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Editor's Choice
  • Liu CW
  • Anih J
  • Lebedeva V
  • Gungor A
  • Wang C
  • et al.
J Clin Anesth. 2024 Jun;94:111417 doi: 10.1016/j.jclinane.2024.111417.
POPULATION:

Patients undergoing non-obstetric surgery (300 trials, n= 53,085).

INTERVENTION:

Intravenous tranexamic acid.

COMPARISON:

Placebo or usual care without tranexamic acid.

OUTCOME:

From all the included studies, 45,958 participants (86.6%) were enrolled in 228 trials (76.0%) that explicitly excluded patients with kidney disease. Definitions of kidney diseased used for exclusion varied widely. Most were non-specific and some corresponded to mild disease. Only 5 trials adjusted dosing for kidney function. Meta-analysis of two large trials found tranexamic acid unlikely to substantially increase or decrease the occurrence of thrombotic events in patients with estimated glomerular filtration rate <60 mL/min/1.73m(2) (RR 0.95; 95% CI [0.83, 1.07]) or ≥ 60 mL/min/1.73m(2) (RR 1.00; 95% CI [0.91, 1.11], but both trials excluded patients with severe kidney disease. No analysis could be performed regarding seizure risk. One large trial in non-cardiac surgery reported similar reduction in bleeding across subgroups of kidney function but excluded patients with creatinine clearance <30 mL/min.

STUDY OBJECTIVE:

To assess how kidney disease is handled in randomized trials evaluating the safety and efficacy of perioperative tranexamic acid, and to evaluate its effects across levels of kidney function.

DESIGN:

Systematic review and meta-analysis of randomized controlled trials.

SETTING:

We screened studies from a previous comprehensive systematic review, and updated its search of PubMed, Embase, and Cochrane CENTRAL to July 31, 2023.

PATIENTS:

Patients undergoing non-obstetric surgery.

INTERVENTIONS:

Intravenous tranexamic acid compared to placebo or usual care without tranexamic acid.

MEASUREMENT:

We summarized the handling of kidney disease in eligibility criteria, dose adjustments for kidney function, and effects of tranexamic acid on thrombotic events, seizures, and bleeding by subgroups of kidney function.

MAIN RESULTS:

We evaluated 300 trials with 53,085 participants; 45,958 participants (86.6%) were enrolled in 228 trials (76.0%) that explicitly excluded patients with kidney disease. Definitions of kidney diseased used for exclusion varied widely. Most were non-specific and some corresponded to mild disease. Only 5 trials adjusted dosing for kidney function. Meta-analysis of two large trials found tranexamic acid unlikely to substantially increase or decrease the occurrence of thrombotic events in patients with eGFR <60 mL/min/1.73m2 (RR, 0.95; 95% CI: 0.83 to 1.07) or ≥ 60 mL/min/1.73m2 (RR, 1.00; 95% CI, 0.91 to 1.11; P for subgroup difference = 0.47), but both trials excluded patients with severe kidney disease. No analysis could be performed regarding seizure risk. One large trial in noncardiac surgery reported similar reduction in bleeding across subgroups of kidney function but excluded patients with creatinine clearance <30 mL/min.

CONCLUSIONS:

The large evidence base supporting perioperative tranexamic acid suffers from broad and unjustified exclusion of patients with kidney disease. Typical perioperative dosing of tranexamic acid is likely safe and effective in patients with creatinine clearance >30 mL/min, but effects in more severe kidney disease are unknown.

Editor's Choice
  • Goltstein LCMJ
  • Grooteman KV
  • Bernts LHP
  • Scheffer RCH
  • Laheij RJF
  • et al.
Gastroenterology. 2024 Apr;166(4):690-703 doi: 10.1053/j.gastro.2023.12.020.
POPULATION:

Patients with refractory anemia due to bleeding gastrointestinal angiodysplasias, enrolled in the OCEAN randomised controlled trial (n= 62).

INTERVENTION:

Octreotide (n= 31).

COMPARISON:

Standard of care (n= 31).

OUTCOME:

The treatment duration was one year. The primary outcome was the mean difference in the number of transfusion units (red blood cell + parental iron) between the octreotide and standard of care groups. The total number of transfusions was lower with octreotide (11.0; 95% CI [5.5, 16.5]) compared to standard of care (21.2; 95% CI [15.7, 26.7]). Octreotide reduced the mean number of transfusion units by 10.2; 95% CI [2.4, 18.1]. Octreotide reduced the annual volume of endoscopic procedures by 0.9; 95% CI [0.3, 1.5].

