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The Korean Journal of Internal Medicine Jan 2024The effectiveness of remdesivir treatment in reducing mortality and the requirement for mechanical ventilation (MV) remains uncertain, as randomized controlled trials... (Meta-Analysis)
Meta-Analysis
BACKGROUND/AIMS
The effectiveness of remdesivir treatment in reducing mortality and the requirement for mechanical ventilation (MV) remains uncertain, as randomized controlled trials (RCTs) have produced conflicting results.
METHODS
We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and other data resources to find RCTs published prior to April 10, 2023. The selection of studies, assessment of risk of bias, and meta-analysis were conducted according to PRISMA guidelines. The primary outcomes were all-cause mortality and the need to initiate MV.
RESULTS
A total of 5,068 articles were screened, from eight RCTs comprising 11,945 patients. The meta-analysis found that, compared to standard care or placebo, remdesivir treatment provided no significant all-cause mortality benefit (pooled risk ratio [RR], 0.93; 95% confidence interval [CI], 0.85-1.02; 8 studies; high certainty evidence), while subgroup analyses revealed a trend towards reduced mortality among patients requiring oxygen but not MV (pooled RR, 0.88; 95% CI, 0.77-1.00; 6 studies; I2 = 4%). The need to initiate MV (pooled RR, 0.74; 95% CI, 0.59-0.94; 7 studies; moderate certainty evidence) in remdesivir-treated patients was also reduced compared to controls. Remdesivir significantly increased clinical improvement and discharge and significantly reduced serious adverse events.
CONCLUSION
In this systematic review and meta-analysis of RCTs, it was found that remdesivir treatment did not show a substantial decrease in the risk of mortality. However, it was linked to a reduction in the necessity for additional ventilatory support, suggesting remdesivir could be beneficial for COVID-19 patients, particularly those who are not on MV.
Topics: Humans; COVID-19; Respiration, Artificial; COVID-19 Drug Treatment; Patient Acuity; Adenosine Monophosphate; Alanine
PubMed: 38151918
DOI: 10.3904/kjim.2023.357 -
AJNR. American Journal of Neuroradiology Mar 2022Rescue therapies are increasingly used in the setting of endovascular therapy for large-vessel occlusion strokes. Among these, cangrelor, a new P2Y12 inhibitor, offers... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND PURPOSE
Rescue therapies are increasingly used in the setting of endovascular therapy for large-vessel occlusion strokes. Among these, cangrelor, a new P2Y12 inhibitor, offers promising pharmacologic properties to join the reperfusion strategies in acute stroke. We assessed the safety and efficacy profiles of cangrelor combined with endovascular therapy in patients with large-vessel-occlusion stroke.
MATERIALS AND METHODS
We performed a retrospective patient data analysis in the ongoing prospective multicenter observational Endovascular Treatment in Ischemic Stroke Registry in France from July 2018 to December 2020 and conducted a systematic review and meta-analysis using several data bases. Indications for cangrelor administration were rescue strategy in case of refractory intracranial occlusion with or without intracranial rescue stent placement, and cervical carotid artery stent placement in case of cervical occlusion (tandem occlusion or isolated cervical carotid occlusion).
RESULTS
In the clinical registry, 44 patients were included (median initial NIHSS score, 12; prior intravenous thrombolysis, 29.5%). Intracranial stent placement was performed in 54.5% ( = 24/44), and cervical stent placement, in 27.3% ( = 12/44). Adjunctive aspirin and heparin were administered in 75% ( = 33/44) and 40.9% ( = 18/44), respectively. Rates of symptomatic intracerebral hemorrhage, parenchymal hematoma, and 90-day mortality were 9.5% ( = 4/42), 9.5% ( = 4/42), and 24.4% ( = 10/41). Favorable outcome (90-day mRS, 0-2) was reached in 51.2% ( = 21/41), and successful reperfusion, in 90.9% ( = 40/44). The literature search identified 6 studies involving a total of 171 subjects. In the meta-analysis, including our series data, symptomatic intracerebral hemorrhage occurred in 8.6% of patients (95% CI, 5.0%-14.3%) and favorable outcome was reached in 47.6% of patients (95% CI, 27.4%-68.7%). The 90-day mortality rate was 22.6% (95% CI, 13.6%-35.2%). Day 1 artery patency was observed in 89.7% (95% CI, 81.4%-94.6%).
