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Aims Clinical utilization of dual antiplatelet therapy (DAPT) in patients with renal impairment (RI) following percutaneous coronary interventions (PCI) represents an urgent, unmet need choosing optimal agents, duration of treatment, and potential dose/regimen adjustment. The lack of any large randomized trials specifically in RI patients, and the absence of the uniformed clinical data reporting policy, clouds the reality. Moreover, triaging RI patients is problematic due to ongoing kidney deterioration, and the fact that RI patients are prone to both vascular occlusions and bleeding. Methods and results Seven hundred and one Korean patients receiving DAPT with aspirin 100 mg/daily and clopidogrel 75 mg/daily after PCI were prospectively enrolled in the study. Patients were dichotomized into five groups according to RI: estimated glomerular filtration rate (eGFR) >90 mL/min/1.73 m2 (RI1), 60–89 mL/min/1.73 m2 (RI2), 30–59 mL/min/1.73 m2 (RI3)

Background and PurposeVorapaxar, a novel platelet thrombin protease-activated receptor 1 blocker, is currently approved for post-myocardial infarction and peripheral artery disease indications on top of clopidogrel or/and aspirin. We sought to summarize the conflicting stroke data after vorapaxar for justifying a secondary stroke prevention trial.MethodsAnalyses of the stroke data after vorapaxar yielded from thrombin-receptor antagonist vorapaxar in acute coronary syndromes (TRACER) and TRA2P clinical trials, and affiliated Food and Drug Administration (FDA) reviews.ResultsThe stroke data are mixed, with catastrophic 2.5 excess of intracranial bleeding risks (HR = 2.52; 95% CI = 1.46–4.36, p ConclusionsVorapaxar may be superior to currently recommended antiplatelet strategies and should be tested as a monotherapy in a randomized outcome-driven secondary stroke prevention trial.

Background Despite advances in modern anti-platelet strategies, clopidogrel still remains the cornerstone of dual anti-platelet therapy (DAPT) in patients undergoing percutaneous coronary interventions (PCI). There is some inconclusive evidence that response after clopidogrel may be impacted by concomitant medications, potentially affecting clinical outcomes. Sustained released nitrates (SRN) are commonly used together with clopidogrel in post-PCI setting for mild vasodilatation and nitric oxide-induced platelet inhibition. Methods We prospectively enrolled 458 patients (64.5±9.6years old, and 73.4% males) following PCI undergoing DAPT with clopidogrel and aspirin. Platelet reactivity was assessed by the VerifyNow™ P 2 Y12 assay at the maintenance outpatient setting. Results Concomitant SRN (n=266) significantly (p=0.008) enhanced platelet inhibition after DAPT (251.6±80.9PRU) when compared (232.1±73.5PRU) to the SRN-free (n=192) patients. Multivariate logistic regression analysis with the cut-off value of 253 PRU for defining heightened platelet reactivity confirmed independent correlation of more potent platelet inhibition during DAPT and use of SRN (Relative risk=1.675; Odds ratio [1.059–2.648]; p=0.027). In contrast, statins, calcium-channel blockers, beta blockers, angiotensin receptor blockers, ACE-inhibitors, diuretics, and anti-diabetic agents did not significantly impact platelet inhibition following DAPT. Conclusion The synergic ability of SRN to enhance response during DAPT may have important clinical implications with regard to better cardiovascular protection, but extra bleeding risks, requiring further confirmation in a large randomized study.

There are consistent data suggesting that elderly patients benefit from less aggressive antiplatelet strategies following acute coronary syndromes. This observation is likely because advanced age is associated with greater bleeding and potentially less efficacy. Oral antiplatelet agents are often prescibed uniformly, without dose adjustments, representing a concerning reality for this patient population. Vorapaxar, a platelet thrombin PAR-1 inhibitor, has been evaluated in the TRA2P and TRACER trials, but drug efficacy and safety, with respect to age, were not discussed in detail. We sought to define the FDA-confirmed age-dependent clinical outcomes after vorapaxar. The mean and median ages in the TRA2P indicated population were about 60 years, with 33.4% greater than 65 years of age and 9.2% greater than 75 years of age. Vorapaxar efficacy was reduced in those aged 72 or older, while bleeding rates gradually increased with age for both arms. For patients aged 75 or older, efficacy numerically favored vorapaxar, but this interaction was not statistically significant (HR=1.18; 95% CI=0.95-1.46; p=0.132). In TRACER, the point estimates by age quintile for the primary endpoint also favored vorapaxar, except for the lowest age quintile ≤56 probably due to overtreatment. GUSTO moderate/severe bleeding was substantially higher with vorapaxar in both trials for the eldest age quintile (5.1% placebo vs. 7.0% vorapaxar in TRA2P; 8.4% placebo vs. 13% vorapaxar in TRACER). In conclusion, the FDA analyses reassure that vorapaxar efficacy is not reduced in the elderly. However, the bleeding risk after vorapaxar is definitely increased with advancing age.

SummaryThe role of anticoagulants and antiplatelet agents in tumour growth and prognosis is not new, and currently under intense investigation. Some randomised data strongly suggest that this association exists, but it is complex, and not necessarily pointed at the same direction. The potential mechanisms responsible for such harmful association include a direct hazard of novel antithrombotics on cancer, indirect promotion of tumour growth, easier metastatic dissemination due to instability of platelet-tumour cell aggregates, or/and inability to keep cancer cells locally in situ are considered. The latest randomised evidence ultimately rejected the drug-specific cancer risks, clearly indicating the class-effect. In lay terms “cancers follow bleeding”, which seems to be true for antithrombotic agents in general. Significant excess of solid cancers which was similar after prasugrel in TRITON, and with vorapaxar in TRACER trials was confirmed by the FDA reviews. Later, extra cancer deaths reported following clopidogrel and prasugrel in DAPT, and after ticagrelor in PEGASUS are also of concern. However, there are remaining controversies with regard to published cancer risks after ticagrelor (PLATO), or another vorapaxar trial (TRA2P), while full disclosure of separate clopidogrel and prasugrel cancer data in DAPT is still lacking. In short, if we apply moderate antiplatelet strategies for over two years, or aggressive regimens including triple therapy for much less than one year, the solid cancer risks emerge. Currently, more delicate platelet inhibition, and shorter exposure to dual oral antiplatelet agents should prevail.

Background: Adequate anticoagulation represents a major problem for left ventricle assist device (LVAD) utilization in patients awaiting heart transplantation as well as for regeneration of the native heart. The proper management of hemostatic abnormalities during LVAD support may improve survival by reducing the incidence of hemorrhagic and/or thromboembolic complications. Case Report: A 40-year-old man with implanted pulsatile LVAD due to dilated cardiomyopathy received aspirin and warfarin. The patient underwent serial weekly monitoring of hemostatic biomarkers including international normalization ratio, prothrombin time, prothrombin activity, activated partial thromboplastin time, fibrinogen, D-dimer, platelet aggregation induced by adenosine diphosphate and arachidonic acid, platelet count, and mean platelet volume. The external pump was exchanged three times - twice because of a clot formation in the blood chamber of the pump, and once according to the standard protocol. Results: LVAD use was consistently associated with enhanced adenosine diphosphate-induced platelet aggregation independent from the timing of clot formation or external pump exchange. Among coagulation indices, increased D-dimer holds predictive value for clot formation. The fibrinogen level peaked before the first pump exchange and was twice as high than the average values. Gradual improvement in exercise capacity was observed 2 years after implantation, after which the patient underwent a controlled stress test in the stop mode of the LVAD and the device was successfully explanted. Conclusions: Serial assessment of hemostatic biomarkers may benefit and triage LVAD patients. Consistent platelet activation during long-term LVAD may justify the addition of clopidogrel, while high D-dimer and/or elevated fibrinogen may indicate adding heparin to the conventional antithrombotic regimen. Randomized evidence is needed to test such a hypothesis.

