Noninferiority trials test whether a new experimental treatment is not unacceptably less efficacious than an active control treatment already in use. With continuous improvements in health technologies, standard care, and clinical outcomes, the incremental benefits of newly developed treatments may be only marginal over existing treatments. Sometimes assigning patients to a placebo is unethical. In such circumstances, there has been increasing emphasis on the use of noninferiority trial designs. Noninferiority trials are more complex to design, conduct, and interpret than typical superiority trials. This paper reviews the concept of noninferiority trials and discusses some important issues related to them.
Humans

A meta-analysis was performed on the immunogenicity of Haemophilus influenzae type b (Hib) conjugate vaccines after 2 (2 and 4 months) and 3 doses (2, 4, and 6 months) in Korean infants. A database search of MEDLINE, KoreaMed, and Korean Medical Database was done. The primary outcome measure was the proportion of infants with anti-polyribosylribitol phosphate (PRP) concentrations > or =1.0 microgram/mL. Eight studies including eleven trials were retrieved. One trial reported on the diphtheria toxoid conjugate vaccine (PRP-D) and 2 trials each on the mutant diphtheria toxin (PRP-CRM) and Neisseria meningitidis outer-membrane protein (PRP-OMP) conjugate vaccine. Heterogeneity in study designs between trials on PRP-CRM was noted and one trial reported on a monovalent and another on a combination PRP-OMP vaccine. Thus, a meta-analysis was conducted only on the tetanus toxoid conjugate vaccine (PRP-T). After a primary series of 2 doses and 3 doses, 80.6% (95% confidence interval [CI]; 76.0-85.1%) and 95.7% (95% CI; 94.0-98.0%) of infants achieved an antibody level > or =1.0 microgram/mL, respectively. The immunogenic response to the PRP-T vaccine was acceptable after a primary series of 3 doses and also 2 doses. A reduced number of doses as a primary series could be carefully considered in Korean infants.
Antibodies/analysis ; Bacterial Capsules/*immunology/metabolism ; Haemophilus Vaccines/*immunology/metabolism ; Humans ; Infant ; Republic of Korea ; Tetanus Toxoid/chemistry/metabolism ; Vaccines, Conjugate/immunology/metabolism

PURPOSE: Surfactants have been used to improve oxygenation for infants with meconium aspiration syndrome (MAS). We evaluated the change of pulmonary indices after surfactant therapy for MAS through a systematic meta-analysis. METHODS: Relevant randomized controlled studies (RCTs) were identified by database searches in MEDLINE, EMBASE, and CENTRAL, up to June 2011, and by additional hand searches. Data were extracted regarding pulmonary indices, such as the oxygen index and arterial alveolar oxygen gradient. Meta-analyses were separately conducted for the studies of surfactant lavage therapy and surfactant bolus therapy. The risk of bias was assessed, and clinical as well as statistical heterogeneities were also investigated. RESULTS: Two RCTs for bolus surfactant therapy and two RCTs for surfactant lavage therapy were identified. The oxygenation index results were heterogeneous between the two studies in which bolus surfactant therapy was given, while a/A PO2 showed significantly better results in the treatment group over time after use of surfactant (12 hours: WMD 0.08, 95% CI 0.04-0.12; 24 hours: WMD 0.17, 95% CI 0.06-0.28). For surfactant lavage therapy, both studies consistently suggested an interventional benefit in terms of the pulmonary indices although it did not reach statistical significance. CONCLUSION: Surfactant therapy appeared to improve oxygenation of infants with MAS. Since a limited number of RCTs are available in the current literature and those studies were also clinically heterogeneous in terms of illness severity and the method of surfactant use, further research is needed to gather evidence to support surfactant therapy in MAS.
Bias (Epidemiology) ; Hand ; Humans ; Infant ; Infant, Newborn ; Meconium ; Meconium Aspiration Syndrome ; Oxygen ; Pulmonary Surfactants ; Surface-Active Agents ; Therapeutic Irrigation

