Efficacy, acceptability, and tolerability of all available treatments for insomnia in the elderly: a systematic review and network meta-analysis.

OBJECTIVES: Symptoms of insomnia are highly prevalent in the elderly. A significant number of pharmacological and non-pharmacological interventions exist, but, up-to-date, their comparative efficacy and safety has not been sufficiently assessed. METHODS: We integrated the randomized evidence from every available treatment for insomnia in the elderly (>65 years) by performing a network meta-analysis. Several electronic databases were searched up to May 25, 2019. The two primary outcomes were total sleep time and sleep quality. Data for other 6 efficacy and 8 safety outcomes were also analyzed. RESULTS: Fifty-three RCTs with 6832 participants (75 years old on average) were included, 43 of which examined the efficacy of one or more drugs. Ten RCTs examined the efficacy of non-pharmacological interventions and were evaluated only with pairwise meta-analyses because they were disconnected from the network. The overall confidence in the evidence was very low primarily due to the small amount of data per comparison and their sparse connectedness. Several benzodiazepines, antidepressants, and z-drugs performed better in both primary outcomes, but few comparisons had data from more than one trial. The limited evidence on non-pharmacological interventions suggested that acupressure, auricular acupuncture, mindfulness-based stress reduction program, and tart cherry juice were better than their control interventions. Regarding safety, no clear differences were detected among interventions due to large uncertainty. CONCLUSIONS: Insufficient evidence exists on which intervention is more efficacious for elderly patients with insomnia. More RCTs, with longer duration, making more direct interventions among active treatments and presenting more outcomes are urgently needed.

Incidence and mortality from cervical cancer and other malignancies after treatment of cervical intraepithelial neoplasia: a systematic review and meta-analysis of the literature.

BACKGROUND: Although local treatments for cervical intraepithelial neoplasia (CIN) are highly effective, it has been reported that treated women remain at increased risk of cervical and other cancers. Our aim is to explore the risk of developing or dying from cervical cancer and other human papillomavirus (HPV)- and non-HPV-related malignancies after CIN treatment and infer its magnitude compared with the general population. MATERIALS AND METHODS: Design: Systematic review and meta-analysis. Eligibility criteria: Studies with registry-based follow-up reporting cancer incidence or mortality after CIN treatment. DATA SYNTHESIS: Summary effects were estimated using random-effects models. OUTCOMES: Incidence rate of cervical cancer among women treated for CIN (per 100 000 woman-years). Relative risk (RR) of cervical cancer, other HPV-related anogenital tract cancer (vagina, vulva, anus), any cancer, and mortality, for women treated for CIN versus the general population. RESULTS: Twenty-seven studies were eligible. The incidence rate for cervical cancer after CIN treatment was 39 per 100 000 woman-years (95% confidence interval 22-69). The RR of cervical cancer was elevated compared with the general population (3.30, 2.57-4.24; P < 0.001). The RR was higher for women more than 50 years old and remained elevated for at least 20 years after treatment. The RR of vaginal (10.84, 5.58-21.10; P < 0.001), vulvar (3.34, 2.39-4.67; P < 0.001), and anal cancer (5.11, 2.73-9.55; P < 0.001) was also higher. Mortality from cervical/vaginal cancer was elevated, but our estimate was more uncertain (RR 5.04, 0.69-36.94; P = 0.073). CONCLUSIONS: Women treated for CIN have a considerably higher risk to be later diagnosed with cervical and other HPV-related cancers compared with the general population. The higher risk of cervical cancer lasts for at least 20 years after treatment and is higher for women more than 50 years of age. Prolonged follow-up beyond the last screening round may be warranted for previously treated women.

No benefit from flexible titration above minimum licensed dose in prescribing antidepressants for major depression: systematic review.

