Aldona Kubica

Meta-Analysis of Impact of Different Types and Doses of Statins on New-Onset Diabetes Mellitus

Recent reports indicate that statins are associated with an increased risk for new-onset diabetes mellitus (DM) compared with placebo and that this relation is dose dependent. The aim of this study was to perform a comprehensive network meta-analysis of randomized controlled trials (RCTs) investigating the impact of different types and doses of statins on new-onset DM. RCTs comparing different types and doses of statins with placebo were searched for using the MEDLINE, Embase, and Cochrane databases. A search of RCTs pertinent to this meta-analysis covering the period from November 1994 to October 2012 was conducted by 2 independent investigators using the MEDLINE, Cochrane, Google Scholar, and Embase databases as well as abstracts and presentations from major cardiovascular meetings. Seventeen RCTs reporting the incidence of new-onset DM during statin treatment and including a total of 113,394 patients were identified. The RCTs compared either a statin versus placebo or high-dose versus moderate-dose statin therapy. Among different statins, pravastatin 40 mg/day was associated with the lowest risk for new-onset DM compared with placebo (odds ratio 1.07, 95% credible interval 0.86 to 1.30). Conversely, rosuvastatin 20 mg/day was numerically associated with 25% increased risk for DM compared with placebo (odds ratio 1.25, 95% credible interval 0.82 to 1.90). The impact on DM appeared to be intermediate with atorvastatin 80 mg/day compared with placebo (odds ratio 1.15, 95% credible interval 0.90 to 1.50). These findings were replicated at moderate doses. In conclusion, different types and doses of statins show different potential to increase the incidence of DM.

Genetic determinants of platelet response to clopidogrel

Antiplatelet agents are the mainstay treatment in the prevention and management of atherothrombotic complications. However, a substantial interpatient variability in response to clopidogrel has been reported. Furthermore, patients with coronary artery disease and lesser platelet inhibition in response to clopidogrel are at increased risk for cardiovascular events. Clopidogrel after absorption requires two-step oxidation by the hepatic cytochrome P450 to generate its active metabolite. Polymorphisms of genes encoding the cytochrome enzymes and P-glycoprotein involved in clopidogrel absorption are regarded as major determinants of the interindividual variability in the clopidogrel-induced platelet inhibition. In our review we discuss the prevalence and clinical significance of various alleles of the genes: CYP2C19 and ABCB1 in the setting of coronary artery disease. Allele CYP2C19*2 is associated with excess of ischaemic events including myocardial infarction and stent thrombosis. On the other hand, CYP2C19*17 allele poses a serious threat of bleeding. Data concerning the prognostic value of genetic variant 3435C→T of ABCB1 remain inconclusive.

Diurnal variation in platelet inhibition by clopidogrel

Morning increase in the occurrence of myocardial infarction, stroke and sudden cardiac death is a well-recognized phenomenon, which is in line with a morning enhancement of platelet aggregation. We investigated whether platelet inhibition during clopidogrel and aspirin therapy varies during the day. Fifty-nine consecutive patients (45 men and 14 women) with first ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary interventions (pPCI) on dual antiplatelet therapy were prospectively enrolled into the study. Blood samples were collected 4 days after start of clopidogrel treatment at 6.00 a.m., 10.00 a.m., 2.00 p.m. and 7.00 p.m. Arachidonic acid and adenosine diphosphate (ADP)-induced platelet aggregation were assessed by impedance aggregometry. Platelet inhibition by clopidogrel was lowest in the midmorning: median ADP-induced platelet aggregation was 55%, 17% and 27% higher at 10.00 a.m. compared to 6.00 a.m., 2.00 p.m. and 7.00 p.m., respectively (p < 0.002). Nonresponsiveness to clopidogrel defined according to the device manufacturer was 2.4-fold more frequent in the midmorning than in the early morning. We observed a more pronounced midmorning increase in ADP-induced platelet aggregation in diabetic patients when compared to non-diabetics. In contrast, no diurnal variation in the antiplatelet effect of aspirin was observed. In conclusion, in patients presenting with STEMI undergoing pPCI, platelet inhibition by clopidogrel is less strong in the midmorning hours. This periodicity in platelet aggregation in patients on dual antiplatelet therapy should be taken into consideration when assessing platelet function in clinical studies.

