Download the Free Unbound MEDLINE PubMed App to your smartphone or tablet.
Available for iPhone, iPad, iPod touch, and Android.
- The impact of renal function on platelet reactivity and clinical outcome in patients undergoing percutaneous coronary intervention with stenting. [JOURNAL ARTICLE]
- Thromb Haemost 2014 Sep 18; 112(5)
Patients with chronic kidney disease (CKD) have an increased risk of cardiovascular disease. Previous studies have suggested that patients with CKD have less therapeutic benefit of antiplatelet therapy. However, the relation between renal function and platelet reactivity is still under debate. On-treatment platelet reactivity was determined in parallel by ADP- and AA-induced light transmittance aggregometry (LTA) and the VerifyNow® System (P2Y12 and Aspirin) in 988 patients on-dual antiplatelet therapy, undergoing elective coronary stenting. Patients were divided into two groups according to the presence or absence of moderate/severe CKD (GFR<60 ml/min/1.73 m²). Furthermore, the incidence of all-cause death, non-fatal acute myocardial infarction, stent thrombosis and stroke at one-year was evaluated. Patients with CKD (n=180) had significantly higher platelet reactivity, regardless of the platelet function test used. Patients with CKD more frequently had high on-clopidogrel platelet reactivity (HCPR) and high on-aspirin platelet reactivity (HAPR) regardless of the platelet function test used. After adjustment for potential confounders, this was no longer significant. The event-rate was the highest in patients with both high on-treatment platelet reactivity (HPR) and CKD compared to those with neither high on-treatment platelet reactivity nor CKD. In conclusion, the magnitude of platelet reactivity as well as the incidence of HPR was higher in patients with CKD. However, since the incidence of HPR was similar after adjustment, a higher rate of co-morbidities in patients with CKD might be the major cause for this observation rather than CKD itself. CKD-patients with HCPR were at the highest risk of long-term cardiovascular events.
- Assessment of the Prophylactic Role of Aspirin and/or Clopidogrel on Experimentally Induced Acute Myocardial Infarction in Hypercholesterolemic Rats. [JOURNAL ARTICLE]
- Drugs R D 2014 Sep 18.
Hyperlipidemia is a risk factor for cardiovascular diseases such as acute infarction. Inflammation and platelet activation are critical phenomena in acute myocardial infarction (AMI).The aim of the study was to assess potential protective effects of aspirin and/or clopidogrel on AMI in hypercholesterolemic rats.Forty adult male Wistar rats were divided into five groups (eight rats in each). Group I included normal healthy rats. The other 32 rats were subjected to induction of hypercholesterolemia by high-fat diet for 3 weeks, followed by induction of AMI by subcutaneous injections of isoproterenol (85 mg/kg/day, for 2 days). Rats were divided into the following groups: group II, rats with induced hypercholesterolemia and AMI; group III, hypercholesterolemic rats that received aspirin 30 mg/kg/day orally for 7 days before induction of AMI; group IV, hypercholesterolemic rats that received clopidogrel 10 mg/kg/day orally for 7 days before induction of AMI; and group V, hypercholesterolemic rats treated with both aspirin and clopidogrel in the same doses for 7 days before induction of AMI. Serum levels of pentraxin 3 (PTX3), transforming growth factor-β1 (TGF-β1), creatine kinase (CK), lactate dehydrogenase (LDH), total cholesterol and triglycerides were estimated in all rats.Isoproterenol-induced AMI in hypercholesterolemic rats was associated with an increase in serum levels of PTX3, TGF-β1, CK and LDH. Aspirin and/or clopidogrel pretreatment for 1 week led to a reduction of their levels as compared with non-treated rats. However, the reduction caused by combination of aspirin and clopidogrel was more than that caused by each drug separately.Combination of aspirin and clopidogrel could be a therapeutic option for hypercholesterolemic patients to attenuate the complex vascular inflammatory process which is a key step in the setting of AMI.
