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Background Direct-acting oral anticoagulants (DOACs) do not require monitoring. Measurement of DOAC effect would be useful in the event of bleeding, trauma, and thromboembolism while on anticoagulation. We evaluated the effectiveness of the investigational DOAC assays on the TEG®6s Hemostasis Analyzer to assess the anticoagulant effect of DOACs in patients treated for atrial fibrillation or deep vein thrombosis (DVT). Methods Patients on treatment for a minimum of 7 days with standard doses of dabigatran, rivaroxaban, and apixaban were included. DOAC plasma concentrations and TEG®6s Reaction (R)-time were measured and correlated. The sensitivity, specificity, and negative predictive value (NPV) of R-time to detect DOAC concentrations of ≥30, ≥50, and ≥100 ng/mL were calculated. Results A total of 189 patients were included, (n = 50) on apixaban, (n = 62) on rivaroxaban, (n = 53) on dabigatran, and (n = 24) on no DOAC were studied. Using the direct thrombin inhibitor (DTI) channel, R-time demonstrated strong linear correlation with dabigatran levels (r = 0.93, p Conclusion R-time measured by TEG®6s DOAC-specific cartridge has a strong correlation with concentrations of the most commonly used DOACs with high sensitivity and NPV for detecting lower drug levels that are considered clinically relevant for patients in need of antidote, or prior to urgent surgery. Further studies to determine the relation of R-time to clinical outcomes are warranted.

In this prospective, 3-arm, repeated-measure multicenter investigation in 280 patients with cardiovascular risk factors, platelet aggregation was measured with the novel AggreGuide A-100 ADP (A-100 ADP) and VerifyNow (VN)-PRU assays at baseline, and after United States Food and Drug Administration approved loading and 7 days maintenance doses of clopidogrel (n = 94), prasugrel (n = 43) or ticagrelor, (n = 143). Based on the predetermined cutoff values of

Introdution COVID-19 is associated with an increased risk of thrombotic events. However, the contribution of platelet reactivity (PR) to the aetiology of the increased thrombotic risk associated with COVID-19 remains unclear. Our aim was to evaluate PR in stable patients diagnosed with COVID-19 and hospitalized with respiratory symptoms (mainly dyspnoea and dry cough), in comparison with a control group comprised of non-hospitalized healthy controls. Methods Observational, case control study that included patients with confirmed COVID-19 (COVID-19 group, n = 60) and healthy individuals matched by age and sex (control group, n = 60). Multiplate electrode aggregometry (MEA) tests were used to assess PR with adenosine diphosphate (MEA-ADP, low PR defined as

Achieving reperfusion immediately after acute myocardial infarction improves outcomes; despite this, patients remain at a high risk for mortality and morbidity at least for the first year after the event. Ischemia-reperfusion injury (IRI) has a complex pathophysiology and plays an important role in myocardial tissue injury, repair, and remodeling.In this review, the authors discuss the various mechanisms and their pharmacological agents currently available for reducing myocardial ischemia-reperfusion injury (IRI). They review important original investigations and trials in various clinical databases for treatments targeting IRI.Encouraging results observed in many preclinical studies failed to show similar success in attenuating myocardial IRI in large-scale clinical trials. Identification of critical risk factors for IRI and targeting them individually rather than one size fits all approach should be the major focus of future research. Various newer therapies like tocilizumab, anakinra, colchicine, revacept, and therapies targeting the reperfusion injury salvage kinase pathway, survivor activating factor enhancement, mitochondrial pathways, and angiopoietin-like peptide 4 hold promise for the future.

Introduction: Platelets play a pivotal role in the occurrence of recurrent ischemic events in coronary artery disease patients who are treated with drug-eluting stents and are on dual antiplatelet therapy (DAPT).Areas covered: High platelet reactivity (HPR) to adenosine diphosphate during clopidogrel therapy is a strong predictor of post-stenting ischemic event occurrences. However, uniform use of potent P2Y12 receptors blockers to overcome HPR is associated with elevated bleeding risk. Selective de-escalation of P2Y12 receptor blocker therapy based on PFT in patients with acute coronary syndrome treated with stenting has been shown to be associated with a similar risk of ischemic event occurrence but with a reduced risk of bleeding. This review aims to discuss the role of PFT in guiding DAPT in patients treated with DES. We searched electronic databases from January 2000 to December 2019 for literatures evaluating the role of platelet function assessment after drug eluting stents.Expert opinion: Platelet function guided therapy improves patient outcomes by lessening bleeding and limiting the overuse of highly potent P2Y12 inhibitors. Interest in this area of de-escalation of therapy will likely grow as the consequences of bleeding are better recognized and the cost of healthcare gains greater focus.

Introduction: Despite current guideline-based, secondary prevention strategies in patients with the acute coronary syndrome, the residual ischemic risk is still at an unacceptable rate, and there is a concomitant high bleeding event rate. These observations mandate investigations of novel treatment strategies to meet the unmet need to improve outcomes in patients with ACS.Areas covered: In this review, the author(s) focus on new agents with ongoing or recently completed phase II trials for the treatment of ACS. We searched MEDLINE and clinicaltrials.org for Phase II trials in ACS patients, and important original investigations are reviewed.Expert opinion: Some of the novel drugs evaluated in the Phase II trials hold promise for future therapies such as AZD5718, anakinra, tocilizumab, CSL112, MEDI 6102, inclisiran, PZ128, selatogrel, and RVX-208. Their efficacy and safety should be evaluated in large scale Phase III trials. The higher cost of the drug will be a major limitation for wide-spread use of novel agents in general practice in future.

BACKGROUND: Vorapaxar is indicated with standard antiplatelet therapy (APT) in patients with a history of myocardial infarction (MI) or peripheral arterial disease (PAD). OBJECTIVES: To evaluate the comparative effects of vorapaxar on platelet-fibrin clot characteristics (PFCC), coagulation, inflammation, and platelet and endothelial function during treatment with daily 81 mg aspirin (A), 75 mg clopidogrel (C), both (C + A), or neither. METHODS: Thrombelastography, conventional platelet aggregation (PA), ex vivo endothelial function by ENDOPAT, coagulation, platelet activation/inflammation marked by urinary 11-dehydrothromboxane B(2) (UTxB(2)) and safety were determined in patients who were APT naïve (n = 21), on C (n = 8), on A (n = 29), and on A + C (n = 23) during 1 month of vorapaxar therapy and 1 month of offset. RESULTS: Vorapaxar had no effect on PFCC, ADP- or collagen-induced PA, thrombin time, fibrinogen, PT, PTT, von Willebrand factor (vWF), D-dimer, or endothelial function (P > .05 in all groups). Inhibition of SFLLRN (PAR-1 activating peptide)-stimulated PA by vorapaxar was accelerated by A + C at 2 hours (P < .05 versus other groups) with nearly complete inhibition by 30 days that persisted through 30 days after discontinuation in all groups (P < .001). SFLLRN-induced PA during offset was lower in APT patients versus APT-naïve patients (P < .05). Inhibition of UTxB(2) was observed in APT-naïve patients treated with vorapaxar (P < .05). Minor bleeding was only observed in C-treated patients. CONCLUSION: Vorapaxar had no influence on PFCC measured by thrombelastography, coagulation, or endothelial function irrespective of APT. Inhibition of protease activated receptor (PAR)-1 mediated platelet aggregation by vorapaxar was accelerated by A + C and offset was prolonged by concomitant APT. Vorapaxar-induced anti-inflammatory effects were observed in non-aspirin-treated patients.

