Hisato Takagi

A further meta-analysis of population-based screening for abdominal aortic aneurysm

PURPOSE It remains unclear whether population-based screening for abdominal aortic aneurysm (AAA) in men reduces all-cause long-term mortality. We performed an updated meta-analysis of randomized controlled trials of AAA screening for prevention of long-term mortality in men. METHODS To identify all randomized controlled trials of population-based AAA screening with long-term (≥ 10 year) follow-up in men, MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials were searched through June 2009. Data regarding AAA-related and all-cause mortality (including Cox regression hazard ratios [HRs] and 95% confidence intervals [CIs]) were abstracted from each individual study. For each study, data regarding mortality in both the screening and control groups were used to generate odds ratios (ORs) and 95% CIs. Study-specific estimates were combined using inverse variance-weighted averages of logarithmic ORs or HRs (or risk ratios where no HR was reported) in both fixed- and random-effects models. RESULTS Our search identified four randomized controlled trials of population-based AAA screening with long-term follow-up in men aged ≥ 65 years. Pooled analysis demonstrated a statistically significant reduction in AAA-related mortality (random-effects OR, 0.55; 95% CI, 0.36 to 0.86; P = .008; P for heterogeneity = .01; absolute risk reduction [ARR], 4 per 1000; number needed to screen [NNS], 238; random-effects HR, 0.55; 95% CI, 0.35 to 0.86; P = .009; P for heterogeneity = .009) and revealed a statistically nonsignificant reduction (but a strong trend toward a significant reduction) in all-cause mortality (fixed-effects OR, 0.98; 95% CI, 0.95 to 1.00 [1.001]; P = .06; P for heterogeneity = .93; ARR, 5 per 1000; NNS, 217; fixed-effects HR, 0.98; 95% CI, 0.96 to 1.00 [1.0001]; P ≥ .05 [P = .052]; P for heterogeneity = .74) with AAA screening relative to control. CONCLUSION The results of our analysis suggest that population-based screening for AAA reduces AAA-related long-term mortality by 4 per 1000 over control in men aged ≥ 65 years. Whereas, screening for AAA shows a strong trend toward a significant reduction in all-cause long-term mortality by 5 per 1000, which does not narrowly reach statistical significance.

A meta-analysis of clinical studies of statins for prevention of abdominal aortic aneurysm expansion

BACKGROUND Despite the absence of a relationship between cholesterol and abdominal aortic aneurysm (AAA) expansion, there is evidence from a number of studies to suggest that statin therapy may influence AAA expansion, presumably through pleiotropic effects. To confirm whether statin therapy is associated with less AAA expansion, we performed a meta-analysis of clinical controlled studies of statin therapy for prevention of AAA expansion. METHODS To identify all clinical studies of statin therapy vs control (no statins) enrolling patients with small (≤ 55 mm) AAA, MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched. For each study, data regarding AAA expansion in both the statin and control groups were used to generate standardized mean differences (SMDs; <0 favoring statin therapy; >0 favoring control) and 95% confidence intervals (CIs). Study-specific estimates were combined using inverse variance-weighted averages of logarithmic SMDs in fixed-effects and random-effects models. RESULTS We identified five clinical controlled studies of statin therapy vs control enrolling patients with small AAA, including no randomized and five observational studies. Our meta-analysis included data on 697 patients with small AAA received statin therapy or no statins. Pooled analysis demonstrated that statin therapy was statistically significantly associated with less expansion rates (random-effects SMD, -0.50; 95% CI, -0.75 to -0.25; P = .0001). There was statistically significant trial heterogeneity of results (P = .03). Exclusion of any single trial from the analysis did not substantively alter the overall result of our analysis. There was no evidence of significant publication bias (P = .81). CONCLUSION Statin therapy is associated with less expansion rates in patients with small AAA. To confirm our results and more accurately assess the effect of statins on AAA expansion, a large randomized trial is needed.

