A methodological review of population-adjusted indirect comparisons reveals inconsistent reporting and suggests publication bias.

OBJECTIVES: Population-adjusted indirect comparisons (PAICs) were developed in the 2010s to allow for comparisons between two treatments evaluated in different trials while accounting for differences in patient characteristics if individual patient data (IPD) are available for only one trial. Such comparisons are increasingly used in market access applications when a pharmaceutical company compares its new treatment (with IPD available) to another treatment developed by a competitor (with only aggregated data available). This study aimed to describe the characteristics of these PAICs, assess their methodology, and describe the reported results. STUDY DESIGN AND SETTING: Original articles reporting the use of at least one PAIC were searched on PubMed between January 1, 2010 and April 2, 2022. Two reviewers independently selected articles and extracted data. RESULTS: We included 133 publications reporting the results of 288 PAICs. Half of the articles were published on or after May 7, 2020, and 71 (53%) pertained to onco-hematology. The pharmaceutical industry was involved in 130 (98%) articles. Key methodological aspects were reported inconsistently, with only three articles adequately reporting all aspects. A total of 161 (56%) articles reported a statistically significant benefit for the treatment evaluated on IPD. Conversely, only one PAIC significantly favored the treatment evaluated on aggregated data. CONCLUSION: Although the number of published PAICs is increasing, the methodology and transparency need to be improved. Moreover, our study strongly suggests a reporting bias. This situation calls for strengthening guidelines to improve trust in PAIC results and thus their reliability in market access applications.

Empirical Antibiotic Therapy for Gram-Negative Bacilli Ventilator-Associated Pneumonia: Observational Study and Pharmacodynamic Assessment.

Background: Strong evidence suggests a correlation between pharmacodynamics (PD) index and antibiotic efficacy while dose adjustment should be considered in critically ill patients due to modified pharmacokinetic (PK) parameters and/or higher minimum inhibitory concentrations (MICs). This study aimed to assess pharmacodynamic (PD) target attainment considering both antibiotics serum concentrations and measured MICs in these patients. Method: A multicentric prospective open-label trial conducted in 11 French ICUs involved patients with Gram-negative bacilli (GNB) ventilator-associated pneumonia (VAP) confirmed by quantitative cultures. Results: We included 117 patients. Causative GNBs were P. aeruginosa (40%), Enterobacter spp. (23%), E. coli (20%), and Klebsiella spp. (16%). Hence, 117 (100%) patients received ß-lactams, 65 (58%) aminoglycosides, and two (1.5%) fluoroquinolones. For ß-lactams, 83% of the patients achieved a Cmin/MIC > 1 and 70% had a Cmin/MIC > 4. In the case of high creatinine clearance (CrCL > 100 mL/min/1.73 m2), 70.4% of the patients achieved a Cmin/MIC ratio > 1 versus 91% otherwise (p = 0.041), and 52% achieved a Cmin/MIC ratio > 4 versus 81% (p = 0.018). For aminoglycosides, 94% of the patients had a Cmax/MIC ratio > 8. Neither ß-lactams nor aminoglycosides PK/PD parameters were associated clinical outcomes, but our data suggest a correlation between ß-lactams Cmin/MIC and microbiological success. Conclusion: In our ICU patients treated for GNB VAP, using recommended antibiotic dosage led in most cases to PK/PD targets attainment for aminoglycosides and ß-lactams. High creatinine clearance should encourage clinicians to focus on PK/PD issues.

Assessment of global longitudinal strain at low-dose anthracycline-based chemotherapy, for the prediction of subsequent cardiotoxicity.

AIMS: We sought to assess whether global longitudinal strain (GLS) measured early during treatment with anthracyclines (at a cumulative dose of 150 mg/m2) can predict subsequent alterations in left ventricular ejection fraction. METHODS AND RESULTS: Eighty-six patients with Hodgkin's disease, non-Hodgkin's lymphoma, or acute leukaemia and receiving anthracyclines were prospectively included. Patients underwent complete echocardiography on four occasions: baseline (V1); after reaching a cumulative dose of 150 mg/m2 (V2); end of treatment (V3); and 1 year follow-up (V4). Six patients developed cardiotoxicity, defined as a decrease in left ventricular ejection fraction of >10 percentage points, to a value <53%, at V4. GLS measured at V1 and V2 was significantly lower in the cardiotoxicity group vs. the controls (P = 0.042 and P = 0.01, respectively). Compared with GLS at V1, GLS obtained at V2 provided incremental predictive information and appeared to be the strongest predictor of cardiotoxicity (area under the receiver-operating-characteristic curve, 0.82). At a threshold of -17.45% for GLS measured at V2, the sensitivity and specificity of detecting cardiotoxicity were 67% (95% confidence interval 33-100) and 97% (95% confidence interval 94-100), respectively. CONCLUSION: GLS greater than -17.45%, obtained after 150 mg/m2 of anthracycline therapy, is an independent predictor of future anthracycline-induced cardiotoxicity. These findings should encourage physicians to perform echocardiography earlier during treatment with anthracyclines.

Clinical assessment for identifying causes of acute respiratory failure in cancer patients.

In cancer patients with acute respiratory failure (ARF), early adequate therapy is associated with better outcomes. We investigated the performance of the DIRECT approach, which uses criteria available at the bedside at admission to the intensive care unit (ICU), to identify causes of ARF in cancer patients. This cohort study included cancer patients with ARF of determined aetiology. Associations of aetiological groups with the selected criteria were evaluated using correspondence analysis. 424 cancer patients were included: 201 (47%) with bacterial pneumonia, 131 (31%) with opportunistic infections and 92 (22%) with noninfectious disorders. Mechanical ventilation (both invasive and noninvasive) was needed in 328 (77%) patients, treatment for shock in 217 (51%) patients and dialysis in 82 (19%) patients. 142 (34%) patients died in the ICU. Correspondence plots showed that bacterial pneumonia was associated with neutropenia, solid tumour, multiple myeloma, <3 days since symptom onset, shock, unilateral crackles and unilateral radiographic pattern. Opportunistic infections were associated with steroids, lymphoproliferative disorders and haematopoietic stem-cell transplantation, whereas noninfectious disorders were associated with acute leukaemia The selected criteria are strongly associated with causes of ARF in cancer patients and could be used to develop an algorithm for selecting first-line diagnostic investigations and empirical treatments.