BACKGROUND & AIMS:

Gastrointestinal angiodysplasias are vascular anomalies that may result in transfusion-dependent anemia despite endoscopic therapy. An individual patient data meta-analysis of cohort studies suggests that octreotide decreases rebleeding rates, but component studies possessed a high risk of bias. We investigated the efficacy of octreotide in reducing the transfusion requirements of patients with angiodysplasia-related anemia in a clinical trial setting.

METHODS:

The study was designed as a multicenter, open-label, randomized controlled trial. Patients with angiodysplasia bleeding were required to have had at least 4 red blood cell (RBC) units or parental iron infusions, or both, in the year preceding randomization. Patients were allocated (1:1) to 40-mg octreotide long-acting release intramuscular every 28 days or standard of care, including endoscopic therapy. The treatment duration was 1 year. The primary outcome was the mean difference in the number of transfusion units (RBC + parental iron) between the octreotide and standard of care groups. Patients who received at least 1 octreotide injection or followed standard of care for at least 1 month were included in the intention-to-treat analyses. Analyses of covariance were used to adjust for baseline transfusion requirements and incomplete follow-up.

RESULTS:

We enrolled 62 patients (mean age, 72 years; 32 men) from 17 Dutch hospitals in the octreotide (n = 31) and standard of care (n = 31) groups. Patients required a mean number of 20.3 (standard deviation, 15.6) transfusion units and 2.4 (standard deviation, 2.0) endoscopic procedures in the year before enrollment. The total number of transfusions was lower with octreotide (11.0; 95% confidence interval [CI], 5.5-16.5) compared with standard of care (21.2; 95% CI, 15.7-26.7). Octreotide reduced the mean number of transfusion units by 10.2 (95% CI, 2.4-18.1; P = .012). Octreotide reduced the annual volume of endoscopic procedures by 0.9 (95% CI, 0.3-1.5).

CONCLUSIONS:

Octreotide effectively reduces transfusion requirements and the need for endoscopic therapy in patients with angiodysplasia-related anemia.

CLINICALTRIALS:

gov, NCT02384122.

Editor's Choice
  • Tabish M
  • Agarwal S
  • Gopi S
  • Rana R
  • Ahmed S
  • et al.
Am J Gastroenterol. 2024 Mar 22; doi: 10.14309/ajg.0000000000002775.
POPULATION:

Patients with cirrhosis and iron deficiency anaemia following variceal bleed (n= 92).

INTERVENTION:

Intravenous ferric-carboxymaltose (IV-FCM) (n= 48).

COMPARISON:

Oral carbonyl iron (n= 44).

OUTCOME:

The primary outcome was change in haemoglobin at 3 months. The median increase in haemoglobin at 3 months in the intravenous and oral arm were 3.65 gm/dl (IQR= 2.55, 5.25) and 1.10 gm/dl (IQR= 0.05, 2.90) respectively. Iron stores normalized in 84.6% and 21% of the intravenous and oral arms, respectively. Anaemia improved in 50% and 21.9% in the intravenous and oral arms, respectively. Patients in the intravenous arm showed a significant improvement in all domains of chronic liver disease quality of life. Liver related adverse events were comparable in both arms. Transient mild/moderate hypophosphataemia developed in 43% of patients receiving IV-FCM.

OBJECTIVE:

Limited evidence exists on the optimal strategy to correct iron deficiency anaemia(IDA) after variceal bleeding(VB) in cirrhosis. This trial compared the efficacy and safety of intravenous ferric-carboxymaltose (IV-FCM) with that of oral iron therapy in this cohort.

DESIGN:

In this open-label single center randomized controlled trial, eligible patients with hemoglobin <10 gm/dL and iron deficiency(Ferritin <100 ng/ml) after VB received either IV-FCM (1500-2000 mg) divided into two doses(n=48) or oral Carbonyl iron(100 mg elemental iron/day)(n=44) for 3 months. Primary outcome was change in hemoglobin at 3 months. Secondary outcomes included improvement in anemia(last hemoglobin>12gm/dL), normalization of iron stores(ferritin>100ng/ml), liver related adverse events, adverse drug reactions and changes in quality-of-life(CLDQOL questionnaire).

