Cardiac Harms of Sofosbuvir: Systematic Review and Meta-Analysis.

INTRODUCTION: Sofosbuvir is a new direct-acting pyrimidine nucleotide analogue antiviral drug that has shown remarkable efficacy in the treatment of hepatitis C in clinical trials. However, observational anecdotal data have recently suggested an increased risk of serious bradycardia among patients treated with sofosbuvir and amiodarone. OBJECTIVE: We aimed to estimate and characterize the cardiac safety of sofosbuvir by performing a systematic review of randomized controlled trials (RCTs). METHODS: We conducted a systematic review of RCTs (PROSPERO 2016: CRD42016033109) comparing sofosbuvir and non-sofosbuvir regimens in patients with chronic hepatitis C by searching the MEDLINE, Embase, and Cochrane Library databases up to January 2017. Non-published data were obtained from the sofosbuvir marketing authorization holder. Random-effects meta-analysis was performed to derive pooled estimates of relative risks (RRs) and corresponding 95% confidence intervals (CIs). RESULTS: Six trials, enrolling 2346 patients (1625 treated with sofosbuvir), were included. The overall risk of bias across studies was moderate. The risk of reported cardiac events (RR 0.87; 95% CI 0.41-1.85), arrhythmias (RR 0.93; 95% CI 0.34-2.51), bradycardia (RR 0.47; 95% CI 0.04-5.20), and tachycardia (RR 0.91; 95% CI 0.20-4.20) were not significantly different between sofosbuvir and non-sofosbuvir regimens. The risks of reported syncope, presyncope, loss of consciousness, or palpitations were similar among those receiving sofosbuvir regimens and controls. CONCLUSIONS: The pooled data from RCTs did not show an increased risk of cardiac outcomes, including arrhythmias (and bradycardia), among sofosbuvir-treated patients, although the overall quality of the evidence supporting this conclusion was very low. Registration: PROSPERO 2016:CRD42016033109 at http://www.crd.york.ac.uk/PROSPERO/ .

Triplet (FOLFOXIRI) versus doublet (FOLFOX or FOLFIRI) backbone chemotherapy as first-line treatment of metastatic colorectal cancer: A systematic review and meta-analysis.

Uncertainty exists regarding the comparative effectiveness of triplet chemotherapy (FOLFOXIRI) as backbone first-line chemotherapy for metastatic colorectal cancer (mCRC). We conducted a systematic review and meta-analysis of randomized-controlled trials (RCTs) comparing triplet versus doublet chemotherapy (FOLFOX or FOLFIRI) as first-line therapy in mCRC. Methods and reporting followed PRISMA and SAMPL guidelines. Eight RCTs were included, comprising 1732 patients. In pooled analysis, FOLFOXIRI was associated with improvements in efficacy outcomes, notably with a 25% survival increase (95%CI: 10-37%). FOLFOXIRI was also associated with increased toxicity, with a non-significant 25% increase in the risk of patients experiencing grade ≥3 adverse events (95% CI: -3 to 61%) and with a 1.83 (95% CI: 1.62-2.07) increase in the rate ratio of grade ≥3 adverse events. Moderate quality evidence suggests that first-line FOLFOXIRI provides clinically meaningful efficacy benefits in this setting, at the expense of increased toxicity. Further research is warranted to better characterize safety and to evaluate the most beneficial combination with targeted agents.

Systematic review and meta-analysis of the risk of severe and life-threatening thromboembolism in cancer patients receiving anti-EGFR monoclonal antibodies (cetuximab or panitumumab).

Cancer-associated thromboembolism is a substantial problem in clinical practice. An increase in the level of fibrinopeptide A (a substance associated with hypercoagulable states) has been observed in humans exposed to fluorouracil. Anti-EGFR monoclonal antibodies cetuximab and panitumumab, which are now widely used in patients with metastatic colorectal cancer, could prolong the uncovering of endothelial structures resulting from flouorouracil or other co-administered agents, thus favouring several factors leading to thromboembolism. We performed a systematic review and meta-analysis of randomised, controlled trials assessing whether cancer patients receiving anti-EGFR monoclonal antibodies cetuximab and panitumumab are at increased risk of thromboembolic events. We searched electronic databases (Medline, Embase, Web of Science, Central) and reference lists. Phase II/III randomised, controlled trials comparing standard anti-cancer regimens with or without anti-EGFR monoclonal antibodies and reporting serious venous thromboembolic events were included in the analysis. Seventeen studies (12,870 patients) were considered for quantitative analysis. The relative risk (RR) for venous thromboembolism (18 comparisons) was 1.46 (95% CI 1.26 to 1.69); the RR of pulmonary embolism, on the basis of eight studies providing nine comparisons, was 1.55 (1.20 to 2.00). Cancer patients receiving anti-EGFR monoclonal antibodies-containing regimens are approximately 1.5 times more likely to experience venous or pulmonary embolism, compared to those treated with the same regimens without anti-EGFR monoclonal antibodies. Clinicians should consider patient's baseline thromboembolic risk when selecting regimens that include cetuximab or panitumumab. Potential non-reporting of these important adverse events remains a concern. PROSPERO registration number is CRD42014009165.