Ticagrelor, but not clopidogrel and prasugrel, prevents ADP-induced vascular smooth muscle cell contraction: A placebo-controlled study in rats

INTRODUCTION Off-target effects of novel antiplatelet agents due to their potential clinical benefits are currently an area of intensive investigation. We aimed to compare the effects of different P2Y(12) antagonists on the reactivity of vascular smooth muscle cells. MATERIALS AND METHODS Wistar rats (n=30) were pretreated with an investigated drug or placebo. Clopidogrel (50mg/kg, n=7), prasugrel (10mg/kg, n=7), ticagrelor (10mg/kg, n=7) or placebo (n=9) were administered orally 12 and 2 hours before experiments. Constrictions of rat tail arteries induced with a stable analogue of adenosine diphosphate (2-MeS-ADP), phenylephrine and arginine vasopressin were measured as an increase in perfusion pressure. Effects of ticagrelor were assessed in the presence of ticagrelor (1μM/L) added to the perfusion solution as this drug reversibly inhibits the P2Y(12) receptor. RESULTS Pretreatment with clopidogrel and prasugrel did not inhibit 2-MeS-ADP-induced contraction while ticagrelor did. Experiments employing endothelium-deprived arteries provided similar results. Clopidogrel and prasugrel did not influence concentration-response curves in the presence of neither phenylephrine nor arginine vasopressin. The curves obtained for both vasopressors in the presence of ticagrelor and 2-MeS-ADP were shifted to the right with a significant reduction in the maximal response. CONCLUSIONS Oral administration of ticagrelor, in contrast to clopidogrel and prasugrel, prevents adenosine diphosphate-induced contraction of vascular smooth muscle cells in a rat model. Both the clinical significance and detailed mechanism of our findings warrant further investigation.

Impact of morphine on antiplatelet effects of oral P2Y12 receptor inhibitors

Abstract Morphine and P2Y12 receptor inhibitors are both recommended in patients with acute myocardial infarction. Morphine may impede gastrointestinal absorption of several oral drugs including P2Y12 platelet receptor inhibitors. The aim of this review was to critically discuss drug–drug interactions between oral P2Y12 receptor inhibitors and morphine according to currently available knowledge based on the findings of experimental, observational and randomized clinical studies. The morphine–clopidogrel pharmacodynamic interaction has been observed in numerous trials and it has been proposed as an explanation for the negative impact of morphine on the clinical outcomes in patients with acute coronary syndromes. An analogous morphine interaction with ticagrelor and prasugrel was found in several observational studies and finally proven in randomized trials in healthy volunteers and acute myocardial infarction patients. Morphine delays and attenuates exposure and antiplatelet action of oral P2Y12 receptor inhibitors in patients with myocardial infarction. Although this interaction may have potentially harmful consequences, routine avoidance of morphine cannot be recommended until clinically powered trials are completed.

Adenosine improves post-procedural coronary flow but not clinical outcomes in patients with acute coronary syndrome: A meta-analysis of randomized trials