East Asians are the most populous race in the world and their health status is an important global issue. Compared with Caucasian populations, East Asian patients have a different benefit/risk ratio when using antithrombotic treatment. Despite this observation, treatment strategies in East Asian patients are mostly based on the American and European guidelines. Despite a lower platelet inhibitory response to clopidogrel, East Asian patients show a similar or even a lower rate of ischemic event occurrence and higher bleeding risk compared with Caucasian patients. For potent P2Y12 inhibitors (ticagrelor and prasugrel), East Asian patients have shown less favorable net clinical benefits compared with Caucasian patients, which may be related to differences in pharmacokinetic/pharmacodynamic profiles and therapeutic zone of antiplatelet effect. This updated consensus mainly focuses on state-of-the-art and current controversies in the East Asian population. In addition, when East Asian patients are administered potent P2Y12 receptor inhibitors, the strategies and ongoing trials to overcome the related hurdles are discussed.

Compared with Caucasian patients, East Asian patients have the unique risk–benefit trade-off and different responsiveness to antithrombotic regimens. The aim of this study was to compare pharmacodynamic profile in East Asian patients with acute coronary syndromes (ACSs) treated with prasugrel standard-dose versus a de-escalation strategy. Before discharge, ACS patients with age Registration URL: https://clinicaltrials.gov. Unique identifier:NCT01951001.

East Asian patients have reduced anti-ischemic benefits and increased bleeding risk during antithrombotic therapies compared with Caucasian patients. As potent P2Y12 receptor inhibitors (e.g., ticagrelor and prasugrel) and direct oral anticoagulants are commonly used in current daily practice, the unique risk–benefit trade-off in East Asians has been a topic of emerging interest. In this article, we propose updated evidence and future directions of antithrombotic treatment in East Asian patients.

Introduction: Tegaserod, an orally active, potent 5-hydroxytryptamine-4 serotonin receptor agonist, was previously indicated for irritable bowel syndrome but was voluntarily withdrawn due to potential cardiovascular side effects. In vitro studies suggested that tegaserod increased platelet aggregation, but these results were not reproduced or were inconclusive. We sought to assess ex vivo effects of tegaserod on platelet aggregation. Methods: In this double-blind, placebo-controlled, crossover study, we randomized a majority of healthy patients with no history of cardiovascular risk factors (n = 21) to receive tegaserod or matching placebo for 7 + 2 days followed by a 7- to 10-day washout period, and then patients were crossed over to the other study drug for the next 7 + 2 days. Unstimulated and agonist-stimulated platelet aggregation; P-selectin expression; serum thromboxane (Tx)B2 and urinary 11-dehydro (11-dh) TxB2; and tegaserod and M29.0 concentrations were serially assessed. Results: There was no significant difference in percentage change in unstimulated or adenosine diphosphate (ADP)- and ADP + serotonin-, collagen- and thrombin receptor activating peptide–induced maximum platelet aggregation and in platelet P-selectin expression in the presence of tegaserod at any time point when compared to placebo. Similarly, there was no significant difference in percentage change in serum TxB2 or urinary 11-dhTxB2 levels between placebo and tegaserod. No new or unexpected findings were observed in evaluations of safety or pharmacokinetic parameters. Conclusion: This comprehensive pharmacodynamic study, by employing established markers used in prior investigations, which have been considered by the Food and Drug Administration to indicate drug-related platelet effects, does not demonstrate any influence of tegaserod treatment on platelet function.

Amlodipine has a potential to reduce clopidogrel bioactivation through the cytochrome P450 3A4 enzyme in vivo, but the clinical impact of this interaction remains controversial. This randomized, open-label, two-period, crossover study was performed to evaluate the influence of amlodipine on the haemostatic profiles of high-risk patients during clopidogrel treatment. We recruited 40 Asian patients (Male/Female: n = 36/4) receiving clopidogrel (75 mg/day), aspirin (100 mg/day) and rosuvastatin for at least 6 months following percutaneous coronary intervention. Patients were randomly assigned to receive either 5 mg daily amlodipine or not for 2 weeks, and then were crossed over to the other treatment for 2 weeks. Haemostatic measurements were conducted with the VerifyNow assay and thromboelastography (TEG). Primary endpoint was P2Y12 Reaction Units (PRU) during on- versus off-amlodipine treatment. The on-amlodipine strategy showed higher level of PRU compared with the off-amlodipine strategy (176.8 ± 75.4 vs. 150.7 ± 65.5 PRU; ∆mean: 26.1 PRU; ∆95% confidence interval [CI]: 4.5–47.7 PRU; p = 0.019). Platelet-fibrin clot strength measured by TEG was lower during on- versus off-amlodipine treatment (7,712 ± 1,889 vs. 8,559 ± 2,174 dyne/cm2; ∆mean: –847 dyne/cm2; ∆95% CI: –1,632 to –62 dyne/cm2; p = 0.035). After amlodipine discontinuation, 27 patients (67.5%) showed a decrease in PRU, which was associated with ‘PRU ≥ 160 on-amlodipine’ in multivariate analysis (odds ratio: 62.014; 95% CI: 2.302–1670.328; p = 0.014). In conclusion, amlodipine increases platelet reactivity and decreases platelet-fibrin clot strength during clopidogrel treatment. In addition, the effect of amlodipine discontinuation on clopidogrel responsiveness is associated with on-amlodipine platelet reactivity.

