Comparative effectiveness of novel oral anticoagulants for atrial fibrillation: evidence from pair-wise and warfarin-controlled network meta-analyses.

INTRODUCTION: Novel oral anticoagulants have been tested against warfarin for atrial fibrillation, yet no direct comparison is available. We thus aimed to perform pair-wise (direct) and warfarin-adjusted network (i.e. indirect) meta-analyses of novel oral anticoagulants for atrial fibrillation. METHODS: Databases were searched for randomized warfarin-controlled trials of novel anticoagulants for non-valvular atrial fibrillation. The primary end-point was long-term stroke/systemic embolism. Odds ratios (95% intervals) were computed with RevMan and WinBUGS. RESULTS: Seven trials (52701 patients) were included, focusing on apixaban, dabigatran, edoxaban and rivaroxaban. Pair-wise meta-analysis showed that after a weighted average of 23 months these novel anticoagulants lead to significant reductions in the risk of stroke/systemic embolism (odds ratio=0.81 [0.71-0.92], I2=23%) and all cause death (odds ratio=0.88 [0.82-0.95], I2=0%) in comparison to warfarin. Network meta-analysis showed that apixaban and dabigatran proved similarly superior to warfarin in preventing stroke/systemic embolism (odds ratio=0.78 [0.62-0.96] for apixaban vs warfarin; odds ratio=0.66 [0.52-0.84] for high-dose dabigatran vs warfarin; odds ratio for apixaban vs high-dose dabigatran=1.17 [0.85-1.63]), but apixaban was associated with fewer major bleedings (odds ratio=0.73 [0.57-0.93]) and drug discontinuations (odds ratio=0.64 [0.52-0.78]) than dabigatran. Rivaroxaban did not reduce stroke/systemic embolism (odds ratio=0.87 [0.71-1.07]) or major bleedings in comparison to warfarin (odds ratio=0.87 [0.71-1.07]) and was associated with more major bleedings in comparison to apixaban (odds ratio=1.52 [1.19-1.92]). Data for edoxaban were inconclusive. CONCLUSIONS: Novel oral anticoagulants appear as a very promising treatment option for atrial fibrillation.

The rough guide to systematic reviews and meta-analyses.

The hierarchy of evidence based medicine postulates that systematic reviews of homogenous randomized trials represent one of the uppermost levels of clinical evidence. Indeed, the current overwhelming role of systematic reviews, meta-analyses and meta-regression analyses in evidence based heath care calls for a thorough knowledge of the pros and cons of these study designs, even for the busy clinician. Despite this sore need, few succinct but thorough resources are available to guide users or would-be authors of systematic reviews. This article provides a rough guide to reading and, summarily, designing and conducting systematic reviews and meta-analyses.

Prediction of functional capacity by low-dose dobutamine stress echocardiography in chronic heart failure.

AIM: The aim of this study was to determine if low-dose dobutamine stress echocardiography (LD-DSE) is associated with functional capacity in unselected elderly patients with chronic heart failure. METHODS: This was a prospective trial. Thirty five consecutive patients were included, with age >65 years and left ventricular dysfunction (12 ischemic), by blindly assessed LD-DSE and cardiopulmonary exercise testing (CPT). Contractile reserve was defined as a change (D) in wall motion score index (WMSI) = or <0.2 at peak dose dobutamine. At CPT treadmill exercise time, peak VO2, %Vo2 and VE/VCO2 slope were determined. Preserved functional capacity was defined as percent of maximal predicted O2 consumption (%VO2) >80%. Baseline NT-proBNP plasma levels were assessed. RESULTS: CPT variables were not related to clinical and baseline echocardiography characteristics but were related to DWMSI (exercise time, P=0.004; peak VO2, P=0.008; %VO2, P<0.001; VE/Vco2, P<0.001). Contractile reserve was present in 16 of 17 patients with preserved functional capacity (sensitivity=94%) and in 2 of 13 patients without (specificity=85%). Baseline NT-proBNP levels were lower in patients with contractile reserve (476+/-365 pg/mL) than in those without (1 345+/-1 219 pg/mL) (P=0.019), but were mildly related to CPT variables (P=0.049 and 0.027 with exercise time and %VO2, respectively). CONCLUSION: Contractile reserve elicited at LD-DSE is associated with functional capacity in unselected elderly patients with chronic heart failure.

Percutaneous coronary intervention with everolimus-eluting stents (Xience V): systematic review and direct-indirect comparison meta-analyses with paclitaxel-eluting stents (Taxus) and sirolimus-eluting stents (Cypher).