CONCLUSIONS
Cangrelor offers promising safety and efficacy profiles, especially considering the complex endovascular reperfusion procedures in which it is usually applied. Further large prospective data are required to confirm these findings.
Topics: Adenosine Monophosphate; Cerebral Hemorrhage; Combined Modality Therapy; Endovascular Procedures; Humans; Ischemic Stroke; Thrombectomy; Treatment Outcome
PubMed: 35241418
DOI: 10.3174/ajnr.A7430 -
Infectious Diseases (London, England) Sep 2021In view of many unanswered clinical questions regarding treatment of COVID-19 with remdesivir, we systematically identified, critically appraised and summarized the... (Meta-Analysis)
Meta-Analysis
BACKGROUND
In view of many unanswered clinical questions regarding treatment of COVID-19 with remdesivir, we systematically identified, critically appraised and summarized the findings from randomized controlled trials (RCTs) of remdesivir for COVID-19.
METHODS
We searched relevant databases/websites (up to September 2020) and selected English-language RCT publications of remdesivir for COVID-19. We conducted meta-analysis using an inverse variance, random-effects model in addition to trial sequential analysis (TSA) for the efficacy outcomes: all-cause mortality, viral burden and clinical progression. Safety outcomes were diarrhoea, nausea, and vomiting. We calculated the relative risk (RR) and 95% confidence interval (CI) for all outcomes. Statistical heterogeneity was calculated using the statistic.
RESULTS
We included five RCTs (7540 participants) from 7237 citations. Most (80%) were of an unclear to high risk of bias. There was no evidence of a significant improvement with remdesivir (100 mg, 10 days) regarding all-cause mortality (RR 0.94, CI 0.82-1.07; = 0%; 4 RCTs; 7143 patients), clinical progression (RR 1.08, CI 0.99-1.18; = 70.4%; 3 RCTs; 1692 patients), or diarrhoea (RR 0.82, CI 0.40-1.66; = 0%; 2 RCTs; 630 patients). Nausea occurred more often with remdesivir (RR 2.77, CI 1.28-6.03; = 0%; 2 RCTs; 630 patients). TSA showed that the required information size was not reached for firm conclusions to be drawn.
CONCLUSIONS AND RELEVANCE
There is insufficient evidence to support the use of remdesivir for treatment of COVID-19. More high-quality RCTs are needed for a stronger evidence. Until then, remdesivir should remain an experimental drug for COVID-19.
Topics: Adenosine Monophosphate; Alanine; Humans; Randomized Controlled Trials as Topic; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 33974479
DOI: 10.1080/23744235.2021.1923799 -
Expert Review of Medical Devices May 2021: The use of mechanical ventilation associated with acute hypoxemic respiratory failure, the most common complication in critically ill COVID-19 patients, defines a high...
: The use of mechanical ventilation associated with acute hypoxemic respiratory failure, the most common complication in critically ill COVID-19 patients, defines a high risk population that requires specific consideration of outcomes and treatment practices.: This review evaluates existing information about mortality rates and effectiveness of antiviral, immune-modulating, and anticoagulation treatments in COVID-19 patients who received mechanical ventilation. The mortality rate and follow-up periods in patients receiving mechanical ventilation ranged widely. Antivirals, including remdesivir and convalescent plasma, have shown no definitive mortality benefit in this population despite positive results in other COVID-19 patients. Dexamethasone was associated with an absolute reduction in 28-day mortality by 12.3% (95% CI, 6.3 to 17.6), after adjusting for age. Reduced mortality has been demonstrated with tocilizumab use alongside corticosteroids. Evidence is inconclusive for therapeutic anticoagulation, and further studies are needed to determine the comparative benefit of prophylactic anticoagulation.: Significant variation and high mortality rates in mechanically ventilated patients necessitate more standardized outcome measurements, increased consideration of risk factors to reduce intubation, and improved treatment practices. Anticoagulation and dexamethasone should be incorporated in the treatment of patients receiving invasive mechanical ventilation, while more rigorous studies are required for other potential treatments.
Topics: Adenosine Monophosphate; Alanine; Antibodies, Monoclonal, Humanized; COVID-19; Humans; Respiration, Artificial; SARS-CoV-2; Treatment Outcome
PubMed: 33836621
DOI: 10.1080/17434440.2021.1915764 -
Drug Safety Jul 2020There is a need to identify effective, safe treatments for COVID-19 (coronavirus disease) rapidly, given the current, ongoing pandemic. A systematic benefit-risk...
