Jacek Kubica

Safety and efficacy outcomes of first and second generation durable polymer drug eluting stents and biodegradable polymer biolimus eluting stents in clinical practice: comprehensive network meta-analysis

Objectives To investigate the safety and efficacy of durable polymer drug eluting stents (DES) and biodegradable polymer biolimus eluting stents (biolimus-ES). Design Network meta-analysis of randomised controlled trials. Data sources and study selection Medline, Google Scholar, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) database search for randomised controlled trials comparing at least two of durable polymer sirolimus eluting stents (sirolimus-ES) and paclitaxel eluting stents (paclitaxel-ES), newer durable polymer everolimus eluting stents (everolimus-ES), Endeavor and Resolute zotarolimus eluting stents (zotarolimus-ES), and biodegradable polymer biolimus-ES. Primary outcomes Safety (death, myocardial infarction, definite or probable stent thrombosis) and efficacy (target lesion and target vessel revascularisation) assessed at up to one year and beyond. Results 60 randomised controlled trials were compared involving 63 242 patients with stable coronary artery disease or acute coronary syndrome treated with a DES. At one year, there were no differences in mortality among devices. Resolute and Endeavor zotarolimus-ES, everolimus-ES, and sirolimus-ES, but not biodegradable polymer biolimus-ES, were associated with significantly reduced odds of myocardial infarction (by 29-34%) compared with paclitaxel-ES. Compared with everolimus-ES, biodegradable polymer biolimus-ES were associated with significantly increased odds of myocardial infarction (by 29%), while Endeavor zotarolimus-ES and paclitaxel-ES were associated with significantly increased odds of stent thrombosis. All investigated DES were similar with regards to efficacy endpoints, except for Endeavor zotarolimus-ES and paclitaxel-ES, which were associated with significantly increased the odds of target lesion and target vessel revascularisations compared with other devices. Direction of results beyond one year did not diverge from the findings for up to one year follow-up. Bayesian probability curves showed a gradient in the magnitude of effect, with everolimus-ES and Resolute zotarolimus-ES offering the highest safety profiles. Conclusions The newer durable polymer everolimus-ES and Resolute zotarolimus-ES and the biodegradable polymer biolimus-ES maintain the efficacy of sirolimus-ES; however, for safety endpoints, differences become apparent, with everolimus-ES and Resolute zotarolimus-ES emerging as the safest stents to date.

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.

Optimal timing of coronary invasive strategy in non-ST-segment elevation acute coronary syndromes: A systematic review and meta-analysis

BACKGROUND The optimal timing of coronary intervention in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACSs) is a matter of debate. Conflicting results among published studies partly relate to different risk profiles of the studied populations. PURPOSE To do the most comprehensive meta-analysis of current evidence on early versus delayed invasive treatment in NSTE-ACS. DATA SOURCES MEDLINE, PubMed Central, and Google Scholar databases; conference proceedings; ClinicalTrials.gov registry; and Current Controlled Trials registry through May 2012. STUDY SELECTION Available randomized, controlled trials (RCTs) and observational studies comparing early versus delayed intervention in the NSTE-ACS population. DATA EXTRACTION Data were extracted for populations, interventions, outcomes, and risk of bias. All-cause mortality was the prespecified primary end point. The longest follow-up available in each study was chosen. The odds ratio with 95% CI was the effect measure. DATA SYNTHESIS Seven RCTs (5370 patients) and 4 observational studies (77 499 patients) were included. Early intervention was less than 20 hours after hospitalization or randomization for RCTs and 24 hours or less for observational studies. Meta-analysis of the RCTs was inconclusive for a survival benefit associated with the early invasive strategy (odds ratio, 0.83 [95% CI, 0.64 to 1.09]; P = 0.180); a similar result emerged from the observational studies. With early versus late intervention, the odds ratios in the RCTs were 1.15 (CI, 0.65 to 2.01; P = 0.63) and 0.76 (CI, 0.56 to 1.04; P = 0.090) for myocardial infarction and major bleeding during follow-up, respectively. LIMITATION Current evidence from RCTs is limited by the small overall sample size, low numbers of events in some trials, and heterogeneity in the timing of intervention and in patient risk profiles. CONCLUSION At present, there is insufficient evidence either in favor of or against an early invasive approach in the NSTE-ACS population. A more definitive RCT is warranted to guide clinical practice.

Morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction: the randomized, double-blind, placebo-controlled IMPRESSION trial

Abstract Aims The currently available data indicate a drug–drug interaction between morphine and oral P2Y12 receptor inhibitors, when administered together. The aim of this trial was to assess the influence of infused morphine on pharmacokinetics and pharmacodynamics of ticagrelor and its active metabolite (AR-C124910XX) in patients with acute myocardial infarction. Methods and results In a single-centre, randomized, double-blind trial, patients were assigned in a 1:1 ratio to receive intravenously either morphine (5 mg) or placebo, followed by a 180 mg loading dose of ticagrelor. Pharmacokinetics was determined with liquid chromatography tandem mass spectrometry and ticagrelor antiplatelet effects were measured with up to three different platelet function tests: vasodilator-stimulated phosphoprotein phosphorylation assay, multiple electrode aggregometry and VerifyNow. The pharmacokinetic and pharmacodynamic assessment was performed in 70 patients (35 in each study group). Morphine lowered the total exposure to ticagrelor and its active metabolite by 36% (AUC(0–12): 6307 vs. 9791 ng h/mL; P = 0.003), and 37% (AUC(0–12): 1503 vs. 2388 ng h/mL; P = 0.008), respectively, with a concomitant delay in maximal plasma concentration of ticagrelor (4 vs. 2 h; P = 0.004). Multiple regression analysis showed that lower AUC(0–12) values for ticagrelor were independently associated with the administration of morphine (P = 0.004) and the presence of ST-segment elevation myocardial infarction (P = 0.014). All three methods of platelet reactivity assessment showed a stronger antiplatelet effect in the placebo group and a greater prevalence of high platelet reactivity in patients receiving morphine. Conclusions Morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction. ClinicalTrials.gov Identifier: NCT02217878.

Safety and efficacy of biodegradable vs. durable polymer drug-eluting stents: evidence from a meta-analysis of randomised trials

AIMS Drug-eluting stents (DES) are a major advance in interventional cardiology; however concerns have been raised regarding their long-term safety due to the permanent nature of the polymer. New generation stents with biodegradable polymers (BDS) have recently been developed. The aim of this study was to perform a meta-analysis of randomised controlled trials (RCTs) comparing the safety and efficacy profile of BDS vs. durable polymer DES. METHODS AND RESULTS The MEDLINE/CENTRAL and Google Scholar databases were searched for RCTs comparing safety and efficacy of BDS vs. DES. Safety endpoints were mortality, myocardial infarction (MI), and stent thrombosis (ST). Efficacy endpoints were target vessel revascularisation (TVR), target lesion revascularisation (TLR) and six-month in-stent late loss (ISLL). The meta-analysis included eight RCTs (n=7,481). At a median follow-up of nine months, as compared to DES, BDS use did not increase mortality (OR [95% CI] = 0.91 [0.69-1.22], p=0.53) or MI (OR [95% CI] = 1.14 [0.90-1.44], p=0.29). Rate of late/very late ST was significantly reduced in BDS patients (OR [95% CI] = 0.60 [0.39-0.91], p=0.02), as was six-month ISLL (mean difference [95% CI] = -0.07 [-0.12; -0.02] mm, p=0.004) in comparison with DES patients. Rates of TVR and TLR were comparable between BDS and DES. CONCLUSIONS BDS are at least as safe as standard DES with regard to survival and MI, and more effective in reducing late ST, as well as six-month ISLL. Further large RCTs with long-term follow-up are warranted to definitively confirm the potential benefits of BDS.

Phenotyping vs. genotyping for prediction of clopidogrel efficacy and safety: the PEGASUS-PCI study

Summary.  Background: Prognostic values of genotyping and phenotyping for assessment of clopidogrel responsiveness have been shown in independent studies.Objectives: To compare different assays for prediction of events during long‐term follow‐up.Methods: In this prospective cohort study polymorphisms of CYP2C19*2 and CYP2C19*17 alleles, vasodilator‐stimulated phosphoprotein phosphorylation (VASP) assay, multiple electrode aggregometry (MEA), cone and platelet analyser (CPA) and platelet function analyser (PFA‐100) were performed in 416 patients undergoing percutaneous coronary intervention. The rates of events were recorded during a 12‐month follow‐up.Results: Platelet aggregation by MEA predicted stent thrombosis (2.4%) better (c‐index = 0.90; P < 0.001; sensitivity = 90%; specificity = 83%) than the VASP assay, CPA or PFA‐100 (c‐index < 0.70; P > 0.05; sensitivity < 70%; specificity < 70% for all) or even the CYP2C19*2 polymorphism (c‐index < 0.56; P > 0.05; sensitivity = 30%; specificity = 71%). Survival analysis indicated that patients classified as poor responders by MEA had a substantially higher risk of developing stent thrombosis or MACE than clopidogrel responders (12.5% vs. 0.3%, P < 0.001, and 18.5% vs. 11.3%, P = 0.022, respectively), whereas poor metabolizers (CYP2C19*1/*2 or *2/*2 carriers) were not at increased risks (stent thrombosis, 2.7% vs. 2.5%, P > 0.05; MACE, 13.5% vs. 12.1%, P = 0.556). The incidence of major bleedings (2.6%) was numerically higher in patients with an enhanced vs. poor response to clopidogrel assessed by MEA (4% vs. 0%) or in ultra‐metabolizers vs. regular metabolizers (CYP2C19*17/*17 vs. CYP2C19*1/*1; 9.5% vs. 2%). The classification tree analysis demonstrated that acute coronary syndrome at hospitalization and diabetes mellitus were the best discriminators for clopidogrel responder status.Conclusions: Phenotyping of platelet response to clopidogrel was a better predictor of stent thrombosis than genotyping.

