Cardiovascular events and all-cause mortality associated with sulphonylureas compared with other antihyperglycaemic drugs: A Bayesian meta-analysis of survival data.

AIM: To conduct a systematic review and meta-analysis to determine the risk of cardiovascular events and all-cause mortality associated with sulphonylureas (SUs) vs other glucose lowering drugs in patients with T2DM (T2DM). MATERIALS AND METHODS: A systematic review of Medline, Embase, Cochrane and clinicaltrials.gov was conducted for studies comparing SUs with placebo or other antihyperglycaemic drugs in patients with T2DM. A cloglog model was used in the Bayesian framework to obtain comparative hazard ratios (HRs) for the different interventions. For the analysis of observational data, conventional fixed-effect pairwise meta-analyses were used. RESULTS: The systematic review identified 82 randomized controlled trials (RCTs) and 26 observational studies. Meta-analyses of RCT data showed an increased risk of all-cause mortality and cardiovascular-related mortality for SUs compared with all other treatments combined (HR 1.26, 95% confidence interval [CI] 1.10-1.44 and HR 1.46, 95% CI 1.21-1.77, respectively). The risk of myocardial infarction was significantly higher for SUs compared with dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium-glucose co-transporter-2 inhibitors (HR 2.54, 95% CI 1.14-6.57 and HR 41.80, 95% CI 1.64-360.4, respectively). The risk of stroke was significantly higher for SUs than for DPP-4 inhibitors, glucagon-like peptide-1 agonists, thiazolidinediones and insulin. CONCLUSIONS: The present meta-analysis showed an association between SU therapy and a higher risk of major cardiovascular disease-related events compared with other glucose lowering drugs. Results of ongoing RCTs, which should be available in 2018, will provide definitive results on the risk of cardiovascular events and all-cause mortality associated with SUs vs other antihyperglycaemic drugs.

CT-guided stellate ganglion blockade vs. radiofrequency neurolysis in the management of refractory type I complex regional pain syndrome of the upper limb.

OBJECTIVE: To describe and evaluate the feasibility and efficacy of CT-guided radiofrequency neurolysis (RFN) vs. local blockade of the stellate ganglion in the management of chronic refractory type I complex regional pain syndrome (CRPS) of the upper limb. METHODS: Sixty-seven patients were included in this retrospective study between 2000 and 2011. All suffered from chronic upper limb type I CRPS refractory to conventional pain therapies. Thirty-three patients underwent stellate ganglion blockade and 34 benefited from radiofrequency neurolysis of the stellate ganglion. CT guidance was used in both groups. The procedure was considered effective when pain relief was ≥50 %, lasting for at least 2 years. RESULTS: Thirty-nine women (58.2 %) and 28 men (41.8 %) with a mean age of 49.5 years were included in the study. Univariate analysis performed on the blockade and RFN groups showed a significantly (P < 0.0001) higher success rate in the RFN group (67.6 %, 23/34) compared with the blockade group (21.2 %, 7/33) with an odds ratio of 7.76. CONCLUSION: CT-guided radiofrequency neurolysis of the stellate ganglion is a safe and successful treatment of chronic refractory type I CRPS of the upper limb. It appears to be more effective than stellate ganglion blockade. KEY POINTS: • Complex regional pain syndrome is painful, disabling and often refractory to treatment. • Sixty-seven percent of patients had lasting pain relief (2 years) after radiofrequency neurolysis. • Retrospective study showed a significantly higher success rate for radiofrequency neurolysis. • CT guidance is mandatory for a successful and safe procedure.

Validation of a new quality of life scale related to multiple sclerosis and relapses.

PURPOSE: Multiple sclerosis (MS) has a significant impact on all aspects of patient quality of life (QoL). Furthermore, the fear of relapses and the feelings of patients during relapses must be taken into account in care. The objective of this work was to validate the PERSEPP scale ("PERception de la Sclérose En Plaques et de ses Poussées"), a new QoL evaluation scale for relapsing-remitting forms of MS. METHODS: Relapsing-remitting patients were included in a multicenter study. Various validation criteria of this scale were analyzed: acceptability, construct validity (internal and external validity), and reliability (internal consistency and reproducibility test-retest). Responsiveness will be studied in order to complete the validation process. RESULTS: The responses of 305 MS patients were analyzed. The process of reducing the items led us to retain 66 items of a total of 112 items. The 66-item PERSEPP scale (final version) was well accepted. Five dimensions (33 items) make up the scale: social support (α = 0.81), relationship difficulties (α = 0.71), fatigue (α = 0.74), state of mind and associated sleep disorders (α = 0.78), and time perspective (α = 0.75). Three additional modules (33 items) explore coping (α = 0.60), symptoms (α = 0.89), and treatment (α = 0.92). Test-retest reliability, measured by the intraclass correlation coefficient (ICC), was acceptable (0.72 < ICC < 0.92). CONCLUSIONS: The PERSEPP scale has been validated and could be used in clinical trials and in daily practice. Additional studies will then complete the validation process.

