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The Cochrane Database of Systematic... Aug 2020A couple may be considered to have fertility problems if they have been trying to conceive for over a year with no success. This may affect up to a quarter of all... (Meta-Analysis)
Meta-Analysis
BACKGROUND
A couple may be considered to have fertility problems if they have been trying to conceive for over a year with no success. This may affect up to a quarter of all couples planning a child. It is estimated that for 40% to 50% of couples, subfertility may result from factors affecting women. Antioxidants are thought to reduce the oxidative stress brought on by these conditions. Currently, limited evidence suggests that antioxidants improve fertility, and trials have explored this area with varied results. This review assesses the evidence for the effectiveness of different antioxidants in female subfertility.
OBJECTIVES
To determine whether supplementary oral antioxidants compared with placebo, no treatment/standard treatment or another antioxidant improve fertility outcomes for subfertile women.
SEARCH METHODS
We searched the following databases (from their inception to September 2019), with no language or date restriction: Cochrane Gynaecology and Fertility Group (CGFG) specialised register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL and AMED. We checked reference lists of relevant studies and searched the trial registers.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) that compared any type, dose or combination of oral antioxidant supplement with placebo, no treatment or treatment with another antioxidant, among women attending a reproductive clinic. We excluded trials comparing antioxidants with fertility drugs alone and trials that only included fertile women attending a fertility clinic because of male partner infertility.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane. The primary review outcome was live birth; secondary outcomes included clinical pregnancy rates and adverse events.
MAIN RESULTS
We included 63 trials involving 7760 women. Investigators compared oral antioxidants, including: combinations of antioxidants, N-acetylcysteine, melatonin, L-arginine, myo-inositol, carnitine, selenium, vitamin E, vitamin B complex, vitamin C, vitamin D+calcium, CoQ10, and omega-3-polyunsaturated fatty acids versus placebo, no treatment/standard treatment or another antioxidant. Only 27 of the 63 included trials reported funding sources. Due to the very low-quality of the evidence we are uncertain whether antioxidants improve live birth rate compared with placebo or no treatment/standard treatment (odds ratio (OR) 1.81, 95% confidence interval (CI) 1.36 to 2.43; P < 0.001, I = 29%; 13 RCTs, 1227 women). This suggests that among subfertile women with an expected live birth rate of 19%, the rate among women using antioxidants would be between 24% and 36%. Low-quality evidence suggests that antioxidants may improve clinical pregnancy rate compared with placebo or no treatment/standard treatment (OR 1.65, 95% CI 1.43 to 1.89; P < 0.001, I = 63%; 35 RCTs, 5165 women). This suggests that among subfertile women with an expected clinical pregnancy rate of 19%, the rate among women using antioxidants would be between 25% and 30%. Heterogeneity was moderately high. Overall 28 trials reported on various adverse events in the meta-analysis. The evidence suggests that the use of antioxidants makes no difference between the groups in rates of miscarriage (OR 1.13, 95% CI 0.82 to 1.55; P = 0.46, I = 0%; 24 RCTs, 3229 women; low-quality evidence). There was also no evidence of a difference between the groups in rates of multiple pregnancy (OR 1.00, 95% CI 0.63 to 1.56; P = 0.99, I = 0%; 9 RCTs, 1886 women; low-quality evidence). There was also no evidence of a difference between the groups in rates of gastrointestinal disturbances (OR 1.55, 95% CI 0.47 to 5.10; P = 0.47, I = 0%; 3 RCTs, 343 women; low-quality evidence). Low-quality evidence showed that there was also no difference between the groups in rates of ectopic pregnancy (OR 1.40, 95% CI 0.27 to 7.20; P = 0.69, I = 0%; 4 RCTs, 404 women). In the antioxidant versus antioxidant comparison, low-quality evidence shows no difference in a lower dose of melatonin being associated with an increased live-birth rate compared with higher-dose melatonin (OR 0.94, 95% CI 0.41 to 2.15; P = 0.89, I = 0%; 2 RCTs, 140 women). This suggests that among subfertile women with an expected live-birth rate of 24%, the rate among women using a lower dose of melatonin compared to a higher dose would be between 12% and 40%. Similarly with clinical pregnancy, there was no evidence of a difference between the groups in rates between a lower and a higher dose of melatonin (OR 0.94, 95% CI 0.41 to 2.15; P = 0.89, I = 0%; 2 RCTs, 140 women). Three trials reported on miscarriage in the antioxidant versus antioxidant comparison (two used doses of melatonin and one compared N-acetylcysteine versus L-carnitine). There were no miscarriages in either melatonin trial. Multiple pregnancy and gastrointestinal disturbances were not reported, and ectopic pregnancy was reported by only one trial, with no events. The study comparing N-acetylcysteine with L-carnitine did not report live birth rate. Very low-quality evidence shows no evidence of a difference in clinical pregnancy (OR 0.81, 95% CI 0.33 to 2.00; 1 RCT, 164 women; low-quality evidence). Low quality evidence shows no difference in miscarriage (OR 1.54, 95% CI 0.42 to 5.67; 1 RCT, 164 women; low-quality evidence). The study did not report multiple pregnancy, gastrointestinal disturbances or ectopic pregnancy. The overall quality of evidence was limited by serious risk of bias associated with poor reporting of methods, imprecision and inconsistency.
