Ghazaleh Gouya

Personalized antiplatelet treatment after percutaneous coronary intervention: The MADONNA study

BACKGROUND AND OBJECTIVES Clopidogrel non-responsiveness is associated with adverse clinical outcome. We aimed to investigate whether individualized antiplatelet treatment in clopidogrel non-responders is an effective and safe strategy. METHODS This was a prospective non-randomized non-blinded study comparing two cohorts (guided and non-guided treatment) with a follow-up of 1-month. Responsiveness to clopidogrel was assessed by multiple electrode aggregometry (MEA) in 798 patients with coronary artery disease undergoing percutaneous coronary intervention (PCI). In the guided group (n=403) clopidogrel non-responders received repeated loading doses of clopidogrel or prasugrel, in the non-guided group (n=395) clopidogrel non-responders did not undergo any change in treatment. RESULTS Stent thrombosis occurred significantly less often in the guided group than in the non-guided group (0.2% vs. 1.9%; p=0.027). The multivariate Cox regression analysis showed that patients in the non-guided group were at a 7.9-fold higher risk to develop stent thrombosis compared to the guided group (OR: 7.9; 95% CI: 1.08-69.2; p=0.048). In line with this, acute coronary syndrome occurred significantly less often in the guided group than in the non-guided group (0% vs. 2.5%; p=0.001) whereas there was no difference in the event rates of cardiac death (2% vs. 1.3%; p=0.422) or major bleedings (1% vs. 0.3%; p=0.186). CONCLUSION Personalized antiplatelet treatment according to the platelet function testing with MEA resulted in an improved efficacy with an equal safety compared to the standard treatment.

Cross validation of the Multiple Electrode Aggregometry - A prospective trial in healthy volunteers

Several test systems exist for assessment of platelet function in patients under clopidogrel or aspirin therapy. The objective was to cross-validate the Multiple Electrode Aggregometry (MEA) with three other methods used for determining platelet reactivity under treatment with clopidogrel and aspirin. Platelet function was assessed by the MEA, Vasodilator Stimulated Phosphoprotein (VASP) phosphorylation assay, Platelet Function Analyzer-100 (PFA-100) and the Cone and Platelet Analyzer. Measurements were performed in blood from nine healthy volunteers at baseline, 2, 4, 6 and 72 hours after clopidogrel and aspirin loading. The apparent effect size for clopidogrel and aspirin was greatest for the MEA: treatment induced a 19-fold difference in the arachidonic acid-induced platelet aggregation and an 11-fold difference in the adenosine diphosphate-induced platelet aggregation before/after treatment. For comparison, aspirin and clopidogrel induced only 2.0- to 2.6 -fold changes in other tests (VASP assay, Cone and Platelet Analyzer and PFA-100). Maximal effects were seen 2 hours after aspirin loading and shorter than 72 hours after clopidogrel loading. In conclusion, aspirin and clopidogrel produce stronger signals in the MEA compared to several other methods.

Antiplatelet Treatment for Prevention of Cerebrovascular Events in Patients With Vascular Diseases A Systematic Review and Meta-Analysis

Background and Purpose— The efficacy and safety of different antiplatelet regimes for prevention of stroke in patients at high risk were investigated in a systematic review and meta-analysis. Methods— We searched the Cochrane Central Register of Controlled Trials, MEDLINE, and Web of Science. Twenty-two studies comprising 173 371 patients were included. Results— In the overall population, dual antiplatelet therapy (DAPT) with aspirin and clopidogrel in comparison to aspirin monotherapy reduced the relative risk of total stroke by 20% (risk ratio [RR], 0.80; 95% confidence interval [CI], 0.73–0.88; P<0.0001; I2=28%) and of ischemic stroke or transient ischemic attack by 23% (RR, 0.77; 95% CI, 0.69–0.85; P<0.0001; I2=18%) without increasing the risk of intracranial hemorrhage. In the secondary prevention cohort, DAPT with aspirin and clopidogrel also reduced the relative risk of total stroke by 24% as compared with aspirin alone (RR, 0.76; 95% CI, 0.68–0.86; P<0.0001; I2=0%). DAPT with prasugrel or ticagrelor and aspirin versus DAPT with clopidogrel and aspirin was not associated with a risk reduction of stroke. Conclusions— DAPT with clopidogrel and aspirin compared with aspirin effectively reduces the risk of total and ischemic stroke in the overall cohort consisting of patients with cardiovascular disease without increase in intracranial hemorrhage, as well as decreases the risk of a recurrent total stroke in patients with a previous stroke/transient ischemic attack. Our meta-analysis suggests that DAPT including low-dose aspirin (75–100 mg) and clopidogrel (75 mg) should be further investigated as a strategy to reduce recurrent strokes. Clinical Trial Registration— URL: http://www.crd.york.ac.uk/prospero. Unique identifier: CRD42011001596.

