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The Cochrane Database of Systematic... May 2020Acne is an inflammatory disorder with a high global burden. It is common in adolescents and primarily affects sebaceous gland-rich areas. The clinical benefit of the... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Acne is an inflammatory disorder with a high global burden. It is common in adolescents and primarily affects sebaceous gland-rich areas. The clinical benefit of the topical acne treatments azelaic acid, salicylic acid, nicotinamide, sulphur, zinc, and alpha-hydroxy acid is unclear.
OBJECTIVES
To assess the effects of topical treatments (azelaic acid, salicylic acid, nicotinamide, zinc, alpha-hydroxy acid, and sulphur) for acne.
SEARCH METHODS
We searched the following databases up to May 2019: the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We also searched five trials registers.
SELECTION CRITERIA
Clinical randomised controlled trials of the six topical treatments compared with other topical treatments, placebo, or no treatment in people with acne.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane. Key outcomes included participants' global self-assessment of acne improvement (PGA), withdrawal for any reason, minor adverse events (assessed as total number of participants who experienced at least one minor adverse event), and quality of life.
MAIN RESULTS
We included 49 trials (3880 reported participants) set in clinics, hospitals, research centres, and university settings in Europe, Asia, and the USA. The vast majority of participants had mild to moderate acne, were aged between 12 to 30 years (range: 10 to 45 years), and were female. Treatment lasted over eight weeks in 59% of the studies. Study duration ranged from three months to three years. We assessed 26 studies as being at high risk of bias in at least one domain, but most domains were at low or unclear risk of bias. We grouped outcome assessment into short-term (less than or equal to 4 weeks), medium-term (from 5 to 8 weeks), and long-term treatment (more than 8 weeks). The following results were measured at the end of treatment, which was mainly long-term for the PGA outcome and mixed length (medium-term mainly) for minor adverse events. Azelaic acid In terms of treatment response (PGA), azelaic acid is probably less effective than benzoyl peroxide (risk ratio (RR) 0.82, 95% confidence interval (CI) 0.72 to 0.95; 1 study, 351 participants), but there is probably little or no difference when comparing azelaic acid to tretinoin (RR 0.94, 95% CI 0.78 to 1.14; 1 study, 289 participants) (both moderate-quality evidence). There may be little or no difference in PGA when comparing azelaic acid to clindamycin (RR 1.13, 95% CI 0.92 to 1.38; 1 study, 229 participants; low-quality evidence), but we are uncertain whether there is a difference between azelaic acid and adapalene (1 study, 55 participants; very low-quality evidence). Low-quality evidence indicates there may be no differences in rates of withdrawal for any reason when comparing azelaic acid with benzoyl peroxide (RR 0.88, 95% CI 0.60 to 1.29; 1 study, 351 participants), clindamycin (RR 1.30, 95% CI 0.48 to 3.56; 2 studies, 329 participants), or tretinoin (RR 0.66, 95% CI 0.29 to 1.47; 2 studies, 309 participants), but we are uncertain whether there is a difference between azelaic acid and adapalene (1 study, 55 participants; very low-quality evidence). In terms of total minor adverse events, we are uncertain if there is a difference between azelaic acid compared to adapalene (1 study; 55 participants) or benzoyl peroxide (1 study, 30 participants) (both very low-quality evidence). There may be no difference when comparing azelaic acid to clindamycin (RR 1.50, 95% CI 0.67 to 3.35; 1 study, 100 participants; low-quality evidence). Total minor adverse events were not reported in the comparison of azelaic acid versus tretinoin, but individual application site reactions were reported, such as scaling. Salicylic acid For PGA, there may be little or no difference between salicylic acid and tretinoin (RR 1.00, 95% CI 0.92 to 1.09; 1 study, 46 participants; low-quality evidence); we are not certain whether there is a difference between salicylic acid and pyruvic acid (1 study, 86 participants; very low-quality evidence); and PGA was not measured in the comparison of salicylic acid versus benzoyl peroxide. There may be no difference between groups in withdrawals when comparing salicylic acid and pyruvic acid (RR 0.89, 95% CI 0.53 to 1.50; 1 study, 86 participants); when salicylic acid was compared to tretinoin, neither group had withdrawals (both based on low-quality evidence (2 studies, 74 participants)). We are uncertain whether there is a difference in withdrawals between salicylic acid and benzoyl peroxide (1 study, 41 participants; very low-quality evidence). For total minor adverse events, we are uncertain if there is any difference between salicylic acid and benzoyl peroxide (1 study, 41 participants) or tretinoin (2 studies, 74 participants) (both very low-quality evidence). This outcome was not reported for salicylic acid versus pyruvic acid, but individual application site reactions were reported, such as scaling and redness. Nicotinamide Four studies evaluated nicotinamide against clindamycin or erythromycin, but none measured PGA. Low-quality evidence showed there may be no difference in withdrawals between nicotinamide and clindamycin (RR 1.12, 95% CI 0.49 to 2.60; 3 studies, 216 participants) or erythromycin (RR 1.40, 95% CI 0.46 to 4.22; 1 study, 158 participants), or in total minor adverse events between nicotinamide and clindamycin (RR 1.20, 95% CI 0.73 to 1.99; 3 studies, 216 participants; low-quality evidence). Total minor adverse events were not reported in the nicotinamide versus erythromycin comparison. Alpha-hydroxy (fruit) acid There may be no difference in PGA when comparing glycolic acid peel to salicylic-mandelic acid peel (RR 1.06, 95% CI 0.88 to 1.26; 1 study, 40 participants; low-quality evidence), and we are uncertain if there is a difference in total minor adverse events due to very low-quality evidence (1 study, 44 participants). Neither group had withdrawals (2 studies, 84 participants; low-quality evidence).