AIMS Adjunctive therapy with adenosine has been shown to improve coronary flow in patients with acute coronary syndromes (ACS); it is unclear, however, whether adenosine can effectively reduce adverse clinical events. The aim of our study was to perform a meta-analysis of all randomized controlled trials (RCTs) investigating angiographic and clinical outcomes in ACS patients undergoing PCI or thrombolysis and receiving adjunctive adenosine therapy vs. placebo. METHODS Medline/CENTRAL/EMBASE and Google Scholar database were scanned. The meta-analysis included ten RCTs (N=3821). All-cause mortality was chosen as primary endpoint. Secondary endpoints were re-infarction (MI), heart failure (HF) symptoms (NYHA class III/IV), no-reflow (defined as TIMI 0 flow) and >50% ST-resolution. RESULTS Adenosine compared to placebo was associated with a significant reduction of post-procedural no-reflow (OR [95% CI]=0.25 [0.08-0.73], p=0.01); however, at a median follow-up of 6 months, prior treatment with adenosine did not confer significant benefits in terms of reduction of mortality (OR(Fixed) [95% CI]=0.87 [0.69-1.09], p=0.23), as well as re-MI (p=0.80), HF symptoms (p=0.44) and ST-resolution (p=0.09). Separate analyses conducted in the subgroups of ST-elevation MI patients treated with either PCI or thrombolysis confirmed the findings found in the overall population. CONCLUSIONS This meta-analysis shows that adenosine adjunctive therapy does not improve survival nor reduce the rates of re-MI and HF symptoms in patients with ACS treated with PCI or thrombolysis. The beneficial effect on post-procedural coronary flow was not associated with consistent advantages on clinical outcomes.

Cangrelor: an emerging therapeutic option for patients with coronary artery disease

Abstract Objectives: To perform a systematic up-to-date review and critical discussion of potential clinical applications of cangrelor based on its pharmacologic properties and the main findings from randomized clinical studies. Methods: A database search (PubMed, CENTRAL and Google Scholar) by two independent investigators, including proceedings from scientific sessions of ACC, AHA, ESC, TCT and EuroPCR, from January 1998 through December 2013. Results: Cangrelor is a potent, intravenous, direct-acting P2Y12 antagonist with rapid onset and quickly reversible action. In contrast to ticagrelor, cangrelor’s interaction with thienopiridines requires termination of cangrelor infusion before switching to clopidogrel or prasugrel. According to randomized trials, a cangrelor–clopidogrel combination is relatively safe and more effective than the standard clopidogrel regimen in both urgent and elective percutaneous coronary intervention (PCI) settings, with the advantage of this drug combination fully evident when the universal definition of myocardial infarction is applied. In contrast to available antiplatelet drugs with delayed onset and offset of action, its favorable properties make cangrelor a desirable agent for ad hoc elective PCI, high risk acute coronary syndromes treated with immediate coronary stenting and for bridging those surgery patients who require periprocedural P2Y12 inhibition. Current evidence on cangrelor therapy is limited by the lack of adequately powered studies assessing cangrelor co-administration either with prasugrel or ticagrelor, suboptimal design of some of the trials favoring cangrelor, potentially attenuated benefits with modern stent design, and finally, by the lack of survival advantage. Conclusions: With its pharmacokinetic and pharmacodynamic advantages, allowing consistent and strong P2Y12 inhibition, and with its rapid onset and swift reversal of action devoid of need for an antidote, cangrelor might improve clinical outcomes in clopidogrel-treated patients by reducing ischemic events, while maintaining a favorable safety profile. However, further studies, addressing the safety and efficacy of cangrelor on top of novel oral P2Y12 inhibitors, are warranted.

Updated evidence on intracoronary abciximab in ST-elevation myocardial infarction: a systematic review and meta-analysis of randomized clinical trials.

BACKGROUND Intracoronary (IC) abciximab administration remains a promising approach aimed to increase a drug concentration in the target area and possibly improve clinical outcomes in the setting of ST-segment elevation myocardial infarction (STEMI). The goal of this literature review and meta-analysis is to update available knowledge comparing IC and intravenous (IV) abciximab administration in STEMI patients. METHODS A total of 7 randomized clinical trials (RCTs) with a median follow-up of 3 months were included in the meta-analysis (n = 3311). All-cause mortality was selected as the primary end point while recurrent myocardial infarction (re-MI), target vessel revascularization (TVR) and major bleeding complications were the secondary end points. RESULTS IC abciximab did not provide any benefits in terms of all-cause mortality as compared with IV abciximab (odds ratio [OR] 0.67; 95% confidence interval [CI] 0.34-1.34). However, this neutral effect was driven by the AIDA STEMI trial. The IC route was associated with a reduced rate of re-MI when compared with IV administration (OR 0.61; 95% CI 0.40-0.92) but the difference disappeared after one of the RCTs was excluded from the analysis. Both strategies were equal regarding TVR (OR 0.66; 95% CI 0.40-1.09) and major bleeding complications (OR 1.18; 95% CI 0.76-1.83). CONCLUSIONS Our updated meta-analysis shows that the clinical superiority of IC over IV abciximab administration in STEMI patients is no longer clear after the release of the AIDA STEMI trial results. Further research in high-risk STEMI patients is warranted to finally determine clinical advantages of IC vs IV abciximab administration.