- How to improve the concept of individualised antiplatelet therapy with P2Y12 receptor inhibitors- is an algorithm the answer? [JOURNAL ARTICLE]
- Thromb Haemost 2014 Sep 18; 112(6)
Within the past decade, high on-treatment platelet reactivity (HTPR) on clopidogrel and its clinical implications have been frequently discussed. Although it has been previously assumed that HTPR is a phenomenon occurring only in patients treated with clopidogrel, recent data show that HTPR might also occur during treatment with prasugrel or ticagrelor in the acute phase of ST-elevation myocardial infarction. Moreover, it has been postulated that there is a therapeutic window for P2Y12 receptor blockers, thus indicating that HTPR is associated with thrombotic events whereas low on-treatment platelet reactivity (LTPR) is associated with bleeding events. The current paper focuses on tools to identify risk factors for HTPR (pharmacogenomic testing, clinical scoring and drug-drug interactions) and on the use of platelet function testing in order to identify patients who might not respond adequately to clopidogrel. The majority of recent clinical randomised trials have not supported the hypothesis that platelet function testing and tailored antiplatelet therapy are providing a favourable clinical outcome. These trials, mainly performed in low-to-moderate risk patients, will be reviewed and discussed. Finally, an algorithm based on current knowledge is suggested, which might be of use for design of clinical trials.
- CYP-independent inhibition of platelet aggregation in rabbits by a mixed disulfide conjugate of clopidogrel. [JOURNAL ARTICLE]
- Thromb Haemost 2014 Sep 18; 112(6)
Dual antiplatelet therapy with clopidogrel and aspirin has been the standard of care in the United States for patients with acute coronary syndromes (ACS) and/or undergoing percutaneous coronary interventions (PCI). However, the effectiveness of clopidogrel varies significantly among different sub-populations due to inter-individual variability. In this study we examined the antiplatelet potential of a novel mixed disulfide conjugate of clopidogrel with the aim to overcome the interindividual variability. In the metabolic studies using human liver microsomes and cDNA-expressed P450s, we confirmed that multiple P450s are involved in the bioactivation of 2-oxoclopidogrel to H4, one of the diastereomers of the pharmacologically active metabolite (AM) possessing antiplatelet activity. Results from kinetic studies demonstrated that 2C19 is the most active in converting 2-oxoclopidogrel to H4 with a catalytic efficiency of 0.027 µM⁻¹min⁻¹ in the reconstituted system. On the basis of this finding, we were able to biosynthesise the conjugate of clopidogrel with 3-nitropyridine-2-thiol, referred to as clopNPT, and examined its antiplatelet activity in male New Zealand white rabbits. After administered as intravenous bolus at 2 mg/kg, the clopNPT conjugate was rapidly converted to the AM leading to the inhibition of platelet aggregation (IPA). Analyses of the blood samples drawn at various time points showed that intravenous administration of clopNPT led to ~70% IPA within 1 hour and the IPA persisted for more than 3 hours. Since the antiplatelet activity of clopNPT does not require bioactivation by P450s, the mixed disulfide conjugate of clopidogrel has the potential to overcome the inter-individual variability in clopidogrel therapy.
- The influence of Erythropoietin on platelet activation, thrombin generation and FVII/active FVII in patients with AMI. [Journal Article]
- Thromb J 2014.:18.