AUTHORS' CONCLUSIONS
In this review, there was low- to very low-quality evidence to show that taking an antioxidant may benefit subfertile women. Overall, there is no evidence of increased risk of miscarriage, multiple births, gastrointestinal effects or ectopic pregnancies, but evidence was of very low quality. At this time, there is limited evidence in support of supplemental oral antioxidants for subfertile women.
Topics: Abortion, Spontaneous; Administration, Oral; Antioxidants; Female; Humans; Infertility, Female; Live Birth; Minerals; Oxidative Stress; Pentoxifylline; Placebos; Pregnancy; Pregnancy Rate; Pregnancy, Multiple; Randomized Controlled Trials as Topic; Vitamins
PubMed: 32851663
DOI: 10.1002/14651858.CD007807.pub4 -
The Cochrane Database of Systematic... Sep 2015Intermittent claudication (IC) is a symptom of peripheral arterial disease (PAD) and is associated with high morbidity and mortality. Pentoxifylline, one of many drugs... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Intermittent claudication (IC) is a symptom of peripheral arterial disease (PAD) and is associated with high morbidity and mortality. Pentoxifylline, one of many drugs used to treat IC, acts by decreasing blood viscosity, improving erythrocyte flexibility and promoting microcirculatory flow and tissue oxygen concentration. Many studies have evaluated the efficacy of pentoxifylline in treating individuals with PAD, but results of these studies are variable. This is an update of a review first published in 2012.
OBJECTIVES
To determine the efficacy of pentoxifylline in improving the walking capacity (i.e. pain-free walking distance and total (absolute, maximum) walking distance) of individuals with stable intermittent claudication, Fontaine stage II.
SEARCH METHODS
For this update, the Cochrane Vascular Group Trials Search Co-ordinator searched the Specialised Register (last searched April 2015) and the Cochrane Register of Studies (2015, Issue 3).
SELECTION CRITERIA
All double-blind, randomised controlled trials (RCTs) comparing pentoxifylline versus placebo or any other pharmacological intervention in patients with IC Fontaine stage II.
DATA COLLECTION AND ANALYSIS
Two review authors separately assessed included studies,. matched data and resolved disagreements by discussion. Review authors assessed the methodological quality of studies by using the Cochrane 'Risk of bias' tool and collected results related to pain-free walking distance (PFWD) and total walking distance (TWD). Comparison of studies was based on duration and dose of pentoxifylline.
MAIN RESULTS
We included in this review 24 studies with 3377 participants. Seventeen studies compared pentoxifylline versus placebo. In the seven remaining studies, pentoxifylline was compared with flunarizine (one study), aspirin (one study), Gingko biloba extract (one study), nylidrin hydrochloride (one study), prostaglandin E1 (two studies) and buflomedil and nifedipine (one study). The quality of the evidence was generally low, with large variability in reported findings.. Most included studies did not report on random sequence generation and allocation concealment, did not provide adequate information to allow selective reporting to be judged and did not report blinding of assessors. Heterogeneity between included studies was considerable with regards to multiple variables, including duration of treatment, dose of pentoxifylline, baseline walking distance and participant characteristics; therefore, pooled analysis was not possible.Of 17 studies comparing pentoxifylline with placebo, 14 reported TWD and 11 reported PFWD; the difference in percentage improvement in TWD for pentoxifylline over placebo ranged from 1.2% to 155.9%, and in PFWD from -33.8% to 73.9%. Testing the statistical significance of these results generally was not possible because data were insufficient. Most included studies suggested improvement in PFWD and TWD for pentoxifylline over placebo and other treatments, but the statistical and clinical significance of findings from individual trials is unclear. Pentoxifylline generally was well tolerated; the most commonly reported side effects consisted of gastrointestinal symptoms such as nausea.
AUTHORS' CONCLUSIONS
Given the generally poor quality of published studies and the large degree of heterogeneity evident in interventions and in results, the overall benefit of pentoxifylline for patients with Fontaine class II intermittent claudication remains uncertain. Pentoxifylline was shown to be generally well tolerated.Based on total available evidence, high-quality data are currently insufficient to reveal the benefits of pentoxifylline for intermittent claudication.
Topics: Ankle Brachial Index; Humans; Intermittent Claudication; Pentoxifylline; Platelet Aggregation Inhibitors; Quality of Life; Randomized Controlled Trials as Topic; Vasodilator Agents; Walking
PubMed: 26417854
DOI: 10.1002/14651858.CD005262.pub3 -
PloS One 2022To evaluate the efficacy and safety of cilostazol, pentoxifylline, beraprost for intermittent claudication due to lower extremity arterial occlusive disease. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To evaluate the efficacy and safety of cilostazol, pentoxifylline, beraprost for intermittent claudication due to lower extremity arterial occlusive disease.
