Several randomized trials and a previous meta-analysis have shown significant benefits from Gp IIb-IIIa inhibitors, especially abciximab. Recent randomized trials (BRAVE-3 and HORIZON trials) have shown no benefits from adjunctive Gp IIb-IIIa inhibitors on the top of clopidogrel administration. However, the relatively low mortality may have hampered the conclusion of these recent trials. Thus, the aim of the current study was to perform an update meta-analysis of randomized trials on adjunctive Gp IIb-IIIa inhibitors in primary angioplasty, and to evaluate by meta-regression analysis, whether the results may be related to risk profile.
We obtained results from all randomized trials evaluating the benefits of adjunctive Gp IIb-IIIa inhibitors among STEMI patients undergoing primary angioplasty. The literature was scanned by formal searches of electronic databases (MEDLINE and CENTRAL) from January 1990 to September 2008. The following key words were used: randomized trial, myocardial infarction, reperfusion, primary angioplasty, Gp IIb-IIIa inhibitors, abciximab, tirofiban, and eptifibatide. Clinical endpoint was mortality at 30 days. Major bleeding complications were assessed as safety endpoint. No language restriction was applied. A total of 16 randomized trials were finally included in the meta-analysis, involving 10 085 patients (5094 or 50.5% in the Gp IIb-IIIa inhibitors group and 4991 or 49.5% in the control group. Gp IIb-IIIa inhibitors did not reduce 30 day mortality (2.8 vs. 2.9%, P = 0.75) or re-infarction (1.5 vs. 1.9%, P = 0.22), but were associated with higher risk of major bleeding complications (4.1 vs. 2.7%, P = 0.0004). However, we observed a significant relationship between patient's risk profile and benefits from adjunctive Gp IIb-IIIa inhibitors in terms of death (P = 0.008) but not re-infarction (P = 0.25).
This meta-analysis shows a significant relationship between benefits in mortality from Gp IIb-IIIa inhibitors and patient's risk profile. Thus, Gp IIb-IIIa inhibitors should be strongly considered among high-risk patients.
To assess the incidence, timing, and relation of drug-eluting stent (DES) thrombosis to discontinuation of clopidogrel therapy.
This prospective observational cohort study included 6816 consecutive patients that underwent successful DES implantation. Primary endpoint was definite stent thrombosis (ST). During 4 years of follow-up, definite ST was observed in 73 patients, corresponding to a cumulative incidence of 1.2%. Cumulative incidence of ST at 30 days was 0.5 and 0.8% at 1 year, respectively. Discontinuation of clopidogrel therapy was significantly associated with ST only in the first 6 months after the procedure (P < 0.001). During that period, the median time interval from clopidogrel discontinuation to ST was 9 days [interquartile range (IQR) 5.5–22.5] while thereafter it was 104.3 days (IQR 7.4–294.8).
The 4 year incidence of ST after DES implantation is low. A relevant number of ST occur early after discontinuation of clopidogrel therapy. The dependence of ST on discontinuation of clopidogrel therapy seems to be mostly confined to the first 6 months after DES implantation. However, specifically designed randomized studies are required to establish the optimal length of clopidogrel therapy after DES implantation.
The ability of mesenchymal stem cells (MSCs) to heal the chronically injured heart remains controversial. Here we tested the hypothesis that autologous MSCs can be safely injected into a chronic myocardial infarct scar, reduce its size, and improve ventricular function.
Female adult Göttingen swine (n = 15) underwent left anterior descending coronary artery balloon occlusion to create reproducible ischaemia–reperfusion infarctions. Bone-marrow-derived MSCs were isolated and expanded from each animal. Twelve weeks post-myocardial infarction (MI), animals were randomized to receive surgical injection of either phosphate buffered saline (placebo, n = 6), 20 million (low dose, n = 3), or 200 million (high dose, n = 6) autologous MSCs in the infarct and border zone. Injections were administered to the beating heart via left anterior thoracotomy. Serial cardiac magnetic resonance imaging was performed to evaluate infarct size, myocardial blood flow (MBF), and left ventricular (LV) function. There was no difference in mortality, post-injection arrhythmias, cardiac enzyme release, or systemic inflammatory markers between groups. Whereas MI size remained constant in placebo and exhibited a trend towards reduction in low dose, high-dose MSC therapy reduced infarct size from 18.2 ± 0.9 to 14.4 ± 1.0% (P = 0.02) of LV mass. In addition, both low and high-dose treatments increased regional contractility and MBF in both infarct and border zones. Ectopic tissue formation was not observed with MSCs.
Together these data demonstrate that autologous MSCs can be safely delivered in an adult heart failure model, producing substantial structural and functional reverse remodelling. These findings demonstrate the safety and efficacy of autologous MSC therapy and support clinical trials of MSC therapy in patients with chronic ischaemic cardiomyopathy.
This study investigated the effects of irbesartan vs. enalapril, with early vs. late treatment, on markers of inflammation and ischaemic heart disease in patients with non-ST-segment elevation acute coronary syndrome (NSTEACS).
