To evaluate the characteristics of the design, analysis, and reporting of crossover trials for inclusion in a meta-analysis of treatment for primary open-angle glaucoma and to provide empirical ...evidence to inform the development of tools to assess the validity of the results from crossover trials and reporting guidelines.
We searched MEDLINE, EMBASE, and Cochrane's CENTRAL register for randomized crossover trials for a systematic review and network meta-analysis we are conducting. Two individuals independently screened the search results for eligibility and abstracted data from each included report.
We identified 83 crossover trials eligible for inclusion. Issues affecting the risk of bias in crossover trials, such as carryover, period effects and missing data, were often ignored. Some trials failed to accommodate the within-individual differences in the analysis. For a large proportion of the trials, the authors tabulated the results as if they arose from a parallel design. Precision estimates properly accounting for the paired nature of the design were often unavailable from the study reports; consequently, to include trial findings in a meta-analysis would require further manipulation and assumptions.
The high proportion of poorly reported analyses and results has the potential to affect whether crossover data should or can be included in a meta-analysis. There is pressing need for reporting guidelines for crossover trials.
Age-related macular degeneration (AMD) is the most common cause of uncorrectable severe vision loss in people aged 55 years and older in the developed world. Choroidal neovascularization (CNV) ...secondary to AMD accounts for most cases of AMD-related severe vision loss. Intravitreous injection of anti-vascular endothelial growth factor (anti-VEGF) agents aims to block the growth of abnormal blood vessels in the eye to prevent vision loss and, in some instances, to improve vision.
• To investigate ocular and systemic effects of, and quality of life associated with, intravitreous injection of three anti-VEGF agents (pegaptanib, ranibizumab, and bevacizumab) versus no anti-VEGF treatment for patients with neovascular AMD• To compare the relative effects of one of these anti-VEGF agents versus another when administered in comparable dosages and regimens SEARCH METHODS: To identify eligible studies for this review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Eyes and Vision Trials Register (searched January 31, 2018); MEDLINE Ovid (1946 to January 31, 2018); Embase Ovid (1947 to January 31, 2018); the Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to January 31, 2018); the International Standard Randomized Controlled Trials Number (ISRCTN) Registry (www.isrctn.com/editAdvancedSearch - searched January 31, 2018); ClinicalTrials.gov (www.clinicaltrials.gov - searched November 28, 2018); and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en - searched January 31, 2018). We did not impose any date or language restrictions in electronic searches for trials.
We included randomized controlled trials (RCTs) that evaluated pegaptanib, ranibizumab, or bevacizumab versus each other or versus a control treatment (e.g. sham treatment, photodynamic therapy), in which participants were followed for at least one year.
Two review authors independently screened records, extracted data, and assessed risks of bias. We contacted trial authors for additional data. We compared outcomes using risk ratios (RRs) or mean differences (MDs). We used the standard methodological procedures expected by Cochrane.