First-generation drug-eluting stents (DES) have brought major improvements in results of percutaneous coronary intervention (PCI). However, there is currently debate on the safety of these first-generation DES, given the potential for late stent thrombosis, especially after discontinuation of dual antiplatelet therapy. Second-generation DES, such as zotarolimus- (Endeavor) and everolimus-eluting stents (Xience V), have recently become available in the USA and/or Europe. Indeed, the Xience V stent holds the promise of superior anti-restenotic efficacy as well as long-term safety, yet there is uncertainty on its risk-benefit balance. Authors conducted a systematic review of basic science and clinical evidence on the Xience V, by thoroughly searching PubMed and online databases (updated September 2007). They also compared the clinical results of Xience V vs paclitaxel-eluting stents (Taxus) and sirolimus-eluting stents (Cypher) by means of direct and indirect comparison meta-analysis. A total of three clinical studies has been retrieved focusing on Xience V, however both most recent and important trials were still unpublished. The first trial compared Xience V vs bare-metal stents, whereas the other two randomized trials compared Xience V vs Taxus. Direct meta-analysis of Xience V vs Taxus showed that Xience V was significantly superior to Taxus in preventing binary angiographic restenosis and target lesion revascularization (P<0.05 for both). Indirect comparison between Xience V and Cypher, exploiting a recent 16-trial large meta-analysis, showed that Xience V was at least as effective as Cypher in preventing target lesion revascularization (P=0.12). Everolimus-eluting stents (Xience V) appear as a major breakthrough in coronary interventions, and superior efficacy has already been demonstrated in comparison to paclitaxel-eluting stents (Taxus). Data available to date also suggest that Xience V is at least as effective as sirolimus-eluting stents (Cypher). Whether long-term results and direct comparison to Cypher will also be favorable remains to be established by future clinical trials.

Assessment of left ventricular systolic dysfunction by tissue Doppler imaging to detect subclinical cardiomyopathy early after anthracycline therapy.

AIM: Anthracycline (ANT) chemotherapy for breast cancer, while associated with high response rates, is fraught by risks of irreversible cardiotoxicity. Unfortunately means to detect such cardiotoxicity early on and at a sublinical stage are lacking. We evaluated the role of systolic tissue Doppler imaging (TDI) in appraising postchemotherapy left ventricular (LV) remodelling. METHODS: Patients undergoing ANT-chemotherapy for breast cancer were enrolled, and underwent baseline and >6-months echocardiography (standard and TDI). According to the pattern of LV-TDI systolic remodelling from baseline to follow-up, patients were stratified in: group 1 (no LV-TDI worsening), group 2 (minor LV-TDI worsening), and group 3 (major LV-TDI worsening). Fifty-six patients were included (follow-up 9+/-6 months). RESULTS: At baseline, no patient had abnormal LV ejection fraction (LVEF), LV-TDI systolic dysfunction or New York Heart Association (NYHA) >1. Follow-up overall analysis showed significant deterioration in LVEF, end-diastolic diameter (EDD) end-systolic diameter (ESD), and TDI-systolic parameters (all P<0.05). Specifically, 29 (51.8%) patients showed no adverse LV-TDI systolic remodelling, while 17 (30.4%) were in group 2, and 10 (17.9%) in group 3. All groups shared similar conditions at baseline. Patients with adverse LV-TDI remodelling had significant increases in EDD and ESD, as well as a significantly decreased LVEF (all P<0.05). No patient in group 1 had abnormal LVEF at follow-up, while 1 patient in group 2 and 2 patients in group 3 had abnormal LVEF (P<0.05). CONCLUSION: Subclinical systolic dysfunction occurs in almost 50% of patients early after chemotherapy for breast cancer, with a more adverse by LV-TDI remodelling implying a more pronounced deterioration of standard echocardiographic parameters.

Impaired coronary and myocardial flow in severe aortic stenosis is associated with increased apoptosis: a transthoracic Doppler and myocardial contrast echocardiography study.

OBJECTIVE: To test the hypothesis that impaired coronary and myocardial blood flow are linked with increased myocyte apoptosis, thus establishing a link between pressure overload and left ventricular (LV) remodelling. METHODS AND RESULTS: Peak diastolic coronary blood flow velocity (CBFV) was evaluated at transthoracic Doppler echocardiography, and signal intensity (SI) and the rate of SI rise (beta) were measured at myocardial contrast echocardiography in 11 patients with severe aortic stenosis and LV hypertrophy. In the same patients, biopsies were obtained from the anterolateral LV free wall during surgery and analysed for cardiomyocyte apoptosis. LV mass corrected CBFV (CBFVI) was significantly lower in patients than in controls (median 0.100 cm.g/s (interquartile range 0.07-0.115) v 0.130 cm.g/s (0.130-0.160), p = 0.002). Similarly, SI*beta was significantly lower in patients than in controls (11 1/s (8-66) v 83 1/s (73-95), p = 0.001). Apoptotic rate was increased in aortic stenosis more than 100-fold versus controls (1.2% (0.8-1.4) v 0.01% (0.01-0.01), p < 0.001) and inversely correlated with lower CBFVI and SI*beta (r = -0.77, p = 0.001 for both). CONCLUSIONS: Patients with severe aortic stenosis and LV hypertrophy have impaired myocardial perfusion, which is associated with enhanced cardiomyocyte apoptosis. Impaired myocardial perfusion and the ensuing oxygen demand-supply imbalance may, at least partially, be responsible for increased apoptosis and possible transition to heart failure, thus establishing a link between pressure overload, LV remodelling, and heart failure.