Viewpoint: "underutilisation of novel antiplatelet agents--myths, generics, and economics".

Two oral antiplatelet agents have been recently introduced for acute coronary syndromes indication providing alternatives for dual therapy with aspirin and clopidogrel. In fact, worldwide prasugrel has been on the market for four years, and ticagrelor for over two years. Despite declared benefits over clopidogrel, including hypothetical cost saving advantages, in real life, the clinical utilisation of both agents is small. Generic clopidogrel, and price differences are claimed as major obstacles to prevent broader prasugrel and ticagrelor use. However, these economic difficulties are barely supported by available evidence, and served mostly to protect questionable management spending, as an exuse to explain why in reality cardiologists are so sceptical about both novel agents, and to convince the sharehoders that their money is not wasted, misleading the owners with regard to future success. Importantly, brand Plavix® is used worldwide 5-10 times more often than new agents, despite heavy generic competition. The future of prasugrel outside Japan, where much lower reasonable dose will be used is not impressive due to lack of further outcome studies, negative results of the latest trials, and less than four years left before patent expiration. The fate of ticagrelor will depend on verification of deaths numbers in the ongoing United States Department of Justice PLATO investigation, and confirmation of the mortality benefit in the PEGASUS TIMI-54 trial.

[The differences between the guidelines of the European Society of Cardiology and the American College of Cardiology/ American Heart Association for oral P2Y12 inhibitor therapy in the management of patients with acute coronary syndromes].

The analysis of the evidence that formed the basis for the current guidelines of the European Society of Cardiology (ESC) on oral therapy by antithrombotic drugs for acute coronary syndromes (ACS), and a comparison with the U.S. guidelines. The ESC guidelines, published during 2011-2012, declared the superiority of prasugrel and ticagrelor over clopidogrel in patients with ACS without ST elevation and myocardial infarction (MI) with ST elevation. These guidelines are based in each case on a subgroup analysis of a single study using either prasugrel (TRITON), or ticagrelor (PLATO). In contrast, the American College of Cardiology (ACC) and the American Heart Association (AHA) guidelines, published in 2012-2013, are more balanced, conservative and present evidence-based outlook, suggesting no proven extra benefit of one P2Y12 antagonist over the other(s). The ESC guidelines regarding the findings of the superiority of prasugrel or ticagrelor over clopidogrel are overly optimistic and not always evidence-based. A small frequency of clinical use of prasugrel and ticagrelor in the world in general and Europe in particular, suggests a discrepancy between the traditionally appointed treatment and published ESC guidelines.

Viewpoint: paradoxical excess mortality in the PLATO trial should be independently verified.

The PLATO trial revealed excess all-cause (4.5%) and vascular (4.0%) mortality after experimental pyrimidine, ticagrelor, and even higher death rates (5.9% and 5.1%, respectively) after clopidogrel, which have never been seen in any previous acute coronary syndrome (ACS) trial. The Food and Drug Administration (FDA) conducted, and recently released the ticagrelor review outlining some paradoxical mortality patterns in PLATO, including the existence of alive patient, who initially was reported dead. The drug was recently approved in Europe, but repeatedly delayed in the USA. The objective of this viewpoint article was to evaluate extremely high death rates in PLATO by scrutinising FDA-released evidence, and comparing mortality patterns in recent ACS trials. These data were first presented as the analytical report submitted to the FDA on October 26, 2010. The available evidence suggest that mortality rates in PLATO, so as death benefit of ticagrelor over clopidogrel are extreme, despite incomplete follow-up, short duration of the trial, frequent preloading with clopidogrel, and gross mismatch between conventional average myocardial infarction rates but disproportionally frequent vascular fatalities, and heavily imbalanced sepsis-related deaths. In contrast to the overall PLATO results, the deaths rates in the USA were much lower (3.2% vs. 3.8%) not only favouring clopidogrel, but more importanly matching very well with identical rates in TRITON (3.2%), and one-year ACUITY (3.6%-3.9%) fatalities. Since the «play of chance¼ cannot explain these discrepancies due to excess death rates in both PLATO arms, and considering that study sponsor self-monitored sites in most countries, but not in the USA, the mortality data are questionable, and should be independently virified. It was concluded that excess mortality rates and delayed timing of the benefit onset in PLATO do not match with any recent ACS trial, and do not look natural. Reevaluation of the survival, especially driven from the several high-volume sponsor monitored sites in Eastern Europe may reveal discrepancies between those reported in PLATO and actual vital records. Future practice of self monitoring in pivotal indication-seeking clinical trials should be completely banned.