BACKGROUND: To investigate the effects of dipeptidyl peptidase-4 (DPP-4) inhibitors on renal outcomes in patients with type 2 diabetes. METHODS: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched to identify randomized controlled trials (RCTs) of DPP-4 inhibitors from inception to September 2017. We selected eligible RCTs comparing DPP-4 inhibitors with placebo or other antidiabetic agents and reporting at least one renal outcome. A meta-analysis was conducted to calculate standardized mean differences, weighted mean differences (WMDs), relative risks (RRs), and 95% confidence intervals (CIs) for each renal outcome. RESULTS: We included 23 RCTs with 19 publications involving 41,359 patients. Overall changes in urine albumin-to-creatinine ratio were comparable between DPP-4 inhibitors and controls (P=0.150). However, DPP-4 inhibitors were associated with significantly lower risk of incident microalbuminuria (RR, 0.89; 95% CI, 0.80 to 0.98; P=0.022) and macroalbuminuria (RR, 0.77; 95% CI, 0.61 to 0.97; P=0.027), as well as higher rates of regression of albuminuria (RR, 1.22; 95% CI, 1.10 to 1.35; P<0.001) compared with controls. Although DPP-4 inhibitors were associated with small but significantly lower estimated glomerular filtration rate (WMD, −1.11 mL/min/1.73 m2; 95% CI, −1.78 to −0.44; P=0.001), there was no difference in the risk of end-stage renal disease between two groups (RR, 0.93; 95% CI, 0.76 to 1.14; P=0.475). CONCLUSION: DPP-4 inhibitors had beneficial renal effects mainly by reducing the risk of development or progression of albuminuria compared with placebo or other antidiabetic agents.
Albuminuria ; Diabetes Complications ; Diabetes Mellitus, Type 2 ; Diabetic Nephropathies ; Dipeptidyl-Peptidase IV Inhibitors ; Glomerular Filtration Rate ; Humans ; Hypoglycemic Agents ; Kidney Failure, Chronic

Purpose: To systematically review and evaluate the beneficial effects of preoperative androgen stimulation (PAS) on penile length, glans width, and postoperative complications in patients with hypospadias using meta-analysis. Materials and Methods: A comprehensive search of the published literature between 1980 and 2022 was done on PubMed, Embase, Google Scholar, Scopus, Web of Science, and Proquest. Studies of patients with 5-alpha reductase deficiency, differentiation sex disorder, or micro-penis without hypospadias were excluded. The full-text screening, quality assessment, and data acquisition were done independently by two reviewers. Meta-analysis was done to quantify the penile growth and postoperative complications. Results: The initial literature search yielded 2,389 records, wherein 32 studies were eligible for the systematic review and meta-analysis. Preoperative testosterone stimulation increased the penile length and glans width by 9.34 mm (95% CI: 6.71–11.97) and 3.26 mm (95% CI: 2.50–4.02), respectively. A longer penis at the baseline led to greater length gain following treatment (1 mm longer at the baseline was likely to gain 0.5 mm more). However, the increase in penile length was not associated with the severity of hypospadias. While the treatment did not affect the overall complication rate, the postoperative fistula risk was lower in those receiving PAS (RR=0.52, 95% CI: 0.30–0.91, p=0.02). Conclusions The beneficial effects of PAS on increasing the penile length and glans width were again confirmed. More gain of penile length was expected in the larger penis at baseline. There are no reported increased postoperative complications in association with PAS.