Objective: Osteopontin (OPN), a sialoprotein present within atherosclerotic lesions, especially in calcified plaques, is linked to the progression of coronary artery disease and heart failure. We assessed the impact of valve surgery on serum OPN and left ventricular (LV) function in patients with mitral regurgitation (MR). Methods: Thirty-two patients with severe MR scheduled for surgery were included in the study. Echocardiography markers were assessed preoperatively and at 3 months following the surgery and matched with the serum OPN levels. Results: Valve surgery was associated with a reduction of the ejection fraction (EF) from 55.2 ± 6.3 to 48.8 ± 7.1% after surgery, p < 0.001. Following surgery, the OPN level was significantly higher than preoperatively (mean 245, range 36-2,284 ng/ml vs. 76, 6-486 ng/ml, p = 0.007). Preoperative OPN exhibited a slight negative correlation with the EF (r = -0.35, p = 0.04), and a moderate correlation with vena contracta (r = -0.38, p = 0.02). There were no other meaningful correlations between conventional echocardiographic parameters and OPN. Conclusion: Following valve surgery due to severe MR, patients exhibited a decrease in EF and an increase in OPN levels. The assessment of preoperative OPN failed to strongly predict probable LV dysfunction.

Although measurement of troponin is widely used for diagnosing acute myocardial infarction (AMI), its diagnostic potential may be increased by a more complete characterization of its molecular appearance and degradation in the blood. The aim of this study was to define the time course of cardiac troponin I (cTnI) degradation in patients with acute ST-elevation myocardial infarction (STEMI). In the ASSENT-2 substudy, 26 males hospitalized with STEMI were randomized to 2 different thrombolytic drugs within 6 hours after onset of symptoms. Blood samples were obtained just before initiation of thrombolysis and at 30 minutes intervals (7 samples per patient). Western blot analysis was performed using anti-cTnI antibodies and compared with serum concentrations of cTnI. All patients exceeded the cTnI cutoff for AMI during the sampling period; at initiation of therapy, 23 had elevated cTnI values. All patients demonstrated 2 bands on immunoblot: intact cTnI and a single degradation product as early as 90 minutes after onset of symptoms. On subsequent samples, 15 of 26 patients showed multiple degradation products with up to 7 degradation bands. The appearance of fragments was correlated with higher levels of cTnI ( P P =0.058). This study defines for the first time the initial time course of cTnI degradation in STEMI. Intact cTnI and a single degradation product were detectable on immunoblot as early as 90 minutes after onset of symptoms with further degradation after 165 minutes. Infarct size and time to initiation of treatment was the major determinant for degradation.

Oxidation-sensitive signals are important in platelet activation. The novel, phenolic, intracellular and extra-cellular antioxidant AGI-1067 inhibits the expression of a number of proinflammatory genes involved in atherosclerosis. The effect of AGI-1067 on human platelets was evaluated. Blood obtained from 20 aspirin-naïve volunteers with multiple risk factors for vascular disease was preincubated with escalating concentrations of AGI-1067 for the assessment of its ex vivo effects on platelet aggregation and expression of major surface receptors flow cytometry, evaluated by flow cytometry. AGI-1067 resulted in significant inhibition of a variety of activation-dependent platelet biomarkers in healthy volunteers, including adenosine diphosphate-induced platelet aggregation and decreased surface platelet expression of glycoprotein IIb/IIIa antigen, activity with PAC-1 antibody, and glycoprotein Ib (CD42b). The effect of AGI-1067 differs from other known antiplatelet agents, suggesting opportunities for therapeutic combination. These data need to be confirmed in subjects receiving orally dosed AGI-1067 to be clinically relevant.

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.

We investigated whether, in primary prevention patients with metabolic syndrome, statins affect the platelet protease-activated receptor-1 (PAR-1) thrombin receptor by performing serial measurements of its activity and the antigen expression level by flow cytometry before and during treatment. Recent data from randomized trials of statins are compatible with the possibility of clinically relevant pleiotropic effects. The use of statins is associated with a reduced thrombosis burden and diminished platelet activity, as shown in animal models and in vitro studies. Seventy patients with the metabolic syndrome who were not taking antiplatelet agents were assigned consecutively at starting doses at the discretion of the responsible clinician to 1 of 6 statins (atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, or simvastatin) or to a no-statin group for 6 weeks. Platelet expression of intact (SPAN12 antibody) and cleaved (WEDE15) PAR-1 thrombin receptors were assessed by flow cytometry at baseline and at weeks 4 and 6 of treatment. At baseline, no difference was found in receptor expression. However, after 4 weeks of treatment, all statins had significantly inhibited (46% to 55%) the activated epitope of PAR-1 expression. After 6 weeks, inhibition remained, despite a slight rebound (22% to 37%). Also, a delayed pattern of inhibition of the intact PAR-1 receptor epitope was found. In conclusion, all statins inhibited the activity and antigen level of the platelet PAR-1 thrombin receptor, which has a major role in regulating platelet activity and thrombin formation. These observational data offer a plausible mechanism for the recently demonstrated pleiotropic effects of statins that may contribute to early clinical benefit.

Aggrenox (Boehringer Ingelheim, Ingelheim, Germany), a novel combination of low-dose aspirin with dipyridamole, represents a safe and promising combination alternative for mild but sustained platelet inhibition, and reduction of both arterial and venous thrombi occurrences. In a large, well-controlled randomized trial (ESPS-2 ) evaluating antiplatelet agents for stroke prevention, Aggrenox was twice as effective as monotherapy with either aspirin or dipyridamole. There is an increasing body of evidence that a delicate strategy with Aggrenox provides modest inhibition of platelet activity, especially in a chronic, long-term setting. Mild platelet inhibition beyond conventional aggregation may represent a substantial advantage over aggressive antiplatelet regimens for the treatment, and especially for secondary prevention, of cerebrovascular ischemic events. Although there is no doubt that the concept of inhibiting platelets is vital for the treatment of vascular ischemic disease in general and ischemic stroke and transient ischemic attack (TIA) in particular, the optimal degree of such inhibition still remains an unsolved mystery. It seems that the concepts of "the more, the better" and "one size fits all" may no longer be valid for ideal antiplatelet protection in such high-risk populations. Without routine individual laboratory assessment of platelet function, mild regimens have the advantage of being more suitable for the majority of patients and will contribute substantially to the success of dipyridamole. Conversely, if we can determine baseline platelet status and intelligently apply therapy based on platelet activity in each particular patient, clinical outcomes may be better. Avoiding excessive bleeding risks after aggressive strategies in patients with normal or already decreased platelet function, but targeting those who exhibit activated platelets, may improve risk stratification and save lives. Therefore, Aggrenox should be considered a drug of choice to prevent the second stroke. Eliminating, or at least minimizing, the most frequent side effect, namely transitory headaches at the beginning of therapy with Aggrenox, will benefit patients and increase the use of this agent. Should the PRoFESS (Prevention Regimen For Effectively avoiding Second Strokes) trial show an advantage in event reduction with Aggrenox over clopidogrel, the increase will be especially dramatic. In short, based on current evidence most guidelines include Aggrenox as a first-line option for secondary prevention of ischemic stroke or TIA, and some recent versions suggest it may be preferable in other clinical scenarios.

Clinical depression has been identified as an independent risk factor for increased mortality during follow-up in patients suffered from acute coronary events, whereas increased platelet activity has been proposed as one of the mechanisms for this association. Some evidence suggests that selective serotonin reuptake inhibitors and/or their metabolites exhibit potent antiplatelet properties.We assessed the in vitro effects of preincubation with escalating (50-200 nmol/L) concentrations of escitalopram (ESC) S-desmethyl-citalopram (S-DCT), and S-di-desmethyl-citalopram, (S-DCT) on platelet aggregation through the expression of major surface receptors using flow cytometry and quantitatively using platelet function analyzers in 20 healthy volunteers.Pretreatment of blood samples with ESC with ESC resulted in a significant inhibition of platelet aggregation induced by ADP (P = 0.0001) and by collagen with the highest dose (P = 0.001). Surface platelet expressions of glycoprotein Ib (CD42) (P = 0.04), lysosome associated membrane protein-3 (CD63) (P = 0.02), and GP37 (CD165) (P = 0.03) was decreased in the ESC-pretreated samples. Closure time by the Platelet Function Analyzer-100 analyzer was prolonged for the 200 nmol/L dose (P = 0.02), indicating platelet inhibition under high shear conditions. Two major metabolites of ESC, namely S-DCT and S-DDCT, did not affect platelet activity.Escitalopram, but not its metabolites, exhibited selective inhibition of human platelet properties. The direct antiplatelet effect of ESC requires further prospective or ex vivo testing to determine the possible clinical advantage of this finding.