INTRODUCTION
There is a need to identify effective, safe treatments for COVID-19 (coronavirus disease) rapidly, given the current, ongoing pandemic. A systematic benefit-risk assessment was designed and conducted to examine the benefit-risk profile of remdesivir in COVID-19 patients compared with standard of care, placebo or other treatments. A key objective of this study was to provide a platform for a dynamic systematic benefit-risk evaluation, which starts with inevitably limited information (to meet the urgent unmet public health need worldwide), then update the benefit-risk evaluation as more data become available.
METHODS
The Benefit-Risk Action Team (BRAT) framework was used to assess the overall benefit-risk of the use of remdesivir as a treatment for COVID-19 compared with standard of care, placebo or other treatments. We searched PubMed, Google Scholar and government agency websites to identify literature reporting clinical outcomes in patients taking remdesivir for COVID-19. A value tree was constructed and key benefits and risks were ranked by two clinicians in order of considered importance.
RESULTS
Using the BRAT method, several key benefits and risks for use of remdesivir in COVID-19 compared with placebo have been identified. In one trial, the benefit of time to clinical improvement was not statistically significant (21 vs 23 days, HR 1.23, 95% CI 0.87-1.75), although the study was underpowered. In another trial, a shorter time to recovery in patients treated with remdesivir was observed (11 vs 15 days), with non-significant reduced mortality risk (8% vs 12%). Risk data were only available from one trial. This trial reported fewer serious adverse events in patients taking remdesivir (18%) compared with the placebo group (26%); however, more patients in the remdesivir group discontinued treatment as a result of an adverse event compared with those patients receiving placebo (12% vs 5%).
CONCLUSIONS
Preliminary clinical trial results suggest that there may be a favourable benefit-risk profile for remdesivir compared with placebo in severe COVID-19 infection and further data on benefits would strengthen this evaluation. There is limited safety data for remdesivir, which should be obtained in further studies. The current framework summarises the key anticipated benefits and risks for which further data are needed. Ongoing clinical trial data can be incorporated into the framework when available to provide an updated benefit-risk assessment.
Topics: Adenosine Monophosphate; Alanine; Antiviral Agents; Betacoronavirus; COVID-19; Coronavirus Infections; Humans; Pandemics; Pneumonia, Viral; Risk Assessment; SARS-CoV-2; Treatment Outcome
PubMed: 32468196
DOI: 10.1007/s40264-020-00952-1 -
The Western Journal of Emergency... May 2020In March 2020, the World Health Organization declared the spread of SARS-CoV-2 a global pandemic. To date, coronavirus disease-2019 (COVID-19) has spread to over 200...
In March 2020, the World Health Organization declared the spread of SARS-CoV-2 a global pandemic. To date, coronavirus disease-2019 (COVID-19) has spread to over 200 countries, leading to over 1.6 million cases and over 99,000 deaths. Given that there is neither a vaccine nor proven treatment for COVID-19, there is currently an urgent need for effective pharmacotherapy. To address the need for an effective treatment of SARS-CoV-2 during the worldwide pandemic, this systematic review of intravenous (IV) remdesivir was performed. Remdesivir, an anti-viral prodrug originally developed to treat Ebola virus disease, has shown broad spectrum activity against the Coronavirus family. A recent case report reported improvement of clinical symptoms with remdesivir in a patient with COVID-19. After conducting a systematic search of 18 clinical trial registries and three large scientific databases, we identified 86 potentially eligible items. Following removal of duplicates (n = 21), eligible studies were reviewed independently by two authors. After the first round of screening, inter-rater agreement was 98.5% (κ = 0.925). After the second round of full-text screening, inter-rater agreement was 100%. A total of seven ongoing and recruiting clinical trials of remdesivir (100-200 milligrams, intravenous [IV]) were included. We identified the following primary outcomes: patients discharged (n = 2); time to clinical status improvement (n = 2); improved O2 saturation (n = 2); body temperature normalization (n = 2); and clinical status (n = 1). Secondary outcomes in all identified studies included documentation of adverse events. Phase 3 trials are expected to be completed between April 2020-2023. Therefore, despite supportive data from in vitro and in vivo studies, the clinical effectiveness of IV remdesivir for treatment of COVID-19 and potential side effects remain incompletely defined in the human population.