PURPOSE: The purpose of this study was to compare the survival of patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) undergoing concurrent chemoradiotherapy (CRT) alone with that of patients undergoing induction chemotherapy (IC) using docetaxel, cisplatin, and 5-fluorouracil (TPF) followed by CRT. MATERIALS AND METHODS: A search of the PubMed, EMBASE, and Cochrane Library databases was performed in April 2015 and abstracts from the American Society of Clinical Oncology meetings (2008-2014) were reviewed. Summaries of the results were pooled using a fixed-effect model, and the risk of bias was evaluated using the Cochrane tool. RESULTS: A total of six relevant trials comprising 1,280 patients were identified. There was no statistically significant overall survival (OS) advantage for TPF prior to CRT (TPF/CRT) over CRT alone (hazard ratio [HR] 0.92; 95% confidence interval [CI], 0.79 to 1.09; p=0.339). Progression-free survival (PFS) was significantly longer in the TPF/CRT arms (HR, 0.82; 95% CI, 0.70 to 0.95; p=0.009). Patients with non-oropharyngeal LA-HNSCC obtained the greatest OS and PFS benefits from TPF (HR, 0.68; 95% CI, 0.47 to 0.99; p=0.043 and HR, 0.67; 95% CI, 0.48 to 0.94; p=0.022, respectively). The complete response rate was significantly increased (risk ratio [RR], 1.34; 95% CI, 1.14 to 1.56; p < 0.001), and the distant metastasis rate tended to decrease (RR, 0.65; 95% CI, 0.40 to 1.04; p=0.071) in the TPF/CRT arms. CONCLUSION: IC with TPF followed by CRT is not superior to CRT alone for OS. However, PFS and the complete response rate were significantly improved in the TPF/CRT arms. TPF/CRT for patients with nonoropharyngeal LA-HNSCC provided clear survival advantages.
Arm ; Bias (Epidemiology) ; Carcinoma, Squamous Cell* ; Chemoradiotherapy ; Cisplatin* ; Disease-Free Survival ; Epithelial Cells* ; Fluorouracil* ; Head and Neck Neoplasms ; Head* ; Humans ; Induction Chemotherapy* ; Medical Oncology ; Neck* ; Neoplasm Metastasis

Despite the recent increase in the use of complementary and alternative medicine (CAM) among the general population and patients, little is known about Korean physicians' attitudes about and interest in CAM. We conducted a web-based survey of knowledge, attitude, and experience in CAM among primary care physicians (PCPs) and academic physicians (APs) in Korea. A total of 826 physicians (341 PCPs and 485 APs) responded. Respondents in both groups felt that they were not sufficiently knowledgeable about CAM. PCPs, however, had a significantly higher composite index score in CAM knowledge than that of APs. Although APs were more skeptical about the scientific evidence of CAM than PCPs, both groups had a positive attitude toward CAM. The level of experience in utilizing CAM in their practice was 23.2% among PCPs, which was much higher than that among APs (2.7%). Experience rates of referring patients to CAM were 11.7% in PCPs and 4.5% in APs (P<0.001). Despite the discrepant rates in CAM education between the two groups (58.7% in PCPs and 26.0% in APs, P<0.001), the majority of doctors in both groups (85.0% in PCPs and 70.0% in APs) expressed an intention to participate in authorized CAM coursework. In conclusion, despite the lack of scientific evidence, both PCPs and APs have an interest in incorporating CAM into their conventional medical practices. To meet physicians' increasing needs for CAM the Korean medical societies should promote education and research about CAM in the conventional medical system.
Complementary Therapies ; Humans ; Intention ; Korea ; Physicians, Primary Care ; Primary Health Care ; Societies, Medical ; Surveys and Questionnaires

Meconium aspiration syndrome (MAS) is an important cause of respiratory distress in neonates. Surfactant therapy has been used to improve oxygenation for infants with MAS recently. The object of this study is to estimate the number of candidates for surfactant use in MAS and the cost for surfactant, and to analyze its cost-effectiveness in Korea. Using Korean Health Insurance Review and Assessment Service reimbursement data, the number of neonates with a diagnosis of MAS receiving mechanical ventilation was counted. The annual cost for surfactant use was calculated using the number of patients receiving mechanical ventilation for at least three days who were considered potential candidates for surfactant use. The cost-effectiveness was evaluated using the effectiveness data from a previous meta-analysis. Infants with a diagnosis of MAS receiving mechanical ventilation were 0.92 per 1,000 live births annually. Among them, 55% were potential candidates for surfactant use. The expected annual cost for surfactant was 990 million Korean won and 500 million Korean won and the number needed to treat was 14.3 and 6.7 in surfactant bolus therapy and surfactant lavage therapy, respectively. Sixty-four million won was estimated as the cost to prevent one infant death by surfactant bolus therapy and 15 million won by surfactant lavage therapy. The surfactant therapy for MAS is presently not covered by the Korean national health insurance and its application to MAS is limited because of the high financial burden to the patients' family. This study's results could help healthcare decision makers establish a policy in the future.
Cost of Illness ; Delivery of Health Care ; Humans ; Infant ; Infant, Newborn ; Insurance, Health ; Korea ; Live Birth ; Meconium ; Meconium Aspiration Syndrome ; National Health Programs ; Oxygen ; Pulmonary Surfactants ; Respiration, Artificial ; Therapeutic Irrigation

