Research from JAMA Internal Medicine — Unintended Medication Discrepancies at the Time of Hospital Admission

Background: Over a quarter of hospital prescribing errors are attributable to incomplete medication histories being obtained at the time of admission. We undertook a systematic review of studies describing the frequency, type and clinical importance of medication history errors at hospital admission. Methods: We searched MEDLINE, EMBASE and CINAHL for articles published from 1966 through April 2005 and bibliographies of papers subsequently retrieved from the search. We reviewed all published studies with quantitative results that compared prescription medication histories obtained by physicians at the time of hospital admission with comprehensive medication histories. Three reviewers independently abstracted data on methodologic features and results. Results: We identified 22 studies involving a total of 3755 patients (range 33–1053, median 104). Errors in prescription medication histories occurred in up to 67% of cases: 10%– 61% had at least 1 omission error (deletion of a drug used before admission), and 13%– 22% had at least 1 commission error (addition of a drug not used before admission); 60%– 67% had at least 1 omission or commission error. Only 5 studies (n = 545 patients) explicitly distinguished between unintentional discrepancies and intentional therapeutic changes through discussions with ordering physicians. These studies found that 27%– 54% of patients had at least 1 medication history error and that 19%– 75% of the discrepancies were unintentional. In 6 of the studies (n = 588 patients), the investigators estimated that 11%–59% of the medication history errors were clinically important. Interpretation: Medication history errors at the time of hospital admission are common and potentially clinically important. Improved physician training, accessible community pharmacy databases and closer teamwork between patients, physicians and pharmacists could reduce the frequency of these errors.

The existence of dimers and oligomers for many G protein-coupled receptors has been described by us and others. Since many G protein-coupled receptor subtypes are highly homologous to each other, we examined whether closely related receptors may interact with each other directly and thus have the potential to create novel signaling units. Using mu- and delta-opioid receptors, we show that each receptor expressed individually was pharmacologically distinct and could be visualized following electrophoresis as monomers, homodimers, homotetramers, and higher molecular mass oligomers. When mu- and delta-opioid receptors were coexpressed, the highly selective synthetic agonists for each had reduced potency and altered rank order, whereas endomorphin-1 and Leu-enkephalin had enhanced affinity, suggesting the formation of a novel binding pocket. No heterodimers were visualized in the membranes coexpressing mu- and delta-receptors by the methods available. However, hetero-oligomers were identified by the ability to co-immunoprecipitate mu-receptors with delta-receptors and vice versa using differentially epitope-tagged receptors. In contrast to the individually expressed mu- and delta-receptors, the coexpressed receptors showed insensitivity to pertussis toxin and continued signal transduction, likely due to interaction with a different subtype of G protein. In this study, we provide, for the first time, evidence for the direct interaction of mu- and delta-opioid receptors to form oligomers, with the generation of novel pharmacology and G protein coupling properties.

In the phase III HIMALAYA study (NCT03298451), STRIDE (Single Tremelimumab Regular Interval Durvalumab) significantly improved overall survival (OS) vs. sorafenib in unresectable HCC and demonstrated long-term survival benefits. We report an updated exploratory analysis of OS after 5 years of follow-up, including survival by multiple tumour response measures. Participants were randomised to STRIDE (tremelimumab plus durvalumab), durvalumab or sorafenib. OS, depth of response and serious adverse events were assessed. Extended long-term survivors (≥48 months beyond randomisation) were described. The updated data cut-off was 01 March 2024. Median (95% CI) follow-up durations were 62.49 (59.47-64.79) months (STRIDE) and 59.86 (58.32-61.54) months (sorafenib). The OS hazard ratio (95% CI) for STRIDE vs. sorafenib was 0.76 (0.65-0.89). OS rates at 60 months for STRIDE vs. sorafenib were 19.6% vs. 9.4% overall, 28.7% vs. 12.7% in participants achieving disease control per RECIST v1.1, and 50.7% vs. 26.3% in participants achieving >25% tumour shrinkage. No late-onset treatment-related serious adverse events were reported for STRIDE. There were more extended long-term survivors with STRIDE (83/393, 21.1%) than sorafenib (45/389, 11.6%), and extended long-term survival occurred across all clinically relevant subgroups. At 5 years, STRIDE sustained an OS benefit vs. sorafenib and maintained a manageable safety profile. OS benefit with STRIDE was improved in participants with disease control. Data suggest that any degree of tumour shrinkage with STRIDE can be associated with improved OS, indicating that conventional response measures may not fully capture the benefits of STRIDE. Nevertheless, participants experiencing deep responses appear to have the greatest benefit. STRIDE continues to set new benchmarks in unresectable HCC with 1 in 5 patients alive at 5 years. NCT03298451. The phase III HIMALAYA study showed that STRIDE (Single Tremelimumab Regular Interval Durvalumab) improved overall survival (OS) vs. sorafenib in participants with unresectable HCC, including after 4 years of follow-up. Understanding the efficacy and safety of STRIDE over the longer term is important for healthcare providers; here, we demonstrate that STRIDE sustained an OS benefit vs. sorafenib and maintained a manageable safety profile after 5 years of follow-up. OS benefit with STRIDE was improved in participants with disease control and any degree of tumour shrinkage, indicating that conventional response measures may not fully capture the benefits of STRIDE. These findings are important as they set new benchmarks in unresectable HCC and may help guide clinical decisions in the future.

