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ABSTRACT: Aggressive dual antiplatelet therapy is associated not only with more bleeding, impaired wound healing, and potentially more solid cancer rates but it also causes higher infection risks including sepsis, and systemic inflammatory response syndrome (SIRS). This may be especially true considering the alarming off-label use of prasugrel. A 65-year-old white male patient with a history of myocardial infarction treated with percutaneous coronary intervention and implantation of 2 bare metal stents, was treated with off-label clopidogrel for 4 years, including a double daily dose (150 mg) for the initial 13 months. Still on clopidogrel, the patient was hospitalized with suspected pneumonia. A diagnostic cardiac catheterization revealed a 60%-70% blockage of the mid left anterior descending, but there was no need for coronary intervention. At discharge, clopidogrel 75 mg/d was switched over to off-label prasugrel 10 mg/d on top of aspirin (81 mg/d). On day 3 after prasugrel was given, a football-sized bruise appeared on the patient's lower right abdomen, but computed tomography results were unremarkable. On day 6 after administration of prasugrel, the patient became dizzy, disoriented, confused, experienced difficulty breathing, severe headache, weakness, intensive petechial rash covering the entire body, and breathing difficulty requiring ventilation. Within 24 hours, the patient was unable to correctly identify his age; his eyes were pale in color to almost colorless and when hearing a sound he would turn his entire head toward the sound and he appeared to be blind. His lungs, liver, and kidneys began to show signs of failure over the next 5-9 days. Sixteen days after the administration of the first prasugrel dose, the patient died of sepsis complicated with SIRS. Aggressive off-label use of clopidogrel (double dose for 13 months, and >4 years overall duration), followed by off-label switchover to the highest daily dose (10 mg) prasugrel may trigger sepsis and fatal SIRS. The mechanism responsible for such harmful association is probably indirect, and involves the weakening of platelet-neutrophil-endothelial crosstalk necessary to combat infections, and/or keep inflammation from spreading.
American journal of therapeutics 05/2013;
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ABSTRACT: In a randomized, double-blind, crossover study of 15 aspirin-naive patients (mean age 48.8 ± 10.2 years) with the metabolic syndrome, statin monotherapy (simvastatin 40 mg daily) was compared to combination therapy (simvastatin 40 mg and ezetimibe 10 mg daily) on biomarkers of inflammation and platelet activity. The addition of ezetimibe to simvastatin over a 4-week period was associated with reduced expression of CD141 (thrombomodulin; p = 0.02), platelet endothelial cell adhesion molecule (p < 0.0001) and CD51/61 (vitronectin receptor; p = 0.048) compared to statin monotherapy. Ezetimibe added to simvastatin improves several indices of platelet reactivity beyond statin monotherapy. However, the clinical relevance of these findings await results of the IMPROVE-IT trial (Improved Reduction of Outcomes: Vytorin Efficacy International Trial).
Cardiology 05/2013; 125(2):74-77. · 1.71 Impact Factor
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Advances in cardiology 01/2012; 47:165.
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Advances in cardiology 01/2012; 47:1-4.
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ABSTRACT: Endothelial progenitor cells (EPCs) play a key role in angiogenesis and vascular repair, although their exact functions are still disputable. The impact of EPC on left ventricular ejection fraction (LVEF) during acute myocardial infarction (MI) in patients treated with primary percutaneous coronary intervention (PCI) is also under investigation. The aim of this study was to assess the impact of different populations of EPC on LVEF during and 6 months after acute MI treated with primary PCI. The study included 34 patients with documented acute anterior wall MI. The control group consisted of 19 apparently healthy subjects. Blood for EPC assessments was obtained during the first 24 hours after MI and at 7 days and 6 months after PCI. CD34⁺/CD133⁺/CD45⁻, CD34⁺/CD31⁺/CD45⁻, CD34⁺/CD105⁺/CD45⁻, and CD31⁺/CD133⁺/CD45⁻ cell types were studied by flow cytometry. Echocardiography has been performed simultaneously with the EPC measurements. We observed a significant elevation of CD34⁺/CD133⁺/CD45⁻, CD34⁺/CD105⁺/CD45⁻, and CD31⁺/CD133⁺/CD45⁻ EPC at 7 days after PCI in comparison with 24 hours and 6 months after the MI. Patients with preserved LVEF at 7 days after PCI had also higher levels of CD31⁺/CD133⁺/CD45⁻. Acute anterior wall MI treated with primary PCI is followed by enhanced mobilization of EPC among which a high level of CD31⁺/CD133⁺/CD45⁻ subtype was strongly associated with the most preserved LVEF for up to 6 months after the index event. These data may provide some insight for future therapeutic strategies.