METHODS
Randomized controlled clinical trials were identified from PubMed, Scopus, EMbase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, SinoMed, Wanfang and Chongqing VIP databases, from the database inception to 31/12/2021. The outcome measures were walking distance measured by treadmill (maximum and pain-free walking distance), ankle-brachial index and adverse events. The quality of included studies was assessed by the Cochrane bias risk assessment tool. A network meta-analysis was carried out with Stata 16.0 software.
RESULTS
There were 29 RCTs included in the study, covering total 5352 patients. Cilostazol was ranked first for both maximum and pain-free walking distance, followed by beraprost and pentoxifylline. For cilostazol, pentoxifylline and beraprost, maximum walking distance increased by 62.93 95%CI(44.06, 81.79), 32.72 95%CI(13.51, 55.79) and 43.90 95%CI(2.10, 85.71) meters, respectively relative to placebo, and pain-free walking distance increased by 23.92 95%CI(11.24, 36.61), 15.16 95%CI(2.33, 27.99) and 19.78 95%CI(-3.07, 42.62) meters. For cilostazol, pentoxifylline, beraprost and cilostazol combined with beraprost, ankle-brachial index increased by 0.06 95%CI(0.04, 0.07), -0.01 95%CI(-0.08, 0.05), 0.18 95%CI(0.12, 0.23) and 0.23 95%CI(0.18, 0.27), respectively relative to placebo. The pentoxifylline and cilostazol was associated with a lower ratio of adverse events than beraprost and cilostazol combined with beraprost.
CONCLUSION
Cilostazol, pentoxifylline and beraprost were all effective treatments for intermittent claudication; cilostazol with good tolerance was likely to be the most effective in walking distance, while beraprost and cilostazol combined with beraprost were more prominent in the ankle-brachial index.
Topics: Humans; Cilostazol; Intermittent Claudication; Network Meta-Analysis; Pentoxifylline; Vasodilator Agents; Randomized Controlled Trials as Topic
PubMed: 36318524
DOI: 10.1371/journal.pone.0275392 -
The Cochrane Database of Systematic... Oct 2020Intermittent claudication (IC) is a symptom of peripheral arterial disease (PAD) and is associated with high morbidity and mortality. Pentoxifylline, one of many drugs... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Intermittent claudication (IC) is a symptom of peripheral arterial disease (PAD) and is associated with high morbidity and mortality. Pentoxifylline, one of many drugs used to treat IC, acts by decreasing blood viscosity, improving erythrocyte flexibility, and promoting microcirculatory flow and tissue oxygen concentration. Many studies have evaluated the efficacy of pentoxifylline in treating people with PAD, but results of these studies are variable. This is the second update of a review first published in 2012.
OBJECTIVES
To determine the efficacy of pentoxifylline in improving the walking capacity (i.e. pain-free walking distance and total (absolute, maximum) walking distance) of people with stable intermittent claudication, Fontaine stage II.
SEARCH METHODS
For this update, the Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases, and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 28 January 2020. There were no language restrictions.
SELECTION CRITERIA
We included all double-blind, randomised controlled trials (RCTs) comparing pentoxifylline versus placebo or any other pharmacological intervention in people with IC Fontaine stage II.
DATA COLLECTION AND ANALYSIS
Two review authors independently selected studies for inclusion, assessed the included studies, matched data and resolved disagreements by discussion. Review authors assessed the methodological quality of studies using the Cochrane 'Risk of bias' tool and collected results related to the outcomes of interest, pain-free walking distance (PFWD), total walking distance (TWD), ankle-brachial pressure index (ABI), quality of life (QoL) and side effects. Comparison of studies was based on duration and dose of pentoxifylline. We used GRADE criteria to assess the certainty of the evidence.
MAIN RESULTS
We identified no new eligible studies for this update. This review includes 24 studies with 3377 participants. Seventeen studies compared pentoxifylline versus placebo. The seven remaining studies compared pentoxifylline with flunarizine (one study), aspirin (one study), Gingko biloba extract (one study), nylidrin hydrochloride (one study), prostaglandin E1 (two studies), and buflomedil and nifedipine (one study). Risk of bias for the individual studies was generally unclear because there was a lack of methodological reporting for many of the included studies, especially regarding randomisation and allocation methods. Most included studies did not provide adequate information to allow selective reporting to be judged and did not report blinding of assessors. Heterogeneity between included studies was considerable with regards to multiple variables, including duration of treatment, dose of pentoxifylline, baseline walking distance and participant characteristics; therefore, pooled analysis for comparisons which included more than one study, was not possible. Pentoxifylline compared to placebo Of 17 studies comparing pentoxifylline with placebo, 11 reported PFWD and 14 reported TWD; the difference in percentage improvement in PFWD for pentoxifylline over placebo ranged from -33.8% to 73.9% and in TWD ranged from 1.2% to 155.9%. It was not possible to pool the data of the studies because data were insufficient and findings from individual trials were unclear. Most included studies suggested a possible improvement in PFWD and TWD for pentoxifylline over placebo (both low-certainty evidence). The five studies which evaluated pre-exercise ABI comparing pentoxifylline and placebo found no evidence of a difference (moderate-certainty evidence). Two of the three studies that evaluated QoL between people who received pentoxifylline and placebo were larger studies that used validated QoL tools and generally found no evidence of a difference between groups. One small, short-term study, which did not specify which QoL tool was used, reported improved QoL in the pentoxifylline group (moderate-certainty evidence). Pentoxifylline generally was well tolerated; the most commonly reported side effects consisted of gastrointestinal symptoms such as nausea (low-certainty evidence). Certainty of the evidence from this review was low or moderate, with downgrading due to risk of bias concerns, inconsistencies between studies and the inability to evaluate imprecision because meta-analysis could not be undertaken. The seven remaining studies compared pentoxifylline with either flunarizine, aspirin, Gingko biloba extract, nylidrin hydrochloride, prostaglandin E1, or buflomedil and nifedipine; data were too limited to allow any meaningful conclusions to be made.