Safety, tolerability and pharmacokinetics of liposomal curcumin in healthy humans.

INTRODUCTION Experimental studies have shown that liposomal curcumin can exert a reduction in tumor growth in pancreatic and colorectal cancer. In this phase I clinical trial we investigated the pharmacokinetics, safety, and tolerability of intravenously administered liposomal curcumin in healthy subjects. MATERIAL AND METHODS 50 male and female participants were included in this randomized, placebo-controlled double-blind phase I dose escalation study. Subjects received a single dose of liposomal curcumin (10 - 400 mg/m2; n = 2 - 6 per group) or placebo over 2 hours intravenously. RESULTS Dose-dependent increases in the plasma concentrations of curcumin and its metabolite tetrahydrocurcumin (THC) were detected. After the end of drug infusion, curcumin and THC plasma concentrations decreased within 6 - 60 minutes below the limit of quantification. Mean urinary excretion was ~ 0.1% of total systemic clearance. Liposomal curcumin was tolerated well, but a transient red blood cell echinocyte formation with concomitant increase in mean cellular volume was observed at dosages ≥ 120 mg/m2. CONCLUSION Short-term intravenous dosing of liposomal curcumin appears to be safe up to a dose of 120 mg/m2. Changes in red blood cell morphology may represent a dose limiting sign of toxicity.

Alpha-lipoic acid improves vascular endothelial function in patients with type 2 diabetes: a placebo-controlled randomized trial

Eur J Clin Invest 2010; 40 (2): 148–154

Association of endostatin with mortality in patients with chronic heart failure.

Experimental data imply that in decompensated heart failure (HF), the anti‐angiogenic factor endostatin is increased. This study aimed to investigate whether the angiogenesis inhibitor endostatin is related to the risk of all‐cause mortality in a prospective cohort study of chronic HF patients.

Human Pharmacokinetics of High Dose Oral Curcumin and Its Effect on Heme Oxygenase-1 Expression in Healthy Male Subjects

Purpose. Heme oxygenase-1 (HO-1) has been proposed to exert pharmacological benefits by its antioxidative and anti-inflammatory effects. HO-1 expression may be affected by the GT length polymorphism in the promoter region of the HO-1 gene. We investigated the inducibility of HO-1 by orally administered curcumin in healthy male subjects and its correlation with the GT length polymorphism. Methods. In an open label uncontrolled phase-1 pilot study, ten male subjects received 12 g of oral curcumin. To investigate the effects of the GT length polymorphism on the inducibility of HO-1, five subjects with homozygous short and five with homozygous long GT genotypes were studied. Plasma concentrations of curcumin, bilirubin, HO-1 mRNA, and protein expression in peripheral blood mononuclear cells (PBMCs) were analyzed over 48 hours. Results. At a detection limit of 1 µg/mL curcumin could not be detected in plasma of any subject. Compared to baseline, HO-1 mRNA and protein levels were not induced in PBMCs at any time point up to 48 hours. There was no correlation between any of the parameters and GT length polymorphism. Conclusions. Oral curcumin administration has low bioavailability and does not induce HO-1 on mRNA or protein level in PBMCs.

The association of mid-regional pro-adrenomedullin and mid-regional pro-atrial natriuretic peptide with mortality in an incident dialysis cohort.