Aims We aimed to determine the efficacy and safety of different anti-platelet regimens after percutaneous coronary intervention (PCI) with drug eluting stent (DES) implantation using a network meta-analysis of randomized controlled trials (RCTs). Methods RCTs comparing shorter duration (≤6 months) of dual antiplatelet therapy (S-DAPT) with either aspirin (ASA) or P2Y12 inhibitor monotherapy against longer duration (≥12 months) DAPT (L-DAPT) after PCI were searched in the MEDLINE, EMBASE and COCHRANE databases. End-points of interest were all-cause death, cardiovascular (CV) death, myocardial infarction (MI), stent thrombosis (ST), major bleeding and major or minor bleeding. Network meta-analyses were performed using frequentist approach. Results Eighteen RCTs with total of 57,942 patients met the inclusion and exclusion criteria. This included 14 RCTs (N = 28,853) of S-DAPT with ASA monotherapy and 4 RCTs (N = 29,089) with P2Y12 inhibitor monotherapy. Compared with L-DAPT, the odds of MI were higher with S-DAPT with ASA monotherapy [OR 1.23; 95% CI 1.01–1.48], but not with P2Y12 inhibitor monotherapy [0.98; 0.85–1.14]. Both S-DAPT regimens lowered rates of major bleeding when compared with L-DAPT; ASA monotherapy [0.70; 0.49–1.00] and P2Y12 monotherapy [0.67; 0.45–0.98]. There were no differences in risks of all-cause or CV death between either regimen of S-DAPT and L-DAPT. However, in the acute coronary syndrome subgroup, ASA monotherapy was associated with increased risk of ST [1.55; 1.021–2.36] but P2Y12 monotherapy was not [0.93; 0.58–1.48]. Conclusion Amongst patients undergoing DES implantation, S-DAPT with P2Y12 inhibitor monotherapy reduces bleeding without increased risk of MI or ST compared with L-DAPT. Prospective trials are needed to evaluate if S-DAPT with P2Y12 monotherapy is superior to S-DAPT with ASA monotherapy for ischemic protection.

COMPASS study demonstrated efficacy of dual pathway inhibition with 2.5 mg twice daily rivaroxaban and aspirin in patients with polyvascular disease (coronary artery disease, peripheral arterial disease or both), the underlying mechanism of which is not clearly understood. In this Phase IV, prospective, open-label and randomized study, we hypothesize that treatment with rivaroxaban is associated with a reduction in platelet activation and aggregation, inflammation and coagulation markers. 30 patients will be randomly treated with aspirin (81 mg q.d.) or aspirin plus rivaroxaban (2.5 mg b.i.d.) for 12 weeks. Platelet aggregation, platelet activation and inflammation markers, thrombin generation kinetics and tissue factor-induced platelet–fibrin clot strength will be measured at baseline, and 4 and 12 weeks after randomization. Trial registration number: NCT04059679

Vorapaxar specifically and effectively inhibits protease activated receptor-1 and may reduce thrombin-mediated ischemic events without interfering primary hemostasis. In the TRA-2P-TIMI 50 trial, vorapaxar reduced the risk of primary ischemic outcome but with increased bleeding risk. In the post hoc analysis, in patients with a history of myocardial infarction, peripheral artery disease, the net clinical outcome favored vorapaxar therapy with 10% reduction in cardiovascular death, myocardial infarction, stroke, urgent coronary revascularization and moderate or severe bleeding. Based on these favorable results, vorapaxar was approved for the reduction of thrombotic cardiovascular events in patients with prior myocardial infarction or with peripheral artery disease on top of standard antiplatelet therapy. A careful patient selection is needed to balance efficacy versus safety.

The concomitant use of low-dose aspirin for cardioprotection and non-steroidal anti-inflammatory agents for pain relief is prevalent, particularly in the elderly for whom cardiovascular disease and pain are common co-morbidities. Non-selective non-steroidal anti-inflammatory drugs (NSAIDs) are known to interfere with the antiplatelet effect of aspirin through competitive binding with COX-1. While the clinical significance of this interference is still unclear, this review sought to assess the body of literature which has evaluated the potential attenuation of the anti-platelet effect of aspirin when dosed concomitantly with an NSAID. This review supports that the pharmacodynamic interaction between aspirin and non-selective NSAIDs occurs, but finds that the interaction varies amongst agents, and is highly dependent on numerous factors including: dose timing, dose of aspirin, and dose of the NSAID in question. Recent findings suggest that patient factors, such as body weight may also be indicators of aspirin's cardiovascular effectiveness. Ultimately, the clinical decision making for concomitant NSAID and low-dose aspirin regimens remains at the patient level.

Introduction: Presence of loss-of-function (LoF) allele of CYP2C19 gene has been associated with poor clopidogrel active metabolite generation, poor antiplatelet response, and elevated risk for car...

This review discusses the response variability to acetylsalicylic acid (ASA) and particularly to clopidogrel, and their relation to adverse recurrent ischaemic events in patients with arterial diseases. The higher rate of ASA resistance reported in the literature may be mainly due to the cyclooxygenase-1 non-specific assays, non-compliance, and underdosing. Clopidogrel response variability and non-responsiveness are established concepts. Moreover, high platelet reactivity (HPR) to adenosine diphosphate during clopidogrel therapy is now a known risk factor for recurrent ischaemic events in high-risk percutaneous coronary intervention/acute coronary syndrome patients. Variable active metabolite generation is the primary explanation for clopidogrel response variability and non-responsivenes. Variable levels of active metabolite generation following clopidogrel administration could be mainly explained by functional variability in hepatic cytochrome (CYP)P450 isoenzyme activity that is influenced by drug-drug interactions and single nucleotide polymorphisms of specific genes encoding CYP450 isoenzymes. Treatment with more potent P2Y12 receptor blockers, such as prasugrel and ticagrelor are credible alternative strategies to overcome HPR during clopidogrel therapy.

Platelet activation and aggregation play a pivotal role in thrombotic complications occurring during percutaneous coronary intervention (PCI), and peri-PCI anti-platelet therapy represents a standard of care. High platelet reactivity prior to PCI has been correlated with an increased incidence of peri-procedural myonecrosis. Pre-PCI platelet reactivity predicts post-PCI platelet reactivity and has a prognostic impact on subsequent ischaemic and bleeding events, so as the platelet inhibition measured post-PCI. Many anti-platelet treatment strategies, including aspirin, glycoprotein IIb/IIIa inhibitors, P2Y12 receptor blockers and vorapaxar, are being used in the routine clinical practice to modify platelet reactivity at each stage, e.g. pre-, during and post-PCI. Anti-platelet strategies with a ‘stronger and faster’ pharmacodynamic effect than clopidogrel have been mostly adopted in patients with acute coronary syndromes. However, several issues regarding the anti-platelet treatment such as benefits/risks of anti-platelet therapy pre-treatment and duration, and definite association between speed and potency of various anti-platelet agents and clinical outcomes remain controversial. We believe that a better understanding of peri-PCI platelet reactivity and its relations to outcomes may lead to the development of more effective and safe treatment strategies.