American journal of therapeutics 01/2012; 19(1):44-50.
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ABSTRACT: Background: Prescription omega-3-acid ethyl esters (PO-3A) have been tested for outcome benefits in patients with coronary artery disease (CAD), arrhythmias and heart failure. Some evidence suggests that PO-3A may exert their benefit via inhibiting platelets. We tested the hypothesis that PO-3A may inhibit platelet activity in patients with documented stable CAD, beyond the antiplatelet properties of aspirin and statins. Methods: Thirty patients with documented CAD and triglycerides over 250 mg/dl treated with aspirin (70-160 mg/daily) and statins (simvastatin equivalence dose: 5-40 mg/daily) were randomized 1:1:1 to Omacor™ 1 g/day (DHA/EPA ratio 1.25:1.0), Omacor 2 g/day, or a placebo for 2 weeks. Platelet tests including aggregometry and flow cytometry and cartridge analyzer readings were performed at baseline and at 1 and 2 weeks following PO-3A therapy. Results: ADP-induced platelet aggregation (p = 0.037), GP IIb/IIIa antigen (p = 0.031) and activity (p = 0.024), and P-selectin (p = 0.041) were significantly reduced after PO-3A, while platelet/endothelial cell adhesion molecule (p = 0.09), vitronectin receptor (p = 0.16), formation of platelet-monocyte microparticles (p = 0.19) and the VerifyNow IIb/IIIa test (p = 0.27) only exhibited nonsignificant trends suggestive of reduced platelet activity. Finally, collagen- and arachidonic acid-induced aggregation, closure time with the PFA-100 device and expression of thrombospondin (CD36), GP Ib (CD42b), LAMP-3 (CD63), LAMP-1 (CD107a), CD40-ligand (CD154), GP37 (CD165), and PAR-1 receptor intact (SPAN 12) and cleaved (WEDE-15) epitopes were not affected by 2 weeks of PO-3A. Conclusion: Independently of the dose and already at 1 week, short-term therapy with PO-3A provided a modest reduction of platelet activity biomarkers, despite concomitant aspirin and statin therapy, when compared to a placebo. The effect of PO-3A is unique, differs from other known antiplatelet agents and suggests potential pleiotropism. These preliminary randomized data call for confirmation in prospective studies.
Cardiology 06/2011; 118(3):187-94. · 1.71 Impact Factor
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Victor L Serebruany
Journal of the American College of Cardiology 06/2011; 57(25):2505-6. · 14.16 Impact Factor
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ABSTRACT: To determine the relative prognostic merits of C-reactive protein (CRP), cardiac troponin T (cTnT) and N-terminal pro-brain natriuretic peptide (NT-pro-BNP) for prediction of all-cause death in patients with end-stage renal disease (ESRD) receiving haemodialysis.
This prospective, controlled cohort study included 109 patients. Biomarkers were sampled at inclusion and considered as categorical and continuous variables in Cox proportional hazard models.
Mean follow-up ± SD was 926 ± 385 days, during which 52 patients (48%) died. All three markers were predictive of death in univariate analysis. In multivariable analysis, elevated cTnT (> 0.01 μg/l) and CRP (> 1.0 mg/dl) remained significantly associated with mortality [hazard ratio (95% confidence interval), 3.2 (1.2-8.5), p = 0.017 for cTnT; 2.0 (1.0-3.8), p = 0.032 for CRP], while NT-pro-BNP lost independent prognostic power. Addition of cTnT and CRP to established risk factors significantly improved the global fit of the model (p < 0.001), increased the c statistic from 0.726 to 0.758 and significantly increased the integrated discrimination improvement (p < 0.001).
The results suggest that cTnT and CRP can be used in combination for risk stratification in patients with ESRD and highlight the additive effect they confer in this regard.