AUTHORS' CONCLUSIONS
Compared to benzoyl peroxide, azelaic acid probably leads to a worse treatment response, measured using PGA. When compared to tretinoin, azelaic acid probably makes little or no difference to treatment response. For other comparisons and outcomes the quality of evidence was low or very low. Risk of bias and imprecision limit our confidence in the evidence. We encourage the comparison of more methodologically robust head-to-head trials against commonly used active drugs.
Topics: Acne Vulgaris; Adapalene; Adolescent; Adult; Anti-Bacterial Agents; Benzoyl Peroxide; Bias; Child; Clindamycin; Dermatologic Agents; Dicarboxylic Acids; Erythromycin; Female; Glycolates; Humans; Keratolytic Agents; Male; Mandelic Acids; Niacinamide; Patient Dropouts; Pyruvic Acid; Quality of Life; Salicylic Acid; Sulfur; Tretinoin; Young Adult; Zinc
PubMed: 32356369
DOI: 10.1002/14651858.CD011368.pub2 -
The Cochrane Database of Systematic... Apr 2015Rosacea is a common chronic skin condition affecting the face, characterised by flushing, redness, pimples, pustules and dilated blood vessels. The eyes are often... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Rosacea is a common chronic skin condition affecting the face, characterised by flushing, redness, pimples, pustules and dilated blood vessels. The eyes are often involved and thickening of the skin with enlargement (phymas), especially of the nose, can occur in some people. A range of treatment options are available but it is unclear which are most effective.
OBJECTIVES
To assess the efficacy and safety of treatments for rosacea.
SEARCH METHODS
We updated our searches, to July 2014, of: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library (2014, Issue 6), MEDLINE (from 1946), EMBASE (from 1974) and Science Citation Index (from 1988). We searched five trials registers and checked reference lists for further relevant studies.
SELECTION CRITERIA
Randomised controlled trials in people with moderate to severe rosacea.
DATA COLLECTION AND ANALYSIS
Study selection, data extraction, risk of bias assessment and analyses were carried out independently by two authors.
MAIN RESULTS
We included 106 studies, comprising 13,631 participants. Sample sizes of 30-100 and study duration of two to three months were most common. More women than men were included, mean age of 48.6 years, and the majority had papulopustular rosacea, followed by erythematotelangiectatic rosacea.A wide range of comparisons (67) were evaluated. Topical interventions: metronidazole, azelaic acid, ivermectin, brimonidine or other topical treatments. Systemic interventions: oral antibiotics, combinations with topical treatments or other systemic treatments, i.e. isotretinoin. Several studies evaluated laser or light-based treatment.The majority of studies (57/106) were assessed as 'unclear risk of bias', 37 'high risk ' and 12 'low risk'. Twenty-two studies provided no usable or retrievable data i.e. none of our outcomes were addressed, no separate data reported for rosacea or limited data in abstracts.Eleven studies assessed our primary outcome 'change in quality of life', 52 studies participant-assessed changes in rosacea severity and almost all studies addressed adverse events, although often only limited data were provided. In most comparisons there were no statistically significant differences in number of adverse events, most were mild and transient. Physician assessments including investigators' global assessments, lesion counts and erythema were evaluated in three-quarters of the studies, but time needed for improvement and duration of remission were incompletely or not reported.The quality of the body of evidence was rated moderate to high for most outcomes, but for some outcomes low to very low.Data for several outcomes could only be pooled for topical metronidazole and azelaic acid. Both were shown to be more effective than placebo in papulopustular rosacea (moderate quality evidence for metronidazole and high for azelaic acid). Pooled data from physician assessments in three trials demonstrated that metronidazole was more effective compared to placebo (risk ratio (RR) 1.98, 95% confidence interval (CI) 1.29 to 3.02). Four trials provided data on participants' assessments, illustrating that azelaic acid was more effective than placebo (RR 1.46, 95% CI 1.30 to 1.63). The results from three studies were contradictory on which of these two treatments was most effective.Two studies showed a statistically significant and clinically important improvement in favour of topical ivermectin when compared to placebo (high quality evidence). Participants' assessments in these studies showed a RR of 1.78 (95% CI 1.50 to 2.11) and RR of 1.92 (95% CI 1.59 to 2.32),which were supported by physicians' assessments. Topical ivermectin appeared to be slightly more effective than topical metronidazole for papulopustular rosacea, based on one study, for improving quality of life and participant and physician assessed outcomes (high quality evidence for these outcomes).Topical brimonidine in two studies was more effective than vehicle in reducing erythema in rosacea at all time points over 12 hours (high quality evidence). At three hours the participants' assessments had a RR of 2.21 (95% CI 1.52 to 3.22) and RR of 2.00 (95% CI 1.33 to 3.01) in favour of brimonidine. Physicians' assessments confirmed these data. There was no rebound or worsening of erythema after treatment cessation.Topical clindamycin phosphate combined with tretinoin was not considered to be effective compared to placebo (moderate quality evidence).Topical ciclosporin ophthalmic emulsion demonstrated effectiveness and improved quality of life for people with ocular rosacea (low quality evidence).Of the comparisons assessing oral treatments for papulopustular rosacea there was moderate quality evidence that tetracycline was effective but this was based on two old studies of short duration. Physician-based assessments in two trials indicated that doxycycline appeared to be significantly more effective than placebo (RR 1.59, 95% CI 1.02 to 2.47 and RR 2.37, 95% CI 1.12 to 4.99) (high quality evidence). There was no statistically significant difference in effectiveness between 100 mg and 40 mg doxycycline, but there was evidence of fewer adverse effects with the lower dose (RR 0.25, 95% CI 0.11 to 0.54) (low quality evidence). There was very low quality evidence from one study (assessed at high risk of bias) that doxycycline 100 mg was as effective as azithromycin. Low dose minocycline (45 mg) was effective for papulopustular rosacea (low quality evidence).Oral tetracycline was compared with topical metronidazole in four studies and showed no statistically significant difference between the two treatments for any outcome (low to moderate quality evidence).Low dose isotretinoin was considered by both the participants (RR 1.23, 95% CI 1.05 to 1.43) and physicians (RR 1.18, 95% CI 1.03 to 1.36) to be slightly more effective than doxycycline 50-100 mg (high quality evidence).Pulsed dye laser was more effective than yttrium-aluminium-garnet (Nd:YAG) laser based on one study, and it appeared to be as effective as intense pulsed light therapy (both low quality evidence).
