Relative efficacy and safety of inhaled corticosteroids in patients with asthma: Systematic review and network meta-analysis.

BACKGROUND: Inhaled corticosteroids (ICSs) are recommended as first-line controller medications for persistent asthma. However, guidelines on the initial ICS doses, step-up and step-down algorithms, and when to switch to combination therapy vary. OBJECTIVE: To understand the ideal starting doses of ICS therapy based on current evidence and to systematically compare low, moderate, and high starting doses of ICSs as monotherapy and in combination with long-acting ß-agonists with respect to efficacy and safety. METHODS: MEDLINE, Embase, and Cochrane databases were searched for relevant English-language articles published from 1980 to November 17, 2018. Randomized controlled trials with adult, steroid-naive, ICS-free (for ≥4 weeks) patients with asthma and a duration of 4 weeks or longer with an ICS treatment arm (monotherapy or combination therapy) were included. Separate fixed-effects Bayesian network meta-analyses were conducted on the extracted data for peak expiratory flow, forced expiratory volume in 1 second, nighttime rescue medication use, nighttime symptom score, and study withdrawal because of an adverse event. RESULTS: A total of 31 randomized controlled trials were analyzed. All starting doses of ICSs were comparable with respect to nighttime rescue medication use, nighttime symptom score, change in forced expiratory volume in 1 second, and study withdrawal because of an adverse event. Significant improvement in morning peak expiratory flow was observed with high-dose ICSs and with low- and moderate-dose ICSs and long-acting ß-agonists than with low-dose ICSs. CONCLUSION: Overall, a high starting dose of ICSs had no additional clinical benefit in 3 of the 4 efficacy parameters compared with low or moderate ICS doses for controlling moderate to severe asthma but might have potential safety concerns.

Safety and Efficacy of Enoxaparin in Pregnancy: A Systematic Review and Meta-Analysis.

INTRODUCTION: International guidelines support the use of low molecular weight heparins for the treatment of thromboembolism and thromboprophylaxis during pregnancy. However, evidence of the benefit and harm associated with specific low molecular weight heparins such as enoxaparin is dated. No current systematic review and meta-analysis describing the safety and efficacy of enoxaparin for thromboembolism and thromboprophylaxis during pregnancy exists. METHODS: PubMed, Embase, and Cochrane databases were searched on August 17, 2018 for clinical trials or observational studies in pregnant women receiving enoxaparin; patients with a prosthetic heart valve were excluded. Risk ratios (RR) with 95% confidence intervals (CI) were calculated using a random effects model, and heterogeneity was measured using the I2 statistic. RESULTS: Of the 485 records identified in the search, 24 studies published clinical trials, and observational studies were found dating back to 2000. Only one observational cohort and one randomized control trial focused on the use of enoxaparin for thromboprophylaxis and therefore efficacy was not assessed; the other studies included women with recurrent pregnancy loss (15 studies), history of placental vascular complications (five studies), and recurrent in vitro fertilization failure (two studies) and were therefore analyzed in terms of safety only. Bleeding events were non-significantly more often reported for enoxaparin compared to untreated controls (RR 1.35 [0.88-2.07]) but less often reported for enoxaparin versus aspirin (RR 0.93 [0.62-1.39]); thromboembolic events, thrombocytopenia, and teratogenicity were rarely reported events; in patients with a history of recurrent pregnancy loss, encouragingly the rates of pregnancy loss were significantly lower for enoxaparin compared to untreated controls (RR 0.58 [0.34-0.96]) and enoxaparin + aspirin versus aspirin alone (RR 0.42 [0.32-0.56]) as well as observably lower for enoxaparin versus aspirin alone (RR 0.39 [0.15-1.01]), though significant heterogeneity was observed (I2 > 60). CONCLUSION: Literature on the efficacy and safety of enoxaparin for thromboembolism and thromboprophylaxis remains scanty, and therefore efficacy was not assessed; in terms of safety, when including other indications for enoxaparin in pregnancy, we found that enoxaparin was associated with significantly lower complications than aspirin. Given differences in study design and study heterogeneity, pregnancy loss results should be interpreted with caution. Moreover, reports of thromboembolic events, thrombocytopenia, and congenital malformations were rare. FUNDING: Sanofi.