Lack of outcome benefit and clopidogrel "resistance." The TRITON trial challenge.

Impaired response to clopidogrel, or "resistance" is a cornerstone concept for justification of more aggressive antiplatelet regimens, and development of new more potent drugs. There are over 1,000 citations (although predominantly reviews, or case reports) in MEDLINE related to clopidogrel "resistance", while about 100 of them attempted to link low response to adverse clinical outcomes. However, most of these studies are woefully small, and not randomised. The TRITON trial assessed head-to-head novel antiplatelet agent prasugrel versus clopidogrel in patients with acute coronary syndromes. This study was the first in a decade to challenge clopidogrel monopoly, and to indirectly test the "resistance" hypothesis. The primary endpoint was the rate of cardiovascular death, non-fatal myocardial infarction, or stroke, and occurred in 12.1% of patients treated with clopidogrel, and 9.9% of patients randomised to prasugrel, suggesting impressive vascular outcome benefit of prasugrel over clopidogrel. However, the Food and Drug Administration (FDA) presented more balanced, and realistic outlook on TRITON. While very early periprocedural benefit exists, long-term prasugrel therapy yielded identical to clopidogrel vascular outcomes among 13,608 TRITON patients challenging the postulate that clopidogrel "resistance" phenomenon is clinically relevant. Despite the fact that prasugrel 10 mg/daily cause 2.5 times more potent platelet inhibition than conventional clopidogrel 75 mg/daily, with fewer patients exhibiting broad response variability, and/or antiplatelet "resistance", the vascular benefit beyond acute phase was identical. Keeping in mind growing over time bleeding, cancer, and mortality risks associated with chronic prasugrel use, small observational studies should be judged with skepticism as hypothesis-generating, pending confirmation in randomised trials.

The TRITON versus PLATO trials: differences beyond platelet inhibition.

Clopidogrel monopoly as an exclusive oral antiplatelet agent used in combination with aspirin or as a monotherapy for treatment or/and prevention of occlusive thrombotic vascular events has been recently challenged. Based on the indirect comparison of TRITON and PLATO trial data, ticagrelor is clearly superior to prasugrel in a population of patients with acute coronary syndrome (ACS) because of absolute mortality reduction, realistic second myocardial infarction (MI) prevention, growing over time vascular outcome benefit, fewer haemorrhagic fatalities, potentially less coronary artery bypass graft (CABG)- related bleeding events, and lack of cancer risks. Despite an unfavourable immediate safety profile, ticagrelor has a lot of room to compensate for agitation, dyspnea, and ventricular pauses, if used in appropriate patients. It will be naïve and wrong to assume that ticagrelor will completely substitute clopidogrel, especially considering higher discontinuation rates after ticagrelor, generic competition, and other health economics issues. However, unless the regulatory authorities discover some unexpected serious flaws with PLATO, the ticagrelor will substantially change the present landscape of oral antiplatelet therapy, especially in high-risk patients, diabetics, and those with repeated vascular events including stent thrombosis. In contrast, a too exclusive trial design, a lack of persistent vascular benefit despite issues with event adjudication, growing-over-time bleeding complications, an issue with cancer, and finally an increase in mortality risk among unstable angina and non ST-elevated myocardial infarction will likely prevent a broad prasugrel implementation, unless more reassuring evidence becomes available.

Effects of aliskiren, a renin inhibitor, on biomarkers of platelet activity, coagulation and fibrinolysis in subjects with multiple risk factors for vascular disease.