BACKGROUND: In fixed-dose antidepressant trials, the lower range of the licensed dose achieves the optimal balance between efficacy and tolerability. Whether flexible upward titration while side-effects permit provides additional benefits is unknown. METHODS: We did a systematic review of placebo-controlled randomized trials that examined selective serotonin reuptake inhibitors (SSRIs), venlafaxine or mirtazapine in the acute treatment of major depression. Our primary outcome was response, defined as 50% or greater reduction in depression severity. Secondary outcomes included drop-outs due to adverse effects and drop-outs for any reason. We conducted random-effects meta-analyses to calculate the ratios of odds ratios (RORs) between trials comparing the flexible dose titrating above the minimum licensed dose against placebo and those comparing the fixed minimum licensed dose against placebo. RESULTS: We included 123 published and unpublished randomized controlled trials (29 420 participants). There was no evidence supporting efficacy of the flexible dosing over the fixed low dose of SSRIs (ROR 0.96, 95% CI: 0.73 to 1.25), venlafaxine (1.24, 0.96 to 1.60) or mirtazapine (0.77, 0.33 to 1.78). No important differences were noted for tolerability or for any subgroup analyses except the superior efficacy of venlafaxine flexible dosing between 75 and 150 mg over the fixed 75 mg (1.30, 1.02 to 1.65). CONCLUSION: There was no evidence to support added value in terms of efficacy, tolerability or acceptability of flexibly titrating up the dosage over the minimum licensed dose of SSRIs or mirtazapine. For venlafaxine, increased efficacy can be expected by flexibly titrating up to 150 mg.

What is a multiple treatments meta-analysis?

Standard meta-analyses are an effective tool in evidence-based medicine, but one of their main drawbacks is that they can compare only two alternative treatments at a time. Moreover, if no trials exist which directly compare two interventions, it is not possible to estimate their relative efficacy. Multiple treatments meta-analyses use a meta-analytical technique that allows the incorporation of evidence from both direct and indirect comparisons from a network of trials of different interventions to estimate summary treatment effects as comprehensively and precisely as possible.

Industry sponsorship and selection of comparators in randomized clinical trials.

BACKGROUND: Most clinical trials on medical interventions are sponsored by the industry. The choice of comparators shapes the accumulated evidence. We aimed to assess how often major companies sponsor trials that involve only their own products. METHODS: Studies were identified by searching ClinicalTrials.gov for trials registered in 2006. We focused on randomized trials involving the 15 companies that had sponsored the largest number of registered trials in ClinicalTrials.gov in that period. RESULTS: Overall, 577 randomized trials were eligible for analysis and 82% had a single industry sponsor [89% (166/187) of the placebo-control trials, 87% (91/105) of trials comparing different doses or ways of administration of the same intervention, and 78% (221/285) of other active control trials]. The compared intervention(s) belonged to a single company in 67% of the trials (89%, 81% and 47% in the three categories respectively). All 15 companies strongly preferred to run trials where they were the only industry sponsor or even the only owner of the assessed interventions. Co-sponsorship typically reflected co-ownership of the same intervention by both companies. Head-to-head comparison of different active interventions developed by different companies occurred in only 18 trials with two or more industry sponsors. CONCLUSIONS: Each company generates a clinical research agenda that is strongly focused on its own products, while comparisons involving different interventions from different companies are uncommon. This diminishes the ability to understand the relative merits of different interventions for the same condition.

Human recombinant activated protein C for severe sepsis.

