On the relative safety of parenteral iron formulations.

BACKGROUND: Intravenous iron is usually required to optimize the correction of anaemia in persons with advanced chronic kidney disease and end-stage renal disease. Randomized clinical trials may have insufficient power to detect differences in the safety profiles of specific formulations. METHODS: We obtained data from the US Food and Drug Administration on reported adverse drug events (ADEs) related to the provision of three formulations of intravenous iron during 1998-2000. We estimated the relative risks [odds ratios (OR)] of ADEs associated with the use of higher molecular weight iron dextran and sodium ferric gluconate complex compared with lower molecular weight iron dextran using 2 x 2 tables. RESULTS: The total number of reported parenteral iron-related ADEs was 1981 among approximately 21,060,000 doses administered, yielding a rate of 9.4 x 10(-5), or approximately 94 per million. Total major ADEs were significantly increased among recipients of higher molecular weight iron dextran (OR 5.5, 95% CI 4.9-6.0) and sodium ferric gluconate complex (OR 6.2, 95% CI 5.4-7.2) compared with recipients of lower molecular weight iron dextran. We observed significantly higher rates of life-threatening ADEs, including death, anaphylactoid reaction, cardiac arrest and respiratory depression among users of higher molecular weight compared with lower molecular weight iron dextran. There was insufficient power to detect differences in life-threatening ADEs when comparing lower molecular weight iron dextran with sodium ferric gluconate complex. CONCLUSIONS: Parenteral iron-related ADEs are rare. Using observational data, overall and most specific ADE rates were significantly higher among recipients of higher molecular weight iron dextran and sodium ferric gluconate complex than among recipients of lower molecular weight iron dextran. These data may help to guide clinical practice, as head-to-head clinical trials comparing different formulations of intravenous iron have not been conducted.     

Hypersensitivity reactions and deaths associated with intravenous iron preparations.

BACKGROUND: Parenteral iron therapy is an accepted adjunctive management of anaemia in kidney disease. Newer agents may have fewer severe hypersensitivity adverse events (AE) compared with iron dextrans (ID). The rate of type 1 AE to iron sucrose (IS) and sodium ferric gluconate (SFG) relative to ID is unclear. We used the US Food and Drug Administration's Freedom of Information (FOI) surveillance database to compare the type 1 AE profiles for the three intravenous iron preparations available in the United States. METHODS: We tabulated reports received by the FOI database between January 1997 and September 2002, and calculated 100 mg dose equivalents for the treated population for each agent. We developed four clinical categories describing hypersensitivity AE (anaphylaxis, anaphylactoid reaction, urticaria and angioedema) and an algorithm describing anaphylaxis, for specific analyses. RESULTS: All-event reporting rates were 29.2, 10.5 and 4.2 reports/million 100 mg dose equivalents, while all-fatal-event reporting rates were 1.4, 0.6 and 0.0 reports/million 100 mg dose equivalents for ID, SFG and IS, respectively. ID had the highest reporting rates in all four clinical categories and the anaphylaxis algorithm. SFG had intermediate reporting rates for urticaria, anaphylactoid reaction and the anaphylaxis algorithm, and a zero reporting rate for the anaphylaxis clinical category. IS had either the lowest or a zero reporting rate in all clinical categories/algorithm. CONCLUSIONS: These findings confirm a higher risk for AE, especially serious type 1 reactions, with ID therapy than with newer intravenous iron products and also suggest that IS carries the lowest risk for hypersensitivity reactions.     

Sodium ferric gluconate complex in haemodialysis patients: a prospective evaluation of long-term safety.

BACKGROUND: A previous single dose placebo-controlled double-blinded trial showed an extremely low (0.4%) intolerance rate of sodium ferric gluconate complex (SFGC) in SFGC-naive haemodialysis patients. No large prospective trials have assessed the safety of SFGC during repeated exposure in the outpatient haemodialysis setting. METHODS: Chronic haemodialysis patients completing the single-dose trial of SFGC were eligible to participate in this prospective, multicentre, open-label, long-term evaluation of SFGC, designed to record adverse events occurring up to 72 h post-dose. Patients received as many as 20 ampules (1250 mg total) of SFGC at an investigator-determined dose and rate over a 9 month evaluation period. RESULTS: Among 1412 enrolled patients at 54 centres, 1321 received 13,151 infusions of SFGC. Most doses (94.8%) were < or =125 mg and the majority were given over 10 min. Infusion rates ranged from <5 to 125 mg/min. There were no life-threatening events. Fifty-one patients (3.9%) experienced an adverse event, possibly related to SFGC. Of these, one experienced a serious event (hypotension). Five patients (0.4%) experienced an event that precluded SFGC readministration: pruritus (three), vasodilatation (one) and loss of taste (one). Among 372 patients (28.2%) receiving angiotensin-converting enzyme inhibitor (ACEI) therapy, adverse events were neither more common nor more severe than in the other patients. CONCLUSIONS: Repeated doses of SFGC are very well tolerated in haemodialysis patients. No life-threatening events were observed in over 13,000 doses administered. Administration of SFGC to patients using ACEI is safe and does not increase the incidence or severity of adverse events to SFGC.     