AUTHORS' CONCLUSIONS
There was high quality evidence to support the effectiveness of topical azelaic acid, topical ivermectin, brimonidine, doxycycline and isotretinoin for rosacea. Moderate quality evidence was available for topical metronidazole and oral tetracycline. There was low quality evidence for low dose minocycline, laser and intense pulsed light therapy and ciclosporin ophthalmic emulsion for ocular rosacea. Time needed to response and response duration should be addressed more completely, with more rigorous reporting of adverse events. Further studies on treatment of ocular rosacea are warranted.
Topics: Anti-Infective Agents; Brimonidine Tartrate; Cyclosporine; Dermatologic Agents; Dicarboxylic Acids; Doxycycline; Female; Humans; Ivermectin; Male; Metronidazole; Middle Aged; Ophthalmic Solutions; Quinoxalines; Randomized Controlled Trials as Topic; Rosacea; Tetracycline
PubMed: 25919144
DOI: 10.1002/14651858.CD003262.pub5 -
Journal of the American Heart... Sep 2022Background Lowering low-density lipoprotein cholesterol (LDL-C) levels decreases major cardiovascular events and is recommended for patients at elevated cardiovascular... (Meta-Analysis)
Meta-Analysis
Network Meta-Analysis of Randomized Trials Evaluating the Comparative Efficacy of Lipid-Lowering Therapies Added to Maximally Tolerated Statins for the Reduction of Low-Density Lipoprotein Cholesterol.
Background Lowering low-density lipoprotein cholesterol (LDL-C) levels decreases major cardiovascular events and is recommended for patients at elevated cardiovascular risk. However, appropriate doses of statin therapy are often insufficient to reduce LDL-C in accordance with current guidelines. In such cases, treatment could be supplemented with nonstatin lipid-lowering therapy. Methods and Results A systematic literature review and network meta-analysis were conducted on randomized controlled trials of nonstatin lipid-lowering therapy added to maximally tolerated statins, including statin-intolerant patients. The primary objective was to assess relative efficacy of nonstatin lipid-lowering therapy in reducing LDL-C levels at week 12. Secondary objectives included the following: LDL-C level reduction at week 24 and change in non-high-density lipoprotein cholesterol and apolipoprotein B at week 12. There were 48 randomized controlled trials included in the primary network meta-analysis. All nonstatin agents significantly reduced LDL-C from baseline versus placebo, regardless of background therapy. At week 12, evolocumab, 140 mg every 2 weeks (Q2W)/420 mg once a month, and alirocumab, 150 mg Q2W, were the most efficacious regimens, followed by alirocumab, 75 mg Q2W, alirocumab, 300 mg once a month, inclisiran, bempedoic acid/ezetimibe fixed-dose combination, and ezetimibe and bempedoic acid used as monotherapies. Primary end point results were generally consistent at week 24, and for other lipid end points at week 12. Conclusions Evolocumab, 140 mg Q2W/420 mg once a month, and alirocumab, 150 mg Q2W, were consistently the most efficacious nonstatin regimens when added to maximally tolerated statins to lower LDL-C, non-high-density lipoprotein cholesterol, and apolipoprotein B levels and facilitate attainment of guideline-recommended risk-stratified lipoprotein levels.
Topics: Anticholesteremic Agents; Apolipoproteins; Cholesterol; Cholesterol, LDL; Dicarboxylic Acids; Double-Blind Method; Ezetimibe; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Network Meta-Analysis; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 36073669
DOI: 10.1161/JAHA.122.025551 -
The Cochrane Database of Systematic... Oct 2015Patients often require a rapid sequence induction (RSI) endotracheal intubation technique during emergencies or electively to protect against aspiration, increased... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Patients often require a rapid sequence induction (RSI) endotracheal intubation technique during emergencies or electively to protect against aspiration, increased intracranial pressure, or to facilitate intubation. Traditionally succinylcholine has been the most commonly used muscle relaxant for this purpose because of its fast onset and short duration; unfortunately, it can have serious side effects. Rocuronium has been suggested as an alternative to succinylcholine for intubation. This is an update of our Cochrane review published first in 2003 and then updated in 2008 and now in 2015.