Most systematic reviews of adverse effects did not include unpublished data.

OBJECTIVES: We sought to identify the proportion of systematic reviews of adverse effects which search for unpublished data and the success rates of identifying unpublished data for inclusion in a systematic review. STUDY DESIGN AND SETTING: Two reviewers independently screened all records published in 2014 in the Database of Abstracts of Reviews of Effects (DARE) for systematic reviews where the primary aim was to evaluate an adverse effect or effects. Data were extracted on the types of adverse effects and interventions evaluated, sources searched, how many unpublished studies were included, and source or type of unpublished data included. RESULTS: From 9,129 DARE abstracts, 348 met our inclusion criteria. Most of these reviews evaluated a drug intervention (237/348, 68%) with specified adverse effects (250/348, 72%). Over a third (136/348, 39%) of all the reviews searched, a specific source for unpublished data, such as conference abstracts or trial registries, and nearly half of these reviews (65/136, 48%) included unpublished data. An additional 13 reviews included unpublished data despite not searching specific sources for unpublished studies. Overall, 22% (78/348) of reviews included unpublished data/studies. CONCLUSION: Most reviews of adverse effects do not search specifically for unpublished data but, of those that do, nearly half are successful.

Risk of grade 3-4 diarrhea and mucositis in colorectal cancer patients receiving anti-EGFR monoclonal antibodies regimens: A meta-analysis of 18 randomized controlled clinical trials.

The anti-Epidermal Growth Factor Receptor monoclonal antibodies (anti-EGFR MoAbs) are beneficial in the treatment of wild type (WT) KRAS colorectal cancer, but are burdened by serious toxicities. We conducted a systematic review and meta-analysis to determine incidence and relative risk (RR) of severe and life-threatening diarrhoea and mucositis in colorectal cancer patients and WT-KRAS subpopulation. PubMed and Embase were searched for trials comparing the same therapeutic regimens with or without anti-EGFR for colorectal cancer. Data on severe and life-threatening diarrhoea and mucositis were extracted from 18 studies involving 13,382 patients. Statistical analyses calculated incidence of AEs, RRs and 95% confidence intervals by using either random or fixed effects models. Patients receiving anti-EGFR MoAbs showed an increased risk of diarrhoea (RR: 1.66, CI 1.52-1.80) and mucositis (RR: 3.44, CI 2.66-4.44). The risk was similar among WT-KRAS patients. Prevention and risk reduction strategies of these AEs are mandatory to optimize clinical outcomes.

The effect of PDRN, an adenosine receptor A2A agonist, on the healing of chronic diabetic foot ulcers: results of a clinical trial.

CONTEXT: Foot ulcer is the principal cause of hospitalization for patients with diabetes. Polydeoxyribonucleotide (PDRN), an adenosine A2A receptor agonist, improves wound healing in diabetic mice. OBJECTIVE: The aim of this study was to evaluate the effect of PDRN on chronic ulcer healing in patients with diabetes. DESIGN AND SETTING: This randomized, double-blind, placebo-controlled trial, involved two medical centers in Italy. INTERVENTION: Patients with diabetes showing hard-to-heal ulcers (Wagner grade 1 or 2) were randomly assigned to receive placebo (n = 106) or PDRN (n = 110). The treatments (PDRN and placebo) were performed for 8 weeks by intramuscular and perilesional route [corrected]. MAIN OUTCOME MEASURES: The primary outcome was complete ulcer healing. Secondary outcomes were the days needed to complete wound closure and the reepithelialization of wound surface (as percentage of the original area). RESULTS: After 8 weeks, 91 placebo and 101 PDRN subjects completed the study. Complete healing was achieved in 18.9% [95% confidence interval (CI) 11.4-26.3] of placebo and in 37.3% (95% CI 28.2-46.3) of PDRN-treated patients (P = .0027). After 8 weeks, PDRN increased the closure of foot ulcers in diabetic subjects (hazard ratio 2.20; 95% CI 1.29-3.75; P = .004). The median time to complete wound healing was 49 days for placebo (range 28-56 d) and 30 days for PDRN-treated subjects (range 14-56 d; P = .0027). The median epithelialized area of the ulcers (expressed as percentage) was 49.3% in the placebo and 82.2% in the PDRN group (P < .001). CONCLUSIONS: PDRN facilitates the healing of Wagner 1 or 2 diabetic foot ulcers.