Chemical reactions of vitamin C with intravenous-iron formulations.

BACKGROUND: Intravenous (IV) iron is widely prescribed for patients on haemodialysis, to replace iron losses during treatment. It releases labile iron, which can induce oxidation of vitamin C and trigger oxidant damage. We examined the stability of vitamin C in the presence of IV iron compounds. We further examined in the ability of vitamin C to release iron from these compounds. METHODS: Vitamin C was measured by high-performance liquid chromatography with electrochemical detection. Iron release from iron sucrose (FeSuc) and ferric gluconate (FeGlu) was determined with the ferrozine method. RESULTS: Vitamin C, in human plasma or fetal calf serum, was oxidized in this order of reactivity: FeSuc > FeGlu > blank reaction. FeSuc and FeGlu also oxidized vitamin C when added to freshly obtained whole human blood. During a 4 h incubation in buffer, vitamin C stimulated the release of 60% of the iron content of FeSuc at p 4, with lesser amounts at pH 3, 5 and 6, and 5% release at pH 7.Vitamin C also triggered the release of iron from FeGlu, but less release was observed than with FeSuc. Using ferrozine reagent, no iron release was detected to heparinized human plasma, following addition of 500 microM concentrations of iron compounds. CONCLUSION: Each IV-iron compound can oxidize substantial amounts of vitamin C when added to plasma or whole blood. The interaction of vitamin C is accompanied by release of iron from the particle at mildly acidic pH, which may explain the ability of high-dose vitamin C to mobilize iron from storage sites for erythropoiesis.     

A randomized, controlled parallel-group trial on efficacy and safety of iron sucrose (Venofer) vs iron gluconate (Ferrlecit) in haemodialysis patients treated with rHuEpo.

BACKGROUND: The objectives of the present trial were to compare the efficacy and safety of two i.v. iron preparations with respect to haemoglobin levels, iron status and recombinant human erythropoetin (rHuEpo) dosage requirements in stable, rHuEpo-treated haemodialysis patients (maintenance phase of iron treatment) over 6 months. METHODS: A total of 59 patients were randomized and assigned to one of two treatment groups and 55 patients were analysed (iron sucrose n=27; iron gluconate n=28). Iron sucrose was administered in a dose of 250 mg iron diluted in 100 ml normal saline given over 60 min once per month, while 62.5 mg iron as iron gluconate was given once per week in a slow push injection (5 min). RESULTS: --Efficacy parameters: Haemoglobin levels could be maintained from baseline to endpoint in both groups. There were, however, more patients in the iron sucrose group than in the iron gluconate group for whom treatment was discontinued because their haemoglobin values exceeded 12.5 g/dl or ferritin values exceeded 1000 ng/ml (five vs two and three vs one patient, respectively). Transferrin saturation and serum ferritin increased significantly in both groups (+255.7 ng/ml with iron sucrose and +278.5 ng/ml with iron gluconate), while rHuEpo dosage did not change significantly throughout the study. --Safety parameters: There were a total of 174 infusions of iron sucrose and 720 injections of iron gluconate during the trial; all of them were well tolerated. In particular, we did not observe anaphylactoid reactions or any events suggestive of iron toxicity such as hypotension, dizziness, or nausea. CONCLUSIONS: High doses of iron sucrose (Venofer((R)) at a dose of 250 mg/month) was equally effective in maintaining haemoglobin and equally well tolerated as low doses of iron gluconate (Ferrlecit((R)) at a dose of 62.5 mg once per week) in stable, rHuEpo treated haemodialysis patients.     

One-year sac regression is associated with freedom from fatal adverse events after endovascular aneurysm repair

ObjectiveAlthough the predictors of long-term prognosis after endovascular aneurysm repair (EVAR) have been investigated, several reports have suggested that early sac shrinkage (ESS) is associated with superior long-term prognosis. However, it was not clear whether ESS was associated with aneurysm-related mortality. The aim of this study was to define fatal adverse events and to examine their association with ESS.MethodsAll consecutive patients who underwent EVAR for an abdominal aortic aneurysm at Nagoya University Hospital between June 2007 and August 2018 were identified. We defined ESS as an aneurysm diameter decrease of 10 mm or more at 1 year after EVAR, and we defined fatal adverse events as aneurysm-related death, aneurysm sac rupture, open conversion, secondary type Ia endoleak, or secondary type IIIa/b endoleak. Then, we evaluated the association between ESS and fatal adverse events and identified predictors of ESS.ResultsDuring the study period, 553 patients were identified and included. Fatal adverse events occurred in 42 patients (7.6%), and the details of the fatal adverse events were as follows: 13 aneurysm-related deaths, 17 aneurysm sac ruptures, 14 open conversions, 13 type Ia endoleaks, and 6 type III endoleaks. ESS occurred in 146 patients (26.4%). Kaplan-Meier curves showed that the ESS group had a significantly lower incidence of fatal adverse events (P < .001). Multivariate analysis showed that there were significant differences in terms of 5 or more preoperatively patent lumbar arteries (odds ratio [OR], 0.67; P = .049; 95% confidence interval [CI], 0.45-1.00), chronic kidney disease (OR, 0.49; P < .01; 95% CI, 0.29-0.84), and Zenith endograft use (OR, 1.76; P < .01; 95% CI, 1.16-2.67). Furthermore, the percentage of cases that achieved an aneurysm diameter of less than 40 mm was significantly higher in the ESS group (76.0% vs 15.5%; P < .01). The use of Zenith endografts showed a significantly higher rate of aneurysm disappearance than the use of Endurant endografts (P < .01) and Excluder endografts (P < .01). In addition, it was found that ESS was more likely to occur with the use of Zenith endografts, even when propensity score matching was performed for the neck morphology.ConclusionsESS was associated with a lower rate of life-threatening adverse events after EVAR. The use of Zenith endografts was a predictor of ESS and was associated with increased rates of long-term sac shrinkage and aneurysm disappearance compared with the Endurant and Excluder endografts. Using the predictors of ESS identified in this study, we may be able to expand the indications for EVAR to patients with a longer life expectancy.     