OBJECTIVES
To determine whether rocuronium creates intubating conditions comparable to those of succinylcholine during RSI intubation.
SEARCH METHODS
In our initial review we searched all databases until March 2000, followed by an update to June 2007. This latest update included searching the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 2), MEDLINE (1966 to February Week 2 2015), and EMBASE (1988 to February 14 2015 ) for randomized controlled trials (RCTs) or controlled clinical trials (CCTs) relating to the use of rocuronium and succinylcholine. We included foreign language journals and handsearched the references of identified studies for additional citations.
SELECTION CRITERIA
We included any RCT or CCT that reported intubating conditions in comparing the use of rocuronium and succinylcholine for RSI or modified RSI in any age group or clinical setting. The dose of rocuronium was at least 0.6 mg/kg and succinylcholine was at least 1 mg/kg.
DATA COLLECTION AND ANALYSIS
Two authors (EN and DT) independently extracted data and assessed methodological quality for the 'Risk of bias' tables. We combined the outcomes in Review Manager 5 using a risk ratio (RR) with a random-effects model.
MAIN RESULTS
The previous update (2008) had identified 53 potential studies and included 37 combined for meta-analysis. In this latest update we identified a further 13 studies and included 11, summarizing the results of 50 trials including 4151 participants. Overall, succinylcholine was superior to rocuronium for achieving excellent intubating conditions: RR 0.86 (95% confidence interval (CI) 0.81 to 0.92; n = 4151) and clinically acceptable intubation conditions (RR 0.97, 95% CI 0.95 to 0.99; n = 3992, 48 trials). A high incidence of detection bias amongst the trials coupled with significant heterogeneity provides moderate-quality evidence for these conclusions, which are unchanged from the previous update. Succinylcholine was more likely to produce excellent intubating conditions when using thiopental as the induction agent: RR 0.81 (95% CI: 0.73 to 0.88; n = 2302, 28 trials). In the previous update, we had concluded that propofol was the superior induction agent with succinylcholine. There were no reported incidences of severe adverse outcomes. We found no statistical difference in intubation conditions when succinylcholine was compared to 1.2 mg/kg rocuronium; however, succinylcholine was clinically superior as it has a shorter duration of action.
AUTHORS' CONCLUSIONS
Succinylcholine created superior intubation conditions to rocuronium in achieving excellent and clinically acceptable intubating conditions.
Topics: Androstanols; Humans; Intubation, Intratracheal; Neuromuscular Depolarizing Agents; Neuromuscular Nondepolarizing Agents; Propofol; Randomized Controlled Trials as Topic; Rocuronium; Succinylcholine
PubMed: 26512948
DOI: 10.1002/14651858.CD002788.pub3 -
The Cochrane Database of Systematic... Nov 2023Multiple sclerosis (MS) is a chronic disease of the central nervous system that affects mainly young adults (two to three times more frequently in women than in men) and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Multiple sclerosis (MS) is a chronic disease of the central nervous system that affects mainly young adults (two to three times more frequently in women than in men) and causes significant disability after onset. Although it is accepted that immunotherapies for people with MS decrease disease activity, uncertainty regarding their relative safety remains.
OBJECTIVES
To compare adverse effects of immunotherapies for people with MS or clinically isolated syndrome (CIS), and to rank these treatments according to their relative risks of adverse effects through network meta-analyses (NMAs).
SEARCH METHODS
We searched CENTRAL, PubMed, Embase, two other databases and trials registers up to March 2022, together with reference checking and citation searching to identify additional studies.
SELECTION CRITERIA
We included participants 18 years of age or older with a diagnosis of MS or CIS, according to any accepted diagnostic criteria, who were included in randomized controlled trials (RCTs) that examined one or more of the agents used in MS or CIS, and compared them versus placebo or another active agent. We excluded RCTs in which a drug regimen was compared with a different regimen of the same drug without another active agent or placebo as a control arm.
DATA COLLECTION AND ANALYSIS
We used standard Cochrane methods for data extraction and pairwise meta-analyses. For NMAs, we used the netmeta suite of commands in R to fit random-effects NMAs assuming a common between-study variance. We used the CINeMA platform to GRADE the certainty of the body of evidence in NMAs. We considered a relative risk (RR) of 1.5 as a non-inferiority safety threshold compared to placebo. We assessed the certainty of evidence for primary outcomes within the NMA according to GRADE, as very low, low, moderate or high.