Aliskiren, an octanamide, is nonpeptide, low molecular weight, orally active renin inhibitor effectively preventing angiotensin and aldosterone release. This drug has been recently approved for the treatment of hypertension. Considering potential links between hypertension, platelets, the coagulation cascade and fibrinolysis we sought to evaluate the effect of aliskiren on human biomarkers of hemostasis. In vitro effects of whole blood preincubation with escalating concentrations of aliskiren (500, 1,000 and 2,000 ng ml(-1)) were assessed in 20 aspirin-naive volunteers with multiple risk factors for vascular disease. A total of 33 biomarkers were measured, of which 18 are related to platelet function, 12 to coagulation and 3 to fibrinolysis. Pretreatment of blood samples with aliskiren 500 ng ml(-1) resulted in a significant increase of antithrombin-III (AT-III) activity (P=0.003). All other tested biomarkers were not significantly affected. Spiking whole blood with the higher aliskiren doses was associated with various trends in biomarker activity, where 1000 ng ml(-1) concentration mostly decreased (7/33), and 2,000 ng ml(-1) mostly increased (6/33) some biomarkers. In the therapeutic concentration of 500 ng ml(-1) aliskiren does not affect hemostatic biomarkers, except for a moderate but highly significant (P=0.003) increase of AT-III activity. Higher aliskiren doses were associated with more profound biomarker changes, but they are likely not to be clinically relevant since they show diverging (that is, both mild antiplatelet and platelet-activating) trends, and considering the 2- to 4-fold safety margin. It is suggested that antithrombotic properties of aliskiren be explored further in an ex vivo clinical setting.

Dyspnoea after antiplatelet agents: the AZD6140 controversy.

Recent randomised studies suggest that experimental oral reversible platelet P2Y12 receptor inhibitor, AZD6140, causes dyspnoea. This also raises similar concerns about the parent compound, and another adenosine triphosphate (ATP) analogue (AR-69931MX or cangrelor), which is currently in Phase 3 trial in patients undergoing coronary interventions. We analysed package inserts, and available clinical trials safety data for antiplatelet agents with regard to the incidence of dyspnoea. We found that dyspnoea is a very rare complication of the presently approved platelet inhibitors, mostly caused by underlying disease, rather than antiplatelet therapy per se. The main reasons for respiratory distress after oral (AZD6140), and intravenous (cangrelor) agents may be the development of mild asymptomatic thrombotic thrombocytopenic purpura, fluid retention and dyspnoea because of the reversible nature of these drugs. Also, these agents are ATP analogues, which rapidly metabolise to adenosine, a well-known bronchoprovocator causing dyspnoea as well. In summary, dyspnoea is seldom considered, there are no treatment algorithms when it does occur, plausible mechanisms exist and despite these plausible mechanisms, the true cause of dyspnoea in these exposed individuals is unknown. Additional pulmonary function testing, immunological investigations and platelet receptor studies are urgently needed to determine the cause of dyspnoea after AZD6140, and to point out how such serious adverse reactions can be prevented, or at least minimised, raising potential concerns about this drug.

Platelet inhibition beyond conventional antiplatelet agents: expanding role of angiotensin receptor blockers, statins and selective serotonin reuptake inhibitors.

Aspirin, dipyridamole, cilostazol, thienopyridines and glycoprotein IIb/IIIa inhibitors represent the classical examples of the established antiplatelet agents commonly used for the secondary prevention in patients after vascular events. Obviously, the era of expanding antiplatelet regimens and indications may require new agents as the substitutes, or additions to the available strategies. However, recent results of the majority of antiplatelet trials strongly suggest boarder line advantages in clinical outcomes, and higher associated bleeding risks with the novel antiplatelet agents or/and regimens. Moreover, unexpected failures, such as lack of efficacy of clopidogrel and aspirin combination for ischaemic stroke prevention (MATCH), or use of the same antiplatelet regimen for the primary vascular prevention (CHARISMA) raise legitimate concerns that the concept 'the more the better' may not be valid. Broad use of statins, angiotensin receptor blockers and selective serotonin reuptake inhibitors may be in part responsible for the lack of impressive results with the antiplatelet therapy because each of these drug classes per se inhibits platelets. In this review, we discuss the available evidence and potential clinical significance of these findings.