BACKGROUND: Sepsis is a common, expensive and frequently fatal condition. There is an urgent need for developing new therapies to further reduce severe sepsis-induced mortality. One of those approaches is the use of human recombinant activated protein C (APC). OBJECTIVES: We assessed the clinical effectiveness of APC for the treatment of patients with severe sepsis or septic shock. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2005, Issue 2); MEDLINE (1966 to 2005); EMBASE (1980 to 2005) and LILACS (1982 to 2005). We contacted researchers and organizations working in the field. We did not have any language restriction. SELECTION CRITERIA: We included randomized controlled trials (RCTs) assessing the effects of APC for severe sepsis in adults and children. We excluded studies on neonates. DATA COLLECTION AND ANALYSIS: We independently performed study selection, quality assessment and data extraction. We estimated relative risks (RR) for dichotomous outcomes. We measured statistical heterogeneity using I-squared (I(2)). We used a random-effects model. MAIN RESULTS: We included four studies involving 4911 participants (4434 adults and 477 paediatric patients). For 28-day mortality, APC did not reduce the risk of death in adult participants with severe sepsis (pooled RR 0.92, 95% confidence interval (CI) 0.72 to 1.18; P = 0.50, I(2) = 72%). The effectiveness of APC did not seem to be associated with the degree of severity of sepsis (two studies): for an APACHE II score less than 25 the RR was 1.04 (95% CI 0.89 to 1.21; P = 0.70), and in participants with an APACHE II score of 25 or more the RR was 0.90 (95% CI 0.54 to 1.49; P = 0.68). APC use was, however, associated with a higher risk of bleeding (RR 1.48 (95% CI 1.07 to 2.06; P = 0.02, I(2) = 8%). Two studies were stopped early because there was little chance of reaching the efficacy endpoint by completion of the trial. AUTHORS' CONCLUSIONS: This updated review found no evidence suggesting that APC should be used for treating patients with severe sepsis or septic shock. Additionally, APC seems to be associated with a higher risk of bleeding. Unless additional RCTs provide evidence of a treatment effect, policy-makers, clinicians and academics should not promote the use of APC.

Human recombinant activated protein C for severe sepsis.

BACKGROUND: Sepsis is a common, expensive and frequently fatal condition. There is an urgent need for developing new therapies to further reduce severe sepsis-induced mortality. One of those approaches is the use of human recombinant activated protein C (APC). OBJECTIVES: We assessed the clinical effectiveness of APC for the treatment of patients with severe sepsis or septic shock. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2005, Issue 2); MEDLINE (1966 to 2005); EMBASE (1980 to 2005) and LILACS (1982 to 2005). We contacted researchers and organizations working in the field. We did not have any language restriction. SELECTION CRITERIA: We included randomized controlled trials (RCTs) assessing the effects of APC for severe sepsis in adults and children. We excluded neonates. DATA COLLECTION AND ANALYSIS: We independently performed study selection, quality assessment and data extraction. We estimated relative risks (RR) for dichotomous outcomes. We measured statistical heterogeneity using I-squared (I(2)). We used a random-effects model. MAIN RESULTS: We included four studies involving 4911 participants (4434 adults and 477 paediatric patients). For 28-day mortality, APC did not reduce the risk of death in adult participants with severe sepsis (pooled RR 0.92, 95% confidence interval (CI) 0.72 to 1.18; P = 0.50, I(2) = 72%). The effectiveness of APC did not seem to be associated with the degree of severity of sepsis (two studies): for an APACHE II score less than 25 the RR was 1.04 (95% CI 0.89 to 1.21; P = 0.70), and in participants with an APACHE II score of 25 or more the RR was 0.90 (95% CI 0.54 to 1.49; P = 0.68). APC use was, however, associated with a higher risk of bleeding (RR 1.48 (95% CI 1.07 to 2.06; P = 0.02, I(2) = 8%). Two studies were stopped early because there was little chance of reaching the efficacy endpoint by completion of the trial. AUTHORS' CONCLUSIONS: This review suggests that APC should not be used in sepsis with an APACHE II score of less than 25 or, in paediatric patients. There is very weak evidence supporting APC use in patients with severe sepsis and at high-risk of death. As a result, policy-makers, clinicians and academics should be cautious when promoting the use of APC to patients with severe sepsis and an APACHE II score of 25 or greater. There is a need for further RCTs to answer with certainty what the role of APC is for patients with severe sepsis and an APACHE II score of at least 25. Those RCTs should be designed and conducted by non-profit organizations.

