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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 -
Drug Design, Development and Therapy 2019Immune checkpoint inhibitors have developed rapidly and have demonstrated antitumor activity in various cancers. To evaluate the safety and efficacy of atezolizumab in...
PURPOSE
Immune checkpoint inhibitors have developed rapidly and have demonstrated antitumor activity in various cancers. To evaluate the safety and efficacy of atezolizumab in treating cancers, we conducted this meta-analysis.
METHODS
Embase, PubMed, MEDLINE, the Central Register of Controlled Trials of the Cochrane Library, and the American Society of Clinical Oncology database were searched for relevant studies. The primary outcomes were any grade adverse events (AEs) and grade ≥3 AEs. The secondary outcomes were overall objective response rate, pooled 6-month progression-free survival (PFS) rate, 1-year overall survival (OS) rate, median PFS, and median OS.
RESULTS
Our meta-analysis was based on 14 clinical trials with 3,266 patients. The total risk of any grade AEs reached 69%, while grade ≥3 AEs happened in only 13% of participants. The overall atezolizumab-related death rate was 0.17%. Major common AEs involved fatigue (24.5%), decreased appetite (13.2%), nausea (12.3%), diarrhea (10.8%), pyrexia (10.7%), pruritus (9.6%), cough (9.5%), edema peripheral (8.6%), and rash (8.4%). The most common severe AEs were fatigue (2.2%), anemia (1.9%), and dyspnea (1.9%). Meanwhile, we found that 6% patients reached complete response and 16% partial response. The pooled 6-month PFS rate and 1-year OS rate were 0.36 (95% CI: 0.31-0.41) and 0.55 (95% CI: 0.49-0.61), respectively. The median PFS varied from 1.5 to 6.1 months, and the median OS ranged from 5.9 to 28.9 months.
CONCLUSION
Atezolizumab has a considerable potential in treating cancers with an acceptable risk profile.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Humans; Neoplasms
PubMed: 30787594
DOI: 10.2147/DDDT.S188893 -
The Clinical Journal of Pain Mar 2019Pregabalin has been approved for the treatment of the neuropathic pain following spinal cord injury (SCI). We performed a systemic review and meta-analysis of... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Pregabalin has been approved for the treatment of the neuropathic pain following spinal cord injury (SCI). We performed a systemic review and meta-analysis of randomized, controlled, multicenter trials to evaluate the efficacy and safety of pregabalin for SCI-induced neuropathic pain.
MATERIALS AND METHODS
Research searching was performed in PubMed and EMBASE databases and the Cochrane library in May 2018. Clinical controlled trials using pregabalin for the pain treatment following SCI in adults (18 y old and above) were included. Pain and safety-related adverse events were considered as outcomes. Meta-analysis was conducted using Revman 5.0 software.
RESULTS
Five publications (pregabalin, patients=261, placebo, patients=216) were included in our study. After at least 4-week's treatment with pregabalin (flexible dose, 150 to 600 mg/d), pregabalin-treated patients showed reduced pain -1.54, 95% confidence interval (CI) (-2.33, -0.75), P=0.0001; improved >30% 1.83, 95% CI (1.37, 2.46), P<0.0001 and >50% pain relief 2.40, 95% CI (1.53, 3.77), P=0.0001; increased adverse events 1.36, 95% CI (1.18, 1.577), P<0.0001; and reduced Hospital Anxiety and Depression Scale - anxiety -1.50, 95% CI (-2.99, -0.00), P=0.05 and - depression -0.34, 95% CI (-0.55, -0.12), P=0.002 scores compared with placebo-treated patients. Stratified meta-analysis showed there was no difference in primary adverse events (drowsiness, dizziness, peripheral edema, and dry mouth) between pregabalin and placebo groups (P≥0.05).
CONCLUSIONS
Our results showed pregabalin was efficacious and might be safe treatment for chronic pain followed SCI.
Topics: Analgesics; Chronic Pain; Humans; Neuralgia; Pregabalin; Randomized Controlled Trials as Topic; Spinal Cord Injuries
PubMed: 30499836
DOI: 10.1097/AJP.0000000000000675 -
BMC Sports Science, Medicine &... 2018Swimming induced pulmonary oedema is an uncommon occurrence and usually presents during strenuous distance swimming in cold water. The prevalence is most likely...
BACKGROUND
Swimming induced pulmonary oedema is an uncommon occurrence and usually presents during strenuous distance swimming in cold water. The prevalence is most likely underreported and the underlying mechanisms are controversial. The purpose of this study was to summarize the evidence with regards to prevalence, pathophysiology and treatment of swimming induced pulmonary oedema in endurance athletes.