Topics: Adenosine Monophosphate; Administration, Intravenous; Alanine; Antiviral Agents; Betacoronavirus; COVID-19; Clinical Trials as Topic; Coronavirus Infections; Humans; Pandemics; Pneumonia, Viral; SARS-CoV-2; Treatment Outcome; COVID-19 Drug Treatment
PubMed: 32726230
DOI: 10.5811/westjem.2020.5.47658 -
Current Drug Research Reviews 2022The novel SARS-CoV-2 is a new disease that has caused severe destruction to human lives across the globe, including infection, mortality and financial crises, for which,...
The novel SARS-CoV-2 is a new disease that has caused severe destruction to human lives across the globe, including infection, mortality and financial crises, for which, scientific researchers have been directed towards the development of treatment and controlling measures against coronavirus. Currently, there has been no approved drug for the treatment of the disease, but several antiviral drugs have shown therapeutic effects from which, remdesivir and favipiravir are two such drugs. These drugs have shown some therapeutic potential in the treatment of COVID-19 by inhibiting viral enzyme RNA-dependent RNA polymerase. The purpose of this systematic review is to provide an overview of the effectiveness of these two drugs based on the clinical trials reported in current published data.
Topics: Adenosine Monophosphate; Alanine; Amides; Humans; Pyrazines; SARS-CoV-2; Treatment Outcome; COVID-19 Drug Treatment
PubMed: 34365935
DOI: 10.2174/2589977513666210806122901 -
Annals of Internal Medicine Feb 2021Few treatments exist for coronavirus disease 2019 (COVID-19).
BACKGROUND
Few treatments exist for coronavirus disease 2019 (COVID-19).
PURPOSE
To evaluate the effectiveness and harms of remdesivir for COVID-19.
DATA SOURCES
Several databases, tables of contents of journals, and U.S. Food and Drug Administration and company websites were searched from 1 January through 31 August 2020.
STUDY SELECTION
English-language, randomized trials of remdesivir treatments for adults with suspected or confirmed COVID-19. New evidence will be incorporated using living review methods.
DATA EXTRACTION
Single-reviewer abstraction and risk-of-bias assessment verified by a second reviewer; GRADE (Grading of Recommendations Assessment, Development and Evaluation) methods used for certainty-of-evidence assessments.
DATA SYNTHESIS
Four randomized trials were included. In adults with severe COVID-19, remdesivir compared with placebo probably improves recovery by a large amount (absolute risk difference [ARD] range, 7% to 10%) and may result in a small reduction in mortality (ARD range, -4% to 1%) and a shorter time to recovery or clinical improvement. Remdesivir may have little to no effect on hospital length of stay. Remdesivir probably reduces serious adverse events by a moderate amount (ARD range, -6% to -8%). Compared with a 10-day remdesivir course, a 5-day course may reduce mortality, increase recovery or clinical improvement by small to moderate amounts, reduce time to recovery, and reduce serious adverse events among hospitalized patients not requiring mechanical ventilation. Recovery due to remdesivir may not vary by age, sex, symptom duration, or disease severity.
LIMITATIONS
Low-certainty evidence with few published trials, including 1 preliminary report and 2 open-label trials. Trials excluded pregnant women and adults with severe kidney or liver disease.
CONCLUSION
In hospitalized adults with COVID-19, remdesivir probably improves recovery and reduces serious adverse events and may reduce mortality and time to clinical improvement. For adults not receiving mechanical ventilation or extracorporeal membrane oxygenation, a 5-day course of remdesivir may provide similar benefits to and fewer harms than a 10-day course.
PRIMARY FUNDING SOURCE
U.S. Department of Veterans Affairs, Veterans Health Administration Office of Research and Development, Health Services Research and Development Service, and Evidence Synthesis Program.
Topics: Adenosine Monophosphate; Alanine; Antiviral Agents; Drug Administration Schedule; Humans; Length of Stay; Randomized Controlled Trials as Topic; SARS-CoV-2; Severity of Illness Index; COVID-19 Drug Treatment
PubMed: 33017170
DOI: 10.7326/M20-5752 -
Current Pharmaceutical Design 2021The antagonistic relationship between adenosine monophosphate-activated protein kinase (AMPK) and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling...
Berberine Exerts Anti-cancer Activity by Modulating Adenosine Monophosphate- Activated Protein Kinase (AMPK) and the Phosphatidylinositol 3-Kinase/ Protein Kinase B (PI3K/AKT) Signaling Pathways.