There have been significant new developments in the treatment of patients with myocardial infarction with respect to oral antithrombotic agents over the past decade. Recent studies have explored the potential utility of targeting the dual pathway inhibition of platelet function with single or dual antiplatelet agents and the thrombin pathway with direct thrombin inhibitors or factor Xa inhibitors.In this review, the authors focus on the recent developments of oral antithrombotic agents including antiplatelet and antithrombin agents. It is based on literature covering: aspirin, P2YSince thrombus formation involves multiple pathways including platelet activation and aggregation and coagulation, simultaneous and optimal blockade of these pathways is essential to prevent thrombotic complications and to avoid excessive bleeding in the myocardial infraction setting. Despite an improved anti-ischemic effect associated with potent P2Y

CSL112 (Apolipoprotein A-I [Human]), an infusible, plasma-derived apolipoprotein A-I, is being developed to reduce cardiovascular events following acute myocardial infarction (AMI). A predecessor compound (CSL111) demonstrated a potential antiplatelet effect. A phase 2a multicentre, randomised, single-ascending dose study in patients with stable atherosclerotic disease receiving dual antiplatelet therapy (DAPT) assessed the potential additive effects of CSL112 administration on platelet function and increase bleeding risk in the subacute period after AMI. Patients (n = 44) on aspirin (75–325 mg/day) and either clopidogrel (75 mg/day, n = 37) or prasugrel (10 mg/day, n = 7) for > 30 days alongside standard-of-care therapy were randomised to a single dose of placebo or CSL112: 1.7, 3.4, or 6.8 g. Light transmission aggregometry was used to assess platelet aggregation in response to 2 mM arachidonic acid, 5 and 20 µM adenosine diphosphate, and 4 µg/mL collagen, pre-dose (baseline) and up to 48 h post-dosing. Compared to placebo, CSL112 had no clinically meaningful time- or dose-dependent effects on maximum platelet aggregation in response to any agonist, by either dose or renal function subgroup (p > 0.05). Coagulation parameters showed little variation over time or between treatment groups (p > 0.05). CSL112, when co-administered with standard DAPT, did not significantly influence platelet aggregation in response to agonists and is, therefore, not expected to significantly increase bleeding risk when administered with antiplatelet therapies. Electronic supplementary material The online version of this article (10.1007/s11239-018-1644-z) contains supplementary material, which is available to authorized users.

The P2Y12 receptor plays a critical role in the amplification of platelet aggregation in response to various agonists and stable thrombus generation at the site of vascular injury leading to deleterious ischemic complications. Therefore, treatment with a P2Y12 receptor blocker is a major effective strategy to prevent ischemic complications in high-risk patients with acute coronary syndrome (ACS) and patients undergoing percutaneous coronary intervention (PCI). The determination of optimal platelet inhibition is based on maximizing antithrombotic properties while minimizing bleeding risk and is critically dependent on individual patient's propensity for thrombotic and bleeding risks. Immediately after ACS and during PCI, where highly elevated thrombotic activity is present, a loading dose administration with a potent P2Y12 receptor blocker such as ticagrelor or prasugrel is preferred. In stable coronary artery disease patients undergoing PCI, clopidogrel is widely used. In addition, in patients with ST-segment elevation myocardial infraction who cannot take oral medications, a fast acting intravenous glycoprotein IIb/IIIa inhibitor or P2Y12 receptor blocker, cangrelor, may add clinical benefits. During long term therapy, a strategy that prevents ischemic risk while avoiding excessive bleeding risk is similarly desired. Although up to one year dual antiplatelet therapy (DAPT) is recommended in patients undergoing elective stenting, the available data support the anti-ischemic benefit of prolonged DAPT (more than1 year) in patients with prior MI. In addition to the DAPT risk calculator tool, future risk assessment methods that analyze intrinsic thrombogenicity and atherosclerotic coronary burden may further identify the optimal candidate for prolonged DAPT to improve net clinical outcomes.

Background Cigarette smoking is associated with enhanced clopidogrel effect and platelet inhibition. However, the effect of smoking cessation on clopidogrel pharmacokinetics (PK) and pharmacodynamics (PD) is unknown. We aimed to determine the effect of smoking cessation, confirmed by cotinine measurement, on clopidogrel PK and PD after percutaneous coronary intervention (PCI). Methods and Results Following successful PCI, patients treated with 75 mg/day clopidogrel who reported smoking ≥10 cigarettes/day with NicAlert urine cotinine level 6 were enrolled. Clopidogrel and its metabolite concentrations, VerifyNow P2Y12 reaction units (PRUs), and NicAlert levels were measured in the study group before and at 30 days after smoking cessation and in a control group. CYP1A2 and CYP2C19 genotypes were determined. At 30-day visit (n = 87), 45 patients continued smoking, whereas 42 patients stopped smoking. Baseline PRUs were similar between groups. At 30 days, the smoking cessation group had higher PRUs (150.5 ± 68.6 vs. 118.4 ± 65.9, p = 0.03), greater absolute PRU change (27.7 ± 39.8 vs. −12.9 ± 55.4, p = 0.0002), greater change of PRUs adjusted for baseline platelet reactivity (38.6 ± 10.0, p Conclusion Smoking cessation in clopidogrel-treated patients after PCI is associated with increased platelet reactivity and greater risk of HPR. Alternative P2Y12 inhibitors may be considered in selected patients who stop smoking after PCI.

The increased risk of non-cardiovascular death in patients receiving clopidogrel or prasugrel in comparison with the placebo group in the dual antiplatelet therapy (DAPT) trial in contrast to the decreased risk of cardiovascular death and all-cause death seen in patients treated with low-dose ticagrelor in the EU label population of the PEGASUS-TIMI 54 trial, resulted in inclusion in the 2020 ESC NSTE-ACS guidelines the recommendation for use of clopidogrel or prasugrel only if the patient is not eligible for treatment with ticagrelor. The prevalence of the primary outcome composed of cardiovascular death, stroke, or myocardial infarction was lower in the low-dose rivaroxaban and acetylsalicylic acid (ASA) group than in the ASA-alone group in the COMPASS trial. Moreover, all-cause mortality and cardiovascular mortality rates were lower in the rivaroxaban-plus-ASA group. Comparison of the PEGASUS-TIMI 54 and COMPASS trial patient characteristics clearly shows that each of these treatment strategies should be addressed at different groups of patients. A greater benefit in post-acute coronary syndrome (ACS) patients with a high risk of ischemic events and without high bleeding risk may be expected with ASA and ticagrelor 60 mg b.i.d. when the therapy is continued without interruption or with short interruption only after ACS. On the other hand, ASA and rivaroxaban 2.5 mg b.i.d. seems to be a better option when indications for dual antithrombotic treatment (DATT) appear after a longer time from ACS (more than two years) and/or from cessation of DAPT (more than one year) and in patients with multiple vascular bed atherosclerosis. Thus, both options of DATTs complement each other rather than compete, as can be presumed from the recommendations. However, a direct comparison between these strategies should be tested in future clinical trials.