High levels of the plasma peptides mid-regional pro-adrenomedullin (MR-proADM) and mid-regional pro-atrial natriuretic peptide (MR-proANP) are associated with clinical outcomes in the general population. Data in patients with chronic kidney disease are sparse. We therefore investigated the association of MR-proANP and MR-proADM levels with all-cause and cardiovascular (CV) mortality, CV events and peripheral arterial disease in 201 incident dialysis patients of the INVOR-Study prospectively followed for a period of up to more than 7 years. The overall mortality rate was 43%, thereof 43% due to CV events. Both baseline MR-proANP and MR-proADM were associated with higher risk of all-cause (HR = 1.44, p = 0.001 and HR = 1.32, p = 0.002, respectively) and CV mortality (HR = 1.75, p<0.001 and HR = 1.41, p = 0.007, respectively) after adjustment for age, sex, previous CV events, diabetes mellitus and time-dependent type of renal replacement therapy. We then stratified patients in high risk (both peptides in the upper tertile), intermediate risk (only one of the two peptides in the upper tertile) and low risk (none in the upper tertile). Although demographic, clinical and laboratory variables were similar among the intermediate and high risk group, to be with both parameters in the upper tertile was associated with a 3-fold higher risk for all-cause (HR = 2.87, p<0.001) and CV mortality (HR = 3.58, p = 0.001). In summary, among incident dialysis patients MR-proANP and MR-proADM were shown to be associated with all-cause and CV mortality, with the highest risk when both parameters were in the upper tertiles.

Effect of systemic high dose vitamin C therapy on forearm blood flow reactivity during endotoxemia in healthy human subjects

OBJECTIVE Acute inflammation induced by administration of Escherichia coli lipopolysaccharide endotoxin (LPS) reduces plasma concentrations of vitamin C and impairs vascular endothelium-derived nitric oxide (NO) bioactivity. We tested the hypothesis that systemically administered high dose vitamin C restores the endogenous anti-oxidant potential and improves NO-dependent vasodilatation in the forearm vasculature. DESIGN & SETTING 36 male subjects were enrolled in this balanced, placebo controlled cross-over study. Forearm blood flow (FBF) reactivity to acetylcholine (ACh) and glyceryl-trinitrate (GTN), a sensitive test for endothelial function, was assessed at baseline and 4h after LPS-administration (20 IU/kg i.v). The effect of two different doses of intravenous vitamin C (Vitamin C-Injektopas®), 320 mg/kg and 480 mg/kg over 2h, or placebo on forearm vascular function was studied after LPS. MAIN RESULTS LPS caused transient flu-like symptoms, decreased plasma vitamin C concentrations and reduced the ACh-dependent increase in FBF by up to 76%. Vitamin C at a mean plasma concentration of 3.2 or 4.9 mmol/L restored the response to ACh compared to baseline. CONCLUSION High dose systemic vitamin C recovers LPS-induced endothelium-dependent vasodilation in the forearm resistance vasculature. This provides a rationale for a further clinical study of the systemic vitamin C effect under inflammatory conditions.

Cross validation of aspirin effect in healthy individuals by Impact-R and PFA-100: A double blind randomized placebo controlled trial

The main objective of this study was to compare testing for aspirin response in healthy volunteers by two high shear methods in a randomized double blind placebo controlled study. Seventeen healthy male individuals were randomized for aspirin 160 mg per day for 7–10 days, and 20 age matched controls for placebo for the same period. At study entry and 7–10 days thereafter we determined high shear-induced platelet adhesion to polystyrene after pre-incubation with arachidonic acid using the Cone and Plate(let) analyzer (Impact-R), and the closure time of collagen/epinephrine cartridges obtained by the PFA-100 (CEPI-CT). Platelet adhesion to polystyrene after preincubation with arachidonic acid was median 3.7% (range 0.6–8.0) before study entry and median 6.7% (range 2.8–11.0) after 7–10 days of aspirin (p < 0.001). Changes were not significant in the placebo group. By the PFA-100 CEPI-CT was median 211 s (range 130–300 s) before aspirin, and 300 s in all individuals taking aspirin for 7–10 days (p < 0.001). Post-treatment data obtained by the Impact-R and PFA-100 were discordant in seven cases from the placebo group, and in one subject on aspirin. The response to aspirin varied considerably among healthy individuals, but both methods were suitable to demonstrate the aspirin effect. There was, however, a significant level of absent concordance between the tests. Since the trial design cannot provide data on the specificity of the different tests, only clinical experience can determine their usefulness.