Cardiac resynchronization therapy (CRT) has been shown to reduce the risk of death and hospitalization in patients with advanced heart failure with left ventricular dysfunction. However, controversy remains regarding who would most benefit from CRT. We performed a meta-analysis, and meta-regression in an attempt to identify factors that determine the outcome after CRT. A total of 23 trials comprising 10,103 patients were selected for this meta-analysis. Our analysis revealed that CRT significantly reduced the risk of all-cause mortality and hospitalization for heart failure compared to control treatment. The odds ratio (OR) of all-cause death had a linear relationship with mean QRS duration (P=0.009). The benefit in survival was confined to patients with a QRS duration > or =145 ms (OR, 0.86; 95% CI, 0.74-0.99), while no benefit was shown among patients with a QRS duration of 130 ms (OR, 1.00; 95% CI, 0.80-1.25) or less. Hospitalization for heart failure was shown to be significantly reduced in patients with a QRS duration > or =127 ms (OR, 0.77; 95% CI, 0.60-0.98). This meta-regression analysis implies that patients with a QRS duration > or =150 ms would most benefit from CRT, and in those with a QRS duration <130 ms CRT implantation may be potentially harmful.
Bundle-Branch Block/physiopathology ; Cardiac Resynchronization Therapy/*methods ; Cardiac Resynchronization Therapy Devices ; Defibrillators, Implantable ; Electrocardiography ; Heart Failure/mortality/physiopathology/*therapy ; Humans ; Myocardial Contraction/*physiology ; Treatment Outcome ; Ventricular Dysfunction, Left/mortality/physiopathology/*therapy

Background: To compare the renal effects of dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium-glucose cotransporter 2 (SGLT2) inhibitors on individual outcomes in patients with type 2 diabetes. Methods: We searched electronic databases (MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials) from inception to June 2019 to identity eligible randomized controlled trials of DPP-4 inhibitors or SGLT2 inhibitors that reported at least one kidney outcome in patients with type 2 diabetes. Outcomes of interest were microalbuminuria, macroalbuminuria, worsening nephropathy, and end-stage kidney disease (ESKD). We performed an arm-based network meta-analysis using Bayesian methods and calculated absolute risks and rank probabilities of each treatment for the outcomes. Results: Seventeen studies with 87,263 patients were included. SGLT2 inhibitors significantly lowered the risks of individual kidney outcomes, including microalbuminuria (odds ratio [OR], 0.64; 95% credible interval [CrI], 0.41 to 0.93), macroalbuminuria (OR, 0.48; 95% CrI, 0.24 to 0.72), worsening nephropathy (OR, 0.65; 95% CrI, 0.44 to 0.91), and ESKD (OR, 0.65; 95% CrI, 0.46 to 0.98) as compared with placebo. However, DPP-4 inhibitors did not lower the risks. SGLT2 inhibitors were considerably associated with higher absolute risk reductions in all kidney outcomes than DPP-4 inhibitors, although the benefits were statistically insignificant. The rank probabilities showed that SGLT2 inhibitors were better treatments for lowering the risk of albuminuria and ESKD than placebo or DPP-4 inhibitors. Conclusion SGLT2 inhibitors were superior to DPP-4 inhibitors in reducing the risk of albuminuria and ESKD in patients with type 2 diabetes.