Biomechanical properties of the calcaneal tendon in vivo assessed by transient shear wave elastography.

OBJECTIVE: The purpose of this study is to assess the elastic and anisotropic properties of normal calcaneal tendon in vivo by transient shear wave elastography (SWE). MATERIALS AND METHODS: This study was approved by our institutional ethics committee. Eighty healthy subjects over 18 years of age were prospectively included. Data on the patients' height, weight, sporting activities, and take-off foot were assessed. The thickness, width, and cross-sectional area of the calcaneal tendons were measured. The shear wave propagation velocity (Vmean) was measured by three radiologists on axial and sagittal SWE images at four different degrees of ankle flexion, enabling to calculate elasticity modulus (Emean), and relative anisotropy coefficient (A) values. RESULTS: In complete plantar flexion, Vmean was 6.8 ± 1.4 m.s(-1) and 5.1 ± 0.8 m.s(-1), respectively, on the sagittal and axial SWE image, resulting in an elastographic anisotropy A of 0.24 ± 0.16. The best interobserver correlation coefficient of Emean and Vmean was 0.43 and 0.46, respectively, in the sagittal SWE for complete plantar flexion. Vmean and Emean significantly increase when the tendon is stretched by ankle dorsiflexion. The maximal values in sagittal SWE were Vmean = 16.1 ± 0.7 m.s(-1), Emean = 779.5 ± 57.1kPa and A = 0.63 ± 0.07. CONCLUSIONS: SWE allows the elastic properties of the calcaneal tendon to be evaluated quantitatively in vivo, but interobserver reproducibility is questionable. It confirms the tendinous elastographic anisotropy and stiffness augmentation of stretched tendon.

Efficacy and Safety of Antiplatelet Therapies in Symptomatic Peripheral Artery Disease: A Systematic Review and Network Meta-Analysis.

BACKGROUND: Clopidogrel monotherapy is guideline-recommended in symptomatic peripheral artery disease (PAD). The advent of new antithrombotic strategies prompts an updated analysis of available evidence on antiplatelet therapy for PAD. METHODS: We searched MEDLINE, Embase and CENTRAL through January 2019 for randomised controlled trials and observational studies comparing antiplatelet therapies as monotherapy, dual therapy, or combination with anticoagulants. Efficacy (major adverse cardiovascular events, acute or chronic limb ischaemia, vascular amputation, peripheral revascularisation) and safety (all-cause mortality and overall bleeding) outcomes were evaluated via Bayesian network meta-analyses. RESULTS: We analysed 26 randomised controlled trials. Clopidogrel (hazard ratio, HR, 0.78; 95% credible interval [CrI] 0.65-0.93) and ticagrelor (HR 0.80; 95% CrI 0.65-0.98) significantly reduced major adverse cardiovascular events risk compared with aspirin. No significant difference was observed for dual antiplatelet therapy with clopidogrel and aspirin. Vorapaxar significantly reduced limb ischaemia and revascularisation compared with placebo, while dual antiplatelet therapy with clopidogrel and aspirin showed a trend for reduced risk of amputation compared with aspirin (risk ratio 0.68; 95% CrI 0.43-1.04). For all-cause mortality, picotamide, vorapaxar, dipyridamole with aspirin, and ticlopidine showed a significantly lower risk of all-cause mortality vs aspirin. Clopidogrel and ticagrelor showed similar overall bleeding risk vs aspirin, while dual antiplatelet therapy with clopidogrel and aspirin significantly increased bleeding risk. CONCLUSION: This updated network meta-analysis confirms that clopidogrel significantly decreases the risk of major adverse cardiovascular events compared with aspirin, without increasing bleeding risk. Clopidogrel should remain a mainstay of PAD treatment, at least in patients at higher bleeding risk.