Gallstones were associated with the gastrointestinal adverse events of cinacalcet in hemodialysis patients with secondary hyperparathyroidism

This study aimed to investigate the association of gastrointestinal (GI) adverse events of cinacalcet with gallstones in the hemodialysis (HD) patients with secondary hyperparathyroidism (SHPT). A total of 23?HD patients under the treatment with cinacalcet and 101 control patients were enrolled in this cross-sectional study. We investigated the prevalence of gallstones and the association of GI adverse events of cinacalcet with gallstones. The prevalence of gallstones was significantly higher in the HD patients with cinacalcet compared with the controls (47.8% vs. 15.8%). The longer time on HD, hypercalcemia, hyperphosphatemia and elevated parathyroid hormone level were observed in the HD patients with cinacalcet. Besides, GI adverse events of cinacalcet were observed more frequently in the HD patients with gallstones compared with those without gallstones (odds ratio 13.5, 95% CI: 1.80–101). Therefore, screening for gallstones before dosing cinacalcet may reduce the risk of GI adverse events in SHPT patients.     

The effect of humidification and smoking habit on the incidence of adverse airway events during deepening of anaesthesia with desflurane

The effect of two levels of humidification on the incidence of adverse airway events was studied in 58 adult female patients during deepening of anaesthesia using up to 12% desflurane. Humidification was provided by a breathing system filter with either low moisture-conserving performance (17.2 mg x l(-1) at 0.5 1 tidal volume, Group L) or high moisture-conserving performance (33.5 mg x l(-1) at 0.5 1 tidal volume, Group H). Forty-eight per cent of patients smoked and there were more smokers in Group L than in Group H. Adverse airway events consisted of coughing and laryngospasm. For coughing, the dominant explanator was smoking. When both humidity and age were included in the analysis, there was a significant smoking-humidity interaction (p < 0.05), such that high humidity decreased the incidence of coughing in nonsmokers but not in smokers. The incidence of laryngospasm was significantly lower in Group H than in Group L (p < 0.05). We conclude that when patients inspire high concentrations of desflurane during induction of anaesthesia, increasing humidification to the levels achieved in this study decreases the incidence of coughing among nonsmokers and of laryngospasm in both smokers and nonsmokers.     

Musculoskeletal immune-related adverse events in 927 patients treated with immune checkpoint inhibitors for solid cancer

ObjectiveThe prevalence of the musculoskeletal immune-related adverse events (irAEs) is probably underestimated, as most studies report only severe side effects. Our aim was to describe and characterize all musculoskeletal irAEs in a large cohort of patients treated with immune checkpoint inhibitors (ICI).MethodsWe conducted a retrospective study among patients who received ICI from 07/27/2014 to 05/08/2020 at the medical oncology department of the Institut Paoli-Calmettes, Marseille, France. All medical files were systemically reviewed by a rheumatologist who collected clinical features, time of occurrence, treatment regimen, irAEs management, course and outcomes. We also assessed tumor response 3 months after introduction of ICI, according to severity and treatments used to manage musculoskeletal irAEs.ResultsAmong 927 patients treated with ICI for a solid tumor, 118 patients (12.7%) presented a musculoskeletal irAE. Their median age was 66.5, 61% were male, and they mainly had a lung (57.6%) or urological cancer (27.1%). The most frequently involved ICI was an anti PD-1. Arthralgias and myalgias were the most frequent musculoskeletal irAEs (9.8%) and inflammatory rheumatic features were reported in 36 patients (3.9%) with elevated acute phase reactants and negative immunological markers. The median time of onset was 2 months (IC 95% 1.8; 2.7). Tumor response at 3 months did not differ according to musculoskeletal irAE severity, type of manifestation (arthralgias/myalgias versus inflammatory rheumatic features), pain patterns (mechanical versus inflammatory) or irAE treatments.ConclusionMusculoskeletal irAEs in this large cohort of patients treated with ICI were frequent (12.7%), mostly mild and well tolerated.