METHODS
Medline, Embase, Scopus and Google Scholar were searched and level I-IV from 1970 to 2017 were included. For clinical studies, only publications reporting on swimming-induced pulmonary oedema were considered. Risk of bias was assessed with the ROBINS-I tool, and the quality of evidence was assessed with the Cochrane GRADE system. For data synthesis and analysis, a best evidence synthesis was used.
RESULTS
A total of 29 studies were included (174 athletes). The most common symptom was cough, dyspnoea, froth and haemoptysis. The risk of bias for the clinical studies included 13 with moderate risk, 3 with serious, and 4 with critical. Four of the pathophysiology studies had a moderate risk, 3 a serious risk, and 1 a critical risk of bias. A best evidence analysis demonstrated a strong association between cold water immersion and in increases of CVP (central venous pressure), MPAP (mean pulmonary arterial pressure), PVR (peripheral vascular resistance) and PAWP (pulmonary arterial wedge pressure) resulting in interstitial asymptomatic oedema.
CONCLUSION
The results of this study suggest a moderate association between water temperature and the prevalence of SIPE. The presence of the clinical symptoms cough, dyspnoea, froth and haemoptysis are strongly suggestive of SIPE during or immediately following swimming. There is only limited evidence to suggest that there are pre-existing risk factors leading to SIPE with exposure to strenuous physical activity during swimming. There is strong evidence that sudden deaths of triathletes are often associated with cardiac abnormalities.
PubMed: 30410770
DOI: 10.1186/s13102-018-0107-3 -
AJNR. American Journal of Neuroradiology Sep 2018Accurate diagnosis of tumefactive demyelinating lesions is clinically important to avoid unnecessary invasive biopsy or inappropriate treatment. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Accurate diagnosis of tumefactive demyelinating lesions is clinically important to avoid unnecessary invasive biopsy or inappropriate treatment.
PURPOSE
We aimed to evaluate conventional and advanced MR imaging findings of tumefactive demyelinating lesions and determine the diagnostic performance of MR imaging for differentiating tumefactive demyelinating lesions from primary brain tumor.
DATA SOURCES
A systematic search of Ovid MEDLINE and EMBASE up to December 6, 2017, was conducted.
STUDY SELECTION
Original articles describing MR imaging findings in patients with tumefactive demyelinating lesions were selected.
DATA ANALYSIS
The pooled incidences of conventional MR imaging findings of tumefactive demyelinating lesions were obtained with the DerSimonian and Liard random-effects model. The pooled sensitivity and specificity of MR imaging for differentiating tumefactive demyelinating lesions from primary brain tumor were obtained using the bivariate random-effects model.
DATA SYNTHESIS
Nineteen eligible studies with 476 patients with tumefactive demyelinating lesions were included. The pooled incidence of open ring or incomplete rim enhancement was 35% (95% CI, 24%-47%), which was significantly higher than the incidence of closed ring or complete rim enhancement (18% [95% CI, 11%-29%]; = .0281). The pooled incidences of T2 hypointense rim, absent or mild mass effect, and absent or mild perilesional edema were 48%, 67%, and 57%, respectively. On advanced MR imaging, tumefactive demyelinating lesions showed a high apparent diffusion coefficient, peripheral restricted diffusion, and low cerebral blood volume. The pooled sensitivity and specificity of MR imaging for differentiating tumefactive demyelinating lesions from primary brain tumor were 89% (95% CI, 82%-93%) and 94% (95% CI, 89%-97%), respectively.
LIMITATIONS
Seventeen of 19 studies were retrospective studies.
CONCLUSIONS
Conventional MR imaging findings may help differentiate tumefactive demyelinating lesions from primary brain tumor, though further study is needed to determine the added value of advanced MR imaging.
Topics: Adult; Brain Neoplasms; Demyelinating Diseases; Diagnosis, Differential; Female; Humans; Magnetic Resonance Imaging; Male; Neuroimaging; Sensitivity and Specificity
PubMed: 30115676
DOI: 10.3174/ajnr.A5775 -
International Journal of Rheumatic... Jun 2018Membranous lupus glomerulonephritis (MLN) is associated with morbidities such as thromboembolism, peripheral edema and/or hyperlipidemia. However, treatment of MLN... (Meta-Analysis)
Meta-Analysis Review
AIM
Membranous lupus glomerulonephritis (MLN) is associated with morbidities such as thromboembolism, peripheral edema and/or hyperlipidemia. However, treatment of MLN remains elusive.