A fresh look at the role of spiramycin in preventing a neglected disease: meta-analyses of observational studies.

PURPOSE: We aimed to investigate the effect of antepartum treatment with spiramycin with or without subsequent pyrimethamine-sulfonamide-folinic acid, compared to no treatment, on the rate of mother-to-child transmission (MTCT) of Toxoplasma gondii (T. gondii) and incidence/severity of sequelae in the offspring. METHODS: Embase and PubMed were searched for literature on spiramycin in pregnant women suspected/diagnosed with T. gondii infection. Meta-analyses were performed using random-effects model. RESULTS: Thirty-three studies (32 cohorts and 1 cross-sectional study), with a total of 15,406 mothers and 15,250 offspring, were pooled for analyses. The MTCT rate for all treated patients was significantly lower than the untreated [19.5% (95% CI 14-25.5%) versus 50.7% (95% CI 31.2-70%), p < 0.001]. The transmission rate in patients on spiramycin monotherapy was also significantly lower than untreated [17.6% (95% CI 9.9-26.8%) versus 50.7% (95% CI 31.2-70%), p < 0.001]. CONCLUSION: Results indicate significant reduction in MTCT rates following spiramycin treatment of suspected/diagnosed maternal T. gondii infection.

Forced vital capacity and cross-domain late-onset Pompe disease outcomes: an individual patient-level data meta-analysis.

BACKGROUND: Late-onset Pompe disease (LOPD) is a rare, metabolic disease primarily affecting the musculoskeletal and respiratory systems. Forced vital capacity (FVC) is commonly used to measure pulmonary function; however, associations between FVC and other LOPD outcomes remain unclear. METHODS: A systematic literature review was conducted on November 2015, updated September 2016 and supplemented with clinical trial data from the sponsor. Outcomes included: 6-min walk test distance (6MWT), FVC, maximal inspiratory/expiratory pressure (MIP/MEP), Medical Research Council-skeletal muscle strength score (MRC), 36-item short-form survey-physical component score (SF-36), Rotterdam Handicap Scale (RHS), Fatigue Severity Scale (FSS) and survival. Individual patient data meta-analysis was used for cross-sectional analyses and longitudinal analyses to determine associations between percent of predicted FVC and LOPD measures and outcomes. RESULTS: Fifteen studies were selected. From cross-sectional analyses, FVC and MRC were most strongly associated. Specifically, patients with 10% higher FVC (a round number for illustrative purposes only) were associated with a 4.72% (95% confidence interval [CI]: 3.37, 6.07) higher MRC score, indicating a positive association. Similarly, slopes for the 6MWT and SF-36 relative to a 10% higher FVC were estimated at 33.2 meters (95% CI 24.0, 42.4) and 1.2% (95% CI 0.24, 2.16%), respectively. From longitudinal analyses, a 10% incremental increase in predicted FVC was associated with an average increase of 4.12% in MRC score (95% CI 1.29, 6.95), 35.6 m in the 6MWT (95% CI 19.9, 51.6), and 1.34% in SF-36 (95% CI 0.08, 2.60). There was insufficient data to conduct analyses for RHS, FSS and survival. CONCLUSIONS: FVC is positively associated with LOPD measures and outcomes across multiple domains. Additionally, longitudinal changes in FVC are positively associated with changes in the 6MWT, MRC and SF-36.

Hypoglycemia: a review of definitions used in clinical trials evaluating antihyperglycemic drugs for diabetes.