Impact of clopidogrel loading dose on clinical outcome in patients undergoing percutaneous coronary intervention: a systematic review and meta-analysis

Context Enhanced platelet inhibition by clopidogrel decreases the risk of ischemic events but carries a risk for a concomitant increase in bleeding. Objectives To compare the efficacy and safety of two clopidogrel loading regimens (300mg vs. 600mg) in patients undergoing percutaneous coronary intervention (PCI) at one month after start of therapy. Data sources A systematic literature search of MEDLINE, EMBASE, CENTRAL, and Web of Science databases using predefined search terms for relevant articles in any language. Study selection and data extraction Randomised controlled trials and non-randomised studies reporting adjusted effect estimates were included. Summary estimates of the risks ratios (RRs) with therapy were calculated using a random-effect model. Outcomes evaluated were combined major adverse cardiovascular events (MACE) and major bleedings. Results Seven studies met the inclusion criteria and included 25,383 patients. A 600mg clopidogrel loading was associated with a 34% relative risk reduction of MACE (RR=0.66; 95% confidence intervals CI=0.52-0.84; p<0.001). Sub-analysis revealed a 47% risk reduction of MACE in randomised trials (RR=0.53; 95%CI=0.32-0.88; p=0.01) and a 31% relative risk reduction in non-randomised trials (RR=0.69; 95%CI=0.54-0.90; p=0.005) in patients receiving 600mg loading with clopidogrel. In patients suffering from acute coronary syndrome, 600mg clopidogrel loading was associated with a 24% relative risk reduction in MACE (RR=0.76; 95%CI=0.60-0.95; p=0.02). Importantly, the 600mg clopidogrel loading dose was not associated with an increased risk of major bleedings (RR=0.91; 95%CI=0.73-1.15; p=0.44). Conclusions This meta-analysis demonstrates that intensified clopidogrel loading with 600mg reduces the rate of major cardiovascular events without increase in major bleeding compared to 300mg in patients undergoing PCI during one month follow-up.

Comprehensive Meta-Analysis of Safety and Efficacy of Bivalirudin Versus Heparin With or Without Routine Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndrome

OBJECTIVES The aim of this meta-analysis was to compare the 30-day safety and efficacy of bivalirudin with those of heparin with or without routine administration of a glycoprotein IIb/IIIa inhibitor (GPI) in patients with acute coronary syndrome (ACS). BACKGROUND Bivalirudin has been a mainstay of anticoagulation in patients with ACS compared with heparin. The extent to which trial results have been affected by the coadministration of heparin with a GPI, however, remains unclear. METHODS A total of 13 randomized, controlled trials involving 24,605 patients were included. RESULTS There was no significant difference in 30-day mortality or myocardial infarction rate with bivalirudin compared with heparin with or without routine GPI administration. A reduction of 30-day major bleeding was observed with bivalirudin compared with heparin that was significant when GPI was routinely administered (odds ratio [OR]: 0.52, 95% confidence interval [CI]: 0.45 to 0.60), p < 0.001) but not with provisionally administered GPI (OR: 0.66, 95% CI: 0.33 to 1.32; p = 0.24). The occurrence of stent thrombosis (ST) at 30 days was significantly increased with bivalirudin compared with heparin plus routinely administered GPI (OR: 1.67, 95% CI: 1.13 to 2.45, p = 0.02), but not compared with heparin plus provisionally administered GPI (OR: 2.08, 95% CI: 0.35 to 12.32, p = 0.42). The rate of acute ST (≤ 24 h), however, was almost 4.5-fold higher with bivalirudin compared with heparin with or without GPI, whereas the rate of subacute ST (24 h to 30 days) did not differ significantly. CONCLUSIONS Overall, bivalirudin in ACS patients is associated with a significant reduction of major bleeding compared with heparin plus routinely administered GPI, but with a marked increase in ST rates compared with heparin with or without GPI.

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.