MAIN RESULTS
This NMA included 123 trials with 57,682 participants Serious adverse events (SAEs) Reporting of SAEs was available from 84 studies including 5696 (11%) events in 51,833 (89.9%) participants out of 57,682 participants in all studies. Based on the absolute frequency of SAEs, our non-inferiority threshold (up to a 50% increased risk) meant that no more than 1 in 18 additional people would have a SAE compared to placebo. Low-certainty evidence suggested that three drugs may decrease SAEs compared to placebo (relative risk [RR], 95% confidence interval [CI]): interferon beta-1a (Avonex) (0.78, 0.66 to 0.94); dimethyl fumarate (0.79, 0.67 to 0.93), and glatiramer acetate (0.84, 0.72 to 0.98). Several drugs met our non-inferiority criterion versus placebo: moderate-certainty evidence for teriflunomide (1.08, 0.88 to 1.31); low-certainty evidence for ocrelizumab (0.85, 0.67 to 1.07), ozanimod (0.88, 0.59 to 1.33), interferon beta-1b (0.94, 0.78 to 1.12), interferon beta-1a (Rebif) (0.96, 0.80 to 1.15), natalizumab (0.97, 0.79 to 1.19), fingolimod (1.05, 0.92 to 1.20) and laquinimod (1.06, 0.83 to 1.34); very low-certainty evidence for daclizumab (0.83, 0.68 to 1.02). Non-inferiority with placebo was not met due to imprecision for the other drugs: low-certainty evidence for cladribine (1.10, 0.79 to 1.52), siponimod (1.20, 0.95 to 1.51), ofatumumab (1.26, 0.88 to 1.79) and rituximab (1.01, 0.67 to 1.52); very low-certainty evidence for immunoglobulins (1.05, 0.33 to 3.32), diroximel fumarate (1.05, 0.23 to 4.69), peg-interferon beta-1a (1.07, 0.66 to 1.74), alemtuzumab (1.16, 0.85 to 1.60), interferons (1.62, 0.21 to 12.72) and azathioprine (3.62, 0.76 to 17.19). Withdrawals due to adverse events Reporting of withdrawals due to AEs was available from 105 studies (85.4%) including 3537 (6.39%) events in 55,320 (95.9%) patients out of 57,682 patients in all studies. Based on the absolute frequency of withdrawals, our non-inferiority threshold (up to a 50% increased risk) meant that no more than 1 in 31 additional people would withdraw compared to placebo. No drug reduced withdrawals due to adverse events when compared with placebo. There was very low-certainty evidence (meaning that estimates are not reliable) that two drugs met our non-inferiority criterion versus placebo, assuming an upper 95% CI RR limit of 1.5: diroximel fumarate (0.38, 0.11 to 1.27) and alemtuzumab (0.63, 0.33 to 1.19). Non-inferiority with placebo was not met due to imprecision for the following drugs: low-certainty evidence for ofatumumab (1.50, 0.87 to 2.59); very low-certainty evidence for methotrexate (0.94, 0.02 to 46.70), corticosteroids (1.05, 0.16 to 7.14), ozanimod (1.06, 0.58 to 1.93), natalizumab (1.20, 0.77 to 1.85), ocrelizumab (1.32, 0.81 to 2.14), dimethyl fumarate (1.34, 0.96 to 1.86), siponimod (1.63, 0.96 to 2.79), rituximab (1.63, 0.53 to 5.00), cladribine (1.80, 0.89 to 3.62), mitoxantrone (2.11, 0.50 to 8.87), interferons (3.47, 0.95 to 12.72), and cyclophosphamide (3.86, 0.45 to 33.50). Eleven drugs may have increased withdrawals due to adverse events compared with placebo: low-certainty evidence for teriflunomide (1.37, 1.01 to 1.85), glatiramer acetate (1.76, 1.36 to 2.26), fingolimod (1.79, 1.40 to 2.28), interferon beta-1a (Rebif) (2.15, 1.58 to 2.93), daclizumab (2.19, 1.31 to 3.65) and interferon beta-1b (2.59, 1.87 to 3.77); very low-certainty evidence for laquinimod (1.42, 1.01 to 2.00), interferon beta-1a (Avonex) (1.54, 1.13 to 2.10), immunoglobulins (1.87, 1.01 to 3.45), peg-interferon beta-1a (3.46, 1.44 to 8.33) and azathioprine (6.95, 2.57 to 18.78); however, very low-certainty evidence is unreliable. Sensitivity analyses including only studies with low attrition bias, drug dose above the group median, or only patients with relapsing remitting MS or CIS, and subgroup analyses by prior disease-modifying treatments did not change these figures. Rankings No drug yielded consistent P scores in the upper quartile of the probability of being better than others for primary and secondary outcomes.
AUTHORS' CONCLUSIONS
We found mostly low and very low-certainty evidence that drugs used to treat MS may not increase SAEs, but may increase withdrawals compared with placebo. The results suggest that there is no important difference in the occurrence of SAEs between first- and second-line drugs and between oral, injectable, or infused drugs, compared with placebo. Our review, along with other work in the literature, confirms poor-quality reporting of adverse events from RCTs of interventions. At the least, future studies should follow the CONSORT recommendations about reporting harm-related issues. To address adverse effects, future systematic reviews should also include non-randomized studies.