Depression is associated with an increased incidence of vascular events and develops after stroke and myocardial infarction. Beside potential clinical outcome benefits of selective serotonin reuptake inhibitors for vascular diseases, bleeding events were reported. We investigated whether paroxetine and aspirin synergistically inhibit platelet function. Paroxetine (20 mg/d) was administered over 18 days to 20 men in a randomized, placebo-controlled, crossover design. Aspirin (100 mg/d) was coadministered within the last 4 study days. Platelet function was assessed by the platelet function analyzer and by flow cytometry. Paroxetine prolonged epinephrine-dependent predictive index within 14 days (P.02). Aspirin enhanced the predictive index (P.004 vs baseline and P.05 between periods). A trend toward decreased thrombin receptor-activating peptide-induced CD62P expression after paroxetine was further enhanced by aspirin treatment (P.05 between periods). The combination of paroxetine and aspirin did not further inhibit platelet plug formation under high shear stress in male smokers.

Background: Although controversial, the phenomenon of aspirin resistance (AR) has been correlated in some small studies with poor clinical outcomes in patients with coronary artery disease. Even less is known regarding the role of AR in the poststroke population. The reason for and the underlying mechanism of AR is unknown. We hypothesized that excessive formation of thrombin on the platelet surface may contribute to this phenomenon and assessed how dipyridamole affects multiple platelet and thrombin generation biomarkers in AR patients after ischemic stroke. Methods: Whole blood samples from 20 poststroke AR patients were pretreated with dipyridamole, simulating the therapeutic range, and then incubated for 45 min at 37°C. Platelet characteristics were assessed by aggregometry, cartridge-based analyzer, and receptor expression by flow cytometry. Markers of thrombin generation were measured in the autologous plasma by ELISA. Results: Pretreatment of blood with dipyridamole resulted in 22–26% diminished expression of intact PAR-1 receptor (p = 0.021 and p = 0.024) and 28–31% decrease of annexin V binding (p = 0.031 and p = 0.02) after incubation with 2 µg/ml and 4 µg/ml of dipyridamole, respectively. Platelet aggregation and thrombin generation markers were not affected in vitro by dipyridamole. Conclusions: Dipyridamole may be capable of overcoming increased prothrombinase complex formation and be in part able to compensate for AR in patients with moderate carotid stenosis. This phenomenon may explain the clinical advantages of Aggrenox®, known to reduce ischemic events in poststroke patients as proven in clinical trials, though an additional antithrombotic benefit beyond the platelet inhibition by aspirin alone.

Background and Purpose— Clopidogrel is widely used in patients after recent ischemic stroke; however, its ability to yield additional antiplatelet protection on top of aspirin has never been explored in a controlled study. To determine whether clopidogrel with aspirin (C+ASA) will produce more potent platelet inhibition than aspirin alone (ASA) in patients after ischemic stroke, we conducted the Plavix Use for Treatment of Stroke trial. Methods— Seventy patients after ischemic stroke were randomly assigned to C+ASA or ASA groups. Platelet studies included aggregometry; cartridge-based analyzers; expression of PECAM-1, P-selectin, GP IIb/IIIa (antigen and activity), vitronectin receptor, and formation of platelet-leukocyte microparticles by flow cytometry. Platelet tests were performed at baseline and after 30 days after randomization. Results— There were no deaths, hospitalizations, or serious adverse events. There were no differences in the baseline platelet characteristics between C+ASA and ASA groups, or significant changes in platelet parameters in the ASA group, except diminished collagen-induced aggregation ( P =0.001). In contrast, therapy with C+ASA resulted in a significant inhibition of platelet activity assessed by ADP- ( P =0.00001) and collagen-induced ( P =0.02) aggregation; closure time prolongation ( P =0.03), and reduction of platelet activation units with Ultegra ( P =0.00001); expression of PECAM-1 ( P =0.01), and GP IIb/IIIa activity with PAC-1 ( P =0.02) when compared with ASA group. Therapy with C+ASA also resulted in the reduced formation of platelet–leukocyte microparticles ( P =0.02). Conclusion— Treatment with C+ASA for 1 month provides significantly greater inhibition of platelet activity than ASA alone in patients after recent ischemic stroke in the frame of the small randomized trial.

Context: Much emphasis has been placed on a ticagrelor-aspirin (ASA) interaction in the Platelet Inhibition and Patient Outcomes (PLATO) trial, despite this particular interaction being inconclusive. However, a potential ticagrelor-statin interplay occurred and may be important in PLATO, especially considering the remarkable and yet unexplained mortality advantage. Objective: To explore the ticagrelor-statin interaction in the PLATO trial. Results: The background statin use in hospital or at discharge was similar between ticagrelor (89.7%) and clopidogrel (89.2%) PLATO arms, respectively. In patients on statins, ticagrelor significantly decreased all-cause mortality (30 day and through study end), vascular mortality (30 day and through study end) and exhibited a trend in benefit for 30-day major adverse cardiovascular events (MACE) compared to clopidogrel: hazard ratio, HR = 0.55, 95% confidence interval, CI = 0.36–0.84 (p = 0.005), and HR = 0.69, 95% CI = 0.52–0.92 (p = 0.012); HR = 0.70, 95% CI = 0.51–0.96 (p = 0.030), and HR = 0.68, 95% CI = 0.49–0.94 (p = 0.020), and HR = 0.75, 95% CI = 0.55–1.01 (p = 0.057), respectively. These results may be attributed to the fact that ticagrelor, in contrast to clopidogrel, significantly increases the potency of CYP3A4-metabolized statins, which in turn may increase the vascular benefit derived from the statin, giving an unfair advantage to ticagrelor. Moreover, inappropriate statin dosing restrictions (underdosing of simvastatin and lovastatin) were deliberately utilized in PLATO, potentially contributing to the beneficial effect of ticagrelor. Conclusions: In patients on statins, both vascular and all-cause mortality rates were significantly reduced with ticagrelor in the PLATO trial. However, this benefit may in part be driven by an increased efficacy of CYP3A4-metabolized statins on top of ticagrelor and/or from the inappropriate dose restriction of simvastatin and lovastatin in the clopidogrel arm.

The European Stroke Prevention Study showed greater stroke prevention for Aggrenox than either for aspirin or dipyridamole alone. To test whether Aggrenox has superior antiplatelet properties to aspirin alone we conducted the AGgrenox versus Aspirin Therapy Evaluation (AGATE) trial. Forty patients with prior ischemic stroke not taking aspirin for at least 30 days were randomized to Aggrenox (2 pills/daily) or aspirin (81 mg plus matching placebo/daily) for 30 days. Platelet function was assessed at baseline, 24 h, and days 3, 7, 15, and 30 by aggregometry, flow cytometry and cartridge-based analyzers. Both Aggrenox and aspirin provided fast and sustained platelet inhibition. Aggrenox(R), however, especially after 15 days, showed significant prolongation of the closure time (P=0.04), diminished expression of platelet/endothelial cell adhesion molecule-1 (PECAM-1) (P=0.01), glycoprotein IIb (GPIIb) antigen (P=0.02), and GPIIb/IIIa activity (P=0.01) by PAC-1 C antibody, CD63 (P=0.03), as well as inhibition of Protease Activated Receptors (PAR-1) associated with intact (SPAN12, P=0.01) and cleaved (WEDE15, P=0.01) thrombin receptors as compared with aspirin. Surprisingly, GPIb expression increased, especially after aspirin. In the randomized trial of small sample size, aspirin and Aggrenox produced fast and sustained platelet inhibition. In 25 of 90 direct comparisons, Aggrenox was superior to aspirin, whereas in 4 of 90, aspirin was superior to Aggrenox. In 61 of 90 direct comparisons, aspirin and Aggrenox were equivalent. Aggrenox was associated with a profound reduction of PAR-1 receptors, an observation that may be related to the greater clinical benefit of Aggrenox compared with Aspirin in preventing recurrent stroke.

