACS were recruited into this multicentre, prospective, observational study. Twelve to 24 hours after receiving 60 mg loading dose of prasugrel, light transmission aggregometry (LTA) and whole blood impedance aggregometry (Multiplate) were used to assess platelet activity. Platelet function measurements were repeated during maintenance phase on reduced (5 mg) or on conventional (10 mg) doses of prasugrel. High platelet reactivity (HPR) was defined according to the consensus document of the Working Group on High On-Treatment Platelet Reactivity (LTA:>46%; Multiplate:>47U). Compared to maintenance doses, 60 mg loading dose of prasugrel provided significantly greater platelet reactivity inhibition (p<0.05). There were no significant differences between the conventional and reduced maintenance doses. Notably, a remarkable inter-patient variability was present in platelet reactivity after all doses of prasugrel, and the prevalence of HPR was significantly higher during the maintenance doses (p<0.05). Although median platelet reactivity values were consistently higher when prasugrel was used in combination with PPIs, these differences were not significant (p≥0.17). Despite potent platelet inhibition, inter-patient variability is present after all tested doses of prasugrel. The 60 mg loading dose is superior to conventional and reduced maintenance doses in terms of platelet reactivity inhibition and regarding the prevention of HPR.

Increased Atherothrombotic Burden in Patients with Diabetes Mellitus and Acute Coronary Syndrome: A Review of Antiplatelet Therapy

Patients with diabetes mellitus presenting with acute coronary syndrome have a higher risk of cardiovascular complications and recurrent ischemic events when compared to nondiabetic counterparts. Different mechanisms including endothelial dysfunction, platelet hyperactivity, and abnormalities in coagulation and fibrinolysis have been implicated for this increased atherothrombotic risk. Platelets play an important role in atherogenesis and its thrombotic complications in diabetic patients with acute coronary syndrome. Hence, potent platelet inhibition is of paramount importance in order to optimise outcomes of diabetic patients with acute coronary syndrome. The aim of this paper is to provide an overview of the increased thrombotic burden in diabetes and acute coronary syndrome, the underlying pathophysiology focussing on endothelial and platelet abnormalities, currently available antiplatelet therapies, their benefits and limitations in diabetic patients, and to describe potential future therapeutic strategies to overcome these limitations.

Loading Effect of 200 mg Cilostazol on Platelet Inhibition in Patients Undergoing Percutaneous Coronary Intervention

To date, most studies conducted on cilostazol have examined its effects as an agent of maintenance-dose therapy, but its loading effects on platelet inhibition have never been reported. This study aimed to determine the loading effects of 200 mg cilostazol in addition to aspirin and clopidogrel on platelet inhibition in patients undergoing percutaneous coronary intervention.Sixty consecutive patients undergoing coronary intervention were enrolled and assigned to receive 300 mg of aspirin and clopidogrel with or without 200 mg of cilostazol. All loading doses were given at least 3 hours before percutaneous coronary intervention and followed by dual or triple maintenance-dose therapy. Platelet function tests were performed just before and at 24 hours and 30 days after percutaneous coronary intervention by light transmittance aggregometry and VerifyNow® P2Y12 assay.There were no significant differences in baseline or angiographic characteristics between the 2 groups. The results of platelet function tests revealed that the adjunctive loading dose of 200 mg of cilostazol induced more potent platelet inhibition compared to a dual regimen at each time point. Cilostazol reduced the incidence of high post-treatment platelet reactivity (HPPR).Adjunctive 200 mg cilostazol can improve platelet responsiveness to clopidogrel in the pre- and postprocedural phases, reducing the prevalence of HPPR.

Current concepts on coronary revascularization in diabetic patients

Diabetic mellitus (DM) patients with coronary artery disease (CAD) are at higher risk of cardiovascular events compared with non-DM individuals. While aggressive cardiovascular prevention and adequate blood glucose control remain cornerstones of therapy, the decision when and how to proceed to coronary revascularization in an individual DM patient should be based on the extent of CAD, ischaemic burden, ventricular function, as well as comorbidities. While in patients with stable symptoms, moderate CAD on coronary angiography and preserved left ventricular function a conservative strategy may be a valuable initial strategy, in patients with acute coronary syndromes (ACS) an early invasive approach should be favoured. The revascularization strategy for DM patients with complex multivessel CAD should be discussed within a heart team consisting of cardiologists, cardiac surgeons, and anaesthesiologists. In general, the threshold for coronary artery bypass surgery (CABG) should be lower for DM than for non-DM individuals. In patients undergoing percutaneous coronary intervention, the use of drug-eluting stents (DES) and--in the setting of ACS--of potent platelet inhibitors, such as prasugrel or ticagrelor, should be favoured. In the near future, multiple strategies may further favourably impact the prognosis of DM patients undergoing coronary revascularization. These include alternative antiplatelet agents such as thromboxane receptor inhibitors, the broad use of second generation DES, and possibly the implantation of bioresorbable stents. Coronary artery bypass surgery outcomes may also further improve by wide implementation of arterial revascularization, reduction in perioperative stroke by avoiding clamping of the aorta, reduction in wound infection by minimally invasive techniques, and optimization of post-operative medical management.