Topics: Male; Female; Young Adult; Humans; Adolescent; Adult; Interferon beta-1a; Immunosuppressive Agents; Glatiramer Acetate; Network Meta-Analysis; Cladribine; Natalizumab; Interferon beta-1b; Alemtuzumab; Dimethyl Fumarate; Daclizumab; Azathioprine; Rituximab; Fingolimod Hydrochloride; Multiple Sclerosis; Immunotherapy
PubMed: 38032059
DOI: 10.1002/14651858.CD012186.pub2 -
Advances in Therapy Jun 2021In patients with chronic obstructive pulmonary disease (COPD) who experience further exacerbations or symptoms, despite being prescribed dual long-acting muscarinic... (Meta-Analysis)
Meta-Analysis
In patients with chronic obstructive pulmonary disease (COPD) who experience further exacerbations or symptoms, despite being prescribed dual long-acting muscarinic antagonist (LAMA)/long-acting β-agonist (LABA) or inhaled corticosteroid (ICS)/LABA therapies, triple ICS/LAMA/LABA therapy is recommended. A previous network meta-analysis showed comparable efficacy of the ICS/LAMA/LABA, budesonide/glycopyrronium bromide/formoterol fumarate (BUD/GLY/FOR) 320/18/9.6 µg, to other fixed-dose and open combination triple therapies at 24 weeks in COPD. Subsequently, the ETHOS study was published, including data for 8509 patients, assessing the efficacy and safety of BUD/GLY/FOR over 52 weeks. This network meta-analysis (NMA) was conducted to compare the relative efficacy, safety, and tolerability of BUD/GLY/FOR 320/18/9.6 µg with other fixed-dose and open combination triple therapies in COPD over 52 weeks, including data from ETHOS. A systematic literature review was conducted to identify ≥ 10-week randomized controlled trials, including ≥ 1 fixed-dose or open combination triple-therapy arm, in patients with moderate-to-very severe COPD. The methodologic quality and risk of bias of included studies were assessed. Study results were combined using a three-level hierarchical Bayesian NMA model to assess efficacy and safety outcomes at or over 24 and 52 weeks. Meta-regression and sensitivity analyses were used to assess heterogeneity across studies. Nineteen studies (n = 37,741 patients) met the inclusion criteria of the review; 15 contributed to the base case network. LAMA/LABA dual combinations were combined as a single treatment group to create a connected network. Across all outcomes for exacerbations, lung function, symptoms, health-related quality of life, safety, and tolerability, the efficacy and safety of BUD/GLY/FOR were comparable to those of other triple ICS/LAMA/LABA fixed-dose (fluticasone furoate/umeclidinium/vilanterol and beclomethasone dipropionate/glycopyrronium bromide/formoterol fumarate) and open combinations at or over 24 and 52 weeks. Sensitivity analyses and meta-regression results for exacerbation outcomes were broadly in line with the base case NMA. In this NMA, BUD/GLY/FOR 320/18/9.6 μg showed comparable efficacy versus other ICS/LAMA/LABA fixed-dose or open combination therapies in terms of reducing exacerbation rates and improving lung function, symptoms and health-related quality of life in patients with moderate-to-very-severe COPD, in line with previously published meta-analysis results of triple combinations in COPD. The safety and tolerability profile of BUD/GLY/FOR was also found to be comparable to other triple combination therapies.
Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Bayes Theorem; Bronchodilator Agents; Budesonide; Drug Combinations; Formoterol Fumarate; Fumarates; Glycopyrrolate; Humans; Muscarinic Antagonists; Network Meta-Analysis; Pulmonary Disease, Chronic Obstructive; Quality of Life
PubMed: 33929661
DOI: 10.1007/s12325-021-01703-z -
The Cochrane Database of Systematic... Jan 2024Different therapeutic strategies are available for the treatment of people with relapsing-remitting multiple sclerosis (RRMS), including immunomodulators,... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Different therapeutic strategies are available for the treatment of people with relapsing-remitting multiple sclerosis (RRMS), including immunomodulators, immunosuppressants and biological agents. Although each one of these therapies reduces relapse frequency and slows disability accumulation compared to no treatment, their relative benefit remains unclear. This is an update of a Cochrane review published in 2015.
OBJECTIVES
To compare the efficacy and safety, through network meta-analysis, of interferon beta-1b, interferon beta-1a, glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab, pegylated interferon beta-1a, daclizumab, laquinimod, azathioprine, immunoglobulins, cladribine, cyclophosphamide, diroximel fumarate, fludarabine, interferon beta 1-a and beta 1-b, leflunomide, methotrexate, minocycline, mycophenolate mofetil, ofatumumab, ozanimod, ponesimod, rituximab, siponimod and steroids for the treatment of people with RRMS.
SEARCH METHODS
CENTRAL, MEDLINE, Embase, and two trials registers were searched on 21 September 2021 together with reference checking, citation searching and contact with study authors to identify additional studies. A top-up search was conducted on 8 August 2022.
SELECTION CRITERIA
Randomised controlled trials (RCTs) that studied one or more of the available immunomodulators and immunosuppressants as monotherapy in comparison to placebo or to another active agent, in adults with RRMS.
DATA COLLECTION AND ANALYSIS
Two authors independently selected studies and extracted data. We considered both direct and indirect evidence and performed data synthesis by pairwise and network meta-analysis. Certainty of the evidence was assessed by the GRADE approach.