RESULTS:

Baseline characteristics, including median CTP score 7[IQR 6-9], MELD score 12[IQR 10-17], blood hemoglobin(8.25 ± 1.06 gm/dl) and ferritin[30.00 ng/ml (15.00, 66.50)] were comparable in both arms. The median increase in hemoglobin at 3 months in the IV and oral arm were 3.65 gm/dl(IQR2.55, 5.25) and 1.10 gm/dl[IQR 0.05, 2.90] gm/dl) (p<0.001) respectively. Iron stores normalized in 84.6% and 21% of the IV and oral arms, respectively(p<0.001). Anaemia improved in 50% and 21.9% in the IV and oral arms, respectively(p<0.009). Patients in IV arm showed a significant improvement in all domains of CLDQOL. Liver related adverse events were comparable in both arms. Transient mild/moderate hypophosphatemia developed in 43% of patients receiving IV-FCM.

CONCLUSION:

Intravenous iron replacement is efficacious and safe to treat IDA after VB in patients with cirrhosis.

Editor's Choice
  • Martens P
  • Augusto SN
  • Mullens W
  • Tang WHW
  • Martens, P.
  • et al.
JACC Heart Fail. 2024 Mar;12(3):525-536 doi: 10.1016/j.jchf.2023.11.006.
POPULATION:

Patients with iron deficiency and heart failure (HF), (14 randomised controlled trials, n= 6,624).

INTERVENTION:

Intravenous iron (n= 3,407).

COMPARISON:

Placebo (n= 3,217).

OUTCOME:

Treatment with intravenous iron resulted in a lower risk for cardiovascular (CV) death (OR: 0.867; 95% CI [0.755, 0.955]), combined CV death and HF admission (OR: 0.838; 95% CI [0.751, 0.936]), first HF admission (OR: 0.855; 95% CI [0.744, 0.983]), and total HF admissions (rate ratio: 0.739; 95% CI [0.661, 0.827]). Significant heterogeneity among trial results was observed for first and total HF admissions. Meta-regression suggested that some of the heterogeneity was related to the baseline transferrin saturation (TSAT) of the enrolled population, with trials enrolling patients with lower TSAT exhibiting a large effect size on HF-related events.

BACKGROUND:

Guidelines recommend that intravenous iron should be considered to improve symptoms of heart failure (HF) and reduce the risk for HF admissions in patients after acute HF.

OBJECTIVES:

This study sought to analyze the effect of intravenous iron on cardiovascular (CV) death and HF admissions in a broad population of HF patients with iron deficiency and the relation with baseline transferrin saturation (TSAT).

METHODS:

A systematic review of all published randomized controlled trials assessing the effect of intravenous iron in patients with iron deficiency and HF between January 1, 2000, and August 26, 2023, was performed. The overall treatment effect was estimated using a fixed effect model for: 1) CV death; 2) CV death and HF admission; 3) first HF admission; and 4) total HF admissions. Metaregression through a mixed effect model was used to explore the impact of baseline TSAT in case of heterogeneity among trial results.

RESULTS:

A total of 14 randomized controlled trials were identified in the systematic review and retained in the meta-analysis. Aggregate-level data were included on 6,624 HF patients, 3,407 of whom were randomized to intravenous iron and 3,217 to placebo. Treatment with intravenous iron resulted in a lower risk for CV death (OR: 0.867 [95% CI: 0.755-0.955]; P = 0.0427), combined CV death and HF admission (OR: 0.838 [95% CI: 0.751-0.936]; P = 0.0015), first HF admission (OR: 0.855 [95% CI: 0.744-0.983]; P = 0.0281), and total HF admissions (rate ratio: 0.739 [95% CI: 0.661-0.827]; P < 0.0001). Significant heterogeneity among trial results was observed for first and total HF admissions. Metaregression suggested that some of the heterogeneity was related to the baseline TSAT of the enrolled population, with trials enrolling patients with lower TSAT exhibiting a large effect size on HF-related events.

CONCLUSIONS:

The totality of data suggests that treatment with intravenous iron reduces both CV death and HF-related events in a broad population with HF. A lower baseline TSAT might be important for the effect on HF-related events.