AUTHORS' CONCLUSIONS
There is a lack of high-certainty evidence for the effects of pentoxifylline compared to placebo, or other treatments, for IC. There is low-certainty evidence that pentoxifylline may improve PFWD and TWD compared to placebo, but no evidence of a benefit to ABI or QoL (moderate-certainty evidence). Pentoxifylline was reported to be generally well tolerated (low-certainty evidence). Given the large degree of heterogeneity between the studies, the role of pentoxifylline for people with IC Fontaine class II remains uncertain.
Topics: Ankle Brachial Index; Humans; Intermittent Claudication; Pentoxifylline; Platelet Aggregation Inhibitors; Quality of Life; Randomized Controlled Trials as Topic; Vasodilator Agents; Walking
PubMed: 33063850
DOI: 10.1002/14651858.CD005262.pub4 -
Journal of Current Ophthalmology 2022To systematically review the role of antioxidants in management of patients with thyroid eye disease (TED). (Review)
Review
PURPOSE
To systematically review the role of antioxidants in management of patients with thyroid eye disease (TED).
METHODS
A literature search of the electronic databases was performed without restrictions on the date of publication till the end of March 2021, using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Clinical trials, case-control studies, cohorts, case series, case reports, and experimental (including ) studies in the English language were included. The primary outcome in human studies was improvement in severity, activity scores, and/or quality of life scores. There was a decrease in the level of HO-dependent oxidative stress, Hyaluronic acid release, reactive oxygen species, cell proliferation, or antifibrotic/antiproliferative actions in the studies.
RESULTS
Out of 374 initially screened articles, 157 studies were selected, the full texts of 82 were reviewed, and 14 papers were finally included. There were 4 clinical and 10 studies from 1993 to 2018. While β-carotene, retinol, Vitamin E, Vitamin C, melatonin, resveratrol, N-acetyl-l-cysteine, and quercetin showed some efficacy in studies; allopurinol, nicotinamide, pentoxifylline, and selenium (Se) were effective in both clinical and experimental reports. Se was the only recommended antioxidant based on one high-level randomized controlled trial.
CONCLUSION
While different antioxidants could potentially be effective in the management of TED, no strong recommendation for any or combination of antioxidants could be made to be implemented in the daily practice.
PubMed: 35620378
DOI: 10.4103/joco.joco_266_21 -
PloS One 2015Pentoxifylline (PTX) is a promising therapeutic approach for reducing inflammation and improving anemia associated to various systemic disorders. However, whether this... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Pentoxifylline (PTX) is a promising therapeutic approach for reducing inflammation and improving anemia associated to various systemic disorders. However, whether this agent may be helpful for anemia management also in CKD patients is still object of debate.
STUDY DESIGN
Systematic review and meta-analysis.
POPULATION
Adults with CKD (any KDOQI stage, including ESKD patients on regular dialysis) and anemia (Hb<13 g/dL in men or < 12 g/dL in women).
SEARCH STRATEGY AND SOURCES
Cochrane CENTRAL, EMBASE, Ovid-MEDLINE and PubMed were searched for studies providing data on the effects of PTX on anemia parameters in CKD patients without design or follow-up restriction.
INTERVENTION
PTX derivatives at any dose regimen.
OUTCOMES
Hemoglobin, hematocrit, ESAs dosage and resistance (ERI), iron indexes (ferritin, serum iron, TIBC, transferrin and serum hepcidin) and adverse events.
RESULTS
We retrieved 11 studies (377 patients) including seven randomized controlled trials (all comparing PTX to placebo or standard therapy) one retrospective case-control study and three prospective uncontrolled studies. Overall, PTX increased hemoglobin in three uncontrolled studies but such improvement was not confirmed in a meta-analysis of seven studies (299 patients) (MD 0.12 g/dL, 95% CI -0.22 to 0.47). Similarly, there were no conclusive effects of PTX on hematocrit, ESAs dose, ferritin and TSAT in pooled analyses. Data on serum iron, ERI, TIBC and hepcidin were based on single studies. No evidence of increased rate of adverse events was also noticed.