OBJECTIVE: To understand the severity and potential impact of heterogeneity in definitions of hypoglycemia used in diabetes research, we aimed to review the hypoglycemia definitions adopted in randomized controlled trials (RCTs). METHODS: We reviewed 109 RCTs included in the Canadian Agency for Drugs and Technologies in Health reports for the second- and third-line therapy for the patients with type 2 diabetes (T2D). RESULTS: Nearly 60% (n=66) of the studies reviewed presented the definitions for overall hypoglycemia, and another 20% (n=22) of the studies reported the results for hypoglycemia but did not report a definition. Among these 66 studies, only 9 (14%) followed the American Diabetes Association/European Medicines Agency specified guidelines to define hypoglycemia, with an exact threshold of plasma glucose ≤3.9 mmol/L. Fifty-two of the 66 studies (79%) used a threshold considerably lower than the recommended ≤3.9 mmol/L, and 16 studies used a threshold between 3.8 and 4.0 mmol/L. The proportion of the trials that used a cutoff value of <3.1 mmol/L appeared to be slightly similar among the more commonly used non-insulin treatments, GLP-1s (7 of 18 [39%]), thiazolidinediones (TZDs; 6 of 11 [55%]), DPP-4s (12 of 19 [64%]), and sulfonylureas (11 of 20 [55%]). Among trials with intermediate-long-acting insulins (neutral protamine Hagedorn insulin, detemir, glargine), 7 of 26 trials (27%) used a cutoff of <3.1 mmol/L. The definition of severe hypoglycemia was also subject to substantial heterogeneity, in both the utilized threshold and accompanying soft definitions. CONCLUSION: This review demonstrates that substantial heterogeneity exists in the definition of overall, severe/major, and nocturnal hypoglycemia across RCTs investigating T2D interventions.

Comparative efficacy and safety of estradiol transdermal preparations for the treatment of vasomotor symptoms in postmenopausal women: an indirect comparison meta-analysis.

OBJECTIVE: Divigel and Estrogel are estradiol gels for the treatment of postmenopausal women with moderate to severe vasomotor symptoms. They differ with respect to several factors including estradiol concentration and surface application, and cannot be compared solely on the basis of their estradiol dose. No randomized clinical trials have compared them head to head, but both have been compared with placebo. Therefore, the objective of this study was to conduct a systematic review and network meta-analysis of the two estradiol gels. METHODS: We performed a comprehensive systematic literature review. One publication reporting on one Divigel trial, three publications reporting on two Estrogel trials, and five publications reporting on other estradiol transdermal preparations were identified. Efficacy outcomes were change from baseline in daily hot flush frequency and change from baseline in daily hot flush severity. Safety outcomes were frequency of treatment-related adverse events (AEs) and frequency of treatment-emergent AEs leading to discontinuation. Bayesian indirect treatment comparison meta-analysis of trial-level data was performed in accordance with the International Society for Pharmacoeconomics and Outcomes Research, Academy of Managed Care Pharmacy, National Pharmaceutical Council (ISPOR-AMCP-NPC) Good Practice Questionnaire. All outcomes were compared with respect to doses of the considered preparations. RESULTS: For hot flush frequency, Divigel 0.25 mg was similar to Divigel 0.5 mg and to Estrogel 0.75 mg, and was statistically significantly superior to Estrogel 1.5 mg. The largest effect was observed with Divigel 1.0 mg (mean difference of 3.91 hot flushes/wk vs placebo), and was statistically significantly superior to all other interventions. The 1.5 mg Estrogel dose was associated with the smallest estimate of efficacy. For hot flush severity, Divigel 0.25 mg was similar to the efficacy of Divigel 0.5 mg, and for 0.25 mg and 0.5 mg of other estradiol gels, but was statistically inferior to Divigel 1.0 mg, Estrogel 0.75 mg, Estrogel 1.5 mg, and the 1.0 and 1.5 mg doses of all other estradiol gels. The estimated efficacy of Divigel 0.5 mg was similar to that of Estrogel 0.75 mg, Estrogel 1.5 mg, and the 0.25 and 0.5 mg doses of other transdermal estradiol preparations. Risks of treatment-related AEs for Divigel 0.25 mg, Divigel 0.5 mg, Estrogel 0.75 mg, and Estrogel 1.5 mg were similar and all were of a slightly higher risk than placebo. Among these, Divigel 1.0 mg, Estrogel 1.5 mg, and other gels 0.5 mg were statistically significantly less safe than placebo. However, for treatment-emergent AEs leading to discontinuation, none of the gels were associated with statistically significantly higher relative risks compared with placebo. In this study, statistically significant refers to the 95% credible intervals used in the Bayesian Network Analysis. CONCLUSIONS: Using network meta-analysis for indirect treatment comparison, we have shown that the efficacy of Divigel 0.25 mg, as measured by reduced hot flush frequency and severity, was similar to that of Divigel 0.5 mg and of Estrogel 0.75 and 1.5 mg. Overall, our analysis showed that Divigel 1.0 mg provided the best efficacy profile, but that this treatment was also associated with a higher risk of AEs. The network meta-analysis also showed that treatment with Estrogel 1.5 mg was associated with the smallest estimate of reduction in frequency of hot flushes.