We included 16 RCTs that had enrolled a total of 6347 participants with neovascular AMD (the number of participants per trial ranged from 23 to 1208) and identified one potentially relevant ongoing trial. Six trials compared anti-VEGF treatment (pegaptanib, ranibizumab, or bevacizumab) versus control, and 10 trials compared bevacizumab versus ranibizumab. Pharmaceutical companies conducted or sponsored four trials but funded none of the studies that evaluated bevacizumab. Researchers conducted these trials at various centers across five continents (North and South America, Europe, Asia, and Australia). The overall certainty of the evidence was moderate to high, and most trials had an overall low risk of bias. All but one trial had been registered prospectively.When compared with those who received control treatment, more participants who received intravitreous injection of any of the three anti-VEGF agents had gained 15 letters or more of visual acuity (risk ratio RR 4.19, 95% confidence interval CI 2.32 to 7.55; moderate-certainty evidence), had lost fewer than 15 letters of visual acuity (RR 1.40, 95% CI 1.27 to 1.55; high-certainty evidence), and showed mean improvement in visual acuity (mean difference 6.7 letters, 95% CI 4.4 to 9.0 in one pegaptanib trial; mean difference 17.8 letters, 95% CI 16.0 to 19.7 in three ranibizumab trials; moderate-certainty evidence) after one year of follow-up. Participants treated with anti-VEGF agents showed improvement in morphologic outcomes (e.g. size of CNV, central retinal thickness) compared with participants not treated with anti-VEGF agents (moderate-certainty evidence). No trial directly compared pegaptanib versus another anti-VEGF agent and followed participants for one year; however, when compared with control treatments, ranibizumab and bevacizumab each yielded larger improvements in visual acuity outcomes than pegaptanib.Visual acuity outcomes after bevacizumab and ranibizumab were similar when the same RCTs compared the same regimens with respect to gain of 15 or more letters of visual acuity (RR 0.95, 95% CI 0.81 to 1.12; high-certainty evidence) and loss of fewer than 15 letters of visual acuity (RR 1.00, 95% CI 0.98 to 1.02; high-certainty evidence); results showed similar mean improvement in visual acuity (mean difference MD -0.5 letters, 95% CI -1.5 to 0.5; high-certainty evidence) after one year of follow-up, despite the substantially lower cost of bevacizumab compared with ranibizumab. Reduction in central retinal thickness was less among bevacizumab-treated participants than among ranibizumab-treated participants after one year (MD -11.6 μm, 95% CI -21.6 to -1.7; high-certainty evidence); however, this difference is within the range of measurement error, and we did not interpret it to be clinically meaningful.Ocular inflammation and increased intraocular pressure (IOP) after intravitreal injection were the most frequently reported serious ocular adverse events. Researchers reported endophthalmitis in less than 1% of anti-VEGF-treated participants and in no cases among control groups. The occurrence of serious systemic adverse events was comparable across anti-VEGF-treated groups and control groups; however, the numbers of events and trial participants may have been insufficient to show a meaningful difference between groups (evidence of low- to moderate-certainty). Investigators rarely measured and reported data on visual function, quality of life, or economic outcomes.
Results of this review show the effectiveness of anti-VEGF agents (pegaptanib, ranibizumab, and bevacizumab) in terms of maintaining visual acuity; studies show that ranibizumab and bevacizumab improved visual acuity in some eyes that received these agents and were equally effective. Available information on the adverse effects of each medication does not suggest a higher incidence of potentially vision-threatening complications with intravitreous injection of anti-VEGF agents compared with control interventions; however, clinical trial sample sizes were not sufficient to estimate differences in rare safety outcomes. Future Cochrane Reviews should incorporate research evaluating variable dosing regimens of anti-VEGF agents, effects of long-term use, use of combination therapies (e.g. anti-VEGF treatment plus photodynamic therapy), and other methods of delivering these agents.
To summarize key findings from a systematic review of the effectiveness and risks of conjunctival autograft (CAG) compared with amniotic membrane transplant (AMT) for pterygium.
Cochrane systematic ...review.
We included only randomized controlled trials (RCTs) in which CAG and AMT had been compared for primary or recurrent pterygia. The primary outcome was recurrence of pterygium ≥1 mm onto the cornea by 3 and 6 months post surgery. We adhered to Cochrane methods for trial selection, data extraction, risk of bias evaluation, and data synthesis.
Twenty RCTs with 1866 participants (1947 eyes) were included. Pterygium recurrence 6 months after surgery ranged from 3.3% to 16.7% in the CAG group and 6.4% to 42.3% in the AMT group based on data from 1021 eyes in 10 RCTs. Estimated risk ratios from meta-analysis indicated that CAG-treated eyes had a 47% lower risk of recurrence 6 months after surgery compared with the AMT group (RR, 0.53, 95% confidence interval CI, 0.33–0.85). For 96 eyes with recurrent pterygium, the risk of recurrence 6 months after CAG was reduced by 55% compared with AMT (risk ratio RR, 0.45, 95% CI, 0.21–0.99). Three-month recurrence rates were similar for CAG and AMT based on data from 538 eyes (6 RCTs).