LIMITATIONS
Small sample size and limited number of studies. High heterogeneity among studies with respect to CKD and anemia severity, duration of intervention and responsiveness/current therapy with iron or ESAs.
CONCLUSIONS
There is currently no conclusive evidence supporting the utility of pentoxifylline for improving anemia control in CKD patients. Future trials designed on hard, patient-centered outcomes with larger sample size and longer follow-up are advocated.
Topics: Adult; Anemia; Anti-Inflammatory Agents; Female; Humans; Male; Pentoxifylline; Phosphodiesterase Inhibitors; Renal Insufficiency, Chronic; Treatment Outcome
PubMed: 26237421
DOI: 10.1371/journal.pone.0134104 -
Systematic Reviews Aug 2023Chronic radiation proctitis (CRP) is a long-term complication of pelvic radiotherapy that manifests as rectal bleeding, diarrhoea, fistula formation and obstruction.... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Chronic radiation proctitis (CRP) is a long-term complication of pelvic radiotherapy that manifests as rectal bleeding, diarrhoea, fistula formation and obstruction. Treatments such as endoscopic argon plasma coagulation, hyperbaric oxygen therapy and rectal topical formalin have imposed a significant medical burden on CRP patients. In contrast, oral therapies offer a more accessible and acceptable option for managing CRP. Here, we conducted a systematic review of the efficacy of oral treatments for CRP to assess their potential as an effective and convenient treatment option for this condition.
METHODS
We searched the Cochrane Central Register of Controlled Trials, PubMed, Web of Science, China National Knowledge Infrastructure and Chinese VIP in February 2021. We included post-radiotherapy participants with CRP that compared oral medicine alone or in combination with other treatments versus control treatments. The primary outcomes were bleeding, diarrhoea and symptom score. Heterogeneity between studies was checked using Cochrane Q test statistics and I test statistics. The Cochrane risk-of-bias tool was used to assess the quality of the included studies.
RESULTS
We included 10 randomised controlled trials (RCTs) and 1 retrospective study with 898 participants. Three placebo-controlled trials evaluated the effects of oral sucralfate on CRP, with meta-analysis showing no significant different with placebo arm. Four trials on TCM demonstrated significant improvement of symptoms, especially for the 3 trials on oral TCM drinks. Retinyl palmitate and high-fibre diet were found to reduce rectal bleeding. The combination of oral pentoxifylline and tocopherol did not significantly change the process of CRP.
CONCLUSIONS
Our study implies that oral TCM drinks, retinyl palmitate and a high-fiber diet showed significant improvement in CRP symptoms, but not with the combination of oral pentoxifylline and tocopherol. Further multicentre, larger-scale RCTs are needed to confirm the efficacy and safety of these treatments and optimize treatment strategies, ultimately improving the quality of life for patients with CRP.
Topics: Humans; Pentoxifylline; Tocopherols; Diarrhea; Proctitis
PubMed: 37608385
DOI: 10.1186/s13643-023-02294-2 -
The Cochrane Database of Systematic... Jul 2017A couple may be considered to have fertility problems if they have been trying to conceive for over a year with no success. This may affect up to a quarter of all... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
A couple may be considered to have fertility problems if they have been trying to conceive for over a year with no success. This may affect up to a quarter of all couples planning a child. It is estimated that for 40% to 50% of couples, subfertility may result from factors affecting women. Antioxidants are thought to reduce the oxidative stress brought on by these conditions. Currently, limited evidence suggests that antioxidants improve fertility, and trials have explored this area with varied results. This review assesses the evidence for the effectiveness of different antioxidants in female subfertility.
OBJECTIVES
To determine whether supplementary oral antioxidants compared with placebo, no treatment/standard treatment or another antioxidant improve fertility outcomes for subfertile women.
SEARCH METHODS
We searched the following databases (from their inception to September 2016) with no language or date restriction: Cochrane Gynaecology and Fertility Group (CGFG) specialised register, the Cochrane Central Register of Studies (CENTRAL CRSO), MEDLINE, Embase, PsycINFO, CINAHL and AMED. We checked reference lists of appropriate studies and searched for ongoing trials in the clinical trials registers.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) that compared any type, dose or combination of oral antioxidant supplement with placebo, no treatment or treatment with another antioxidant, among women attending a reproductive clinic. We excluded trials comparing antioxidants with fertility drugs alone and trials that only included fertile women attending a fertility clinic because of male partner infertility.
DATA COLLECTION AND ANALYSIS
Two review authors independently selected eligible studies, extracted the data and assessed the risk of bias of the included studies. The primary review outcome was live birth; secondary outcomes included clinical pregnancy rates and adverse events. We pooled studies using a fixed-effect model, and calculated odds ratios (ORs) with 95% confidence intervals (CIs) for the dichotomous outcomes of live birth, clinical pregnancy and adverse events. We assessed the overall quality of the evidence by applying GRADE criteria.
