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Archives of Cardiovascular Diseases 2020The risk of cardiovascular adverse events from rapidly accelerated fibrosarcoma B-type (BRAF) and mitogen-activated extracellular signal-regulated kinase (MEK)... (Meta-Analysis)
Meta-Analysis
Cardiovascular safety of rapidly accelerated fibrosarcoma B-type and/or mitogen-activated extracellular signal-regulated kinase inhibitors: A mixed approach combining a meta-analysis and a pharmacovigilance disproportionality analysis.
BACKGROUND
The risk of cardiovascular adverse events from rapidly accelerated fibrosarcoma B-type (BRAF) and mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors is not fully characterized.
AIM
To evaluate the cardiovascular adverse events risks related to BRAF and/or MEK inhibitors in randomized placebo-controlled clinical trials and in the real-life setting.
METHODS
We used two approaches. First, we conducted a systematic review and meta-analysis of randomized placebo-controlled clinical trials reporting the incidence of cardiovascular adverse events for BRAF and/or MEK inhibitors in cancer patients. Second, we performed a disproportionality analysis, using age- and sex-adjusted reporting odds ratios (arORs) and their 95% confidence intervals (CIs) from the World Health Organization's pharmacovigilance database (VigiBase®) of anticancer drug-associated reports, to investigate real-life data.
RESULTS
MEK inhibitors increased the risk of ejection fraction decrease (odds ratio [OR] 3.35, 95% CI 1.58-7.07), peripheral oedema (OR 2.87 95% CI 1.93-4.27) and syncope (OR 6.71, 95% CI 3.00-14.99) compared with placebo in randomized placebo-controlled clinical trials. BRAF and MEK inhibitor combination therapy further increased the risk of ejection fraction decrease. In the disproportionality analysis, we found over-reporting of ejection fraction decrease (arOR 8.42, 95% CI 7.03-10.09), peripheral oedema (arOR 1.39, 95% CI 1.17-1.66), syncope (arOR 1.56, 95% CI 1.22-1.99), torsade de pointes/QT prolongation (arOR 6.13, 95% CI 5.04-7.47) and supraventricular arrhythmias (arOR 1.50, 95% CI 1.21-1.85) for BRAF and MEK inhibitors. BRAF and MEK inhibitors were not associated with hypertension in either approach.
CONCLUSIONS
In conclusion, MEK inhibitors increase the risk of ejection fraction decrease, peripheral oedema and syncope in randomized placebo-controlled clinical trials. Real-life data confirm these findings, and suggested additional risks of torsade de pointes/QT prolongation and supraventricular arrhythmias with BRAF/MEK inhibitors.
Topics: Adverse Drug Reaction Reporting Systems; Aged; Antineoplastic Agents; Cardiovascular Diseases; Databases, Factual; Female; Fibrosarcoma; Humans; Male; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Patient Safety; Pharmacovigilance; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Treatment Outcome
PubMed: 32418884
DOI: 10.1016/j.acvd.2020.03.014 -
Frontiers in Pharmacology 2019Whereas the cardiovascular safety of sodium-glucose co-transporter 2 (SGLT2) inhibitors has been well reported, there is limited data from controlled clinical trials...
Appraisal of Non-Cardiovascular Safety for Sodium-Glucose Co-Transporter 2 Inhibitors: A Systematic Review and Meta-Analysis of Placebo-Controlled Randomized Clinical Trials.
Whereas the cardiovascular safety of sodium-glucose co-transporter 2 (SGLT2) inhibitors has been well reported, there is limited data from controlled clinical trials regarding the non-cardiovascular safety. This was the focus of our study. We systematically searched MEDLINE, EMBASE, and Cochrane Library (5 Sep 2018) for randomized controlled trials (RCTs) that reported safety data for SGLT2 inhibitors and placebo. Relative risks (RRs) and their 95% confidence intervals (CIs) were pooled using random-effects models. Seventy RCTs (83 studies enrolling 36,958 patients in 78 publications) were identified. SGLT2 inhibitors were associated with a lower risk of serious adverse events (RR 0.90, 95% CI 0.86 to 0.94, < 0.001), death (RR 0.78, 95% CI 0.64 to 0.94, < 0.05), gastroenteritis (RR 0.38, 95% CI 0.20 to 0.72, < 0.05), arthralgia (RR 0.72, 95% CI 0.54 to 0.96, < 0.05), hypertension (RR 0.61, 95% CI 0.50 to 0.75, < 0.001), and edema/peripheral edema (RR 0.49, 95% CI 0.33 to 0.72, < 0.001) compared to placebo. SGLT2 inhibitors were associated with higher risk of infections compared to placebo (RR 1.27, 95% CI 1.17 to 1.37, < 0.001), especially for genital mycotic infection (GMI) (RR 3.71, 95% CI 3.19 to 4.32, < 0.001). Other significant effects were observed for osmotic diuresis-related AEs (RR 2.73, 95% CI 2.20 to 3.40, < 0.001), volume-related AEs (RR 1.26, 95% CI 1.08 to 1.46, < 0.05), renal-related AEs (RR 1.36, 95% CI 1.02 to 1.80, < 0.05), hypoglycemia (RR 1.18, 95% CI 1.10 to 1.26, < 0.001), and increased blood ketone bodies (RR 2.00, 95% CI 1.01 to 3.97, < 0.05). Subgroup and sensitivity analyses strengthened the robustness of primary results. Results from RCTs confirmed lower risk of death, serious adverse events, hypertension, and edema associated with type 2 diabetes mellitus (T2DM) patients treated with SGLT2 inhibitors when compared with placebo. The use of SGLT2 inhibitors were associated with higher risk of infection, osmotic diuresis, volume depletion effects, renal related AEs, and higher blood ketone bodies when compared with placebo.