CAG was more effective than AMT to prevent pterygium recurrence by 6 months post surgery, especially in recurrent pterygia. CAG-treated eyes had half the recurrence rates of AMT-treated eyes. Future RCTs should assess changes in patient-reported outcomes (symptoms, cosmesis) and visual acuity, and evaluate effects of surgical variations.
Age-related macular degeneration (AMD) is the most common cause of uncorrectable severe vision loss in people aged 55 years and older in the developed world. Choroidal neovascularization (CNV) ...secondary to neovascular AMD accounts for most AMD-related severe vision loss. Anti-vascular endothelial growth factor (anti-VEGF) agents, injected intravitreally, aim to block the growth of abnormal blood vessels in the eye to prevent vision loss and, in some instances, improve vision.
To investigate: (1) the ocular and systemic effects of, and quality of life associated with, intravitreally injected anti-VEGF agents (pegaptanib, ranibizumab, and bevacizumab) for the treatment of neovascular AMD compared with no anti-VEGF treatment; and (2) the relative effects of one anti-VEGF agent compared with another when administered in comparable dosages and regimens.
We searched Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group Trials Register) (2014, Issue 3), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to March 2014), EMBASE (January 1980 to March 2014), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to March 2014), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We used no date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 27 March 2014.
We included randomized controlled trials (RCTs) that evaluated pegaptanib, ranibizumab, or bevacizumab versus each other or a control treatment (e.g., sham treatment or photodynamic therapy). All trials followed participants for at least one year.
Two review authors independently screened records, extracted data, and assessed risks of bias. We contacted trial authors for additional data. We analyzed outcomes as risk ratios (RRs) or mean differences (MDs). We used the standard methodological procedures expected by The Cochrane Collaboration.
We included 12 RCTs including a total of 5496 participants with neovascular AMD (the number of participants per trial ranged from 28 to 1208). One trial compared pegaptanib, three trials ranibizumab, and two trials bevacizumab versus controls; six trials compared bevacizumab with ranibizumab. Four trials were conducted by pharmaceutical companies; none of the eight studies which evaluated bevacizumab were funded by pharmaceutical companies. The trials were conducted at various centers across five continents (North and South America, Europe, Asia and Australia). The overall quality of the evidence was very good, with most trials having an overall low risk of bias.When compared with control treatments, participants who received any of the three anti-VEGF agents were more likely to have gained 15 letters or more of visual acuity, lost fewer than 15 letters of visual acuity, and had vision 20/200 or better after one year of follow up. Visual acuity outcomes after bevacizumab and ranibizumab were similar when the same regimens were compared in the same RCTs, despite the substantially lower cost for bevacizumab compared with ranibizumab. No trial directly compared pegaptanib with other anti-VEGF agents; however, when compared with controls, ranibizumab or bevacizumab yielded larger improvements in visual acuity outcomes than pegaptanib.Participants treated with anti-VEGFs showed improvements in morphologic outcomes (e.g., size of CNV or central retinal thickness) compared with participants not treated with anti-VEGF agents. There was less reduction in central retinal thickness among bevacizumab-treated participants than among ranibizumab-treated participants after one year (MD -13.97 μm; 95% confidence interval (CI) -26.52 to -1.41); however, this difference is within the range of measurement error and we did not interpret it as being clinically meaningful.Ocular inflammation and increased intraocular pressure after intravitreal injection were the most frequently reported serious ocular adverse events. Endophthalmitis was reported in fewer than 1% of anti-VEGF treated participants; no cases were reported in control groups. The occurrence of serious systemic adverse events was comparable across anti-VEGF-treated groups and control groups; however, the numbers of events and trial participants may have been insufficient to detect a meaningful difference between groups. Data for visual function, quality of life, and economic outcomes were sparsely measured and reported.
The results of this review indicate the effectiveness of anti-VEGF agents (pegaptanib, ranibizumab, and bevacizumab) in terms of maintaining visual acuity; ranibizumab and bevacizumab were also shown to improve visual acuity. The information available on the adverse effects of each medication do not suggest a higher incidence of potentially vision-threatening complications with intravitreal injection compared with control interventions; however, clinical trial sample sizes may not have been sufficient to detect rare safety outcomes. Research evaluating variable dosing regimens with anti-VEGF agents, effects of long-term use, combination therapies (e.g., anti-VEGF treatment plus photodynamic therapy), and other methods of delivering the agents should be incorporated into future Cochrane reviews.