Scandinavian Journal of Urology and Nephrology 03/2011; 45(2):151-8. · 0.99 Impact Factor
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Victor L Serebruany
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ABSTRACT: To summarize the available evidence regarding whether or not a higher aspirin maintenance dose inversely affects the ticagrelor benefit observed in the US cohort of the PLATO trial.
In the recent PLATO trial, the daily aspirin dosages in the USA were split between 81 and 325 mg while the vast majority of dosing outside of the USA was 75 or 100 mg. The FDA conducted exhaustive analyses of the aspirin dosage in a framework of primary clinical efficacy. Considering the post hoc, not prespecified nature of such analyses as well as multiple confounding problems with biologic plausibility, sensitivity to reclassification of small numbers of cases regarding loading versus maintenance aspirin dosing, and the distribution of events in high-dose aspirin observed outside of the USA, the FDA documents clearly suggest that aspirin dosing does not explain the disparate outcome results. In addition, the Advisory Committee members found no evidence to establish a reasonable link, and they uniformly rejected the hypothesis that aspirin dose affects the heterogeneity of outcomes in PLATO.
Additional evidence driven from the FDA review on aspirin dose and PLATO outcomes is reassessed.
The wide distribution of outcomes differing from country to country, and inconsistency in European data despite identical aspirin doses, preclude the acceptance of the hypothesis that aspirin affects PLATO outcomes in general or adversely impacts the benefit of ticagrelor in the US cohort in particular. Differences in primary site monitoring by the study sponsor in most countries versus a third-party CRO in the USA represent an alternative explanation and deserve further attention.
There is no solid evidence that aspirin dose affects outcomes after ticagrelor. Reevaluation of the overall endpoint differences, especially focusing on mortality, driven from sponsor-monitored sites versus outcomes observed by independent CROs is neccessary. The practice of self-monitoring in pivotal indication-seeking clinical trials should be avoided in the future.
Cardiology 02/2011; 117(4):280-3. · 1.71 Impact Factor
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Victor L Serebruany
Cardiology 01/2011; 118(2):139. · 1.71 Impact Factor
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Victor L Serebruany
Journal of the American College of Cardiology 03/2010; 55(13):1308-9. · 14.16 Impact Factor
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Victor L Serebruany
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ABSTRACT: Central adjudication of clinical events in randomized controlled trials represents an attractive but still controversial approach since the adjudicated data usually match well with the investigator-reported event rates but increase affiliated costs.
The aim was to assess the timing of clinical event adjudication in the TRITON trial.
A review of the FDA action package for prasugrel was conducted.
Adjudications for deaths and strokes were distributed evenly throughout the study period. Bleeding event adjudications were performed predominantly in the later stages of the study. Adjudications for myocardial infarction and especially stent thrombosis were significantly delayed.
Among all clinical events, only deaths and strokes in TRITON were adjudicated without delays. Late adjudication of myocardial infarction and stent thrombosis are uncommon but at least can be explained by lack or change of event definitions. However, the delays with adjudications of revascularization procedures and especially timely recording of bleeding complications lack reasonable explanation. The regulatory authorities should consider independent audits when there is a major disagreement between centrally adjudicated and site-reported events influencing the results of a major clinical trial.
Cardiology 03/2010; 115(3):217-20. · 1.71 Impact Factor
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ABSTRACT: Warfarin is a cornerstone of oral anticoagulation for stroke prevention. Anticoagulation with warfarin in patients with atrial fibrillation is over twice as effective in secondary prevention of stroke as any other tested alternatives, including all other antithrombotic drugs or surgical interventions. General belief is that warfarin is capable of preventing 20 ischemic strokes for every hemorrhagic one it causes. However, warfarin is one of the most feared agents as a result of its woeful safety profile and difficulties in maintaining the proper daily dose. Recent research in pharmacogenetics predominantly focused on elucidating the influence of individual genetic predispositions to administered warfarin. Although the incorporation of genotype information improves the accuracy of adequate dose prediction, an improvement in anticoagulation control or a reduction in hemorrhagic complications has not been yet convincingly demonstrated. It is clear that identifying an individual patient's risk for hemorrhage on warfarin will require more broad clinical and genetic studies. Future research focused on patients with stroke should concentrate on defining the possible differences, especially focusing on predicting bleeding events in general and intracranial hemorrhages in particular. The purpose of this review is to summarize the existing evidence about pharmacogenetics of warfarin in general, especially focusing on stroke prevention.