Validation of a VerifyNow-P2Y12 cartridge for monitoring platelet inhibition with clopidogrel.

Despite common use of clopidogrel in patients with vascular disease, monitoring of platelet inhibition is still not conventional in clinical practice. Considering substantial response variability, when some patients may experience inadequate protection, and/or increased risk of bleeding, simple and reliable methods to control adequate antiplatelet regimen is mandatory. We validated a new VerifyNow-P2Y12 assay to measure inhibition of the P2Y12 platelet receptors by clopidogrel by evaluating its receptor specificity, precision, and potential interference with platelet count, hematocrit, age, cholesterol, triglycerides, and other antiplatelet agents. Platelet aggregation induced by ADP or ADP + prostaglandin E1 (ADP + PGE1) in the presence of specific P2Y12 inhibitor 2-methylthio-AMP (2MeSAMP) for the assessment of assay specificity was performed in 10 volunteers. Seventeen medications were used for the VerifyNow-P2Y12 interference testing, and assay interplay with blood constituents was evaluated in a clinical setting in 131 patients with coronary artery disease. In the presence of 2MeSAMP, the average residual aggregation level across the 10 donors was 27% for ADP and 5% for ADP + PGE1. There also was a strong agreement between ADP + PGE1 aggregometry and VerifyNow-P2Y12 assay (93% vs. 95% average inhibition across all donors). The coefficient of variation for the test precision was less than 8%. The VerifyNow-P2Y12 readings were not influenced by age, platelet count, hematocrit, fibrinogen, cholesterol, or triglycerides level. There was an interference with abciximab before P2Y12 inhibition; however, after platelet suppression with cilostazol, the interference with all tested substances was minimal. VerifyNow-P2Y12 is a reliable, simple, and sensitive device suitable for monitoring of P2Y12 platelet receptor inhibitors in the clinical arena.

Rebound platelet activation after termination of prasugrel and aspirin therapy due to confirmed non-compliance in patient enrolled in the JUMBO Trial.

Therapy with aspirin and/or adenosine diphosphate (ADP) receptor blockers is associated with better outcomes via inhibition of platelet activity, and subsequent reduction of ischemic vascular events. Non-compliance (NC) is a well-recognised hazard limiting the clinical utility of antiplatelet agents, and, probably worsening outcomes. However, comprehensive platelet characteristics of a confirmed NC patient after acute vascular event have never been reported within a major randomised trial with ADP-receptor antagonists. A 48-year-old male patient, well-educated, was among patients enrolled in the platelet sub-study for the JUMBO trial. He received 325 mg of aspirin daily for 9 months, presented with unstable angina for urgent coronary intervention, and was successfully reperfused with two intracoronary stents. The patient was randomised to a 60 mg prasugrel loading dose, and 10 mg of prasugrel daily for 30 days. Platelets were assessed at baseline, 4 and 24 h, and at 30 days after acute coronary event utilising ADP-, and collagen-induced conventional aggregometry, rapid cartridge-based analyser and flow cytometry. Loading with prasugrel resulted in significant inhibition of platelet activity during and after stenting. However, after assessing platelet biomarkers at 30 days, voluntary withdrawal from the antiplatelet agents was suspected. Based on the platelet activity characteristics, NC was later confirmed, and the patient admitted that he stopped taking both prasugrel and aspirin shortly after discharge due to minor bleeding episodes after shaving. Major platelet activity biomarkers of the index NC patient were compared with those from compliant prasugrel-, clopidogrel-treated patients, and healthy controls. The platelet tests uniformly revealed rebound activation by all platelet measures (at least twofold increase) while being especially high for ADP-, and collagen-induced aggregation, platelet/endothelial cell adhesion molecule-1 (PECAM-1), glycoprotein (GP)Ib, GPIIb/IIIa activity, P-selectin, protease activated receptor (PAR)-1 thrombin receptor (activated and intact epitopes), and thrombospondin expression. The clinical benefits of antiplatelet agents are not only denied in NC outpatients, but may put them at additional risk for worsened vascular outcomes due to the rebound platelet activation. Proclaimed 'resistance' to antiplatelet agents may at least in part be a result of NC, especially in the chronic uncontrolled setting. Enforcing compliance will improve outcomes in the clinical trials, and save lives of patients really receiving antiplatelet therapy.