Platelets play a pivotal role during arterial thrombotic event occurrences in patients undergoing percutaneous coronary intervention (PCI). Inhibition of the platelet COX-1 enzyme by aspirin and the P2Y12-ADP interaction by P2Y12 receptor inhibitors is a major pharmacologic strategy to prevent acute as well as long-term thrombotic event occurrences following PCI. Clopidogrel, the most widely used P2Y12 receptor inhibitor, is associated with wide response variability, and one in three patients exhibit no or negligible antiplatelet response. High on-treatment platelet reactivity (HPR) during clopidogrel therapy is a strong predictor for post-PCI ischemic event occurrences. The concept of a “therapeutic window” of P2Y12 receptor reactivity associated with both ischemic event occurrence (upper threshold) and bleeding risk (lower threshold) has been proposed. These observations provided a strong rationale to measure the platelet response to ADP during P2Y12 receptor inhibitor therapy and to personalize antiplatelet therapy. Potent P2Y12 receptor inhibitors, prasugrel and ticagrelor, are credible alternatives to clopidogrel. Chronic kidney disease (CKD) is commonly present in patients undergoing PCI and is associated with an increased risk for both thrombosis and bleeding. The effect of CKD on platelet function remains controversial. Studies in patients with CKD on dual antiplatelet therapy have demonstrated an elevated risk for HPR, and some studies correlated HPR to clinical outcomes. At this time the guidelines do not suggest a difference in antiplatelet therapy in patients undergoing PCI with and without CKD.

New guideline recommendations prefer direct oral anticoagulants (DOACs) over warfarin in DOAC-eligible patients with atrial fibrillation and patients with venous thromboembolism. As expected with all antithrombotic agents, there is an associated increased risk of bleeding complications in patients receiving DOACs that can be attributed to the DOAC itself, or other issues such as acute trauma, invasive procedures, or underlying comorbidities. For the majority of severe bleeding events, the widespread approach is to withdraw the DOAC, then provide supportive measures and "watchful waiting" with the expectation that the bleeding event will resolve with time. However, urgent reversal of anticoagulation may be advantageous in patients with serious or life-threatening bleeding or in those requiring urgent surgery or procedures. Until recently, the lack of specific reversal agents, has affected the uptake of these agents in clinical practice despite a safer profile compared to warfarin in clinical trials. In cases of life-threatening or uncontrolled bleeding or when patients require emergency surgery or urgent procedures, idarucizumab has been recently approved for reversal of anticoagulation in dabigatran-treated patients and andexanet alfa for factor Xa inhibitor-treated treated patients. The current review summarizes the current clinical evidence and scope of these agents with the potential impact on DOAC use in clinical practice.

Cardiovascular diseases, including acute coronary syndromes, are a major cause of death among tobacco smokers. Epidemiological studies have demonstrated that long‑term prognosis is worse in smokers with acute coronary syndromes than in nonsmokers. However, some studies have suggested that clopidogrel‑treated active smokers have better in‑hospital and short‑term follow‑up outcomes, a phenomenon regarded as the smoker's paradox. The smoker's paradox may be due to enhanced platelet response to clopidogrel therapy in active smokers as compared with nonsmokers caused by hepatic cytochrome P450 activation resulting in an increased generation of clopidogrel active metabolite. Another paradox has been reported after smoking cessation. Smoking cessation in clopidogrel‑treated patients after percutaneous coronary intervention is associated with increased platelet reactivity and a greater risk of high platelet reactivity. The smoking cessation paradox may increase the risk of thrombotic complications in patients treated with clopidogrel. More potent P2Y12 inhibitors may be considered in selected patients who stopped smoking after percutaneous coronary intervention. Further studies are required to determine the optimal antiplatelet strategy for stented patients who effectively quit smoking during clopidogrel treatment. The aim of this review is to discuss the risk of smoking and the potential elevated thrombotic risk related to smoking cessation.

International audience; Dual-antiplatelet therapy (DAPT) with aspirin and a P2Y(12) receptor inhibitor is the standard treatment for patients undergoing percutaneous coronary intervention. The availability of different P2Y(12) receptor inhibitors (clopidogrel, prasugrel, ticagrelor) with varying levels of potency has enabled physicians to contemplate individualized treatment regimens, which may include escalation or de-escalation of P2Y(12)-inhibiting therapy. Indeed, individualized and alternative DAPT strategies may be chosen according to the clinical setting (stable coronary artery disease vs. acute coronary syndrome), the stage of the disease (early-vs. long-term treatment), and patient risk for ischemic and bleeding complications. A tailored DAPT approach may be potentially guided by platelet function testing (PFT) or genetic testing. Although the routine use of PFT or genetic testing in percutaneous coronary intervention-treated patients is not recommended, recent data have led to an update in guideline recommendations that allow considering selective use of PFT for DAPT de-escalation. However, guidelines do not expand on when to implement the selective use of such assays into decision making for personalized treatment approaches. Therefore, an international expert consensus group of key leaders from North America, Asia, and Europe with expertise in the field of antiplatelet treatment was convened. This document updates 2 prior consensus papers on this topic and summarizes the contemporary updated expert consensus recommendations for the selective use of PFT or genotyping in patients undergoing percutaneous coronary intervention. (c) 2019 by the American College of Cardiology Foundation.

Antiplatelet therapy is the mainstay for the treatment of acute and chronic arterial disease involving the coronary and peripheral beds. However, questions remain about optimal antithrombotic therapy for long-term treatment of chronic vascular disease. The observation that dual antiplatelet therapy with acetylsalicylic acid and clopidogrel was associated with lower thrombotic event rates than acetylsalicylic acid monotherapy in patients with acute coronary syndromes and those undergoing percutaneous coronary intervention changed the treatment paradigm. Moreover, the demonstration that more pharmacodynamically potent P2Y12inhibitors than clopidogrel were associated with fewer thrombotic event occurrences further solidified the dual antiplatelet therapy approach. However, recurrent thrombotic events occur in ≈1 in 10 patients in the first year following an acute coronary syndrome event, despite treatment with the most potent P2Y12inhibitors, a limitation that has stimulated interest in exploring the efficacy and safety of approaches using anticoagulants on top of antiplatelet therapy. These investigations have included treatment with very-low-dose oral anticoagulation, and even its replacement of acetylsalicylic acid in the presence of a P2Y12inhibitor, in patients stabilized after an acute coronary syndrome event. Recent basic and translational studies have suggested noncanonical effects of coagulation factor inhibition that may further modulate clinical benefits. This in-depth review will discuss developments in our understanding of the roles that platelets and coagulation factors play in atherothrombosis and review the rationale and clinical evidence for combining antiplatelet and oral anticoagulant therapy in patients with coronary and peripheral artery disease.