Diabetic retinopathy is a common complication of diabetes and a leading cause of visual impairment and blindness. Research has established the importance of blood glucose control to prevent ...development and progression of the ocular complications of diabetes. Concurrent blood pressure control has been advocated for this purpose, but individual studies have reported varying conclusions regarding the effects of this intervention.
To summarize the existing evidence regarding the effect of interventions to control blood pressure levels among diabetics on incidence and progression of diabetic retinopathy, preservation of visual acuity, adverse events, quality of life, and costs.
We searched several electronic databases, including CENTRAL, and trial registries. We last searched the electronic databases on 3 September 2021. We also reviewed the reference lists of review articles and trial reports selected for inclusion.
We included randomized controlled trials (RCTs) in which either type 1 or type 2 diabetic participants, with or without hypertension, were assigned randomly to more intense versus less intense blood pressure control; to blood pressure control versus usual care or no intervention on blood pressure (placebo); or to one class of antihypertensive medication versus another or placebo.
Pairs of review authors independently reviewed the titles and abstracts of records identified by the electronic and manual searches and the full-text reports of any records identified as potentially relevant. The included trials were independently assessed for risk of bias with respect to outcomes reported in this review.
We included 29 RCTs conducted in North America, Europe, Australia, Asia, Africa, and the Middle East that had enrolled a total of 4620 type 1 and 22,565 type 2 diabetic participants (sample sizes from 16 to 4477 participants). In all 7 RCTs for normotensive type 1 diabetic participants, 8 of 12 RCTs with normotensive type 2 diabetic participants, and 5 of 10 RCTs with hypertensive type 2 diabetic participants, one group was assigned to one or more antihypertensive agents and the control group to placebo. In the remaining 4 RCTs for normotensive participants with type 2 diabetes and 5 RCTs for hypertensive type 2 diabetic participants, methods of intense blood pressure control were compared to usual care. Eight trials were sponsored entirely and 10 trials partially by pharmaceutical companies; nine studies received support from other sources; and two studies did not report funding source. Study designs, populations, interventions, lengths of follow-up (range less than one year to nine years), and blood pressure targets varied among the included trials. For primary review outcomes after five years of treatment and follow-up, one of the seven trials for type 1 diabetics reported incidence of retinopathy and one trial reported progression of retinopathy; one trial reported a combined outcome of incidence and progression (as defined by study authors). Among normotensive type 2 diabetics, four of 12 trials reported incidence of diabetic retinopathy and two trials reported progression of retinopathy; two trials reported combined incidence and progression. Among hypertensive type 2 diabetics, six of the 10 trials reported incidence of diabetic retinopathy and two trials reported progression of retinopathy; five of the 10 trials reported combined incidence and progression. The evidence supports an overall benefit of more intensive blood pressure intervention for five-year incidence of diabetic retinopathy (11 studies; 4940 participants; risk ratio (RR) 0.82, 95% confidence interval (CI) 0.73 to 0.92; I
= 15%; moderate certainty evidence) and the combined outcome of incidence and progression (8 studies; 6212 participants; RR 0.78, 95% CI 0.68 to 0.89; I
= 42%; low certainty evidence). The available evidence did not support a benefit regarding five-year progression of diabetic retinopathy (5 studies; 5144 participants; RR 0.94, 95% CI 0.78 to 1.12; I
= 57%; moderate certainty evidence), incidence of proliferative diabetic retinopathy, clinically significant macular edema, or vitreous hemorrhage (9 studies; 8237 participants; RR 0.92, 95% CI 0.82 to 1.04; I
= 31%; low certainty evidence), or loss of 3 or more lines on a visual acuity chart with a logMAR scale (2 studies; 2326 participants; RR 1.15, 95% CI 0.63 to 2.08; I
= 90%; very low certainty evidence). Hypertensive type 2 diabetic participants realized more benefit from intense blood pressure control for three of the four outcomes concerning incidence and progression of diabetic retinopathy. The adverse event reported most often (13 of 29 trials) was death, yielding an estimated RR 0.87 (95% CI 0.76 to 1.00; 13 studies; 13,979 participants; I
= 0%; moderate certainty evidence). Hypotension was reported in two trials, with an RR of 2.04 (95% CI 1.63 to 2.55; 2 studies; 3323 participants; I
= 37%; low certainty evidence), indicating an excess of hypotensive events among participants assigned to more intervention on blood pressure.