Worse long-term survival after off-pump than on-pump coronary artery bypass grafting

OBJECTIVE To determine whether off-pump coronary artery bypass grafting (CABG) is associated with worse long-term survival compared with on-pump CABG. We performed a meta-analysis of adjusted observational studies and randomized controlled trials. METHODS MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched through March 2014. Eligible studies were randomized controlled trials and adjusted observational studies (in which appropriate statistical methods adjusting for confounders had been used) of off-pump versus on-pump CABG that had reported long-term (≥5-year) all-cause mortality as an outcome. RESULTS Of 478 potentially relevant studies screened initially, 5 randomized trials and 17 observational studies, enrolling a total of 104,306 patients, were identified and included. A pooled analysis of all 22 studies demonstrated a statistically significant 7% increase in long-term all-cause mortality with off-pump relative to on-pump CABG (hazard ratio, 1.07; 95% confidence interval, 1.03-1.11; P=.0003). Although a pooled analysis of 5 randomized trials (1486 patients) demonstrated a statistically nonsignificant 14% increase in mortality with off-pump relative to on-pump CABG (hazard ratio, 1.14; 95% confidence interval, 0.84-1.56; P=.39), another pooled analysis of 17 observational studies (102,820 patients) demonstrated a statistically significant 7% increase in mortality with off-pump relative to on-pump CABG (hazard ratio, 1.07; 95% confidence interval, 1.03-1.11; P=.0004). CONCLUSIONS A meta-analysis of 22 studies, enrolling a total of >100,000 patients, showed that off-pump CABG is likely associated with worse long-term (≥5-year) survival compared with on-pump CABG.

Review and Meta-Analysis of Randomized Controlled Clinical Trials of Remote Ischemic Preconditioning in Cardiovascular Surgery

To determine whether remote ischemic preconditioning (RIPC) is beneficial for patients who undergo cardiovascular surgery (CVS), a systematic review and meta-analysis of randomized controlled clinical trials of RIPC for the prevention of myocardial injury in CVS was performed. All prospective randomized controlled clinical trials of RIPC versus control that enrolled patients who underwent CVS were identified using a 2-level search strategy. First, a public-domain database (Medline) was searched using a Web-based search engine (PubMed). Second, relevant studies were identified through a manual search of secondary sources, including references of initially identified reports and a search of reviews and commentaries. The search identified 4 prospective randomized controlled clinical trials of RIPC versus control that enrolled patients who underwent CVS. In total, this meta-analysis included data on 184 patients who underwent CVS randomized to RIPC or control. Pooled analysis of the 4 trials demonstrated a statistically significant reduction in biomarkers of myocardial injury with RIPC relative to control (standardized mean difference -0.81, 95% confidence interval -1.29 to -0.33, p = 0.0010). In conclusion, the present study, the first systematic review and meta-analysis of randomized controlled clinical trials, demonstrated a statistically significant benefit of RIPC over control for reduction in biomarkers of myocardial injury in CVS patients.

Circulating matrix metalloproteinase-9 concentrations and abdominal aortic aneurysm presence: a meta-analysis.

To summarize the present evidence for an association between matrix metalloproteinase-9 (MMP-9) and abdominal aortic aneurysm (AAA) presence, we performed a meta-analysis of case-control studies that compared circulating MMP-9 concentrations between patients with AAA and subjects without AAA. MEDLINE database was searched to identify all case-control studies. For each study, data regarding serum or plasma MMP-9 concentrations in both the AAA and control groups were used to generate standardized mean differences (SMDs) and 95% confidence intervals (CIs). Study-specific estimates were combined using inverse variance-weighted average of logarithmic SMDs in both fixed- and random-effects models. Our search identified eight eligible studies including 580 patients with AAA and 258 subjects without AAA. Pooled analysis demonstrated significantly higher circulating MMP-9 concentrations in the AAA group than those in the control group in random-effect models (SMD, 0.70; 95% CI, 0.23-1.17; P=0.004). There was significant study heterogeneity of results (P<0.00001) but no evidence of significant publication bias (P=0.1376). We found that, based on a systematic review and meta-analysis, circulating MMP-9 concentrations are higher in patients with AAA than those in subjects without AAA. Higher circulating MMP-9 concentrations are associated with AAA presence.