METHODS
We performed systematic searches on MEDLINE, EMBASE and Cochrane Library database up to November, 2017. Eligible studies included randomized trials or cohort studies which evaluated different immunosuppressants in adult patients with pathologically proved MLN. No language restrictions were applied. Endpoints included complete remission (CR) as the primary outcome, and CR plus partial remission (PR) and proteinuria-reducing effect as secondary outcomes. Frequentist estimation of a network meta-analysis (NMA) random-effect model was performed.
RESULTS
Eight studies (206 patients) were included with a total of six immunosuppressants as an induction therapy for MLN. NMA results showed that both mycophenolate mofetil (MMF) and calcineurin inhibitors (CNI) are effective in the induction of CR and CR plus PR when compared with corticosteroids (CS) alone, but MMF and CNI are also associated with higher infection rates when compared with CS.
CONCLUSION
Our NMA demonstrated that both MMF and CNI are more effective than CS for induction therapy in MLN patients. However, there are limitations due to intra- and inter-study variability.
Topics: Adult; Female; Glomerulonephritis, Membranous; Humans; Immunocompromised Host; Immunosuppressive Agents; Induction Chemotherapy; Lupus Nephritis; Male; Odds Ratio; Opportunistic Infections; Proteinuria; Remission Induction; Risk Factors; Treatment Outcome
PubMed: 29879319
DOI: 10.1111/1756-185X.13321 -
European Journal of Emergency Medicine... Feb 2018Rapid and accurate diagnosis of patients with a new episode of acute dyspnea is a common challenge for Primary Care or Emergency Physicians. (Review)
Review
INTRODUCTION
Rapid and accurate diagnosis of patients with a new episode of acute dyspnea is a common challenge for Primary Care or Emergency Physicians.
OBJECTIVE
To determine the diagnostic accuracy of signs and symptoms in adult patients with a new episode of acute dyspnea presenting to a GP or an Emergency Physician (EP).
PATIENTS AND METHODS
This was a diagnostic systematic review. Using MEDLINE, Cumulative Index to Nursing and Allied Health Literature, EMBASE, tracing references, and by contacting experts, studies were identified on the diagnostic accuracy of additional signs and symptoms in adult patients with acute or suddenly worsening dyspnea, presenting to a GP or an EP. Study quality was assessed using QUADAS and results were pooled using a random-effects model. Sensitivity, specificity, positive and negative likelihood ratio (NLR), and positive and negative predictive values for a diagnosis of heart failure (HF) were calculated for the combination of acute dyspnea and each additional sign or symptom in the selected studies.
RESULTS
Eight of the 24 identified studies were carried out in the ED and provided us with all the required data, including 4737 patients. All publications reported HF; two studies additionally investigated pulmonary embolism, acute exacerbations of chronic obstructive pulmonary disease or asthma, acute pulmonary infectious diseases, or acute coronary syndrome. The prevalence of HF in patients with acute dyspnea ranged from 25 to 59%. Heterogeneity was present in all analyses.Comparing signs and symptoms, sensitivity was very poor for the presence of fever (0.05) and sputum production (0.06), and poor for fatigue (0.36-0.76), orthopnea (0.2-0.76), paroxysmal nocturnal dyspnea (0.23-0.70), elevated jugular venous pressure (0.19-0.70), rales (0.32-0.88), and peripheral edema (0.29-0.77). Specificity was poor for fatigue (0.28-0.69), moderate for the presence of fever (0.76-0.88), sputum production (0.73-0.89), orthopnea (0.49-0.92), paroxysmal nocturnal dyspnea (0.52-0.93), and rales (0.31-0.98), and good for elevated jugular venous pressure (0.75-0.97) and peripheral edema (0.67-0.89).For all other signs and symptoms, sensitivities varied between 0.20 and 0.43; specificities for symptoms varied widely between 0.37 and 0.91 and those of signs between 0.20 and 1.0.The pooled sensitivities, however, remained poor: below 0.55. Pooled specificity of most signs ranged between 0.69 and 0.88. The positive likelihood ratio was between 0.64 and 4.11 and the NLR was between 0.59 and 1.29 with one outlier: rales (pooled NLR=0.35).
CONCLUSION
This systematic review, which only included patients from ED settings, did not identify any single sign or symptom that had acceptable sensitivity to be useful in ruling out a diagnosis of HF, chronic obstructive pulmonary disease, asthma, or pulmonary embolism. Elevated jugular venous pressure (0.88, pooled odds ratio: 7), added third heart sound (0.97), and lung crepitations (0.77, pooled odds ratio: 11) are useful in ruling in HF.
Topics: Acute Coronary Syndrome; Adult; Asthma; Dyspnea; Emergency Service, Hospital; Heart Failure; Humans; Male; Physical Examination; Pulmonary Disease, Chronic Obstructive
PubMed: 29252938
DOI: 10.1097/MEJ.0000000000000429