Background: CYP2C19 polymorphisms affect clopidogrel metabolism and clinical outcomes in patients undergoing percutaneous coronary intervention (PCI). Although FDA recommended pharmacogenetic testing and alternative antiplatelet agents in CYP2C19 loss-of-function (LoF) allele carriers, implementation in practice has been minimal. Our goal is to personalize antiplatelet therapy using point-of-care (POC) assay to genotype patients immediately prior to PCI in a hospital cardiac catheterization lab. Methods: Appropriate P2Y 12 receptor antagonist therapy following non-emergent PCI based on bedside genetic testing (SpartanRx system) was initiated at Inova Heart and Vascular institute catheterization laboratory in February 2017. Patients were genotyped using buccal swab technique before proceeding to the catheterization laboratory. A best practice advisory (BPA) was implemented into the EPIC EMR prescription medication ordering system based on genotype. Poor (*2/*2, and *2/*3) and intermediate metabolizers (*1/*2, *1/*3, and *2/*17) were recommended more potent P2Y12 inhibitor therapy using BPA. Demographics, BPA compliance and 1 year outcomes including major adverse cardiac events (Cardiovascular death, MI, Ischemic stroke) and NACE (MACE + major bleeding) were collected. Results: Between 2/2017 to 12/2017, 1050 patients underwent POC genetic testing. The frequency of poor, intermediate, extensive, and ultra-rapid metabolizer status was 2.9%, 26.8%, 42.5%, and 27.9%, respectively. The highest percentage of poor metabolizers were observed in Middle-Eastern (12.1%) and Asian (8.9%) populations as compared to African Americans (n=3.4%) and Caucasians (1.1%). In patients treated with PCI (n=429), 28.9% were intermediate (n=112) or poor (n=12) clopidogrel metabolizers, with 87.1% of these patients receiving ticagrelor (n=84) or prasugrel (n=24) based on the BPA from genotype consortium. MACE (0.7%) and NACE (0.9%) rates were minimal as compared to historical controls (5-10%). Conclusions: CYP2C19 genotyping at the bedside facilitated early personalization of antiplatelet therapy according to BPA and is associated with low one year MACE and NACE rates.

Objectives: To evaluate the effect of clopidogrel vs. aspirin monotherapy on vascular function and hemostatic measurement. Background: Monotherapy with P2Y12 receptor inhibitor vs. aspirin can be a useful alterative to optimize clinical efficacy and safety in high-risk patients with coronary artery disease (CAD). Methods: We performed a randomized, open-label, two-period crossover study in stented patients receiving at least 6-month of dual antiplatelet therapy (DAPT). Thirty CAD patients with moderate-to-high ischemic risk were randomly assigned to receive either 75 mg of clopidogrel or 100 mg of aspirin daily for 4 weeks, and were crossed over to the other strategy for 4 weeks. Vascular function was evaluated with reactive hyperemia-peripheral arterial tonometry (RH-PAT) and brachial-ankle pulse wave velocity (baPWV). Hemostatic profiles were measured with VerifyNow and thromboelastography (TEG). The primary endpoint was the reactive hyperemia index (RHI) during clopidogrel or aspirin monotherapy. Results: Clopidogrel vs. aspirin monotherapy was associated with better endothelial function (RHI: 2.11 ± 0.77% vs. 1.87 ± 0.72%, p = 0.045), lower platelet reactivity (130 ± 64 vs. 214 ± 50 P2Y12 reaction unit [PRU], p &lt, 0.001) and prolonged reaction time (TEG R: 5.5 ± 1.2 vs. 5.1 ± 1.1 min, p = 0.037). In multivariate analysis, normal endothelial function (RHI ≥ 2.1) was significantly associated with clot kinetics (TEG angle ≤ 68 degree) and ‘PRU ≤ 132’. ‘PRU ≤ 132’ was achieved in 46.2% vs. 3.8% during clopidogrel administration vs. aspirin monotherapy (odds ratio 21.4, 95% confidence interval 2.7 to 170.1, p &lt, 0.001). Conclusions: In CAD patients, clopidogrel vs. aspirin monotherapy was associated with better endothelial function, greater platelet inhibition and lower coagulation activity, suggesting pleiotropic effects of clopidogrel on endothelial function and hemostatic profiles.

SummaryThe role of platelet-leukocyte interaction in the infarct myocardium still remains unveiled. We aimed to determine the linkage of platelet activation to post-infarct left ventricular remodelling (LVR) process. REMODELING was a prospective, observational, cohort trial including patients (n = 150) with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention. Patients were given aspirin plus clopidogrel therapy (600 mg loading and 75 mg daily). Platelet reactivity (PRU: P2Y12 Reaction Units) was assessed with VerifyNow P2Y12 assay on admission. Transthoracic echocardiography was performed on admission and at one-month follow-up. The primary endpoint was the incidence of LVR according to PRU-based quartile distribution. LVR was defined as a relative ≥ 20 % increase in LV end-diastolic volume (LVEDV) between measurements. Adverse LVR was observed in 36 patients (24.0 %). According to PRU quartile, LVR rate was 10.8 % in the first, 23.1 % in the second, 27.0 % in the third, and 35.1 % in the fourth (p = 0.015): the optimal cut-off of PRU was ≥ 248 (area under curve: 0.643; 95 % confidence interval: 0.543 to 0.744; p = 0.010). LVR rate also increased proportionally according to the level of high sensitivity-C reactive protein (hs-CRP) (p = 0.012). In multivariate analysis, the combination of PRU (≥ 248) and hs-CRP (≥ 1.4 mg/l) significantly increased the predictive value for LVR occurrence by about 21-fold. In conclusion, enhanced levels of platelet activation and inflammation determined the incidence of adverse LVR after STEMI. Combining the measurements of these risk factors increased risk discrimination of LVR. The role of intensified antiplatelet or anti-inflammatory therapy in post-infarct LVR process deserves further study.