Patients hospitalized with ischaemic symptoms and evidence of NSTEACS were randomized to early (at hospitalization) or late (at hospital discharge) treatment with irbesartan 150 mg/day followed by 300 mg/day on day 15 (n = 212) or enalapril 10 mg/day followed by 20 mg/day on day 15 (n = 217) to day 60. The primary endpoint was the change from baseline in high-sensitivity C-reactive protein (hs-C-reactive protein) at day 60; secondary endpoints included changes in troponin I, B-type natriuretic peptide, microalbuminuria, interleukin 6, myeloperoxidase, secretory non-pancreatic type II phospholipase A2, ischaemia-modified albumin, soluble CD40 ligand, matrix metalloproteinase-9, aldosterone, and blood pressure. High-sensitivity C-reactive protein levels were comparable in both the irbesartan and enalapril treatment arms. There were no treatment-related differences in any of the biomarkers measured. Changes in inflammatory markers were unaffected by the timing of treatment initiation. Both treatments were well tolerated, with no differences in major adverse cardiac events.
In patients with NSTEACS, inflammatory markers decreased over time in both treatment arms, with no differences between irbesartan and enalapril.
Type II secretory phospholipase A2 (sPLA2-IIA) is widely expressed in various cell types and may trigger local inflammatory responses. We sought to evaluate whether systemic sPLA2 is associated with prognosis in patients with coronary heart disease (CHD).
Plasma concentrations of sPLA2 (ELISA) and sPLA2 activity (selective fluorometric assay) were measured at baseline in a cohort of 1024 patients aged 30–70 years with CHD. The Cox-proportional hazards model was used to determine the prognostic value of sPLA2 on a combined cardiovascular disease (CVD) endpoint after adjustment for covariates. During a mean follow-up of 4.1 years, 93 patients (9.1%) experienced a secondary CVD event. In a multivariable model, sPLA2 mass and activity were associated with hazard ratios of secondary CVD events of 2.07 (95% CI, 1.17–3.66) and 1.65 (95% CI 0.96–2.84) for mass and activity, respectively, when extreme tertiles were compared. Further adjustment for cystatin C, N-terminal-probrain natriuretic peptide, C-reactive protein, and lipoprotein-associated phospholipase A2 attenuated the associations, still showing a positive trend for mass but a less clear pattern for activity. However, when sPLA2 mass and activity were analysed as continuous variables both still showed a statistically significant increase in risk in all models.
Secretory phospholipase A2 mass and activity appear to be predictive of secondary CVD events in patients with CHD.
The aim of this study was to determine whether growth differentiation factor-15 (GDF-15) predicts mortality and morbidity after cardiac resynchronization therapy (CRT). Growth differentiation factor-15, a transforming growth factor-β-related cytokine which is up-regulated in cardiomyocytes via multiple stress pathways, predicts mortality in patients with heart failure treated pharmacologically.
Growth differentiation factor-15 was measured before and 360 days (median) after implantation in 158 patients with heart failure [age 68 ± 11 years (mean ± SD), left ventricular ejection fraction (LVEF) 23.1 ± 9.8%, New York Class Association (NYHA) class III (n = 117) or IV (n = 41), and QRS 153.9 ± 28.2 ms] undergoing CRT and followed up for a maximum of 5.4 years for events. In a stepwise Cox proportional hazards model with bootstrapping, adopting log GDF-15, log NT pro-BNP, LVEF, and NYHA class as independent variables, only log GDF-15 [hazard ratio (HR), 3.76; P = 0.0049] and log NT pro-BNP (HR, 2.12; P = 0.0171) remained in the final model. In the latter, the bias-corrected slope was 0.85, the optimism (O) was –0.06, and the c-statistic was 0.74, indicating excellent internal validity. In univariate analyses, log GDF-15 [HR, 5.31; 95% confidence interval (CI), 2.31–11.9; likelihood ratio (LR) 2 = 14.6; P < 0.0001], NT pro-BNP (HR, 2.79; 95% CI, 1.55–5.26; LR 2 = 10.4; P = 0.0004), and the combination of both biomarkers (HR, 7.03; 95% CI, 2.91–17.5; LR 2 = 19.1; P < 0.0001) emerged as significant predictors. The biomarker combination was associated with the highest LR 2 for all endpoints.
Pre-implant GDF-15 is a strong predictor of mortality and morbidity after CRT, independent of NT pro-BNP. The predictive value of these analytes is enhanced by combined measurement.
To investigate the efficacy and safety of a cardiac resynchronization therapy with cardioverter–defibrillator (CRT-D) device with simplified ventricular tachycardia management in patients with non-ischaemic heart failure (HF) and primary prevention implantable cardioverter defibrillator (ICD) indication.
Prospective, controlled, parallel, multicentre, non-randomized study enrolling 324 primary prevention non-ischaemic HF patients implanted with CRT-D devices from 2004 to 2007: Protect group, 164 patients implanted with a Medtronic Insync III Protect device and Control group, 160 patients utilizing other Medtronic CRT-D devices.
Efficacy was assessed by computing appropriate and inappropriate detections and therapies during follow-up; safety compared hospitalizations and syncopal events between groups. Ninety per cent of both ventricular and supraventricular tachyarrhythmias terminated within the 13–29 beat detection interval with the Protect algorithm. The Protect group showed a significantly better event-free survival to first delivered therapy for total (P = 0.0001), appropriately treated (P = 0.002), and inappropriately treated episodes (P = 0.017). The total number of delivered shocks was significantly lower in the Protect group (22 vs. 59, P < 0.0001). In the Protect group, a significantly reduced HF hospitalization (hazard ratio 0.38, 95% CI 0.15–0.98, P = 0.044) was observed without any increase of syncope or death.
A simplified CRT-D device with fixed long detection reduced overall ICD therapy burden and HF hospitalizations without entailing any additional adverse events in primary prevention non-ischaemic HF patients.