PubMed: 31616297
DOI: 10.3389/fphar.2019.01066 -
Journal of Oral and Maxillofacial... Dec 2019Evidence exists to support the peripheral analgesic effect of local administration of ketamine (LAK) after third molar surgery. The aim of the present systematic review... (Meta-Analysis)
Meta-Analysis
PURPOSE
Evidence exists to support the peripheral analgesic effect of local administration of ketamine (LAK) after third molar surgery. The aim of the present systematic review and meta-analysis was to determine the efficacy of LAK in the control of pain, swelling, and trismus after third molar surgery.
MATERIALS AND METHODS
The study design was a systematic review with a meta-analysis of the effect of LAK after third molar surgery. A search in electronic databases was performed from September 2017 to February 2019. Only prospective clinical trials and randomized controlled trials that had evaluated LAK after third molar surgery were included. The meta-analysis was based on the random effects model. The outcome measures evaluated were postoperative acute pain, swelling, and trismus. The estimated overall effect size was a standardized mean difference (SMD).
RESULTS
A total of 110 study subjects (men and women aged 18 to 50 years) were evaluated for the analgesic effect. The SMD showed a significant analgesic effect (postoperative pain control) favoring LAK (SMD, -1.7403; 95% confidence interval [CI], -2.45 to -1.04). Evaluation of the anti-inflammatory effect of LAK included 105 study subjects and resulted in significantly less swelling in the first postoperative day (SMD, -0.6169; 95% CI, -1.1654 to -0.0683). However, LAK did not reduce the incidence of trismus after third molar surgery (SMD, -0.7241; 95% CI, -2.2765 to 0.8284).
CONCLUSIONS
The use of LAK can reduce the incidence and severity of postoperative pain after third molar surgery and had an anti-inflammatory effect, although only in the first postoperative day. However, LAK had no effect on trismus reduction after third molar surgery.
Topics: Adolescent; Adult; Analgesia; Analgesics; Edema; Female; Humans; Ketamine; Male; Middle Aged; Molar, Third; Pain, Postoperative; Postoperative Complications; Prospective Studies; Tooth Extraction; Tooth, Impacted; Trismus; Young Adult
PubMed: 31404519
DOI: 10.1016/j.joms.2019.07.002 -
Acta Neurologica Belgica Sep 2019The use of levodopa for treatment of Parkinson's disease is a well-established clinical practice. Data about the true incidence and severity of cutaneous complications...
The use of levodopa for treatment of Parkinson's disease is a well-established clinical practice. Data about the true incidence and severity of cutaneous complications associated with the use of levodopa are largely lacking. Aim of this review was to evaluate the quality of evidence referring to the skin disorders caused by levodopa treatment for Parkinson's disease. Thirty of 1084 studies were included; 8 randomized controlled trials and 22 case reports in a total of 2749 patients. Malignant melanoma was the most frequent oral levodopa-related skin disorder followed by allergic cutaneous reactions, alopecia, vitiligo, skin hyperpigmentation, Laugier-Hunziker syndrome, Henoch-Schönlein syndrome, pseudobullous morphea and scleroderma-like illness. Naranjo scores ranged from 2 to 8. Regarding levodopa clinical trials, the most frequent skin complication was peripheral edema, followed by malignant melanoma. Although evidence is not robust, melanoma is the most frequent and possible fatal levodopa-associated skin disorder, while other skin allergic or immunological reactions are less common and reversible. Although levodopa treatment may induce melanogenesis and promote melanomagenesis, existing evidence does not support an association between levodopa therapy and induction or progression of malignant melanoma. The suggested association with melanoma may reflect the well-documented association of Parkinson's disease with melanoma rather than the exposure to the drug. Nevertheless, until a solid conclusion can be drawn, the use of levodopa in the context of malignant melanoma should be considered with caution. Well-designed prospective studies are needed to determine the cause and effect relationship between levodopa and skin disorders.
Topics: Antiparkinson Agents; Humans; Levodopa; Parkinson Disease; Skin Diseases
PubMed: 31338806
DOI: 10.1007/s13760-019-01195-3