Platelet inhibition with prasugrel (CS-747) compared with clopidogrel in patients undergoing coronary stenting: the subset from the JUMBO study.

BACKGROUND: Based on the preclinical and phase 1 studies, prasugrel, a novel platelet ADP P2Y12 receptor blocker, may be a more potent platelet inhibitor than clopidogrel. This study compared the antiplatelet properties of prasugrel in a small subset of patients enrolled in the JUMBO trial, and compared with historic clopidogrel treated controls. METHODS AND RESULTS: Nine patients undergoing coronary stenting were randomised to one of three arms of prasugrel (40 mg loading, and 7.5 mg maintenance, n = 1; 60/10 mg, n = 4; or 60/15 mg, n = 2), or clopidogrel (300/75 mg, n = 2). Aspirin and GP IIb/IIIa inhibitors were permitted. Platelet activity was assessed at baseline, at 4, and 24 hours, and at 30 days after stent implantation in substudy participants, and compared with 124 historic controls who received clopidogrel. Independent of the loading, or maintenance dose, patients treated with prasugrel exhibited significantly more potent platelet inhibition as determined by ADP, and collagen induced aggregation, Ultegra Analyser, and surface expression of PECAM-1, GPIIb/IIIa antigen, and activity with PAC-1 antibody, GPIb, P-selectin, CD40-ligand, GP37, and thrombospondin receptor expression when compared with those treated with clopidogrel. There were no differences between antiplatelet agents with regard to vitronectin, LAMP-1, PAR-1 (intact and cleaved epitopes) thrombin receptor expression, or formation of platelet-monocyte microparticles. Expression of GPIIb antigen, vitronectin, and LAMP-3 receptor were not affected by both agents. Two patients treated with prasugrel 10 mg/daily exhibited complete inhibition of collagen induced aggregation at 30 days. CONCLUSION: At the dosing regimens chosen in the JUMBO trial, it seems that prasugrel is a more potent antiplatelet agent than clopidogrel. Two episodes of profound platelet inhibition, which are not seen with clopidogrel, raise the possibility of higher bleeding risks especially during long term prasugrel use. Whether stronger platelet inhibition will yield better clinical outcomes and/or increased bleeding remains to be determined in an ongoing comparative phase 3 superiority trial (TRITON).

Criticality of pH for accurate fluorometric measurements of dipyridamole levels in biological fluids.

Extended release dipyridamole (DIP) is widely used in clinical practice as an Aggrenox formulation, which is proven to improve outcomes for secondary stroke prevention in patients after acute vascular events. However, presently established fluorometry techniques are not suitable for trace amount determinations, because of the variable background fluorescence. The authors sought to determine whether biological fluid pH is important for the serial measures of DIP levels in the animal experiments and in patients treated with Aggrenox after ischemic stroke. Post-stroke patient (n = 34) and mice (n = 25) samples were tested to determine DIP levels by established techniques with FluoroMax 3 spectrofluorometer. Both the absorption and emission spectra of DIP were affected by modifications in pH. Fluorescence of DIP was found to be maximal at a wavelength of 490 nm (excitation 420 nm) and the spectral pattern was independent of pH. The intensity of fluorescence, however, was drastically lower at low pH (at pH 2.6, fluorescence was 4% of intensity at pH 9.8). Background plasma fluorescence, however, was completely unaffected by changes in pH. Using these fluorometric characteristics, a regression model that facilitates the efficient and sensitive determination of DIP concentration in biological fluids was formulated. Exploiting pH-dependent characteristics of DIP versus serum fluorescence patterns permits a convenient mathematical model to determine DIP concentration. This relatively inexpensive and time-efficient procedure can quantify drug levels in human/animal plasma/serum, thereby directly determining the level of patient adherence to the prescribed drug regimen, be it in the context of clinical trials or compliance with the animal protocol.