Aspirin, compared with placebo, reduces the risk of cardiovascular events by 25% in populations of patients with and without known arterial vascular disease. However, the phenomena of 'aspirin resistance' that has been described in 5'--50% of this population may critically reduce aspirin's efficacy. One study has suggested that aspirin-resistant patients have a 3.5 times higher risk of cardiovascular death. Presently, there are no established, simple, broadly used methods determining antiplatelet properties of aspirin, while conventional aggregometry requires special equipment and trained personnel. We sought to determine the validity of an Ultegra analyzer with the novel aspirin-sensitive cartridge before and after one pill of non-enteric coated aspirin (325 mg) in subjects with multiple risk factors for coronary artery disease. One hundred and fifty-four volunteers were enrolled into the multicenter study, but six of them were excluded. Data from 148 participants were analyzed. Platelets were assessed twice at baseline (pre-aspirin), and after 2-30 h (post-aspirin). We employed 5 micromol/l epinephrine-induced conventional aggregometry, and aspirin response units stimulated by propyl gallate with the point-of-care Ultegra analyzer. A single pill of aspirin reduced platelet-rich plasma aggregation from 72 +/- 21% to 25 +/- 10%, and diminished aspirin reduction units from 647 +/- 95 to 436 +/- 69. The overall agreement between the two methods was 87% with 85% sensitivity for Ultegra and 88% for platelet aggregation, respectively. The correlation between the two methods was 0.902. Timely determination of aspirin resistance represents an indispensable application in current medicine. The Ultegra RPFA-ASA analyzer is a novel, fast method that could be used in clinical practice for monitoring efficacy of aspirin, and for triaging the aspirin-resistant population. The clinical implications of these data need to be proven in randomized trials.

Valsartan selectively blocks angiotensin II binding to the AT1 receptor. ince platelet activation plays a key role in the pathogenesis of vascular disease, and because AT1 receptors are present on the platelet surface, we assessed the in vitro effects of valsartan and its metabolite, valeryl 4-hydroxy valsartan (V4HV), on platelets in 30 subjects with multiple risk factors for cardiovascular disease. Platelet characteristics in blood samples pretreated and incubated with 10 nmol to 100 micromol concentrations of valsartan and V4HV were assessed by aggregometry, rapid platelet analyzers, and by flow cytometry. Pretreatment of blood with valsartan and V4HV resulted in inhibition of conventional plasma (ADP, P = 0.0001, valsartan; epinephrine, P = 0.0001, V4HV) and whole blood collagen-induced (P = 0.01, valsartan; P =.0001, V4HV) platelet aggregation. Closure time was delayed (P = 0.02, valsartan; P = 0.03, 4VHV), indicating platelet inhibition in whole blood under high shear conditions. Expression of many surface platelet receptors, namely GP IIb/IIIa antigen, and activity, vitronectin, p-selectin, and LAMP-1 was significantly reduced compared with autologous baseline activity. Intensity of platelet-leukocyte formation and other platelet activation markers remained unchanged. Platelet inhibition was not dose dependent and was more potent for 4VHV than valsartan in the therapeutic range.Valsartan and 4VHV exhibited significant in vitro inhibition of human platelets. Their antiplatelet properties, especially more potent activity of the metabolite appear to be independent of those of other antiplatelet agents. Whether valsartan reduces vascular ischemic events via additional pathways of platelet inhibition in patients with myocardial infarction and ischemic stroke requires further clinical research.

Introduction : Platelets play an important role in the natural history of ischemic stroke, and are known to be activated in the acute phase. Although aspirin reduces risks of myocardial infarction, stroke and cardiovascular death, the extent of platelet action and the effect of aspirin on platelet function in patients recovering from stroke remain unclear. Methods : We studied 120 individuals divided into three equal groups: aspirin-free patients after ischemic stroke, post-stroke patients receiving aspirin (81–650 mg/daily), and aspirin-free subjects with multiple risk factors for vascular disease. Conventional platelet aggregation induced by 5 μM ADP and 5 μM epinephrine, cartridge-based analyzers (Ultegra®, and PFA-100™) readings, and expression of CD31, CD41a, CD42b, GPIIb/IIIa activity, CD51/CD61, CD62p, CD63, CD107a, CD154, CD165, formation of platelet–monocyte aggregates, intact (SPAN12), and cleaved (WEDE15) PAR-1 thrombin receptors by flow cytometry were analyzed. Results : There were no differences between aspirin-free post-stroke patients and aspirin-free controls. Although aggregation was slightly higher, 12 out of the 14 receptor analyses, were surprisingly lower in the post-stroke cohort. Aspirin-treated patients exhibited highly significant inhibition of epinephrine-induced aggregation ( p =0.0001), prolongation of the closure time ( p =0.03), and reduction of the aspirin reactive units ( p =0.02) measured by the Ultegra® device. In addition, surface platelet expression of thrombospondin ( p =0.001), GPIIb/IIIa activity ( p =0.04), P-selectin ( p =0.03), CD40-ligand ( p =0.04), CD165 ( p =0.02), the formation of the platelet–monocyte aggregates ( p =0.01), and intact epitope of PAR-1 thrombin receptor ( p =0.03) were significantly lower in the aspirin-treated group. Conclusions : Platelets are not activated in aspirin-free patients after ischemic stroke. Platelet function is significantly inhibited in those treated with aspirin when compared with healthy subjects with risk factors for vascular disease. Bleeding complications and hemorrhagic transformations after aggressive antiplatelet regimens could be related to the decreased or normal baseline platelet characteristics in such patients. Further analysis of platelet heterogeneity and its clinical significance remains to be determined in randomized trials.

Persistent platelet activation may contribute to thrombotic events in patients with congestive heart failure (CHF). Chronic use of mild platelet inhibitors could therefore represent an independent avenue to improve morbidity, mortality, and quality of life in this expanding population. Although clopidogrel is widely used in patients with acute coronary syndromes and ischemic stroke, the ability of this novel ADP-receptor antagonist to inhibit platelet function in patients with CHF is unknown. We assessed antiplatelet properties of clopidogrel with aspirin (C+A) versus aspirin alone (A) in patients with CHF with heightened platelet activity.Patients with left ventricular ejection fraction40%, or CHF symptoms in the setting of preserved systolic function and New York Heart Association class II-IV were screened. Patients were considered to have platelet activation when 4 of the following 5 parameters were met: ADP-induced platelet aggregation60%; collagen-induced aggregation70%; whole blood aggregation18 ohms; expression of GP IIb/IIIa220 log MFI; and P-selectin cell positivity8%. All patients were treated with 325 mg of acetylsalycilic acid (ASA) for at least 1 month. Patients receiving an antithrombotic agent other than ASA were excluded. Patients meeting clinical and laboratory criteria were randomly assigned to C+A (n=25), A (n=25) groups, or represent screen failures (n=38). Platelet studies (conventional and whole blood aggregometry, shear-induced activation, expression of 10 major receptors and formation of platelet-leukocyte microparticles) were performed at baseline and after 30 days of therapy.There were no deaths, hospitalizations, or serious adverse events. There were no changes in platelet parameters in the A group. In contrast, therapy with C+A resulted in a significant inhibition of platelet activity assessed by ADP-induced (P =.00001), and epinephrine-induced (P =.0016) aggregation, closure time (P =.04), expression of PECAM-1 (P =.009), GP Ib (P =.006), GP IIb/IIIa antigen (P =.0001), GP IIb/IIIa activity with PAC-1 (P =.0021), and CD151 (P =.0026) when compared with the A group. Therapy with C+A also resulted in the reduced formation of platelet-leukocyte microparticles (P =.021). Collagen-induced aggregation in plasma and in whole blood, expression of vitronectin receptor, P-selectin, CD63, CD107a, and CD107b did not differ among groups.Treatment with C+A for 1 month provides significantly greater inhibition of platelet activity than ASA alone in patients with CHF. Patients with CHF with heightened platelet activity represent a potential target population in which addition of clopidogrel may decrease mortality rates by reducing the incidence of thrombotic vascular events.