Hypertension is a well-known risk factor for several chronic conditions for which lowering blood pressure has proven to be beneficial. The available evidence supports a modest beneficial effect of intervention to reduce blood pressure with respect to preventing diabetic retinopathy for up to five years, particularly for hypertensive type 2 diabetics. However, there was a paucity of evidence to support such intervention to slow progression of diabetic retinopathy or to affect other outcomes considered in this review among normotensive diabetics. This weakens any conclusion regarding an overall benefit of intervening on blood pressure in diabetic patients without hypertension for the sole purpose of preventing diabetic retinopathy or avoiding the need for treatment for advanced stages of diabetic retinopathy.
Glaucoma is an acquired degeneration of the optic nerve and a leading cause of blindness worldwide. Medical and surgical treatments that decrease intraocular pressure may prevent visual impairment ...and blindness.
To compare the effectiveness of medical, laser, and surgical treatments in adults with open-angle glaucoma with regard to decreasing intraocular pressure and preventing optic nerve damage, vision loss, and visual impairment.
MEDLINE, CENTRAL, and an existing database for systematic reviews (through 2 March 2011); MEDLINE, EMBASE, LILACS, and CENTRAL for primary studies (through 30 July 2012).
English-language systematic reviews; randomized, controlled trials; and quasi-randomized, controlled trials for most outcomes and observational studies for quality of life and harms.
Two investigators abstracted or checked information about study design, participants, and outcomes and assessed risk of bias and strength of evidence.
High-level evidence suggests that medical, laser, and surgical treatments decrease intraocular pressure and that medical treatment and trabeculectomy reduce the risk for optic nerve damage and visual field loss compared with no treatment. The direct effect of treatments on visual impairment and the comparative efficacy of different treatments are not clear. Harms of medical treatment are primarily local (ocular redness, irritation); surgical treatment carries a small risk for more serious complications.
Heterogeneous outcome definitions and measurements among the included studies; exclusion of many treatment studies that did not stratify results by glaucoma type.
Medical and surgical treatments for open-angle glaucoma lower intraocular pressure and reduce the risk for optic nerve damage over the short to medium term. Which treatments best prevent visual disability and improve patient-reported outcomes is unclear.
We previously reported durable responses in relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) patients treated with CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T-cell ...immunotherapy after ibrutinib failure. Because preclinical studies showed that ibrutinib could improve CAR T cell-antitumor efficacy and reduce cytokine release syndrome (CRS), we conducted a pilot study to evaluate the safety and feasibility of administering ibrutinib concurrently with CD19 CAR T-cell immunotherapy. Nineteen CLL patients were included. The median number of prior therapies was 5, and 17 patients (89%) had high-risk cytogenetics (17p deletion and/or complex karyotype). Ibrutinib was scheduled to begin ≥2 weeks before leukapheresis and continue for ≥3 months after CAR T-cell infusion. CD19 CAR T-cell therapy with concurrent ibrutinib was well tolerated; 13 patients (68%) received ibrutinib as planned without dose reduction. The 4-week overall response rate using 2018 International Workshop on CLL (iwCLL) criteria was 83%, and 61% achieved a minimal residual disease (MRD)-negative marrow response by IGH sequencing. In this subset, the 1-year overall survival and progression-free survival (PFS) probabilities were 86% and 59%, respectively. Compared with CLL patients treated with CAR T cells without ibrutinib, CAR T cells with concurrent ibrutinib were associated with lower CRS severity and lower serum concentrations of CRS-associated cytokines, despite equivalent in vivo CAR T-cell expansion. The 1-year PFS probabilities in all evaluable patients were 38% and 50% after CD19 CAR T-cell therapy, with and without concurrent ibrutinib, respectively (P = .91). CD19 CAR T cells with concurrent ibrutinib for R/R CLL were well tolerated, with low CRS severity, and led to high rates of MRD-negative response by IGH sequencing.