Selective serotonin reuptake inhibitors yield additional antiplatelet protection in patients with congestive heart failure treated with antecedent aspirin.

Clinical depression has been identified as an independent risk factor for increased mortality in patients with coronary artery disease. Enhanced platelet activity has been suggested as the mechanism responsible for this adverse association. Selective serotonin reuptake inhibitors (SSRIs) are known to inhibit platelets in patients undergoing coronary stenting. We sought to determine whether concomitant therapy with SSRIs would yield additional anti-platelet benefit in patients with congestive heart failure (CHF) already treated with antecedent aspirin. A total of 88 patients with left ventricular ejection fraction (LVEF) <40% or CHF symptoms in the setting of preserved systolic function and NYHA Class II-IV were analyzed. Of these, 23 patients (26%) were chronic SSRI users (SSRI+), and 65 patients were free from SSRI therapy (SSRI-). All patients received aspirin (325 mg) for at least 1 month prior to platelet studies. Platelets were assessed by aggregometry, flow cytometry and a rapid analyzer. The SSRI+ group exhibited a substantial decrease in platelet activity when compared with SSRI- patients, as manifested by a significant reduction in ADP- (P=0.001), and collagen-induced (P=0.02) aggregation, and the expression of PECAM-1 (P=0.03), GPIb (P=0.03), GP IIb/IIIa antigen (P=0.02) and GP IIb/IIIa activity with PAC-1 antibody (P=0.04) and P-selectin (P=0.02). Therapy with SSRIs also resulted in the reduced formation of platelet-leukocyte microparticles (P=0.01). Epinephrine-induced aggregation in plasma, collagen-induced whole blood aggregation, closure time and expression of vitronectin receptor, CD63, CD107a, CD107b and CD151 did not differ between groups. In patients with CHF already on aspirin, SSRI therapy was associated with further inhibition of platelet function. This observation may help to explain some of the clinical benefits associated with SSRI therapy. Further clinical trials may help to elucidate the potential outcome benefits of SSRIs in other potential thrombotic circumstances.

Whole blood impedance aggregometry for the assessment of platelet function in patients with congestive heart failure (EPCOT Trial).

OBJECTIVE: Data from small studies have shown the presence of platelet abnormalities in patients with congestive heart failure (CHF). We sought to characterize the diagnostic utility of the whole blood aggregometry (WBA) in a random outpatient CHF population. METHODS: Blood samples were obtained for measurement of whole blood aggregation, shear-induced closure time, platelet contractile force, expression of GP IIb/IIIa, and P-selectin in 100 consecutive patients with CHF. RESULTS: Substantial inter-individual variability of platelet characteristics exists in patients with CHF. There were no statistically significant differences when patients were divided by the incidence of vascular events, emergency revascularization needs, survival, or etiology of heart failure. Surprisingly, aspirin use did not affect instrument readings as well. Whole blood aggregometry correlates well with the closure time (r(2)=0.587), and with GP IIb/IIIa expression (r(2)=0.435). Significant but less strong correlation has been observed for the WBA with platelet P-selectin expression (r(2)=0.295), and no correlation was present for the platelet contractile force measures (r(2)=0.030). CONCLUSIONS: Despite the fact that patients with heart failure enrolled in the EPCOT trial exhibited marginal, sometimes oppositely directed changes, in their platelet characteristics, whole blood impedance aggregometry is indeed capable to serve as a valuable diagnostic tool, and may be successfully used as an established screening device in this population. Ability of the whole blood aggregometry to predict clinical outcomes, or for the monitoring of anti-platelet agents in CHF patients, will be evaluated in the ongoing clinical trials.

Paradoxical activation of major platelet receptors in the methadone-maintained patients after single pill of aspirin.