Platelets play a key role in the progression of acute coronary syndromes (ACS). Clinical depression alone is also associated with enhanced platelet activation. The purpose of this study was to compare concentrations of established biomarkers of enhanced platelet/endothelial activation in clinically depressed versus non-depressed patients enrolled in recent clinical trials for ACS. Two hundred and eighty-one baseline plasma samples from patients with acute myocardial infarction (ASSENT-2; n = 41), with ACS (PRONTO; n = 126) and with clinical depression plus previous acute coronary syndrome within 6 months (SADHART; n = 64), and from normal healthy controls (n = 50) were analyzed. Blood was drawn before applying any therapeutic strategies including interventions, thrombolytics, infusions, and selective serotonin re-uptake inhibitors. Platelet factor 4, beta-thromboglobulin, platelet/endothelial cell adhesion molecule-1, P-selectin, thromboxane, prostacyclin, vascular cell adhesion molecule-1, and E-selectin were measured by enzyme-linked immunosorbent assay by a single core laboratory. Patients with ACS exhibited a higher degree of platelet activation than controls independently of the presence of depression. Plasma levels of P-selectin, thromboxane, prostacyclin, and vascular cell adhesion molecule-1 were the highest in the acute myocardial infarction group when compared with ACS despite the presence or absence of clinical depression. Surprisingly, patients with ACS and depression exhibited the highest levels of platelet factor 4, beta-thromboglobulin, and platelet/endothelial cell adhesion molecule-1 when compared with myocardial infarction or angina patients without clinical depression. E-selectin plasma level was constantly elevated compared with controls but did not differ among the groups dependent on the incidence of depression. The depressed plus ACS group had higher plasma levels of all biomarkers compared with the non-depressed patients. Retrospective analysis of the data from several clinical trials reveals that clinical depression is associated with enhanced activation of platelet/endothelial biomarkers even above the level expected in ACS. These findings may contribute to the unfavorable outcome associated with clinical depression in patients with ACS.

Background— Depression after acute coronary syndromes (ACSs) has been identified as an independent risk factor for subsequent cardiac death. Enhanced platelet activation has been hypothesized to represent 1 of the mechanisms underlying this association. Selective serotonin reuptake inhibitors (SSRIs) are known to inhibit platelet activity. Whether treatment of depressed post-ACS patients with SSRIs alters platelet function was not known. Accordingly, we serially assessed the release of established platelet/endothelial biomarkers in patients treated with sertraline vs placebo in the Sertraline AntiDepressant Heart Attack Randomized Trial (SADHART). Methods and Results— Plasma samples (baseline, week 6, and week 16) were collected from patients randomized to sertraline (n=28) or placebo (n=36). Anticoagulants, aspirin, and ADP-receptor inhibitors were permitted in this study. Platelet factor 4, β-thromboglobulin (βTG), platelet/endothelial cell adhesion molecule-1, P-selectin, thromboxane B 2 , 6-ketoprostaglandin F 1a , vascular cell adhesion molecule-1, and E-selectin were measured by ELISA. Treatment with sertraline was associated with substantially less release of platelet/endothelial biomarkers than was treatment with placebo. These differences attained statistical significance for βTG ( P =0.03) at weeks 6 and 16 and for P-selectin ( P =0.04) at week 16. Repeated-measures ANOVA revealed a significant advantage for sertraline vs placebo for diminishing E-selectin and βTG concentrations across the entire treatment period. Conclusions— Treatment with sertraline in depressed post-ACS patients is associated with reductions in platelet/endothelial activation despite coadministration of widespread antiplatelet regimens including aspirin and clopidogrel. The antiplatelet and endothelium-protective properties of SSRIs might represent an attractive additional advantage in patients with depression and comorbid coronary artery and/or cerebrovascular disease.

Background— Statins primarily metabolized by cytochrome P450 3A4 (CYP3A4) reportedly reduce clopidogrel’s metabolism to active metabolite, thus attenuating its inhibition of platelet aggregation ex vivo. However, the clinical impact of this interaction has not been evaluated. Methods and Results— Clopidogrel for the Reduction of Events During Observation (CREDO) was a double-blind, placebo-controlled, randomized trial comparing pretreatment (300 mg) and 1-year (75 mg/d) clopidogrel therapy (clopidogrel) with no pretreatment and 1-month clopidogrel therapy (75 mg/d) (control) after a planned percutaneous coronary intervention. All patients received aspirin. The 1-year primary end point was a composite of death, myocardial infarction, and stroke. We performed a post hoc analysis to evaluate the clinical efficacy of concomitant clopidogrel and statin administration, categorizing baseline statin use to those predominantly CYP3A4-metabolized (atorvastatin, lovastatin, simvastatin, and cerivastatin) (CYP3A4-MET) or others (pravastatin and fluvastatin) (non-CYP3A4-MET). Of the 2116 patients enrolled, 1001 received a CYP3A4-MET and 158 a non-CYP3A4-MET statin. For the overall study population, the primary end point was significantly reduced in the clopidogrel group (8.5% versus 11.5%, RRR 26.9%; P =0.025). This clopidogrel benefit was similar with statin use, irrespective of treatment with a CYP3A4-MET (7.6% clopidogrel, 11.8% control, RRR 36.4%, 95% CI 3.9 to 57.9; P =0.03) or non-CYP3A4-MET statin (5.4% clopidogrel, 13.6% control, RRR 60.6%, 95% CI −23.9 to 87.4; P =0.11). Patients given atorvastatin or pravastatin had similar 1-year event rates. Additionally, concomitant therapy with statins had no impact on major or minor bleeding rates. Conclusions— Although ex vivo testing has suggested a potential negative interaction when coadministering a CYP3A4-metabolized statin with clopidogrel, this was not clinically observed statistically in a post hoc analysis of a placebo-controlled study.

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)

Despite the common practice of clopidogrel loading for coronary stenting, the time dependence and degree of platelet inhibition after this therapy are not well defined. We sought to establish an optimal clopidogrel dosing regimen for sustained platelet inhibition in stented patients.Platelets were assessed by conventional aggregation with 5 micromol/L adenosine diphosphate (ADP), 1 microg/mL collagen (COLL), and 750 micromol/L arachidonic acid; whole blood aggregation by 1 microg/mL collagen (WBA); shear-induced closure time (CT); contractile force (CF); and expression of 9 surface receptors by flow cytometry in 100 patients undergoing elective stent placement without glycoprotein (GP) IIb/IIIa receptor antagonists. Blood was obtained at baseline and serially over 5 days poststenting after different clopidogrel loading regimens: 300 mg 24 hours before (Group A), 12 hours before (Group B), 3 to 6 hours before (Group C), and 75 mg at the time of intervention (Group D). Before stenting, ADP, COLL, CT, and WBA were reduced by clopidogrel loading (P.05). CF was not affected by clopidogrel. Before stenting, GP IIb/IIIa expression increased in groups A through C (P.05), whereas PECAM-1 and CD107a were reduced (P.05). At 2 hours and 2 days poststenting, platelets, in general, exhibited an increase in activity that was most inhibited by clopidogrel loading. Clopidogrel inhibited GP Ib, platelet/endothelial cell adhesion molecule-1, CD 107a, CD 151, and GP IIb/IIIa expression at day 5 poststenting.A 300 mg clopidogrel load given 3 to 24 hours before stenting inhibits platelets at the time of the procedure and reduces poststent activity more than a 75 mg dose given at the time of the procedure. The inhibition of adhesive molecule expression may also contribute an antithrombotic effect. Poststent activation of platelets may warrant higher periprocedural dosing.