MAIN RESULTS
We included 50 studies involving 36,541 participants (68.6% female and 31.4% male). Median treatment duration was 24 months, and 25 (50%) studies were placebo-controlled. Considering the risk of bias, the most frequent concern was related to the role of the sponsor in the authorship of the study report or in data management and analysis, for which we judged 68% of the studies were at high risk of other bias. The other frequent concerns were performance bias (34% judged as having high risk) and attrition bias (32% judged as having high risk). Placebo was used as the common comparator for network analysis. Relapses over 12 months: data were provided in 18 studies (9310 participants). Natalizumab results in a large reduction of people with relapses at 12 months (RR 0.52, 95% CI 0.43 to 0.63; high-certainty evidence). Fingolimod (RR 0.48, 95% CI 0.39 to 0.57; moderate-certainty evidence), daclizumab (RR 0.55, 95% CI 0.42 to 0.73; moderate-certainty evidence), and immunoglobulins (RR 0.60, 95% CI 0.47 to 0.79; moderate-certainty evidence) probably result in a large reduction of people with relapses at 12 months. Relapses over 24 months: data were reported in 28 studies (19,869 participants). Cladribine (RR 0.53, 95% CI 0.44 to 0.64; high-certainty evidence), alemtuzumab (RR 0.57, 95% CI 0.47 to 0.68; high-certainty evidence) and natalizumab (RR 0.56, 95% CI 0.48 to 0.65; high-certainty evidence) result in a large decrease of people with relapses at 24 months. Fingolimod (RR 0.54, 95% CI 0.48 to 0.60; moderate-certainty evidence), dimethyl fumarate (RR 0.62, 95% CI 0.55 to 0.70; moderate-certainty evidence), and ponesimod (RR 0.58, 95% CI 0.48 to 0.70; moderate-certainty evidence) probably result in a large decrease of people with relapses at 24 months. Glatiramer acetate (RR 0.84, 95%, CI 0.76 to 0.93; moderate-certainty evidence) and interferon beta-1a (Avonex, Rebif) (RR 0.84, 95% CI 0.78 to 0.91; moderate-certainty evidence) probably moderately decrease people with relapses at 24 months. Relapses over 36 months findings were available from five studies (3087 participants). None of the treatments assessed showed moderate- or high-certainty evidence compared to placebo. Disability worsening over 24 months was assessed in 31 studies (24,303 participants). Natalizumab probably results in a large reduction of disability worsening (RR 0.59, 95% CI 0.46 to 0.75; moderate-certainty evidence) at 24 months. Disability worsening over 36 months was assessed in three studies (2684 participants) but none of the studies used placebo as the comparator. Treatment discontinuation due to adverse events data were available from 43 studies (35,410 participants). Alemtuzumab probably results in a slight reduction of treatment discontinuation due to adverse events (OR 0.39, 95% CI 0.19 to 0.79; moderate-certainty evidence). Daclizumab (OR 2.55, 95% CI 1.40 to 4.63; moderate-certainty evidence), fingolimod (OR 1.84, 95% CI 1.31 to 2.57; moderate-certainty evidence), teriflunomide (OR 1.82, 95% CI 1.19 to 2.79; moderate-certainty evidence), interferon beta-1a (OR 1.48, 95% CI 0.99 to 2.20; moderate-certainty evidence), laquinimod (OR 1.49, 95 % CI 1.00 to 2.15; moderate-certainty evidence), natalizumab (OR 1.57, 95% CI 0.81 to 3.05), and glatiramer acetate (OR 1.48, 95% CI 1.01 to 2.14; moderate-certainty evidence) probably result in a slight increase in the number of people who discontinue treatment due to adverse events. Serious adverse events (SAEs) were reported in 35 studies (33,998 participants). There was probably a trivial reduction in SAEs amongst people with RRMS treated with interferon beta-1b as compared to placebo (OR 0.92, 95% CI 0.55 to 1.54; moderate-certainty evidence).
AUTHORS' CONCLUSIONS
We are highly confident that, compared to placebo, two-year treatment with natalizumab, cladribine, or alemtuzumab decreases relapses more than with other DMTs. We are moderately confident that a two-year treatment with natalizumab may slow disability progression. Compared to those on placebo, people with RRMS treated with most of the assessed DMTs showed a higher frequency of treatment discontinuation due to AEs: we are moderately confident that this could happen with fingolimod, teriflunomide, interferon beta-1a, laquinimod, natalizumab and daclizumab, while our certainty with other DMTs is lower. We are also moderately certain that treatment with alemtuzumab is associated with fewer discontinuations due to adverse events than placebo, and moderately certain that interferon beta-1b probably results in a slight reduction in people who experience serious adverse events, but our certainty with regard to other DMTs is lower. Insufficient evidence is available to evaluate the efficacy and safety of DMTs in a longer term than two years, and this is a relevant issue for a chronic condition like MS that develops over decades. More than half of the included studies were sponsored by pharmaceutical companies and this may have influenced their results. Further studies should focus on direct comparison between active agents, with follow-up of at least three years, and assess other patient-relevant outcomes, such as quality of life and cognitive status, with particular focus on the impact of sex/gender on treatment effects.
Topics: Adult; Humans; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting; Glatiramer Acetate; Interferon beta-1a; Fingolimod Hydrochloride; Natalizumab; Interferon beta-1b; Cladribine; Alemtuzumab; Dimethyl Fumarate; Daclizumab; Network Meta-Analysis; Immunologic Factors; Recurrence
PubMed: 38174776
DOI: 10.1002/14651858.CD011381.pub3 -
Journal of Strength and Conditioning... May 2020Gonzalez, AM and Trexler, ET. Effects of citrulline supplementation on exercise performance in humans: A review of the current literature. J Strength Cond Res 34(5):...