•CD19 CAR T cells with concurrent ibrutinib for R/R CLL were well tolerated, with low CRS severity and high response rates by iwCLL criteria.•The 1-year PFS probabilities were 38% and 50% after CD19 CAR T cells, with or without concurrent ibrutinib, respectively (P = .91).
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Autologous T cells engineered to express a CD19-specific chimeric antigen receptor (CAR) have produced impressive minimal residual disease–negative (MRD-negative) complete remission (CR) rates in ...patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, the factors associated with durable remissions after CAR T-cell therapy have not been fully elucidated. We studied patients with relapsed/refractory B-ALL enrolled in a phase 1/2 clinical trial evaluating lymphodepletion chemotherapy followed by CD19 CAR T-cell therapy at our institution. Forty-five (85%) of 53 patients who received CD19 CAR T-cell therapy and were evaluable for response achieved MRD-negative CR by high-resolution flow cytometry. With a median follow-up of 30.9 months, event-free survival (EFS) and overall survival (OS) were significantly better in the patients who achieved MRD-negative CR compared with those who did not (median EFS, 7.6 vs 0.8 months; P < .0001; median OS, 20.0 vs 5.0 months; P = .014). In patients who achieved MRD-negative CR by flow cytometry, absence of the index malignant clone by IGH deep sequencing was associated with better EFS (P = .034). Stepwise multivariable modeling in patients achieving MRD-negative CR showed that lower prelymphodepletion lactate dehydrogenase concentration (hazard ratio HR, 1.38 per 100 U/L increment increase), higher prelymphodepletion platelet count (HR, 0.74 per 50 000/μL increment increase), incorporation of fludarabine into the lymphodepletion regimen (HR, 0.25), and allogeneic hematopoietic cell transplantation (HCT) after CAR T-cell therapy (HR, 0.39) were associated with better EFS. These data allow identification of patients at higher risk of relapse after CAR T-cell immunotherapy who might benefit from consolidation strategies such as allogeneic HCT. This trial was registered at www.clinicaltrials.gov as #NCT01865617.
•Baseline platelet count, lactate dehydrogenase, and lymphodepletion regimen impact EFS in patients in MRD-negative CR after CD19 CAR T-cell.•Allogeneic HCT after CD19 CAR T-cell therapy is well tolerated and may improve EFS.
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Patients with follicular lymphoma (FL) with early relapse after initial chemoimmunotherapy, refractory disease, or histologic transformation (tFL) have limited progression-free and overall survival. ...We report efficacy and long-term follow-up of 21 patients with relapsed/refractory (R/R) FL (n = 8) and tFL (n = 13) treated on a phase 1/2 clinical trial with cyclophosphamide and fludarabine lymphodepletion followed by infusion of 2 × 106 CD19-directed chimeric antigen receptor–modified T (CAR-T) cells per kilogram. The complete remission (CR) rates by the Lugano criteria were 88% and 46% for patients with FL and tFL, respectively. All patients with FL who achieved CR remained in remission at a median follow-up of 24 months. The median duration of response for patients with tFL was 10.2 months at a median follow-up of 38 months. Cytokine release syndrome occurred in 50% and 39%, and neurotoxicity in 50% and 23% of patients with FL and tFL, respectively, with no severe adverse events (grade ≥3). No significant differences in CAR-T cell in vivo expansion/persistence were observed between FL and tFL patients. CD19 CAR-T cell immunotherapy is highly effective in adults with clinically aggressive R/R FL with or without transformation, with durable remission in a high proportion of FL patients. This trial was registered at clinicaltrials.gov as #NCT01865617.
•CD19 CAR-T cell immunotherapy results in high CR rates in FL with or without transformation.•Sustained remissions were observed in all patients with FL without transformation achieving CR.
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