Antiplatelet therapy has been the focus of extensive clinical investigations over the last two decades. A variety of agents and regimens have been advanced for the prevention and treatment of vascular disease. Despite the proven life-saving clinical benefits of inhibiting platelets, this therapy is associated with an increased risk of bleeding. The objective of this study was to determine the risk of hemorrhage in the major classes of antiplatelet agents. Data from clinical trials published 1988-2002 in English were retrieved from MEDLINE, OVID, and CARDIOSOURCE. Only those studies in which patients had clinical follow-up for at least 1 month and in which a full description of hemorrhagic complications was reported were included. Information on sample size, study design, duration, agent, patient characteristics, and bleeding severity was independently and blindly reviewed. Data from 51 clinical trials with a total of 338,191 patients were analyzed. The antiplatelet agents were divided into 6 groups: aspirin (ASA)100 mg; ASAor = 100 mg; dipyridamole, thienopyridines; intravenous and oral GP IIb/IIIa inhibitors. The variance estimate and confidence intervals were calculated for each treatment assignment. Low-dose aspirin and dipyridamole therapy were associated with the lowest risk of bleeding (3.6% and 6.7%, respectively). The highest rate of bleeding complications (44.6%) was associated with the GP IIa/IIIb inhibitors. Despite substantial differences in the reporting patterns of bleeding complications, low-dose ASA and dipyridamole therapy were associated with the lowest risk. Surprisingly, doses of ASA/= 100 mg caused a relatively high hemorrhagic event rate, which was comparable to that of ADP-receptor blockers. These findings should be considered when using combination antiplatelet and/or anticoagulant therapy with conventional doses of ASA.

SummaryCentral adjudication in randomised controlled outcome-driven trials represents a traditional approach to maintain data integrity by applying uniformed rules for assessment of clinical events. It was the purpose of this investigation to determine the patterns of myocardial infarction (MI) adjudication in the TRITON, RECORD, and PLATO trials. We were matching centrally-adjudicated MI’s (CAMI’s) from the official trial publication with the site-reported MI (SRMI’s) count from the Food and Drug Administration’s secondary analyses for the investigational compounds prasugrel (TRITON), rosiglitazone (RECORD), and ticagrelor (PLATO). CAMI numbers showed a remarkable discrepancy to SRMI’s by more than a doubling of the difference: from 72 to 145 events in TRITON favoring prasugrel (from a hazard ratio [HR]=0.76, p=0.08; to a HR=0.76, p

Platelet inhibition after moderate alcohol consumption in patients with ischaemic heart disease may contribute to reducing the risk for developing acute coronary syndromes. However, the mechanism by which ethanol affects platelets is not clarified. We sought to determine the in vitro effects of alcohol on the surface expression of human platelet receptors using whole blood flow cytometry. Blood samples from 10 healthy volunteers were incubated for 30 min with 25 and 50 mmol l(-1) of phosphate buffered saline diluted grain ethanol, concentrations often used in in vitro studies. The surface expression of platelet receptors was determined by flow cytometry after fixation with 2% paraformaldehyde using the following monoclonal antibodies: CD 41 (GP IIb/IIIa), CD 42b (GP Ib), CD 62p (P-selectin), CD 51/CD 61 (vitronectin receptor), CD 31 (PECAM-1), CD 107a (LAMP-1), CD 107b (LAMP-2), CD 63 (LIMP, LAMP-3) and CD 151 (PETA-3). Dose-dependent inhibition of GP IIb/IIIa, P-selectin, CD 63 and CD 107a receptor expression was observed in the ethanol-treated whole blood samples. This study for the first time establishes a direct effect of ethanol on selective major platelet receptors. Beneficial cardiovascular properties of moderate alcohol consumption may be explained by ethanol's antiplatelet action.

Aspirin has become an established therapy in patients for preventing recurrent stroke and the incidence of acute coronary events. Aggrenox®, a novel combination of low-dose aspirin with dipyridamole, represents a safe and promising combination alternative for mild but sustained platelet inhibition and the reduction of occurrences of both arterial and venous thrombi. In a recent, large, well-controlled trial (European Stroke Prevention Study 2; ESPS-2) evaluating antiplatelet agents for stroke prevention, Aggrenox was twice as effective as either aspirin or dipyridamole. Results of experimental studies show that dipyridamole combined with aspirin at ratios of about 10:1 or higher effectively inhibit thrombus formation, whereas a ratio of 1:1 has little effect. Indeed, one of the reasons that the ESPS-2 trial appears so convincing was the fact that a high dose of extended-release dipyridamole was combined with low-dose aspirin at a dose ratio of 8:1. Combination therapy with Aggrenox inhibits platelet aggregation much more strongly than aspirin or dipyridamole alone, and it may gain an additional clinical benefit due to synergic targeting of leukocytes, through an increase in endothelial nitric oxide production. Based on in vitro data showing that platelet adhesivity and aggregation induced by adenosine diphosphate (ADP), adrenaline and collagen is diminished, as well as through measurements of malondialdehyde production (marker of free radical production), it is known that dipyridamole and aspirin indeed exhibit a potentiated synergism as platelet inhibitors. On the other hand, clopidogrel, a novel thienopyridine and a potent ADP receptor blocker, has also been proven to yield a clinical benefit in unstable angina patients and during coronary interventions. Considering recent trends to combine clopidogrel with aspirin, it remains to be seen which combination will better serve various clinical scenarios in the near future. Further well-designed and carefully conducted clinical trials should elucidate possible benefits of Aggrenox during coronary interventions, especially in conjunction with new and aggressive reperfusion techniques. The benefits of Aggrenox in an expanding array of clinical conditions, including ischemic stroke, may be directly related to platelet inhibition. Moreover, marginal clinical benefits and recently reported severe bleeding events in some patients after oral platelet glycoprotein IIb/IIIa therapy may advance Aggrenox as a safe and efficient alternative for patients with vascular disease. This review summarizes the latest and often confusing data on the effects of aspirin, dipyridamole and Aggrenox on platelets and attempts to relate these data to bleeding complications and clinical outcomes.

Background: Receptors other than GP IIb/IIIa may mediate leukocyte-platelet-endothelial interactions that obstruct the microvasculature in acute coronary syndromes (ACS) and cause microinfarcts. The effect of eptifibatide on these receptors was investigated in a substudy of the EARLY Trial. Methods: Patients received early (in the Emergency Department, n = 27) or late (12–24 h, n = 28) eptifibatide. Ten platelet receptors by flow cytometry and platelet aggregation (10 μmol/L ADP) were measured serially at baseline, and at 3, 6, 12 and 24 h after randomization. Results: Platelet aggregation was rapidly inhibited by early eptifibatide therapy (baseline, 72 +/− 20%; 3 h post, 7 +/− 9%; p < 0.001). No significant differences were seen in either group for CD 31, CD 63, CD 107a, CD 107b, CD 41 (GPIIb/IIIa expression), or CD 62p. Leukocyte-platelet aggregate formation (mean fluorescense intensity) trended upward after presentation (early baseline, 43.1 +/− 26.0 versus 65.8 +/− 35.6, p = .09). PAC-1 (GP IIb/IIIa activity), CD 51/61 (vitronectin receptor) and CD 42b (GP Ib) were inhibited by eptifibatide (p < .05). Conclusions: In Emergency Department patients with unstable angina, early eptifibatide rapidly and profoundly inhibits platelet aggregation and reduces GP IIb/IIIa activity and the expression of CD51/61 and CD 42b; the latter two effects may also contribute to the drug's anti-thrombotic effect. However, platelet-leukocyte aggregate formation, a marker of platelet activity rises within 24 h after presentation despite eptifibatide therapy and is a potential mechanism for microvascular obstruction.