MAIN RESULTS
We included 50 trials involving 6510 women. Investigators compared oral antioxidants, including combinations of antioxidants, N-acetyl-cysteine, melatonin, L-arginine, myo-inositol, D-chiro-inositol, carnitine, selenium, vitamin E, vitamin B complex, vitamin C, vitamin D+calcium, CoQ10, pentoxifylline and omega-3-polyunsaturated fatty acids versus placebo, no treatment/standard treatment or another antioxidant.Very low-quality evidence suggests that antioxidants may be associated with an increased live birth rate compared with placebo or no treatment/standard treatment (OR 2.13, 95% CI 1.45 to 3.12, P > 0.001, 8 RCTs, 651 women, I = 47%). This suggests that among subfertile women with an expected live birth rate of 20%, the rate among women using antioxidants would be between 26% and 43%.Very low-quality evidence suggests that antioxidants may be associated with an increased clinical pregnancy rate compared with placebo or no treatment/standard treatment (OR 1.52, 95% CI 1.31 to 1.76, P < 0.001, 26 RCTs, 4271 women, I = 66%). This suggests that among subfertile women with an expected clinical pregnancy rate of 22%, the rate among women using antioxidants would be between 27% and 33%. Heterogeneity was moderately high.There was insufficient evidence to determine whether there was a difference between the groups in rates of miscarriage (OR 0.79, 95% CI 0.58 to 1.08, P = 0.14, 18 RCTs, 2834 women, I = 23%, very low quality evidence). This suggests that, among subfertile women with an expected miscarriage rate of 7%, use of antioxidants would be expected to result in a miscarriage rate of between 4% and 7%. There was also insufficient evidence to determine whether there was a difference between the groups in rates of multiple pregnancy (OR 1.00, 95% CI 0.73 to 1.38, P = 0.98, 8 RCTs, 2163 women, I = 4%, very low quality evidence). This suggests that among subfertile women with an expected multiple pregnancy rate of 8%, use of antioxidants would be expected to result in a multiple pregnancy rate between 6% and 11%. Likewise, there was insufficient evidence to determine whether there was a difference between the groups in rates of gastrointestinal disturbances (OR 1.55, 95% CI 0.47 to 5.10, P = 0.47, 3 RCTs, 343 women, I = 0%, very low quality evidence). This suggests that among subfertile women with an expected gastrointestinal disturbance rate of 2%, use of antioxidants would be expected to result in a rate between 1% and 11%. Overall adverse events were reported by 35 trials in the meta-analysis, but there was insufficient evidence to draw any conclusions.Only one trial reported on live birth, clinical pregnancy or adverse effects in the antioxidant versus antioxidant comparison, and no conclusions could be drawn.Very low-quality evidence suggests that pentoxifylline may be associated with an increased clinical pregnancy rate compared with placebo or no treatment (OR 2.07, 95% CI 1.20 to 3.56, P = 0.009, 3 RCTs, 276 women, I = 0%). This suggests that among subfertile women with an expected clinical pregnancy rate of 25%, the rate among women using pentoxifylline would be between 28% and 53%.There was insufficient evidence to determine whether there was a difference between the groups in rates of miscarriage (OR 1.34, 95% CI 0.46 to 3.90, P = 0.58, 3 RCTs, 276 women, I = 0%) or multiple pregnancy (OR 0.78, 95% CI 0.20 to 3.09, one RCT, 112 women, very low quality evidence). This suggests that among subfertile women with an expected miscarriage rate of 4%, the rate among women using pentoxifylline would be between 2% and 15%. For multiple pregnancy, the data suggest that among subfertile women with an expected multiple pregnancy rate of 9%, the rate among women using pentoxifylline would be between 2% and 23%.The overall quality of evidence was limited by serious risk of bias associated with poor reporting of methods, imprecision and inconsistency.
AUTHORS' CONCLUSIONS
In this review, there was very low-quality evidence to show that taking an antioxidant may provide benefit for subfertile women, but insufficient evidence to draw any conclusions about adverse events. At this time, there is limited evidence in support of supplemental oral antioxidants for subfertile women.
Topics: Abortion, Spontaneous; Administration, Oral; Antioxidants; Female; Humans; Infertility, Female; Live Birth; Oxidative Stress; Pentoxifylline; Pregnancy; Pregnancy Rate; Pregnancy, Multiple; Randomized Controlled Trials as Topic
PubMed: 28752910
DOI: 10.1002/14651858.CD007807.pub3 -
The Cochrane Database of Systematic... Dec 2017Exercise programmes are a relatively inexpensive, low-risk option compared with other, more invasive therapies for treatment of leg pain on walking (intermittent... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Exercise programmes are a relatively inexpensive, low-risk option compared with other, more invasive therapies for treatment of leg pain on walking (intermittent claudication (IC)). This is the fourth update of a review first published in 1998.
OBJECTIVES
Our goal was to determine whether an exercise programme was effective in alleviating symptoms and increasing walking treadmill distances and walking times in people with intermittent claudication. Secondary objectives were to determine whether exercise was effective in preventing deterioration of underlying disease, reducing cardiovascular events, and improving quality of life.