BACKGROUND
The antagonistic relationship between adenosine monophosphate-activated protein kinase (AMPK) and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling play a vital role in cancer development. The anti-cancer effects of berberine have been reported as a main component of the traditional Chinese medicine Rhizoma coptidis, although the roles of these signaling pathways in these effects have not been systematically reviewed.
METHODS
We searched the PubMed database for studies with keywords including ["berberine"] and ["tumor" or "cancer"] and ["AMPK"] or ["AKT"] published between January 2010 and July 2020, to elucidate the roles of the AMPK and PI3K/AKT pathways and their upstream and downstream targets in the anti-cancer effects of berberine.
RESULTS
The anti-cancer effects of berberine include inhibition of cancer cell proliferation, promotion of apoptosis and autophagy in cancer cells, and prevention of metastasis and angiogenesis. The mechanism of these effects involves multiple cell kinases and signaling pathways, including activation of AMPK and forkhead box transcription factor O3a (FOXO3a), accumulation of reactive oxygen species (ROS), and inhibition of the activity of PI3K/AKT, rapamycin (mTOR) and nuclear factor-κB (NF-κB). Most of these mechanisms converge on regulation of the balance of AMPK and PI3K/AKT signaling by berberine.
CONCLUSION
This evidence supports the possibility that berberine is a promising anti-cancer natural product, with pharmaceutical potential in inhibiting cancer growth, metastasis and angiogenesis via multiple pathways, particularly by regulating the balance of AMPK and PI3K/AKT signaling. However, systematic preclinical studies are still required to provide scientific evidence for further clinical studies.
Topics: AMP-Activated Protein Kinases; Adenosine Monophosphate; Berberine; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt
PubMed: 32988344
DOI: 10.2174/1381612826666200928155728 -
Journal of Cancer Research and... Dec 2021To evaluate the efficacy, safety, and potential advantages of Poly (ADP-ribose) polymerase inhibitors (PARPi) in treating BRCA-mutated breast cancer, we performed a... (Meta-Analysis)
Meta-Analysis
BACKGROUND
To evaluate the efficacy, safety, and potential advantages of Poly (ADP-ribose) polymerase inhibitors (PARPi) in treating BRCA-mutated breast cancer, we performed a meta-analysis of published studies.
MATERIALS AND METHODS
Four randomized controlled trials (RCTs) were included in the meta-analysis. Data analysis was conducted in Review Manager 5.4.
RESULTS
The progression-free survival (PFS) of the patients with triple-negative (hazard ratio [HR] 0.81; 95% confidence interval [CI] 0.74-0.88; P < 0.00001) or hormone receptor-positive (HR 0.83; 95% CI 0.77-0.91; P < 0.0001) BRCA-mutated breast cancer was significantly extended in the containing PARPi therapy arm versus the chemotherapy arm. PFS of the patients who did not receive platinum-based therapy (HR 0.78; 95% CI 0.70-0.86; P < 0.0001) was significantly extended in the PARPi monotherapy arm versus the chemotherapy arm. The objective response rate of patients treated by PARPi monotherapy (risk ratio [RR] 2.51; 95% CI 1.81-3.47; P < 0.00001) was significantly higher than that of patients treated by chemotherapy. The incidence of thrombocytopenia in patients received PARPi combined therapy was obviously increased compared with chemotherapy group (RR 1.36; 95% CI 1.07-1.72; P = 0.01). PARPi monotherapy markedly increased the incidence of anemia (RR 5.83; 95% CI 2.64-12.88; P < 0.0001) versus chemotherapy. However, the risk of neutropenia (RR 0.48; 95% CI 0.29-0.81; P = 0.006) was reduced in the PARPi monotherapy arm. There were no statistical differences in other adverse events among these three groups.
CONCLUSIONS
PARPi combined therapy and monotherapy improved PFS of patients with BRCA-mutated breast cancer compared with standard chemotherapy, which was unrelated to type of BRCA mutation and status of hormone receptor. PARPi therapy has slightly higher hematological toxicity and better overall safety and tolerance.
PROSPERO REGISTRATION NUMBER
CRD42020204385.
Topics: Adenosine Diphosphate; Breast Neoplasms; Female; Humans; Ovarian Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Progression-Free Survival; Ribose
PubMed: 35381738
DOI: 10.4103/jcrt.jcrt_2085_21