Data from small studies have suggested the presence of platelet abnormalities in patients with congestive heart failure (CHF). We sought to characterize the diagnostic utility of different platelet parameters and platelet-endothelial biomarkers in a random outpatient CHF population investigated in the EPCOT (‘Whole Blood Impedance Aggregometry for the Assessment of Platelet Function in Patients with Congestive Heart Failure’) Trial. Blood samples were obtained for measurement of platelet contractile force (PCF), whole blood aggregation, shear-induced closure time, expression of glycoprotein (GP) IIb/IIIa, and P-selectin in 100 consecutive patients with CHF. Substantial interindividual variability of platelet characteristics exists in patients with CHF. There were no statistically significant differences when patients were grouped according to incidence of vascular events, emergency revascularization needs, survival, or etiology of heart failure. Aspirin use did not affect instrument readings either. PCF correlates very poorly with whole blood aggregometry (r2 = 0.023), closure time (r2 = 0.028), platelet GP IIb/IIIa (r2 = 0.0028), and P-selectin (r2 = 0.002) expression. Furthermore, there was no correlation with brain natriuretic peptide concentrations, a marker of severity and prognosis in heart failure reflecting the neurohumoral status. Patients with heart failure enrolled in the EPCOT Trial exhibited a marginal, sometimes oppositely directed change in platelet function, challenging the diagnostic utility of these platelet parameters and biomarkers to serve as useful tools for the identification of platelet abnormalities, for predicting clinical outcomes, or for monitoring antiplatelet strategies in this population. The usefulness of these measurements for assessing platelets in the different clinical settings remains to be explored. Taken together, opposite to our expectations, major clinical characteristics of heart failure did not correlate well with the platelet characteristics investigated in this study.

Regulators are often accused of delaying approval of new drugs by slow processes. Tom Marciniak and Victor Serebruany use FDA data to determine whether this view is justified

Objective: To detect residual platelet aggregation following the switch from generic (GC) to brand clopidogrel (BC) in male patients after ST-elevated myocardial infarction (STEMI). Methods: The study was designed as an open-label, prospective cohort trial. Thirty-three male STEMI patients were enrolled. All patients received dual antiplatelet therapy with aspirin (100 mg/daily) and one of six GC at a daily dose of 75 mg. After 2 weeks, all patients were switched to BC. Adrenaline- and adenosine diphosphate (ADP)-induced platelet aggregation was assessed twice: on day 14 (before the switch) and on day 21 (after 1 week of BC therapy). Results: Adrenaline-induced platelet aggregation did not differ among clopidogrel formulations. In contrast, residual 5 µM ADP-induced platelet aggregation after BC differs from GC by 14% (28.0 ± 2.5 vs. 23.9 ± 2.1%; p = 0.03). When 20 µM ADP was used as agonist, the difference was smaller (36.2 ± 2.9 vs. 34.6 ± 2.8%) but still significant (p = 0.04) favoring BC. Conclusions: After 2 weeks of therapy, switching from GC to BC was associated with a mild but significant reduction in ADP-induced platelet aggregation in male post-STEMI patients. The observed differences between GC and BC should be confirmed in a larger randomized study, but may represent a risk in underdeveloped countries, where GC therapy is mandatory for post-MI inpatients.

ABSTRACT: Numerous clinical trials testing the efficacy of aspirin for the secondary prevention of cardiovascular disease have been published. We reviewed the literature pertaining to aspirin dose in acute coronary syndrome patients. Clinical trials assessing the comparative efficacy of different doses of aspirin are scarce. This complex antiplatelet therapy landscape makes it difficult to identify the best aspirin dose for optimizing efficacy and minimizing risk of adverse events, while complying with the various guidelines and recommendations. Despite this fact, current evidence suggests that aspirin doses of 75–100 mg/day may offer the optimal benefit:risk ratio in acute coronary syndrome patients.

Contrast-induced nephropathy (CIN) accounts for 10% of hospital-acquired renal failure, causes a prolonged in-hospital stay and represents a powerful predictor of poor clinical outcome. The underlying mechanism of the CIN development remains unclear and seems to be multifactorial. The potential link between platelet indices such as mean platelet volume (MPV) and platelet distribution width (PDW) with CIN is unknown. Herein, we aimed to investigate the correlation between MPV and PDW levels with the development of CIN. The incidence of CIN (20.5%) was prospectively evaluated in 430 patients with diagnosis of acute coronary syndrome. Initial creatinine (1.13 ± 0.25 vs. 1.05 ± 0.27 mg/dl, P = 0.01) and PDW (40.1 ± 20.2 vs. 34.5 ± 19.9%, P = 0.02) levels and the total volume of contrast media used (121 ± 61 vs. 94 ± 42 ml, P = 0.01) were higher in patients who developed CIN. MPV was similar between the two groups (P = 0.80). In a univariate regression analysis, age, increased creatinine, uric acid, phosphate, PDW levels and higher total volume of contrast media used were significantly correlated with CIN incidence. However, in a multivariate analysis, only total volume of CM used [odds ratio (OR) 1.011, 95% confidence interval (CI) 1.006-1.016; P = 0.01], increased age (OR 1.026, 95% CI 1.00-1.052; P = 0.05) and increased PDW levels (OR 1.009, 95% CI 1.00-1.022; P = 0.04) remained as the independent predictors of CIN. Among platelet indices, PDW, but not MPV, was associated with CIN development. The clinical significance of such link remains unclear, but may indicate involvement of platelet activation in CIN pathogenesis.

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. (Am Heart J 2001;142:611-6.)

Background: 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 platelet function analyzer (PFA-100) in the CHF population. Methods: Blood samples were obtained for measurement of adenosine diphosphate (ADP)/collagen and epinephrine/collagen shear-induced closure time (CT), whole blood aggregation, platelet contractile force, activity of glycoprotein (GP) IIb/IIIa, and P-selectin receptors in 100 consecutive outpatients with CHF. Results: Substantial interindividual 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. Aspirin use did not affect instrument readings as well. CT correlates well with whole blood aggregometry (r2=.587) and less with GP IIb/IIIa activity (r2=.326). No correlation has been observed for the CT with the platelet-bound P-selectin (r2=.041) and platelet contractile force measures (r2=.028). Conclusions: PFA-100 is indeed capable to serve as a platelet analyzer and may be successfully used as a screening device. However, patients with heart failure enrolled in the EPCOT trial exhibited a marginal, sometimes oppositely directed changes in the platelet function, challenging the diagnostic utility of PFA-100 to serve as a useful tool for the identification of platelet abnormalities, predicting clinical outcomes, or for the monitoring of antiplatelet strategies in this population.

Knowledge of the pathogenesis of congestive heart failure (CHF) has improved greatly in recent years. Nevertheless, this disease still causes high morbidity and mortality in the Western world. In particular, there have been many advancements in our understanding, treatment and prophylaxis of CHF in recent years, yet the incidence of this disease continues to rise. Due to the staggering numbers of patients afflicted, CHF is becoming the most expensive burden on the health care system. The relationship between the deterioration of cardiac function and ongoing ischemic events has not been fully investigated and could conceivably be both monitored and modulated via various biomarkers. Recent data also indicate that heart failure is associated with altered hemostasis, i.e. a prothrombotic state which can lead to complications arising from occlusive and/or thromboembolic phenomena. Although the incidence of overt and clinically apparent thrombotic events is low, it is possible that subclinical events contribute to the increasing morbidity and mortality from this disease. These subclinical events may include silent ischemic events or microinfarcts which are being recognized as contributing to the progression of heart failure. As far as nonpharmacologic approaches to heart failure are concerned, the use of uniform exercise training regimens in heart failure is still a very controversial topic. Before more definitive recommendations can be made regarding the justification of such procedures, further large-scale studies investigating the effects of physical exercise on the development and progression of heart failure are needed. Furthermore, these studies must have sufficient statistical power to detect effects on clinical outcomes, specifically mortality. The purpose of this review article is to bridge the gap between biomarkers, exercise training and heart failure by discussing our current knowledge of different markers of platelet activation, thrombin generation, inflammation, endothelial dysfunction and myocardial necrosis in CHF patients undertaking physical exercise.