Erythropoietin (Epo) has been shown to improve myocardial function in models of experimental myocardial infarction, but has also been associated with a rise in thromboembolic events. Thus, the aim of this study was to investigate the influence of Epo on platelet activation and coagulation in patients with acute myocardial infarction (AMI).The study was designed as a substudy of the randomised, double-blind, placebo controlled REVIVAL-3 (REgeneration of VItal Myocardium in ST-Segment EleVation MyocardiAL Infarction by Erythropoietin) study that investigated the effects of recombinant human Epo in AMI. Serial venous blood samples were collected before and after study medication. Circulating prothrombin fragment F1 + 2, FVII, active FVII, beta thromboglobulin (TG) and P-Selectin were measured before and 60 hours after randomization by immunoassay (n = 94). In a randomly selected subgroup platelet aggregation was measured using whole blood aggregometry (Multiplate Analyzer, n = 45).After 5 days an increase in FVII was observed after Epo as compared to placebo (P = 0.02), yet active FVII and prothrombin fragment F1 + 2 remained unchanged. Moreover, no statistically significant differences in circulating TG or P-selectin were observed between the groups. As an expected response to peri-interventional therapy with clopidogrel and aspirin, platelet aggregation after stimulation with ADP, TRAP, ASPI or collagen decreased 12 hours and 2 days after PCI. However, no difference between the Epo and the placebo group was observed.After treatment with Epo in patients with AMI a slight increase in circulating FVII after Epo was not associated with an increase in active FVII, prothrombin fragment F1 + 2, TG or P-selectin. Moreover, platelet aggregation was not altered after treatment with Epo as compared to placebo.ClinicalTrials.gov Identifier: NCT01761435.
- Health economic analysis of ticagrelor in patients with acute coronary syndromes intended for non-invasive therapy. [JOURNAL ARTICLE]
- Heart 2014 Sep 16.
To investigate the cost effectiveness of ticagrelor versus clopidogrel in patients with acute coronary syndromes (ACS) in the Platelet Inhibition and Patient Outcomes (PLATO) study who were scheduled for non-invasive management.A previously developed cost effectiveness model was used to estimate long-term costs and outcomes for patients scheduled for non-invasive management. Healthcare costs, event rates and health-related quality of life under treatment with either ticagrelor or clopidogrel over 12 months were estimated from the PLATO study. Long-term costs and health outcomes were estimated based on data from PLATO and published literature sources. To investigate the importance of different healthcare cost structures and life expectancy for the results, the analysis was carried out from the perspectives of the Swedish, UK, German and Brazilian public healthcare systems.Ticagrelor was associated with lifetime quality-adjusted life-year (QALY) gains of 0.17 in Sweden, 0.16 in the UK, 0.17 in Germany and 0.13 in Brazil compared with generic clopidogrel, with increased healthcare costs of €467, €551, €739 and €574, respectively. The cost per QALY gained with ticagrelor was €2747, €3395, €4419 and €4471 from a Swedish, UK, German and Brazilian public healthcare system perspective, respectively. Probabilistic sensitivity analyses indicated that the cost per QALY gained with ticagrelor was below conventional threshold values of cost effectiveness with a high probability.Treatment of patients with ACS scheduled for 12 months' non-invasive management with ticagrelor is associated with a cost per QALY gained below conventional threshold values of cost effectiveness compared with generic clopidogrel.NCT000391872.
- Switching from Generic to Brand Clopidogrel in Male Patients after ST-Elevated Myocardial Infarction. [JOURNAL ARTICLE]
- Cardiology 2014 Sep 10; 129(2):103-105.
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. © 2014 S. Karger AG, Basel.
- Nationwide trends in development of heart failure and mortality after first-time myocardial infarction 1997-2010: A Danish cohort study. [JOURNAL ARTICLE]
- Eur J Intern Med 2014 Sep 12.