A P2Y12 inhibitor plus aspirin is the most widely used antiplatelet strategy to prevent adverse outcomes in the setting of atherothrombotic vascular disease. Areas covered: A paucity of robust evidence for an optimal dose, gastrointestinal toxicity, ineffectiveness in high-risk patients and interactions with other antiplatelet agents, are major controversies associated with aspirin therapy. Ticagrelor is a reversibly binding oral P2Y12 receptor blocker that mediates potent inhibition of adenosine diphosphate-induced platelet function. It is more effective than clopidogrel in preventing thrombotic events in acute coronary syndrome patients. The absence of a beneficial effect for ticagrelor versus clopidogrel in ACS observed in the North American subgroup of the PLATelet inhibition and patient Outcomes (PLATO) trial has been attributed to a higher concomitant aspirin dose. Expert commentary: Ongoing studies are now investigating the plausibility of removing aspirin therapy in the setting of potent P2Y12 receptor blockade via ticagrelor monotherapy or replacing aspirin with an oral anticoagulant.

Statin and aspirin form the therapeutic cornerstone in patients with coronary artery disease (CAD) and diabetes. Little is known about relationship of statins with blood thrombogenicity and inflammation in these patients.Two hundred nine consecutive patients with diabetes and suspected CAD undergoing elective cardiac catheterization were divided in groups based on statin treatment in the Multi-Analyte, Thrombogenic, and Genetic Markers Atherosclerosis study. Urinary 11-dehydrothromboxane B2 (11-dh-TxB2), lipid profile and oxLDL/β2GPI were measured by AspirinWorks™ ELISA assay, vertical density gradient ultracentrifugation and immunoassay respectively. Thrombelastography, and ADP- and collagen-induced light transmittance aggregometry assessed thrombogenicity. CAD was classified as none/minor [20% diameter stenosis (DS)], moderate (20-75% DS), or severe (75% DS).Severe, moderate, and no CAD was observed in 66, 19, and 15% of patients respectively. Patients on statins had significantly lower 11-dh-TxB2, collagen-induced aggregation, total cholesterol, total LDL, LDL3, oxidized-LDL, Apo B100, and ApoB100/A1 ratio (p0.01 for all). Statin therapy demonstrated a lower proportion of patients with high urinary 11-dh-TxB2 (1500pg 11-dh-TxB2/mg creatinine) (25 vs. 57%, p=0.01).Statins along with aspirin, confers additional anti-inflammatory and antithrombotic effect in diabetics with CAD. Urinary 11-dh-TxB2 may be a useful biomarker for personalizing statin therapy.

Aspirin has been the bedrock of antiplatelet treatment strategies for the secondary prevention of recurrent cardiovascular and cerebrovascular events for the last 3 decades. The limitations of standard aspirin therapy include bleeding, gastrotoxicity, and loss of antiplatelet effect over a 24-hour period in selected high-risk patients. An extended-release (ER) aspirin formulation, Durlaza® (New Haven Pharmaceuticals, Inc., North Haven, CT), has been developed to address some of the latter limitations and may provide an alternative to standard aspirin in the secondary prevention of cardiovascular disease.We searched articles describing the use aspirin for secondary prevention of stroke and cardiovascular events in PubMed published until May 2016. This is a comprehensive review which describes active- and placebo-controlled clinical trials, overview of American and European recommendations, controversies surrounding standard aspirin use, and a description of pharmacodynamics of standard and extended release aspirin formulations. Expert commentary: Available data indicates an increased bleeding risk with the use of standard aspirin therapy in conjunction with potent P2Y12 receptor blockers, and/or oral anticoagulants. Trials evaluating the efficacy of replacing aspirin with a low-dose oral anticoagulant in patients with stable cardiovascular disease or acute coronary syndrome are ongoing. Future studies are warranted to determine if the use of ER-ASA formulation may obviate safety concerns surrounding standard aspirin therapy.

The pivotal role that platelets play in thrombosis and resultant ischemic event occurrences in patients with high-risk coronary artery disease is well established. This role provides the fundamental basis for the current wide implementation of dual antiplatelet therapy with aspirin and a P2Y 12 receptor inhibitor. The development of user friendly point-of-care methods to assess platelet reactivity to adenosine diphosphate has increased the frequency of platelet function testing in clinical practice. Recent large observational studies have established an independent relation between the results of point-of-care platelet function testing and clinical event occurrence in patients undergoing coronary artery stenting. However, prospective, randomized trials have failed to demonstrate that personalized antiplatelet therapy based on point-of-care assessment of platelet function is effective in reducing ischemic event occurrences. Important limitations were associated with these trials. In addition, the concept of a therapeutic window of P2Y 12 receptor reactivity with an upper threshold associated with ischemic event occurrence and a lower threshold associated with bleeding has also been proposed. In the absence of strong prospective evidence to support personalized antiplatelet therapy, clinical decision making about antiplatelet therapy rests on the large body of observational data and the fundamental importance of platelet physiology in catastrophic event occurrence in patients with high-risk coronary artery disease.

Thrombelastography (TEG) measured by the TEG5000 Hemostasis Analyzer is an established but the labor-intensive method for assessing global hemostasis. The first true point-of-care TEG, the TEG6s system, uses resonance-frequency viscoelasticity measurements and a disposable multi-channel microfluidic cartridge to assess hemostasis and response to antiplatelet therapy. TEG assays (n = 5,100) were performed on the blood of healthy volunteers (n = 157) and patients undergoing coronary revascularization at three hospitals (n = 300). The results from the TEG6s were compared with the conventional TEG5000 in accordance with Clinical and Laboratory Standards Institute (CLSI) and FDA recommendations. Precision testing was conducted using blood from healthy donors, all assays were run for 5 consecutive days in duplicate using multiple operators, lots, and instruments. Reference ranges were comparable between the TEG systems. Deming regression analysis demonstrated a strong correlation between the two systems for the standard hemostasis tests (R r = 0.932, MA r = 0.972, LY30 r = 0.938). Method comparison analysis showed an acceptable agreement between PlateletMapping (PM) assays for measuring arachidonic acid (indicator of aspirin response)- and adenosine diphosphate (indicator of P2Y12 inhibitor response)-induced platelet aggregation (total agreement = 90%, and 72%, respectively). TEG6s precision testing yielded low variability (CV 0-13%) in all measures. The new point-of-care TEG6s is associated with greater ease of use than the TEG5000 and provides precise results. The results correlated between methods for all variables. TEG6s is a promising device for near-patient hemostasis monitoring and future trials of personalized therapy designed to reduce bleeding and thrombosis.