American journal of therapeutics 03/2010; 18(3):e55-66.
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ABSTRACT: The PLATO trial revealed a remarkable advantage of ticagrelor over clopidogrel in ACS patients. Unless the regulatory authorities discover serious flaws with the study, which is unlikely, the drug may substantially change the present landscape of oral antiplatelet therapy, especially in high-risk patients. Despite a somewhat unfavourable safety profile, ticagrelor has a lot of room to compensate for these well-defined side effects based on a documented absolute mortality reduction, solid prevention of MI, and convincing pattern of benefit growing over time.
European Heart Journal 12/2009; 31(7):764-7. · 10.48 Impact Factor
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Thrombosis and Haemostasis 07/2009; 101(6):1041-3. · 5.04 Impact Factor
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Victor L Serebruany
Cardiology 07/2009; 114(2):126-9. · 1.71 Impact Factor
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Victor L Serebruany
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ABSTRACT: The TRITON-TIMI 38 was a head-to-head trial to assess the efficacy and safety of the experimental antiplatelet agent prasugrel vs. standard care with clopidogrel on top of aspirin. Besides some ischemic protection at expense of overwhelming bleeding disadvantage, prasugrel treated patients experienced three times higher rate of colonic neoplasms then after clopidogrel, and this difference was significant. Importantly, known gastrointestinal bleeding preceded the diagnosis of colonic neoplasms only in half of the patients. Three potential mechanisms responsible for such harmful association are reviewed, namely: (i) direct hazard of the experimental drug on cancer occurrence and progression; (ii) indirect modulation of tumor growth; and (iii) enhanced metastatic dissemination due to instability of platelet-tumor cell aggregates, or/and inability to keep the disease locally due by much more potent long-term platelet inhibition should be considered. Significant excess of cancer after prasugrel is alarming, and can be reasonably explained, with critical clinical implications not only for prasugrel further development, but also for existing and future chronic antiplatelet strategies. If the hypothesis that oral aggressive platelet inhibition cause higher cancer risks will turn out to be true, then intensity of platelet inhibition, and especially duration of chronic antiplatelet therapy should be reconsidered. More delicate platelet inhibition, and shorter exposure to oral antiplatelet agents will prevail.
Fundamental and Clinical Pharmacology 07/2009; 23(4):411-7. · 1.80 Impact Factor
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ABSTRACT: The term 'resistance' should be restricted to very specialized physiologic circumstances, if not abandoned altogether. The term 'non-responder' needs to be placed in the context of the question: 'Non-responder to what?' Even if we would somehow magically know what an optimal response to antiplatelet therapy was, it will still be challenging to demonstrate an 'inadequate' response to antiplatelet therapy. At present there are two alternatives--give more drug or give additional drugs. Both strategies may work in further inhibiting platelet function, but both strategies can also be associated with an increased risk of bleeding. The trick, for the future, much as with our antihypertensive and lipid-lowering armamentaria, will be to know in whom to do what with which drug, and why. Single isolated measurements are not useful--if you don't know where you started, how we would know that antiplatelet drug is producing an 'adequate' clinical effect? There is no evidence of any sort of absolute 'threshold' that must be exceeded for treatment to be effective, and in the absence of this, if we are to evaluate the effect of a given drug, we have to have baseline values (off drug), therapeutic values (on drug), and some sort of assessment of both resting (unstimulated) and agonist-provoked (stimulated) platelet function. Moreover, given all of the different things that platelets do, the ideal assessment of platelet function and drug responsiveness will need to incorporate more than one agonist and some sort of assessment of both platelet activation and platelet aggregation. No one man (or test) tells us everything; it is the totality of the information that gives us the most complete picture. And, ultimately, we need to more firmly establish how the variability in platelet function and drug-associated changes in that function correlates with long-term, hard-endpoint clinical events.
Fundamental and Clinical Pharmacology 03/2009; 23(1):11-8. · 1.80 Impact Factor
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Cerebrovascular Diseases 11/2008; 26(5):563-4. · 2.72 Impact Factor
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European Heart Journal 11/2008; 29(23):2833-4. · 10.48 Impact Factor