SEARCH METHODS
For this update, the Cochrane Vascular Information Specialist searched the Specialised Register (last searched 15 November 2016) and the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 10) via the Cochrane Register of Studies Online, along with trials registries.
SELECTION CRITERIA
Randomised controlled trials of an exercise regimen versus control or versus medical therapy for people with IC due to peripheral arterial disease (PAD). We included any exercise programme or regimen used for treatment of IC, such as walking, skipping, and running. Inclusion of trials was not affected by duration, frequency, or intensity of the exercise programme. Outcome measures collected included treadmill walking distance (time to onset of pain or pain-free walking distance and maximum walking time or maximum walking distance), ankle brachial index (ABI), quality of life, morbidity, or amputation; if none of these was reported, we did not include the trial in this review.
DATA COLLECTION AND ANALYSIS
For this update (2017), RAL and AH selected trials and extracted data independently. We assessed study quality by using the Cochrane 'Risk of bias' tool. We analysed continuous data by determining mean differences (MDs) and 95% confidence intervals (CIs), and dichotomous data by determining risk ratios (RRs) and 95% CIs. We pooled data using a fixed-effect model unless we identified significant heterogeneity, in which case we used a random-effects model. We used the GRADE approach to assess the overall quality of evidence supporting the outcomes assessed in this review.
MAIN RESULTS
We included two new studies in this update and identified additional publications for previously included studies, bringing the total number of studies meeting the inclusion criteria to 32, and involving a total of 1835 participants with stable leg pain. The follow-up period ranged from two weeks to two years. Types of exercise varied from strength training to polestriding and upper or lower limb exercises; supervised sessions were generally held at least twice a week. Most trials used a treadmill walking test for one of the primary outcome measures. The methodological quality of included trials was moderate, mainly owing to absence of relevant information. Most trials were small and included 20 to 49 participants. Twenty-seven trials compared exercise versus usual care or placebo, and the five remaining trials compared exercise versus medication (pentoxifylline, iloprost, antiplatelet agents, and vitamin E) or pneumatic calf compression; we generally excluded people with various medical conditions or other pre-existing limitations to their exercise capacity.Meta-analysis from nine studies with 391 participants showed overall improvement in pain-free walking distance in the exercise group compared with the no exercise group (MD 82.11 m, 95% CI 71.73 to 92.48, P < 0.00001, high-quality evidence). Data also showed benefit from exercise in improved maximum walking distance (MD 120.36 m, 95% CI 50.79 to 189.92, P < 0.0007, high-quality evidence), as revealed by pooling data from 10 studies with 500 participants. Improvements were seen for up to two years.Exercise did not improve the ABI (MD 0.04, 95% CI 0.00 to 0.08, 13 trials, 570 participants, moderate-quality evidence). Limited data were available for the outcomes of mortality and amputation; trials provided no evidence of an effect of exercise, when compared with placebo or usual care, on mortality (RR 0.92, 95% CI 0.39 to 2.17, 5 trials, 540 participants, moderate-quality evidence) or amputation (RR 0.20, 95% CI 0.01 to 4.15, 1 trial, 177 participants, low-quality evidence).Researchers measured quality of life using Short Form (SF)-36 at three and six months. At three months, the domains 'physical function', 'vitality', and 'role physical' improved with exercise; however this was a limited finding, as it was reported by only two trials. At six months, meta-analysis showed improvement in 'physical summary score' (MD 2.15, 95% CI 1.26 to 3.04, P = 0.02, 5 trials, 429 participants, moderate-quality evidence) and in 'mental summary score' (MD 3.76, 95% CI 2.70 to 4.82, P < 0.01, 4 trials, 343 participants, moderate-quality evidence) secondary to exercise. Two trials reported the remaining domains of the SF-36. Data showed improvements secondary to exercise in 'physical function' and 'general health'. The other domains - 'role physical', 'bodily pain', 'vitality', 'social', 'role emotional', and 'mental health' - did not show improvement at six months.Evidence was generally limited in trials comparing exercise versus antiplatelet therapy, pentoxifylline, iloprost, vitamin E, and pneumatic foot and calf compression owing to small numbers of trials and participants.Review authors used GRADE to assess the evidence presented in this review and determined that quality was moderate to high. Although results showed significant heterogeneity between trials, populations and outcomes were comparable overall, with findings relevant to the claudicant population. Results were pooled for large sample sizes - over 300 participants for most outcomes - using reproducible methods.
AUTHORS' CONCLUSIONS
High-quality evidence shows that exercise programmes provided important benefit compared with placebo or usual care in improving both pain-free and maximum walking distance in people with leg pain from IC who were considered to be fit for exercise intervention. Exercise did not improve ABI, and we found no evidence of an effect of exercise on amputation or mortality. Exercise may improve quality of life when compared with placebo or usual care. As time has progressed, the trials undertaken have begun to include exercise versus exercise or other modalities; therefore we can include fewer of the new trials in this update.