Editor's Choice
  • Park GN
  • Lee KH
  • Moon JE
  • Choi SJ
  • Park MY
  • et al.
Kidney Res Clin Pract. 2024 Jan 23; doi: 10.23876/j.krcp.23.074.
POPULATION:

Patients with chronic kidney disease not on dialysis (n= 40).

INTERVENTION:

Darbepoetin alfa (DA), (n= 20).

COMPARISON:

Continuous erythropoietin receptor activator (CERA), (n= 20).

OUTCOME:

The patients received the study drug once in 4 weeks during 10- or 12-week correction period and 24-week efficacy evaluation period. The primary outcomes were the mean difference in the changes in haemoglobin levels between baseline and efficacy evaluation period and haemoglobin response rates during the correction period. DA was non-inferior to CERA for anaemia correction; the mean difference in the change in haemoglobin levels between the groups was -0.070 g/dL (95% confidence interval [-0.730, 0.590 g/dL]). Haemoglobin response rates were 100% with DA and 94.1% with CERA. Adverse events were comparable. The mean cost of DA was approximately one-third that of CERA (34,100 ± 7,600 Korean won/4 weeks vs. 115,500 ± 23,600 Korean won/4 weeks).

BACKGROUND:

For anemia management in patients with chronic kidney disease not on dialysis, darbepoetin alfa (DA), which has a shorter half-life but is more inexpensive than continuous erythropoietin receptor activator (CERA), is preferred in Korea. This study evaluated the efficacy, safety, and cost-effectiveness of once-in-4-weeks DA compared with once-in-4-weeks CERA in patients with chronic kidney disease not on dialysis.

METHODS:

In this randomized, prospective, non-inferiority study, 40 erythropoiesis-stimulating agent-naïve patients with chronic kidney disease not on dialysis were randomized 1:1 to the DA group and CERA group. They received the study drug once in 4 weeks during 10- or 12-week correction period and 24-week efficacy evaluation period. The primary outcomes were the mean difference in the changes in hemoglobin levels between baseline and efficacy evaluation period and hemoglobin response rates during the correction period. The secondary outcomes included differences in adverse events and costs.

RESULTS:

DA was non-inferior to CERA for anemia correction; the mean difference in the change in hemoglobin levels between the groups was -0.070 g/dL (95% confidence interval, -0.730 to 0.590 g/dL). Hemoglobin response rates were 100% with DA and 94.1% with CERA. Adverse events were comparable. The mean cost of DA was approximately one-third that of CERA (34,100 ± 7,600 Korean won/4 weeks vs. 115,500 ± 23,600 Korean won/4 weeks; p < 0.001).

CONCLUSION:

Once-in-4-weeks DA safely corrects anemia in erythropoiesis-stimulating agent-naïve patients with chronic kidney disease not on dialysis and is more cost-effective than once-in-4-weeks CERA.

Editor's Choice
  • Damarlapally N
  • Thimmappa V
  • Irfan H
  • Sikandari M
  • Madhu K
  • et al.
Cureus. 2023 Oct 21;15(10):e47430 doi: 10.7759/cureus.47430.
POPULATION:

Patients with chronic kidney disease regardless of their dialysis status, who also exhibited anaemia (19 randomised controlled trials, n= 22,151).

INTERVENTION:

Hypoxia-inducible factor-prolyl hydroxylase domain inhibitors (HIF-PHIs): roxadustat, daprodustat, and vadadustat (n= 11,234).

COMPARISON:

Erythropoiesis-stimulating agents (ESA) (n= 10,917).

OUTCOME:

HIF-PHI yielded a slight but significant increase in change in mean haemoglobin levels (MD 0.06; 95% CI [0.00, 0.11]), with the maximum significant increase shown in roxadustat followed by daprodustat as compared to ESA. There was a significant decrease in efficacy outcomes such as change in mean iron (MD -1.54; 95% CI [-3.01, -0.06]), change in mean hepcidin (MD -21.04; 95% CI [-28.92, -13.17]), change in mean ferritin (MD -16.45; 95% CI [-27.17, -5.73]) with roxadustat showing maximum efficacy followed by daprodustat.