Tackling the thrombotic burden in patients with acute coronary syndrome and diabetes mellitus

Patients with diabetes mellitus (DM) and coronary artery disease, particularly those presenting with acute coronary syndromes (ACS), have a higher risk of developing ischemic complications than their nondiabetic counterparts. Although ACS patients with DM benefit more than normoglycemic ACS patients from early coronary angiography and revascularization, they remain at a higher risk of complications following percutaneous coronary intervention and bypass surgery. The DM-associated prothrombotic state has been implicated in the pathogenesis of these complications and growing data supports the notion that potent platelet inhibition is of paramount importance in order to optimize outcomes of DM patients presenting with ACS. This article focuses on the evidence supporting the concept that augmented platelet reactivity and impaired responsiveness to oral antiplatelet agents are influential drivers of the increased propensity of DM patients with ACS to develop thrombotic complications. In particular, strategies to enhance platelet P2Y12 receptor inhibition, a key factor to improve outcomes in this patient population, are reviewed.

Anti-platelet Aggregation Activity of Lignans Isolated from Schisandra chinensis Fruits

Anti-platelet aggregation activities of Schisandra chinensis fruits against platelet aggregation induced by arachidonic acid (AA), collagen, platelet activation factor (PAF), and thrombin were evaluated and compared with those of aspirin. The active constituents of S. chinensis fruits were isolated as gomisin N and pregomisin. Based on the IC50 values, pregomisin and gomisin N were effective in inhibiting platelet aggregation induced by AA (96.5 and 153.3 μM) and PAF (49.3 and 122.4 μM). Pregomisin and gomisin N were more potent platelet inhibitors than aspirin against PAF. Taken together, these results indicate that gomisin N and pregomisin may be useful for the inhibition of PAF.

Ticagrelor: From Discovery to Phase III Clinical Trial

Ticagrelor (AZD6140), a cyclopentyl-triazolo-pyrimidine, is the first orally available antagonist of the ADP receptor of the P2Y12 subtype. Ticagrelor inhibits platelets in a reversible manner and does not require hepatic bioactivation. The pharmacology of ticagrelor indicates that it provides more consistent, more rapid and more potent platelet inhibition than clopidogrel. Preclinical and clinical studies with ticagrelor have demonstrated that this drug has excellent oral bioavailability. The Phase III clinical study of Platelet Inhibition and Patient Outcomes (PLATO) has shown that ticagrelor reduced ischemic events and all-cause mortality without an increase in major bleeding complications. Potential advantages of ticagrelor include more flexibility in its use if rapid onset of action is needed before percutaneous coronary interventions or when cessation is required before coronary artery bypass graft surgery. Potential disadvantages include more side effects such as dyspnea, ventricular pauses or an increase in concentrations of uric acid and creatinine. However, ticagrelor did not only reduce death due to vascular causes but also all-cause mortality. Further clinical trials in indications other than acute coronary syndrome are awaited.

Safety evaluation of tirofiban

Importance of the field: Heightened platelet activity is pivotal in the thrombosis underlying acute coronary syndrome (ACS). The glycoprotein IIb/IIIa inhibitor tirofiban is a powerful platelet inhibitor with demonstrated efficacy and safety across the spectrum of ACS. Despite tirofiban's impact on the platelet compared with placebo, only an excess in minor and importantly not major bleeding has been observed. Thrombocytopenia with tirofiban seems to be extremely rare and immediately reversible on infusion discontinuation.Areas covered in this review: The review includes the rationale for potent antiplatelet therapy in the management of ACS, particularly patients at high risk for ischemic complications. Additionally, it provides an overview of tirofiban's pharmacology and summary of the clinical efficacy and safety data of two dosing regimens.What the reader will gain: The reader will gain a perspective on the efficacy and safety data from the key trials of tirofiban.Take home message: Tirofiban is safe and effective in patients with ACS. The single bolus dose regimen produces potent platelet inhibition resulting in significant improvement in clinical events over placebo when initiated just prior to percutaneous coronary intervention and at first medical contact. When compared with abciximab, tirofiban demonstrates similar efficacy though significantly lower rates of thrombocytopenia.