Hepatocyte growth factor gene transfer into the liver via the portal vein using electroporation attenuates rat liver cirrhosis

Although a variety of gene transfer methods to the liver have been designed, there are some problems such as the transfection efficiency and safety. In the present study, we developed a modified method of gene transfer into the liver by infusion of plasmid DNA via the portal vein followed by electroporation. After green fluorescence protein gene transfer, transgene expressions were detected in 24 h, and then maximally at 3 days, and persisted for 3 weeks. Histological analysis revealed that very mild tissue damage was induced in the liver to which electroporation was applied. In the second study, human hepatocyte growth factor (HGF) was more detected in the liver injected with 500 μg of human HGF gene than 100 μg of human HGF gene. However, serum HGF did not increase with 100 or 500 μg of human HGF gene. Moreover, 500 μg of HGF gene transfer into the liver by using this method could achieve the long survival of all dimethylnitrosamine-treated rats and attenuate the fibrous regions in the liver. These results suggest that HGF gene transfer into the liver via the portal vein using electroporation might be one of the useful methods for the treatment of various liver diseases.

Off-Pump Coronary Artery Bypass May Increase Late Mortality: A Meta-Analysis of Randomized Trials

BACKGROUND Although a lot of randomized trials of off-pump coronary artery bypass grafting (CABG) versus on-pump CABG were conducted, the majority of them reported only early outcomes. Previous meta-analyses of a few randomized trials found no differences for 1-year to 2-year mortality. METHODS We focused late (> or = 1 year) all-cause mortality and performed a meta-analysis of randomized controlled trials of off-pump versus on-pump CABG. The MEDLINE, the EMBASE, and the Cochrane Central Register of Controlled Trials were searched using PubMed and OVID. For each study, data regarding all-cause mortality in both the off-pump and on-pump groups were used to generate risk ratios (RRs) and 95% confidence intervals. Study-specific estimates were combined using inverse variance-weighted averages of logarithmic RRs in both fixed-effects and random-effects models. RESULTS Our search identified 11 results of 12 randomized trials (4,326 patients) of off-pump versus on-pump CABG. Pooled analysis demonstrated a statistically significant increase in midterm all-cause mortality by a factor of 1.37 with off-pump relative to on-pump CABG (RR, 1.373; 95% confidence interval, 1.043 to 1.808). Exclusion of any single result, except for the largest (>2,000 patients) trial, from the analysis did not substantively alter the overall result of our analysis. Eliminating the largest trial demonstrated a statistically nonsignificant benefit of on-pump over off-pump CABG for midterm all-cause mortality (RR, 1.344; 95% confidence interval, 0.952 to 1.896). CONCLUSIONS The results of our analysis suggest that off-pump CABG may increase late all-cause mortality by a factor of 1.37 over on-pump CABG. Longer term mortality from randomized trials of off-pump versus on-pump CABG is needed.

A contemporary meta-analysis of Dacron versus polytetrafluoroethylene grafts for femoropopliteal bypass grafting

BACKGROUND The present study provides a contemporary and comprehensive summation of midterm patency rates of polyester (Dacron) or polytetrafluoroethylene (PTFE) grafts in femoropopliteal bypass grafting based on a meta-analysis consisting only of randomized controlled trials. METHODS MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched to identify all randomized controlled trials of Dacron vs PTFE grafts in femoropopliteal bypass grafting. Seven trials were found. Survival data were combined to yield the pooled cumulative primary patency. We estimated the log hazard ratio (HR) for each 1-month interval and then combined the HRs in a stratified way across intervals to obtain an overall log HR for each trial. Study-specific estimates were combined using inverse variance-weighted averages of logarithmic HRs in fixed-effects and random-effects models. RESULTS The pooled cumulative primary patency of Dacron and PTFE grafts was, respectively, 60.2% (95% confidence interval [CI], 56.4%-64.0%) and 53.8% (95% CI, 46.8%-60.9%) at 3 years, and 49.2% (95% CI, 45.6%-52.7%) and 38.4% (95% CI, 32.2%-44.6%) at 5 years. Pooled analysis of the seven trials demonstrated no difference in HR for graft occlusion with Dacron relative to PTFE grafts (random-effects HR, 0.87; 95% CI, 0.67-1.12; P = .27 for effect; P = .03 for heterogeneity). CONCLUSION Either Dacron or PTFE grafts can be used in femoropopliteal bypass grafting with no significant differences in midterm graft patency at 5 years (49.2% vs 38.4%) when the autologous saphenous vein is unavailable.