BACKGROUND: Chronic drug abuse is an established cause of acute coronary events and sudden death. The association between use of narcotics and platelet abnormalities is well described. However, it is still not clear, how aspirin affects expression of major platelet receptors in chronic drug users with coronary artery disease, especially those recovering in the methadone clinic maintenance program. We sought to compare how a single pill of non-enteric coated aspirin (325-mg) affects human platelets in patients with coronary artery disease dependent on methadone use. METHODS: Data from 30 subjects were analyzed, eight of them were the chronic drug addicts, and participated in a methadone recovery program. Platelets were assessed twice at baseline (pre-aspirin), and after 3-24 hours (post-aspirin). The expression of platelet receptors was determined by using the following monoclonal antibodies: CD31 (PECAM-1), CD41 (GPIIb), CD42b (GPIb), CD51/CD61 (vitronectin receptor), CD62p (P-selectin), CD63 (LIMP or LAMP-3), CD107a (LAMP-1), CD151 (PETA-3), and PAC-1 for fibrinogen-platelet binding determination (PharMingen, San Diego, CA). Platelet-leukocyte interactions were assessed by using dual antibodies for a pan-platelet marker (CD151), together with CD14, a monocyte/macrophage marker. RESULTS: In a drug free group, digestion of a single tablet of aspirin resulted in a significantly (p<0.05) diminished expression of PECAM-1, GP IIb, fibrinogen binding with PAC-1 antibody, GP Ib, P-selectin, and CD151. In contrast, patients receiving methadone exhibited opposite trends, resultant in a paradoxical activation of major platelet receptors after digestion of aspirin. These differences reached statistical significance (p<0.05) for PECAM-1, GPIIb, and P-selectin expression. CONCLUSION: There are some fundamental differences in the responsiveness to aspirin in chronic methadone users when compared with drug-free patients. Suspecting narcotics abuse may be critical in patients with limited aspirin efficacy, or those who developed an aspirin resistance. Unexpected platelet activation may indeed represent a missing link between use of narcotics and enhanced incidence of vascular death in this high-risk population.

Uniform platelet activation exists before coronary stent implantation despite aspirin therapy.

BACKGROUND: Platelets play an important role in the natural history of coronary artery disease. Enhanced platelet aggregation and receptor expression unquestionably occur after coronary stent implantation; however, the functional characteristics of platelets before stenting have not been fully elucidated. METHODS: Platelets were assessed before intervention by platelet-rich plasma aggregation (PA) with 5 mmol adenosine diphosphate (ADP) and 1 mg/mL collagen; whole blood aggregation (WBA) by 1 mg/mL collagen; shear-induced closure time (CT); contractile force (CF); and expression of 9 surface receptors by flow cytometry in 126 patients undergoing elective coronary artery stent placement. All patients received aspirin for at least 7 days. The data were compared with those from 64 healthy volunteers. RESULTS: Each test revealed sustained platelet activation in patients undergoing coronary stenting compared with control values. These differences were significant for collagen-induced PA (P =.031); CF (P =.0001); expression of glycoprotein (GP) IIb/IIIa (P =.0001); P-selectin (P =.0008); platelet/endothelial cell adhesion molecule (PECAM)-1 (P =.0001); CD107a (P =.0001); CD107b (P =.0004); and CD63 (P =.009). CONCLUSION: Platelets are indeed activated before coronary stenting despite antecedent therapy with aspirin.

Platelet activation as a universal trigger in the pathogenesis of acute coronary events after cocaine abuse.

Numerous reports document the widespread use of cocaine in most parts of the world, which confers an increased risk of vascular morbidity and mortality. The mechanisms responsible for this association are multifactorial, but platelet activation might play a substantial role linking these events. Contradictory data exist regarding the cellular mechanisms of cocaine's effects on thrombocytes. In terms of therapeutic interventions, a possible activation of platelets would conceptually require more aggressive anti-platelet therapy with aspirin, clopidogrel or other compounds, however, no data exist to date to support this approach. Further studies elucidating these issues are warranted. This review summarizes the latest and often confusing data on the interaction between cocaine and platelets in certain in vitro, animal and clinical scenarios.