Gonzalez, AM and Trexler, ET. Effects of citrulline supplementation on exercise performance in humans: A review of the current literature. J Strength Cond Res 34(5): 1480-1495, 2020-L-citrulline, a nonessential amino acid found primarily in watermelon, has recently garnered much attention for its potential to augment L-arginine bioavailability, nitric oxide production, and exercise performance. Over the past decade, L-citrulline has received considerable scientific attention examining potentially ergogenic properties for both aerobic and anaerobic exercise performance. Thus, the purpose of this article is to summarize the theoretical rationale behind L-citrulline supplementation and to comprehensively review the available scientific evidence assessing the potential ergogenic value of L-citrulline supplementation on vascular function and exercise performance in humans. In addition, research that has investigated the potential synergistic effects of L-citrulline with other dietary ingredients (e.g., arginine, antioxidants, nitrates, and branched-chain amino acids) is reviewed. Oral L-citrulline and citrulline malate supplementation have shown to increase plasma citrulline and arginine concentrations, along with total nitrate and nitrite concentrations. Although blood flow enhancement is a proposed mechanism for the ergogenic potential of L-citrulline, evidence supporting acute improvements in vasodilation and skeletal muscle tissue perfusion after supplementation is scarce and inconsistent. Nevertheless, several studies have reported that L-citrulline supplementation can enhance exercise performance and recovery. Given the positive effects observed from some investigations, future studies should continue to investigate the effects of both acute and chronic supplementation with L-citrulline and citrulline malate on markers of blood flow and exercise performance and should seek to elucidate the mechanism underlying such effects.
Topics: Amino Acids, Branched-Chain; Antioxidants; Arginine; Biomarkers; Citrulline; Dietary Supplements; Drug Therapy, Combination; Exercise; Humans; Malates; Muscle, Skeletal; Nitrates
PubMed: 31977835
DOI: 10.1519/JSC.0000000000003426 -
Frontiers in Immunology 2023Kidney stone disease (KSD) is one of the earliest medical diseases known, but the mechanism of its formation and metabolic changes remain unclear. The formation of...
Kidney stone disease (KSD) is one of the earliest medical diseases known, but the mechanism of its formation and metabolic changes remain unclear. The formation of kidney stones is a extensive and complicated process, which is regulated by metabolic changes in various substances. In this manuscript, we summarized the progress of research on metabolic changes in kidney stone disease and discuss the valuable role of some new potential targets. We reviewed the influence of metabolism of some common substances on stone formation, such as the regulation of oxalate, the release of reactive oxygen species (ROS), macrophage polarization, the levels of hormones, and the alternation of other substances. New insights into changes in substance metabolism changes in kidney stone disease, as well as emerging research techniques, will provide new directions in the treatment of stones. Reviewing the great progress that has been made in this field will help to improve the understanding by urologists, nephrologists, and health care providers of the metabolic changes in kidney stone disease, and contribute to explore new metabolic targets for clinical therapy.
Topics: Humans; Kidney Calculi; Reactive Oxygen Species; Oxalates
PubMed: 37228601
DOI: 10.3389/fimmu.2023.1142207 -
European Journal of Clinical... Nov 2023This systematic review and meta-analysis was conducted to synthesize the efficacy and safety of bempedoic acid in patients requiring lipid-lowering therapy. (Meta-Analysis)
Meta-Analysis Review
AIM
This systematic review and meta-analysis was conducted to synthesize the efficacy and safety of bempedoic acid in patients requiring lipid-lowering therapy.
METHODS
PubMed, Embase, and Scopus databases were searched for randomized controlled trials from inception till June 2023. The primary outcome was major adverse cardiovascular events (MACE), and secondary outcomes were all-cause mortality, serum lipid profile, and adverse events between bempedoic acid and comparators. ROB2 was used for risk of bias assessment. We pooled mean differences or relative risks (RR) along with 95% confidence intervals (random-effects model).
RESULTS
Five-hundred and thirty-one studies were screened and 17 (n = 21,131) were included for review. There was a significant reduction in the risk of MACE [RR, 0.88 (95% CI: 0.77 to 0.99), p = 0.03)] and all-cause mortality [RR, 0.90 (95% CI: 0.82 to 0.98), p = 0.02] following bempedoic acid treatment. Treatment with bempedoic acid led to a significant reduction in the mean serum total cholesterol [- 34.41 mg/dl (95% CI: - 42.43 to - 26.39), p < 0.001], low-density lipoprotein cholesterol (LDL-C) [- 33.91 mg/dl (95% CI: - 39.66 to - 28.17), p < 0.001], as well as high-density lipoprotein cholesterol (HDL-C) [- 2.40 mg/dl (95% CI: - 3.09 to - 1.71), p < 0.001] levels. However, there was a significant increase in the risk of hyperuricemia [RR, 2.05 (95% CI: 1.81 to 2.33), p < 0.001] following bempedoic acid treatment. The number needed to harm was large for all safety outcomes. The GRADE of evidence was moderate for all outcomes.
CONCLUSION
Bempedoic acid reduces the risk of MACE and all-cause mortality, lowers serum total cholesterol and LDL-C levels, and has a favorable safety profile. Trial registration ClinicalTrial.gov Identifier: CRD42023412837.
Topics: Humans; Cholesterol, LDL; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Randomized Controlled Trials as Topic; Dicarboxylic Acids; Fatty Acids
PubMed: 37672112
DOI: 10.1007/s00228-023-03555-8