Background: Myocardial injury and platelet activation play important roles in the pathogenesis of unstable coronary syndromes. We sought to determine whether the combined measurement of platelet and necrosis markers would improve risk stratification, and yield higher diagnostic utility in patients presenting to the emergency department with chest pain. Methods and Results: Platelet and soluble P-selectin together with myoglobin, creatine kinase, CK-MB fraction, and troponin I were measured from the autologous samples in 122 consecutive patients. Statistical analysis revealed strong Spearman correlation coefficients (0.141–0.412; p 0.7) for acute myocardial infarction, while plasma P-selectin exhibited random distribution. Elevated soluble P-selectin and myoglobin were the most valuable in identifying patients with congestive heart failure. None of the markers were useful for triaging chest pain patients with unstable angina. Analysis of incremental gains (Chi-squares) reveals that with respect to platelet P-selectin, myoglobin adds 50%% to AMI diagnostic value, and creatine kinase yields an additional 20%% in triaging these patients. The diagnostic value of soluble P-selectin is substantially (72%%) increased by myoglobin measurements, and enhanced even further (44%%) by adding cardiac troponin I for identifying heart failure patients among the chest pain population. Conclusion: Simultaneous determination of platelet and necrosis markers improve the early diagnosis of acute myocardial infarction and congestive heart failure among patients with chest pain presenting into the Emergency Department. Well controlled clinical trials are needed to prove the advantage of combining platelet and necrosis data over presently used techniques in emergency medicine.

Fibrinolytic therapy is sthe established treatment for the management of patients with ST elevation acute myocardial infarction (AMI). Present fibrinolytic regimens have a number of shortcomings, including the failure to produce early and sustained reperfusion, as well as failure to prevent reocclusion in at least some patients. Platelets play an important role in coronary thrombosis responsible for AMI. The effect of coronary fibrinolysis on platelets has been extensively debated in the literature with evidence of both platelet activation and inhibition. Among fibrinolytic agents, tissue plasminogen activator (t-PA) is considered to be the mainstay in the treatment of coronary artery disease. The native t-PA molecule has been modified in an attempt to achieve improved lytic characteristics with less risk of bleeding. The result is a group of mutant t-PA variants considered third-generation plasminogen activators. TNK-t-PA is one bioengineered variant of t-PA. Another third-generation plasminogen activator is reteplase (r-PA). Like TNK-t-PA, it is a variant of t-PA that has been developed to establish a more rapid, complete, and stable coronary artery patency, thus promising reduced mortality. Both r-PA and TNK-t-PA are effective when given as bolus therapy. This feature may facilitate more rapid treatment as well as decrease overall costs of treatment. New fibrinolytic regimens include potent antiplatelet agents that may improve sustained reperfusion. This review summarizes the latest and often confusing data on the interaction between fibrinolytic therapy and platelets in certain in vitro, animal and clinical scenarios.

Fibrinolytic therapy is the established treatment for the management of patients with ST elevation acute myocardial infarction (AMI). Present thrombolytic regimens have a number of limitations, including the failure to produce early and sustained reperfusion, as well as an inability to prevent reocclusion in at least some patients. Platelets play an important role in coronary thrombosis responsible for AMI. The effect of coronary thrombolysis on platelets has been extensively debated in the literature, with controversial evidence of both platelet activation and inhibition. Among fibrinolytic agents, tissue plasminogen activator (t-PA) is considered to be the cornerstone in the treatment of acute coronary occlusion. The native t-PA molecule has been modified in an attempt to achieve improved lytic characteristics with less risk of bleeding events. Extensive research has led to a group of mutant t-PA variants referred to as third-generation plasminogen activators. TNK-t-PA is one bioengineered variant of t-PA; another is reteplase (r-PA). They have been developed to establish more rapid, complete and stable coronary artery patency, thus promising reduced mortality. Both r-PA and TNK-t-PA are effective when given as bolus therapy, a feature that may facilitate earlier treatment initiation as well as lower treatment costs. New acute coronary treatment regimens include potent antiplatelet agents on top of thrombolysis that may improve sustained reperfusion. This review summarizes the latest and often contradictory data on the interaction between fibrinolytic therapy and platelets in certain in vitro, animal and clinical scenarios.

Background Pulmonary arterial hypertension (PAH) is a chronic progressive disease characterized by persistent elevation of pulmonary artery pressure. Regardless of the initial trigger, the elevated pulmonary arterial pressure and vascular resistance in patients with PAH are primarily caused by remodeling and thrombosis of small- and medium-sized pulmonary arteries and arterioles, as well as sustained vasoconstriction. Recent studies have emphasized the relevance of several biomarkers of hemostasis in the PAH progression. However, there is no agreement whether hemostatic indices are indeed distinguishing PAH patients from controls. Methods Plasma fibrinogen, D-dimer, platelet count, and mean platelet volume, and platelet aggregation induced by ADP and collagen were serially measured in 34 patients with PAH, and 34 matched by age and sex normal volunteers. Results Hemostatic indices were significantly higher for fibrinogen (p = 0.0001), D-dimer (p = 0.001), mean platelet volume (p = 0.001), and platelet aggregation induced by ADP-, and collagen (p = 0.0001 for both) in PAH pstients when compared to healthy controls. In contrast, platelet counts were almost identical between both groups. Conclusions Patients with PAH exhibit activation of hemostatic indices compared to healthy controls. These data support previous observations that hemostatic abnormalities including platelet activation may directly impact pathogenesis of PAH, and need to be confirmed in larger randomized studies with more comprehensive assessment of hemostatic indices for justification of antithrombotic strategies.

SummaryClopidogrel 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 discontinu-ation 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.

Background It has been reported that selectins participate in the pathogenesis of acute coronary syndromes by modulating platelet-leukocyte-endothelium interactions. Elevated P-selectin level also has been observed in the clinical setting of myocardial ischemia and reperfusion; however, its utility in differentiating cardiac from noncardiac origins of chest pain is unknown. Methods and Results Soluble and platelet fractions of P-selectin were measured for 122 patients with chest pain and 14 healthy persons acting as controls. Patients with a cardiac problem (unstable angina, congestive heart failure, acute myocardial infarction) had significantly elevated levels of soluble P-selectin (156.0 ± 58.8 ng/mL, P =.002) and platelet-bound P-selectin (11.7% ± 6.4% positive cells, P =.013) compared with the P-selectin profile among controls (102.6 ± 29.0 ng/mL, 4.1% ± 1.2% positivity) and among patients with noncardiac chest pain (114.7 ± 36.6 ng/mL, 5.7% ± 2.9% positivity). With a cutpoint of 10% positivity for membrane and 120 ng/mL for soluble P-selectin, the sensitivities were 0.442 and 0.558, and the specificities were 0.915 and 0.553. Conclusions When a patient arrives in the emergency department, measurement of membrane P-selectin may serve as an additional diagnostic tool to detect heightened platelet activity, which is most prevalent among patients with a cardiac origin of chest pain. However, low sensitivity limits the utility of the P-selectin profile alone in suitably differentiating acute coronary syndromes within the overall population of patients with chest pain.

Each year, at least 5 million patients in the United States present to hospital emergency departments with the complaint of chest pain, and more than 10% of them will be diagnosed with acute myocardial infarction. One of the foremost tasks of the emergency department physician is to avoid unnecessary admissions and concomitantly to minimize the number of patients discharged home inappropriately. Currently available diagnostic tools, including the electrocardiogram and myocardial markers, have several shortcomings, including low specificity, and delayed sensitivity for the timely detection of myocardial necrosis. Therefore, the search for better methods of rapidly identifying patients with unstable coronary syndromes is one of the utmost priorities of modern emergency medicine. Available biochemical diagnostic tools are discussed in this review, focusing on the potential benefits of combining myocardial necrosis markers with indicators of platelet activation. It is hypothesized that such a combined approach may be more powerful in myocardial infarction risk stratification than separate marker determination.