Human recombinant activated factor VII for upper gastrointestinal bleeding in patients with liver diseases.

BACKGROUND: Mortality from upper gastrointestinal bleeding in patients with liver disease is high. The human recombinant activated factor VII is one of the suggested treatments for upper gastrointestinal bleeding in these patients. OBJECTIVES: To assess the beneficial and harmful effects of human recombinant factor VIIa in patients with liver disease and upper gastrointestinal bleeding. SEARCH STRATEGY: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, ISI Web of Knowledge, and LILACS. The search strategies used are given in Table 01. We sought additional randomised trials from the reference lists of the trials and reviews identified through the electronic searches. SELECTION CRITERIA: All randomised clinical trials irrespective of design, publication status, and language comparing human recombinant activated factor VII versus placebo, or any other control intervention for patients with liver disease and upper gastrointestinal bleeding, irrespectively of aetiology. DATA COLLECTION AND ANALYSIS: We estimated relative risks (RR) for dichotomous outcomes and mean differences for continuous data. Since only one trial was identified, meta-analysis was not possible. MAIN RESULTS: We included one trial with 242 adult patients. In this study, human recombinant activated factor VII administration did not reduce the risk of death (mortality within five days (RR 1.75, 95% confidence interval (CI) 0.53 to 5.82), and mortality within 42 days (RR 1.45, 95% CI 0.70 to 3.00)). AUTHORS' CONCLUSIONS: We found no evidence that human recombinant activated factor VII reduces the risk of death in patients with liver disease and upper gastrointestinal bleeding. However, we made our conclusion on a single randomised clinical trial. More randomised clinical trials having low risk of bias are necessary in order to determine the role of human recombinant factor VIIa in clinical practice.

Estimation of the general threshold limit values for dust.

In 1997 the German MAK Commission set new general threshold limit values for dust. The procedure has recently been assessed (McLaughlin et al. 2001). One of the points raised was the use of inappropriate statistical methods. We want to address this point to a greater extent by discussing several alternatives implied by the already established threshold models, and we present results from a new approach that has been refined in the meantime: the use of the additive isotonic model. The underlined assumption of monotonicity regarding the dose-response relationship has been extensively investigated. One very flexible model, based on smoothing splines, shows in some of the samples a decline in the risk over a certain range of the exposure compared to the risk at baseline. Another approach with fractional polynomials and segmented regression lines shows that this result can be explained by chance. These methods show an increasing risk with increasing exposure. Additionally, permutation tests are used to prove the trend within the isotonic framework. The results from the additive isotonic model confirm previous assessments of the general threshold limit value.

Time independence of the prognostic impact of tumor cell detection in the bone marrow of primary breast cancer patients.

PURPOSE: Tumor cell detection (TCD) in bone marrow is an outstanding prognostic factor in breast cancer. There is only one other study that has investigated more than 300 patients with a median follow-up of more than 5 years (J. L. Mansi et al., Lancet, 354:197-202, 1999). We report data from 727 patients with a median follow-up period of 6.5 years. EXPERIMENTAL DESIGN: In a prospective study, intraoperatively aspirated bone marrow was screened for micrometastatic cancer cells. We used an immunocytological method (monoclonal mucin antibody 2E11; the avidin-biotin complex method). RESULTS: Forty-three percent of the patients were TCD positive. Sixty percent of the patients with distant metastases were tumor cell positive (155 of 258 patients). Forty-nine percent of the patients with positive TCD developed distant metastases (155 of 315 patients). TCD was an independent prognostic factor for clinical outcome after a median follow-up time of 6.5 years. The prognostic impact of TCD and tumor size remains constant with the time, whereas the impact of grading and progesterone receptor on risk seems to decrease with longer follow-up time. CONCLUSIONS: TCD remains an independent prognostic factor The impact of TCD does not change with longer follow-up time. TCD is a reliable prognostic factor and provides important information about the process of metastasis.