Hypoxia-inducible factor-prolyl hydroxylase domain inhibitors (HIF-PHIs) are a novel group of drugs used to treat renal anemia, but their benefits vary among different trials. Our meta-analysis aims to assess the safety and efficacy of HIF-PHI versus erythropoiesis-stimulating agents (ESA) in managing anemia among patients with chronic kidney disease (CKD), regardless of their dialysis status. PubMed, Embase, and Google Scholar were queried to discover eligible randomized controlled trials (RCTs). To quantify the specific effects of HIF-PHI, we estimated pooled mean differences (MDs) and relative risks (RR) with 95% CIs. Our meta-analysis involved 22,151 CKD patients, with 11,234 receiving HIF-PHI and 10,917 receiving ESA from 19 different RCTs. The HIF-PHI used included roxadustat, daprodustat, and vadadustat. HIF-PHI yielded a slight but significant increase in change in mean hemoglobin (Hb) levels (MD: 0.06, 95% CI (0.00, 0.11); p = 0.03), with the maximum significant increase shown in roxadustat followed by daprodustat as compared to ESA. There was a significant decrease in efficacy outcomes such as change in mean iron (MD: -1.54, 95% CI (-3.01, -0.06); p = 0.04), change in mean hepcidin (MD: -21.04, 95% CI (-28.92, -13.17); p < 0.00001), change in mean ferritin (MD: -16.45, 95% CI (-27.17,-5.73); p = 0.03) with roxadustat showing maximum efficacy followed by daprodustat. As for safety, HIF-PHI showed significantly increased incidence in safety outcomes such as diarrhea (MD: 1.3, 95% CI (1.11, 1.51); p = 0.001), adverse events leading to withdrawal (MD: 2.03, 95% CI (1.5, 2.74), p = 0.00001) among 25 various analyzed outcomes. This meta-analysis indicates that HIF-PHIs present a potentially safer and more effective alternative to ESAs, with increased Hb levels and decreased iron usage in CKD patients without significantly increasing adverse events. Therefore, in these patients, we propose HIF-PHI alongside renal anemia treatment.

Editor's Choice
  • Li L
  • Zheng X
  • Deng J
  • Zhou J
  • Ou J
  • et al.
Ren Fail. 2022 Dec;44(1):1112-1122 doi: 10.1080/0886022X.2022.2094273.
POPULATION:

Chronic kidney disease (CKD) patients with hyperphosphataemia and anaemia (16 randomised controlled trials, n= 1,754).

INTERVENTION:

Ferric citrate treatment.

COMPARISON:

Control drugs, including placebo and positive drugs.

OUTCOME:

The meta-analysis showed that ferric citrate could significantly reduce the serum phosphorus in CKD patients compared to the placebo control groups (MD -1.76 mg/dL; 95% CI [-2.78, -0.75]). The difference between ferric citrate treatment and active controls, such as non-iron-based phosphate binders, sevelamer, calcium carbonate, lanthanum carbonate and sodium ferrous citrate, was not statistically significant (MD -0.09 mg/dL; 95% CI [-0.35, 0.17]). Ferric citrate could effectively improve haemoglobin levels when compared to the active drug (MD 0.43 g/dL; 95% CI [0.04, 0.82]) and placebo groups (MD 0.39 g/dL; 95% CI [0.04, 0.73]). According to eight studies, ferric citrate was found to be cost-effective treatment in comparison to control drugs. Most of the adverse events following ferric citrate treatment were mild at most.

BACKGROUND:

Hyperphosphatemia and anemia, which are common complications of chronic kidney disease (CKD), can independently contribute to cardiovascular events. Several previous studies have found that the iron-based phosphate binder, ferric citrate (FC), could be beneficial to both hyperphosphatemia and anemia.

METHODS:

Relevant literature from PUBMED, EMBASE, the Cochrane Central Register of Controlled Trials (CCRCT) and MEDLINE databases were searched up to 21 February 2022, in order to conduct a meta-analysis to investigate the efficacy, safety and economic benefits of ferric citrate treatment in CKD patients with hyperphosphatemia and anemia. The meta-analysis was conducted independently by two reviewers using the RevMan software (version 5.3).