Atrial fibrillation (AF) is associated with an increased risk of stroke and thromboembolism (TE). The WATCHMANTM left atrial appendage (LAA) closure device is indicated to reduce the risk of TE from the LAA in patients with non-valvular AF. Here, we present a case of a patient with device-related thrombus who suffered a TE event two months after WATCHMANTM LAA closure and two weeks after switching from aspirin plus warfarin to aspirin plus clopidogrel therapy. Laboratory investigation identified the patient to be hypercoagulable and to be a non-responder to clopidogrel therapy. We discuss the potential role of platelet function testing to prevent device-related thrombi.

Early assessment of thrombogenicity and antithrombotic drug effects may be important for therapeutic decision making in patients presenting with acute stroke. In this prospective, single center, pilot study, a bedside thrombelastography assay (TEG6s) was used to measure thrombogenicity and antithrombotic drug response in serial patients presenting emergently with symptoms of acute stroke (n = 90). TEG6s measures were compared against diagnosis obtained by NIH Stroke Scale/Score and imaging. Acute ischemic stroke (AIS) was diagnosed in 30 patients, intracerebral hemorrhage (ICH) in 19, transient ischemic attack (TIA) in 10 and stroke mimic (SM) in 31. Patients with AIS had a higher prevalence of A-Fib (33.3% vs. 11.6%, p = 0.01), and ACE inhibitor use (56.3% vs. 21.6%, p 50% ADP-induced platelet aggregation). Patients receiving tissue plasminogen activator had significant reduction in clot strength and near complete lysis at 30 min which normalized within 2 h after treatment (p

Peripheral artery disease (PAD) is associated with increased risk of cardiovascular events. The benefits of dual antiplatelet therapy (DAPT) vs single antiplatelet therapy (SAPT) with aspirin in patients with PAD remain subject of ongoing debate.We performed a meta-analysis of studies comparing DAPT vs aspirin monotherapy in PAD. Incidence rate ratios (RR) and respective 95% confidence intervals (CI) were used as summary statistics. The primary outcome was mortality. Secondary endpoints were ischemic and bleeding outcomes. Ten studies including 65,675 patients have been included. Compared to SAPT, DAPT was associated with a significant reduction in mortality: RR, 0.89; 95% CI, 0.86-0.92; P 0.001. Results were consistent across patients with symptomatic PAD and those undergoing bypass or percutaneous transluminal angioplasty (PTA). Similarly, DAPT significantly reduced the risk of repeat peripheral revascularizations (RR, 0.80; 95% CI, 0.69-0.92; P = 0.002). No significant increase of major bleeding complications was observed with DAPT as compared to SAPT (RR, 1.21; 95% CI, 0.87-1.68 P = 0.26).DAPT, as compared to SAPT, significantly reduces mortality in patients with PAD, with no significant increase in bleeding complications. These findings support DAPT as the mainstay antiplatelet therapeutic regimen in patients with PAD.

Dual antiplatelet therapy with aspirin, a platelet cyclooxygenase-1 inhibitor and P2Y12 receptor blockers, remains the major drug strategy to prevent ischemic event occurrence in patients with acute coronary syndromes and in patients undergoing coronary stenting, but there some limitations that can be overcome by targeting novel targets. Unlike direct thrombin inhibitors that bind directly to thrombin, targeting the platelet thrombin receptor, protease activated receptor (PAR)-1, may offer a better choice for the attenuation of atherosclerosis progression, thrombus-mediated ischemic events and restenosis without interfering with primary hemostasis. Vorapaxar - a synthetic analogue of himbacine, is a high affinity and highly selective PAR-1 antagonist that can effectively inhibit thrombin-induced platelet aggregation. In the TRACER trial, the addition of vorapaxar to standard therapy in patients with non-stent thrombosis-elevation- acute coronary syndromes did not significantly reduce the primary composite end point occurrence of cardiovascular (CV) death, myocardial infarction (MI), stroke, hospitalization for ischemia, or urgent revascularization, but significantly increased the GUSTO moderate and severe bleeding (p < 0.001) and intracranial hemorrhage (ICH). In the TRA 2°P-TIMI 50 trial, in patients with a history of MI and peripheral arterial disease (PAD) (67% of the total population), the end point of CV death, MI, or stroke was significantly (20%) reduced with vorapaxar whereas GUSTO moderate or severe bleeding was increased (1.5-fold), but not ICH or fatal bleeding and the net clinical outcome favoring the vorapaxar therapy. Based on these favorable results, the FDA approved vorapaxar for the reduction of thrombotic cardiovascular events in patients with prior MI or with PAD for long term therapy. A careful patient selection is needed to balance efficacy versus safety. At this time, patients with high risk for recurrent ischemic event occurrence such as patients with diabetes mellitus and previous MI can be safely treated with vorapaxar for long-term therapy.

Both ST-segment elevation myocardial infarction and percutaneous coronary intervention (PCI) are associated with a highly prothrombotic state, and thrombin plays a critical role during occlusive clot generation and subsequent occurrence of an ischemic event. Therefore, a strategy of anticoagulation plus dual antiplatelet therapy has been regarded as de facto standard therapy during primary PCI (pPCI). Recently, there has been great controversy surrounding the role of bivalirudin versus unfractionated heparin in pPCI. Earlier, the results of the HORIZONS-AMI trial, particularly those regarding the long-lasting mortality benefit, provided a strong rationale for recommending bivalirudin therapy in pPCI. However, the mortality benefit of bivalirudin observed in HORIZONS-AMI has not been repeated in more contemporary studies or demonstrated in recent meta-analyses. The current report will provide a concise review of the controversy surrounding the optimal anticoagulant therapy for pPCI. Recent evidence suggests that unfractionated heparin deserves strong reconsideration despite the reports of pharmacologic weaknesses, particularly when used with a strategy of selective glycoprotein IIb/IIIa therapy, and it appears that a strategy of bivalirudin therapy in pPCI should be reserved for patients at high bleeding risk.

Patients with diabetes mellitus (DM) have accelerated atherosclerosis with an increased risk for atherothrombotic cardiovascular complications. A state of high platelet reactivity and activation, hypercoagulability (prothrombotic state) and a subdued response to standard antiplatelet agents may explain high rate of adverse cardiovascular events in patients with DM. Several antithrombotic treatment strategies have been developed to control the prothrombotic state in patients with DM: dose modification of commonly used agents; use of potent agents; and addition of a third antithrombotic drug (triple therapy) to commonly prescribed dual antiplatelet therapy of aspirin and a P2Y12 inhibitor. The present review aims to provide an overview of the current knowledge on platelet abnormalities in patients with DM, focusing on the challenges and perspectives of antiplatelet treatment strategies in this population.