Pharmacological and revascularization strategies following myocardial infarction (MI) have changed substantially during the last two decades. We investigated the temporal trends in heart failure (HF) incidence and mortality during the first 90days following first-time MI between 1997 and 2010 in Denmark.Through administrative nationwide registers we identified 89,389 patients without prior HF hospitalized with first MI. The number of patients treated with percutaneous coronary intervention (PCI) days 0-1 after index MI increased from 2.5% in 1997-98 to 38.2% in 2009-10. Treatment with clopidogrel increased from 0.02% in 1997-98 to 68.1% in 2009-10 and statins from 8.1% in 1997-98 to 78.3% in 2009-10. The incidence of HF (defined as HF diagnosis or incident use of loop diuretics) decreased from 23.6% in 1997-98 to 19.6% in 2009-10 (p<0.001). Adjusted for age, sex, and comorbidity, hazard ratio was 0.77 (95% confidence interval [CI] 0.74-0.79) for developing HF in 2009-10, compared with 1997-98. Adjusted for coronary interventions, and pharmacotherapy HR increased to 0.82 (95% confidence interval (CI) 0.79-0.85) compared with 1997-98. The 90-day mortality decreased from 19.6% in 1997-98 to 11.7% in 2009-10 (p<0.001). Adjusted for age, sex, and comorbidity HR was 0.59 (CI 0.55-0.64) in 2009-10 compared with 1997-98; upon additional adjustment for coronary interventions and pharmacotherapy the estimate was 0.75 (95% CI 0.69-0.81).We found a temporal decrease in HF incidence and mortality during the first 90days after MI in 1997-2010. This could partly be explained by changes in interventional and pharmacological treatment strategies.
- An HPLC-MS/MS method for simultaneous determination of the active metabolites of febuxostat (67M-1, 67M-2 and 67M-4) in human plasma. [JOURNAL ARTICLE]
- J Chromatogr B Analyt Technol Biomed Life Sci 2014 Sep 6.:24-30.
An HPLC-MS/MS method for simultaneously determination of the active metabolites (67M-1, 67M-2 and 67M-4) in human plasma using clopidogrel as the internal standard was developed and validated. The compounds were extracted by protein precipitation using acetonitrile and separated using a C8 column by a gradient elution with the mobile phase consisting of acetonitrile (containing 0.1% formic acid) and 0.1% formic acid. Quantification was performed using multiple reaction monitoring in positive mode with m/z transitions of 333.1-261.0, 333.1-261.0, 347.0-261.0 and 322.2-184.1 for 67M-1, 67M-2, 67M-4 and clopidogrel (Internal Standard), respectively. This method was validated in terms of specificity, linearity, precision, accuracy, and stability. The lower limit of quantification of this method was 0.5ng/mL and the calibration curve was linear over the concentration range of 0.5-150ng/mL. The intra- and inter-run precision was less than 11.67% and 8.64%, respectively, with the accuracy between 98.33% and 108.38%. The samples were stable under all the tested conditions. This method has been successfully applied to the pharmacokinetic study of febuxostat in healthy Chinese volunteers following oral administration of 40mg and 80mg febuxostat.
- Clopidogrel bioactivation and risk of bleeding in patients co-treated with ACE inhibitors after myocardial infarction: A proof of concept study. [JOURNAL ARTICLE]
- Clin Pharmacol Ther 2014 Sep 15.
Clopidogrel is an oral antiplatelet prodrug, the majority of which is hydrolyzed to an inactive metabolite by hepatic carboxylesterase 1 (CES1). Most angiotensin-converting enzyme inhibitors (ACEIs) are also metabolized by this enzyme. We examined effects of ACEIs on clopidogrel bioactivation in vitro and linked the results with a pharmaco-epidemiological study. In vitro, ACEIs inhibited CES1-mediated hydrolysis of a model substrate, and trandolapril and enalapril increased formation of clopidogrel active metabolite. In 70 934 patients with myocardial infarction, hazard ratios for clinically significant bleeding in ACEI-treated patients co-treated with or without clopidogrel were 1.10 (95% confidence interval [CI] 0.97-1.25, P=0.124) and 0.90 (95% CI 0.81-0.99, P=0.025) compared to patients that did not receive ACEIs. This difference was statistically significant (P=0.002). We conclude that co-treatment with selected ACEIs and clopidogrel may increase the risk of bleeding. Combination of in vitro and pharmaco-epidemiological studies may be a useful paradigm for assessment of drug-drug interactions.Clinical Pharmacology & Therapeutics (2014); Accepted article preview online 15 September 2014. doi:10.1038/clpt.2014.183.