RESULTS:

In total, this study included 16 randomized clinical trials (RCT) involving 1754 participants. The meta-analysis showed that ferric citrate could significantly reduce the serum phosphorus in CKD patients compared to the placebo control groups (MD -1.76 mg/dL, 95% CI (-2.78, -0.75); p = 0.0007). In contrast, the difference between ferric citrate treatment and active controls, such as non-iron-based phosphate binders, sevelamer, calcium carbonate, lanthanum carbonate and sodium ferrous citrate, was not statistically significant (MD - 0.09 mg/dL, 95% CI (-0.35, 0.17); p = 0.51). However, ferric citrate could effectively improve hemoglobin levels when compared to the active drug (MD 0.43 g/dL, 95% CI (0.04, 0.82); p = 0.03) and placebo groups (MD 0.39 g/dL, 95% CI (0.04, 0.73); p = 0.03). According to eight studies, ferric citrate was found to be cost-effective treatment in comparison to control drugs. Most of the adverse events (AE) following ferric citrate treatment were mild at most.

CONCLUSION:

Collectively, our review suggests that iron-based phosphate binder, ferric citrate is an effective and safe treatment option for CKD patients with hyperphosphatemia and anemia. More importantly, this alternative treatment may also less expensive. Nevertheless, more scientific studies are warranted to validate our findings.

Editor's Choice
  • Sepah YJ
  • Nguyen QD
  • Yamaguchi Y
  • Otsuka T
  • Majikawa Y
  • et al.
Kidney Int Rep. 2022 Jan 19;7(4):763-775 doi: 10.1016/j.ekir.2022.01.1045.
POPULATION:

Patients with anaemia of chronic kidney disease (CKD), (2 randomised controlled trials: CL-0307 (n= 302 dialysis-dependent (DD) patients) and CL-310 (n= 262 non-DD patients)).

INTERVENTION:

Roxadustat (CL-0307, n= 150); (CL-310, n= 131).

COMPARISON:

Darbepoetin alfa (DA) (CL-0307, n= 152); (CL-310, n= 131).

OUTCOME:

Ophthalmic imaging and assessments of visual acuity were performed up to week 24 or at study discontinuation. Proportions of DD patients with new or worsening retinal hemorrhages (RHs) in the roxadustat group and DA group were 32.4% (46 of 142) and 36.6% (53 of 145), respectively. Proportions of non-DD patients with CKD with new or worsening RH in the roxadustat and DA groups were 31.4% (38 of 121) and 39.8% (51 of 128), respectively. Similar trends were apparent in subgroup analyses: patients with/without RH at baseline and with/without diabetes mellitus at baseline. In both studies, there were no differences in retinal thickness, visual acuity, presence of hard exudates or cotton wool spots, or presence of intra- and subretinal fluid between groups, at any given time point.

INTRODUCTION:

Roxadustat is an orally administered hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor that represents a novel therapeutic option for patients with anemia of chronic kidney disease (CKD).

METHODS:

Conducted in Japan, CL-0307 (NCT02952092) and CL-310 (NCT02988973) were phase 3, darbepoetin alfa (DA)-controlled studies conducted in dialysis-dependent (DD) and non-DD (NDD) patients with CKD, respectively, where patients were randomized to receive roxadustat or DA. Ophthalmic imaging and assessments of visual acuity were performed up to week 24 or at study discontinuation. Ophthalmic imaging was centrally evaluated by independent readers masked to the study treatment.

RESULTS:

In CL-0307, 302 patients (roxadustat, n = 150; DA, n = 152) received ≥1 dose of the study drug and were included in this analysis. In CL-0310, 262 patients (roxadustat, n = 131; DA, n = 131) received ≥1 dose of the study drug and were included in this analysis. Proportions of DD patients with new or worsening retinal hemorrhages (RHs) in the roxadustat group and DA group were 32.4% (46 of 142) and 36.6% (53 of 145), respectively. Proportions of NDD patients with CKD with new or worsening RH in the roxadustat and DA groups were 31.4% (38 of 121) and 39.8% (51 of 128), respectively. Similar trends were apparent in subgroup analyses: patients with/without RH at baseline and with/without diabetes mellitus at baseline. In both studies, there were no differences in retinal thickness, visual acuity, presence of hard exudates or cotton wool spots, or presence of intra- and subretinal fluid between groups, at any given time point.

CONCLUSION:

In these studies, roxadustat, compared with DA, was not associated with an increased risk of adverse ophthalmologic events in these cohorts.