Time-related changes in determinants of antiplatelet effect of clopidogrel in patients after myocardial infarction☆

Substantial variability of antiplatelet action is an important limitation of clopidogrel. The aim of this study was to evaluate time-related changes in determinants of clopidogrel responsiveness in patients after myocardial infarction. The study population comprised 191 consecutive patients treated with primary percutaneous coronary intervention for acute myocardial infarction. Follow-up visits were scheduled at 3, 6 and 9 months after discharge. ADP-induced platelet aggregation was tested with Multiplate Analyzer. Patients with ADP-PA>46.8U were defined as clopidogrel non-responders. The prevalence of clopidogrel non-responsiveness was highest during hospitalization and at 9 month follow-up visit, while it was lowest at 3 and 6 months after myocardial infarction (P=0.004). According to multivariate analysis, platelet count, mean platelet volume, concentration of hsCRP and leukocyte count influenced ADP-induced platelet aggregation in multiple assessment points. BMI, concentrations of hemoglobin, glycated hemoglobin, and BNP, hematocrit, adherence to medication, and patient׳s age were found to be independent predictors of high on-treatment ADP-induced platelet aggregation only at a single follow-up visit. Determinants of clopidogrel responsiveness in patients after myocardial infarction change within the long-term therapy. During hospitalization and early after discharge only biological factors affect ADP-induced platelet aggregation, while non-adherence to antiplatelet therapy may be a significant factor in determining clopidogrel non-responsiveness during late follow-up visits.

Intracoronary versus intravenous abciximab administration in STEMI patients: overview of current status and open questions

Abstract Objectives: To perform a systematic review to provide rationale for intracoronary (IC) abciximab administration in patients with ST-segment elevation myocardial infarction (STEMI), to summarize recent studies comparing IC vs. intravenous (IV) abciximab administration in this setting and to define questions that need to be answered in future trials determining the optimal abciximab regimen. Methods: A search covering the period from January 1993 to June 2011 was conducted by two independent investigators using MEDLINE, CENTRAL and Google Scholar databases. Proceedings from the scientific sessions of ACC, AHA, ESC, TCT and EuroPCR were also considered. Results: IC administration allows one to obtain a much higher concentration of abciximab than IV injection at the culprit lesion. Therefore it is hypothesized that IC abciximab administration provides more efficient GP IIb/IIIa receptor inhibition and more pronounced additional dose-dependent antiplatelet, antithrombotic, and anti-inflammatory effects when compared to the IV route. Numerous observational and randomized studies comparing IC vs. IV abciximab in STEMI patients indicated improvement in different surrogate end points (infarct size, obstruction of coronary microcirculation, ST segment resolution, inflammatory mediators and markers of platelet activation) related to IC administration. The evidence supporting clinical benefits associated with IC injection of abciximab comes from one randomized and several non-randomized trials as most of the studies were underpowered to assess clinical outcomes. No difference in bleeding complications was observed between IC and IV regimens. Issues that need to be addressed in future studies include: the use of IC abciximab in combination with thrombectomy, the role of selective delivery systems, and the necessity of a prolonged IV infusion of abciximab after IC bolus administration. Conclusions: An accumulating body of evidence suggests the superiority of IC over IV abciximab administration in STEMI patients. However, further trials are warranted to establish the optimal strategy of abciximab treatment in this setting.