Skeletal muscle targeting in vivo electroporation-mediated HGF gene therapy of bleomycin-induced pulmonary fibrosis in mice

Lung fibrosis is a common feature of interstitial lung diseases, and apoptosis and fibrinogenesis play critical roles in its formation and progression. Hepatocyte growth factor (HGF) is one of the ideal therapeutic agents for prevention of lung fibrosis because of its antiapoptotic and fibrinolytic effects. The aim of this study is to establish nonviral HGF gene therapy of bleomycin-induced lung fibrosis avoiding the viral vector-related side effects. C57BL/6 mice were injected with 3.0 mg/kg body weight of bleomycin intratracheally. Following bleomycin injection, 50 μl of pUC-HGF (1 mg/ml) was injected into each of the quadriceps muscle. Immediately after plasmid injection, in vivo electroporation was performed with pulse generator. Skeletal muscle-targeting electroporation induced transgene expression on day 1 and persisted for 4 weeks, and human HGF was also detected in the lung. In mice transferred with HGF, pathological score (1.0±0.3 vs 3.2±0.6), TUNEL-positive cell index (4.5±1.1 vs 14.2±3.1), and hydroxyproline content (9.0±1.3 vs 14.4±5.1 μmol/g) were significantly reduced compared with the control. Furthermore, survival rate of HGF mice was significantly improved compared with the control. Our data indicate that HGF gene therapy with a single skeletal muscle-targeting electroporation has a therapeutic potential for bleomycin-induced lung fibrosis and this strategy can be applied as a practical gene therapy protocol for various organs.

A meta-analysis of adjusted hazard ratios from 20 observational studies of bilateral versus single internal thoracic artery coronary artery bypass grafting

OBJECTIVE In 2001, a landmark meta-analysis of bilateral internal thoracic artery (BITA) versus single internal thoracic artery (SITA) coronary artery bypass grafting for long-term survival included 7 observational studies (only 3 of which reported adjusted hazard ratios [HRs]) enrolling approximately 16,000 patients. Updating the previous meta-analysis to determine whether BITA grafting reduces long-term mortality relative to SITA grafting, we exclusively abstracte, then combined in a meta-analysis, adjusted (not unadjusted) HRs from observational studies. METHODS MEDLINE and EMBASE were searched until September 2013. Eligible studies were observational studies of BITA versus SITA grafting and reporting an adjusted HR for long-term (≥4 years) mortality as an outcome. Meta-regression analyses were performed to determine whether the effects of BITA grafting were modulated by the prespecified factors. RESULTS Twenty observational studies enrolling 70,897 patients were identified and included. A pooled analysis suggested a significant reduction in long-term mortality with BITA relative to SITA grafting (HR, 0.80; 95% confidence interval, 0.77 to 0.84). When data from 6 pedicled and 6 skeletonized internal thoracic artery studies were separately pooled, BITA grafting was associated with a statistically significant 26% and 16% reduction in mortality relative to SITA grafting, respectively (P for subgroup differences=.04). A meta-regression coefficient was significantly negative for the proportion of men (-0.00960; -0.01806 to -0.00114). CONCLUSIONS Based on an updated meta-analysis of exclusive adjusted HRs from 20 observational studies enrolling more than 70,000 patients, BITA grafting seems to significantly reduce long-term mortality. As the proportion of men increases, BITA grafting is more beneficial in reducing mortality.