Topics: Amputation, Surgical; Ankle Brachial Index; Exercise Therapy; Female; Humans; Intermittent Claudication; Male; Pain Management; Quality of Life; Randomized Controlled Trials as Topic; Time Factors; Walking
PubMed: 29278423
DOI: 10.1002/14651858.CD000990.pub4 -
The Cochrane Database of Systematic... Jun 2021Peripheral arterial disease (PAD) affects between 4% and 12% of people aged 55 to 70 years, and 20% of people over 70 years. A common complaint is intermittent... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Peripheral arterial disease (PAD) affects between 4% and 12% of people aged 55 to 70 years, and 20% of people over 70 years. A common complaint is intermittent claudication (exercise-induced lower limb pain relieved by rest). These patients have a three- to six-fold increase in cardiovascular mortality. Cilostazol is a drug licensed for the use of improving claudication distance and, if shown to reduce cardiovascular risk, could offer additional clinical benefits. This is an update of the review first published in 2007.
OBJECTIVES
To determine the effect of cilostazol on initial and absolute claudication distances, mortality and vascular events in patients with stable intermittent claudication.
SEARCH METHODS
The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL, and AMED databases, and the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registries, on 9 November 2020.
SELECTION CRITERIA
We considered double-blind, randomised controlled trials (RCTs) of cilostazol versus placebo, or versus other drugs used to improve claudication distance in patients with stable intermittent claudication.
DATA COLLECTION AND ANALYSIS
Two authors independently assessed trials for selection and independently extracted data. Disagreements were resolved by discussion. We assessed the risk of bias with the Cochrane risk of bias tool. Certainty of the evidence was evaluated using GRADE. For dichotomous outcomes, we used odds ratios (ORs) with corresponding 95% confidence intervals (CIs) and for continuous outcomes we used mean differences (MDs) and 95% CIs. We pooled data using a fixed-effect model, or a random-effects model when heterogeneity was identified. Primary outcomes were initial claudication distance (ICD) and quality of life (QoL). Secondary outcomes were absolute claudication distance (ACD), revascularisation, amputation, adverse events and cardiovascular events.
MAIN RESULTS
We included 16 double-blind, RCTs (3972 participants) comparing cilostazol with placebo, of which five studies also compared cilostazol with pentoxifylline. Treatment duration ranged from six to 26 weeks. All participants had intermittent claudication secondary to PAD. Cilostazol dose ranged from 100 mg to 300 mg; pentoxifylline dose ranged from 800 mg to 1200 mg. The certainty of the evidence was downgraded by one level for all studies because publication bias was strongly suspected. Other reasons for downgrading were imprecision, inconsistency and selective reporting. Cilostazol versus placebo Participants taking cilostazol had a higher ICD compared with those taking placebo (MD 26.49 metres; 95% CI 18.93 to 34.05; 1722 participants; six studies; low-certainty evidence). We reported QoL measures descriptively due to insufficient statistical detail within the studies to combine the results; there was a possible indication in improvement of QoL in the cilostazol treatment groups (low-certainty evidence). Participants taking cilostazol had a higher ACD compared with those taking placebo (39.57 metres; 95% CI 21.80 to 57.33; 2360 participants; eight studies; very-low certainty evidence). The most commonly reported adverse events were headache, diarrhoea, abnormal stools, dizziness, pain and palpitations. Participants taking cilostazol had an increased odds of experiencing headache compared to participants taking placebo (OR 2.83; 95% CI 2.26 to 3.55; 2584 participants; eight studies; moderate-certainty evidence).Very few studies reported on other outcomes so conclusions on revascularisation, amputation, or cardiovascular events could not be made. Cilostazol versus pentoxifylline There was no difference detected between cilostazol and pentoxifylline for improving walking distance, both in terms of ICD (MD 20.0 metres, 95% CI -2.57 to 42.57; 417 participants; one study; low-certainty evidence); and ACD (MD 13.4 metres, 95% CI -43.50 to 70.36; 866 participants; two studies; very low-certainty evidence). One study reported on QoL; the study authors reported no difference in QoL between the treatment groups (very low-certainty evidence). No study reported on revascularisation, amputation or cardiovascular events. Cilostazol participants had an increased odds of experiencing headache compared with participants taking pentoxifylline at 24 weeks (OR 2.20, 95% CI 1.16 to 4.17; 982 participants; two studies; low-certainty evidence).
AUTHORS' CONCLUSIONS
Cilostazol has been shown to improve walking distance in people with intermittent claudication. However, participants taking cilostazol had higher odds of experiencing headache. There is insufficient evidence about the effectiveness of cilostazol for serious events such as amputation, revascularisation, and cardiovascular events. Despite the importance of QoL to patients, meta-analysis could not be undertaken because of differences in measures used and reporting. Very limited data indicated no difference between cilostazol and pentoxifylline for improving walking distance and data were too limited for any conclusions on other outcomes.
Topics: Aged; Bias; Cilostazol; Humans; Intermittent Claudication; Middle Aged; Myocardial Infarction; Pentoxifylline; Peripheral Vascular Diseases; Placebos; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Stroke; Tetrazoles; Walking
PubMed: 34192807
DOI: 10.1002/14651858.CD003748.pub5