Drug-induced immune hemolytic anemia: detection of new signals and risk assessment in a nationwide cohort study.

ABSTRACT: More than 130 drugs have been suspected to induce immune hemolytic anemia. Comparative studies measuring the risk of drug-induced immune hemolytic anemia (DIIHA) are lacking. We aimed (1) to detect new signals of DIIHA, excluding vaccines, and (2) to assess the association between all suspected drugs and the occurrence of immune hemolytic anemia in a nationwide comparative study. The new signals were identified using a disproportionality study (case/noncase design) in the World Pharmacovigilance Database, Vigibase, among the cases of adverse drug reactions reported up to February 2020 (>20 million). We then conducted a comparative study in the French National health database that links sociodemographic, out-of-hospital, and hospital data for the entire population (67 million individuals). Associations between exposure to drugs (those already reported as DIIHA, plus new signals identified in Vigibase) and incident cases of immune hemolytic anemia (D59.0 and D59.1 diagnosis codes of the International Classification of Diseases, version 10) from 2012 to 2018 were assessed with case-control and case-crossover designs. In Vigibase, 3371 cases of DIIHA were recorded. Fifty-nine new signals were identified resulting in a final list of 112 drugs marketed in France and measurable in the nationwide cohort (n = 4746 patients with incident immune hemolytic anemia included in the case-control analysis matched with 22 447 controls from the general population). We identified an association between immune hemolytic anemia occurrence and some antibiotics, antifungal drugs, ibuprofen, acetaminophen, furosemide, azathioprine, and iomeprol.

Standardization of bleeding assessment in immune thrombocytopenia: report from the International Working Group.

In a previous publication on new terminology, definitions, and outcome criteria for immune thrombocytopenia (ITP), the International Working Group (IWG) on ITP acknowledged that response to treatment should consist of clinically meaningful end points such as bleeding manifestations and that platelet count may not be the ideal parameter for capturing the benefits of therapy. The IWG now proposes a consensus-based ITP-specific bleeding assessment tool (ITP-BAT) with definitions and terminology consistent with those adopted for other bleeding disorders. Bleeding manifestations were grouped into three major domains: skin (S), visible mucosae (M), and organs (O), with gradation of severity (SMOG). Each bleeding manifestation is assessed at the time of examination. Severity is graded from 0 to 3 or 4, with grade 5 for any fatal bleeding. Bleeding reported by the patient without medical documentation is graded 1. Within each domain, the same grade is assigned to bleeding manifestations of similar clinical impact. The "worst bleeding manifestation since the last visit" (observation period) is graded (a suitable database collection form is provided), and the highest grade within each domain is recorded. The SMOG system provides a consistent description of the bleeding phenotype in ITP, and the IWG unanimously supports its adoption and validation in future clinical studies.

Costs of managing severe immune thrombocytopenia in adults: a retrospective analysis.

This study aims to report resource utilisation and annual cost for chronic immune thrombocytopenia (ITP) patients enrolled consecutively and followed for 1 year. A single-centre, single-arm, retrospective 1-year observational cohort study of adult patients with chronic ITP from a French hospital was conducted. Healthcare resource utilisation and mean cost per patient (with 95% confidence intervals) were estimated for the whole group. Patients requiring at least one hospitalisation formed subgroup 1. Patients with the most severe category of disease formed subgroup 2 [defined as hospitalised patients with ≥1 immunoglobulin (IVIg) infusion (usually reserved for those with bleeding score>8)]. Fifty-seven patients (42F/15M) with a mean age of 48 years (SD=19) at ITP diagnosis were studied. Mean platelet count at diagnosis was 28±26×109/L. Mean duration of ITP was 3.1 years (SD=2); eight patients had undergone splenectomy at baseline. Subgroup 1 included 27 patients who were hospitalised (full hospitalisation, n=23; and/or day hospitalisation, n=8). Of those, 12 patients received at least one IVIg infusion during hospitalisation (subgroup 2). Total mean cost per patient for the 1-year study period was €7,293 (95% CI=3,369-13,584) for the whole group, €15,334 (95% CI=7,876-27,459) for subgroup 1 and €26,581 (95% CI=12,241-50,578) for subgroup 2. IVIg accounted for 33% of costs for subgroup 1 and up to 43% of costs for patients with more severe disease (subgroup 2). Management of adults with chronic ITP is costly in France, especially for patients with severe disease. IVIg use was a major cost driver.

A randomized, controlled clinical trial of ketoprofen for sickle-cell disease vaso-occlusive crises in adults.

Vaso-occlusive crisis (VOC) is the primary cause of hospitalization of patients with sickle-cell disease. Treatment mainly consists of intravenous morphine, which has many dose-related side effects. Nonsteroidal antiinflammatory drugs have been proposed to provide pain relief and decrease the need for opioids. Nevertheless, only a few underpowered trials of nonsteroidal antiinflammatory drugs for sickle-cell VOC have been conducted, and conflicting results were reported. We conducted a phase 3, double-blind, randomized, placebo-controlled trial with ketoprofen (300 mg/day for 5 days), a nonselective cyclooxygenase inhibitor, for severe VOC in adults. A total of 66 VOC episodes were included. The primary efficacy outcome was VOC duration. The secondary end points were morphine consumption, pain relief, and treatment failure. Seven VOC episodes in each group were excluded from the analysis because of treatment failures. No significant between-group differences were observed for the primary outcome or the secondary end points. Thus, although ketoprofen was well-tolerated, it had no significant efficacy as treatment of VOC requiring hospitalization. These findings argue against its systematic use in this setting.

Assessment of a therapeutic strategy for adults with severe autoimmune thrombocytopenic purpura based on a bleeding score rather than platelet count.

BACKGROUND AND OBJECTIVES: The optimal treatment for patients with autoimmune thrombocytopenic purpura (AITP) and a platelet count < or =20x10(9)/L is intravenous immunoglobulin (IVIg) but this treatment is expensive and steroids are a good alternative in less severe cases. Since the occurrence of life-threatening hemorrhage in adult AITP is a rare event, the aim of our study was to validate a therapeutic strategy based on a bleeding score for the short-term management of adults with AITP and a platelet count < or =20x10(9)/L. DESIGN AND METHODS: We developed a method to quantify hemorrhage in adults with AITP. Bleeding severity was graded on a numerical scale based on physical examination. When the bleeding score was < or =8, the patients were treated with steroids alone. For scores >8, patients received IVIg (1 to 2 g/kg) in combination with oral steroids. A good response was defined as the lowering of the initial bleeding score within 2 days after treatment initiation regardless of the platelet count. RESULTS: We applied this strategy for the management of 60 consecutive adults (mean age 48+/-23 years) with AITP and a platelet count < or =20x10(9)/L/L (mean platelet count 6+/-5x10(9)/L/L). Based on this strategy, IVIg was required in only 50% of the patients and no life-threatening bleeding occurred in patients treated with steroids alone. INTERPRETATION AND CONCLUSIONS: A therapeutic strategy based on a bleeding score rather than the platelet count appears to be relevant and safe and is a good IVIg-sparing strategy.