Benefits and Risks of Clopidogrel vs. Aspirin Monotherapy after Recent Ischemic Stroke: A Systematic Review and Meta-Analysis.

AIM: Though combination of clopidogrel added to aspirin has been compared to aspirin alone in patients with stroke or transient ischemic attack, limited data exists on the relative efficacy and safety between clopidogrel and aspirin monotherapy in patients with a recent ischemic stroke. We aimed to compare clopidogrel versus aspirin monotherapy in this population. METHODS: PubMed, Embase, and CENTRAL databases were searched from inception to May 2018 to identify clinical trials and observational studies comparing clopidogrel versus aspirin for secondary prevention in patients with recent ischemic stroke within 12 months. Pooled effect estimates were calculated using a random effects model and were reported as risk ratios with 95% confidence intervals. RESULTS: Five studies meeting eligibility criteria were included in the analysis. A total of 29,357 adult patients who had recent ischemic stroke received either clopidogrel (n = 14, 293) or aspirin (n = 15, 064) for secondary prevention. Pairwise meta-analysis showed a statistically significant risk reduction in the occurrence of major adverse cardiovascular and cerebrovascular events (risk ratio 0.72 [95% CI, 0.53-0.97]), any ischemic or hemorrhagic stroke (0.76 [0.58, 0.99), and recurrent ischemic stroke (0.72 [0.55, 0.94]) in patients who received clopidogrel versus aspirin. The risk of bleeding was also lower for clopidogrel versus aspirin (0.57 [0.45, 0.74]). There was no difference in the rate of all-cause mortality between the two groups. CONCLUSIONS: The analysis showed lower risks of major adverse cardiovascular or cerebrovascular events, recurrent stroke, and bleeding events for clopidogrel monotherapy compared to aspirin. These findings support clinical benefit for single antiplatelet therapy with clopidogrel over aspirin for secondary prevention in patients with recent ischemic stroke.

De-escalation from ticagrelor to clopidogrel in acute coronary syndrome patients: a systematic review and meta-analysis.

De-escalation from ticagrelor to clopidogrel in acute coronary syndrome (ACS) may occur for a variety of reasons, including side effects (bleeding and non-bleeding) and costs. This study sought to assess the prevalence of de-escalation from ticagrelor to clopidogrel and the occurrence of adverse clinical outcomes following de-escalation. We conducted a systematic review of clinical trials and real-world studies in ACS patients treated with ticagrelor. Real-world data on the prevalence of de-escalation during hospitalization or at discharge, after hospital discharge, and during the whole study period were included for meta-analysis. Major adverse cardiovascular events (MACE) and bleeding events occurring after de-escalation were also assessed. A total of 12 studies were eligible for meta-analysis of the prevalence of de-escalation. De-escalation from ticagrelor to clopidogrel therapy occurred with a mean prevalence of 19.8% [95% confidence interval (CI) 11.2-28.4%]. De-escalation occurred more frequently in-hospital or at discharge than after hospital discharge (23.7% vs. 15.8%). For assessment of clinical outcomes, a total of six studies were eligible for meta-analysis. Mean rate of MACE for patients with de-escalation was 2.1% (95% CI 1.1-4.1%) and the rate of major bleeding events was 1.3% (95% CI 0.4-4.5%). In conclusion, de-escalation commonly occurs in real-world practice. Although rates of major cardiovascular and bleeding events in this analysis were generally low, the profile of patients suitable for de-escalation, the impact of de-escalation on adverse clinical outcomes and how this is affected by the timing after index ACS warrants further large-scale investigation.