Importance Previous communication has reported significant improvement in overall survival (OS) when using doxorubicin plus sorafenib in the treatment of advanced hepatocellular cancer (HCC). Objective To determine if doxorubicin added to sorafenib therapy improves OS, with stratification for locally advanced and metastatic disease. Design, Setting, and Participants This unblinded randomized phase 3 clinical trial was led by Alliance in collaboration with Eastern Cooperative Oncology Group–American College of Radiology Imaging Network, Canadian Cancer Trials Group, and Southwest Oncology Group. It was launched in February 2010 and completed in May 2015; data were also analyzed during this time frame. Patients with histologically proven advanced HCC, no prior systemic therapy, Child-Pugh grade A score, Eastern Cooperative Oncology Group performance status of 0 to 2 (later amended to 0-1), and adequate hematologic, hepatic, renal, and cardiac function were eligible. The OS primary end point had a final analysis planned with 364 events observed among 480 total patients with 90% power to detect a 37% increase in median OS. Interventions or Exposures Patients received either 60 mg/m²of doxorubicin every 21 days plus 400 mg of sorafenib orally twice daily or the sorafenib alone, adjusted to half doses for patients with bilirubin levels of 1.3 to 3.0 mg/dL. Main Outcomes and Measures The primary end point was OS, and progression-free survival (PFS) was a secondary end point. Results Of 356 patients included in the study, the mean (SD) age was 62 (10.1) years, and 306 (86.0%) were men. Although it was planned to include 480 patients, the study was halted after accrual of 356 patients (180 patients treated with doxorubicin plus sorafenib and 176 with sorafenib alone) with a futility boundary crossed at a planned interim analysis. Median OS was 9.3 months (95% CI, 7.3-10.8 months) in the doxorubicin plus sorafenib arm and 9.4 months (95% CI, 7.3-12.9 months) in the sorafenib alone arm (hazard ratio, 1.05; 95% CI, 0.83-1.31). The median PFS was 4.0 months (95% CI, 3.4-4.9 months) in the doxorubicin plus sorafenib arm and 3.7 months (95% CI, 2.9-4.5 months) in the sorafenib alone arm (hazard ratio, 0.93; 95% CI, 0.75-1.16). Grade 3 or 4 neutropenia and thrombocytopenia adverse events occurred in 61 (36.8%) and 29 (17.5%) patients, respectively, being treated with doxorubicin plus sorafenib vs 1 (0.6%) and 4 (2.4%) patients treated with sorafenib. Conclusions and Relevance This multigroup study of the addition of doxorubicin to sorafenib therapy did not show improvement of OS or PFS in patients with HCC. Trial Registration ClinicalTrials.gov identifier:NCT01015833

Purpose: The phase III CELESTIAL study demonstrated improved overall survival (OS) and progression-free survival (PFS) with cabozantinib versus placebo in patients with previously treated, advanced hepatocellular carcinoma (HCC). We analyzed outcomes by baseline alpha-fetoprotein (AFP) and on-treatment AFP changes. Patients and Methods: Serum AFP was measured every 8 weeks by blinded, centralized testing. Outcomes were analyzed by baseline AFP bifurcated at 400 ng/mL and by on-treatment AFP response (≥20% decrease from baseline at Week 8). The optimal cutoff for change in AFP at Week 8 was evaluated using maximally selected rank statistics. Results: Median OS for cabozantinib versus placebo was 13.9 versus 10.3 months [HR, 0.81; 95% confidence interval (CI), 0.62–1.04] for patients with baseline AFP <400 ng/mL, and 8.5 versus 5.2 months (HR, 0.71; 95% CI, 0.54–0.94) for patients with baseline AFP ≥400 ng/mL. Week 8 AFP response rate was 50% for cabozantinib versus 13% for placebo. In the cabozantinib arm, median OS for patients with and without AFP response was 16.1 versus 9.1 months (HR, 0.61; 95% CI, 0.45–0.84). AFP response was independently associated with longer OS. The optimal cutoff for association with OS in the cabozantinib arm was ≤0% change in AFP at Week 8 [AFP control; HR 0.50 (95% CI, 0.35–0.71)]. HRs for PFS were consistent with those for OS. Conclusions: Cabozantinib improved outcomes versus placebo across a range of baseline AFP levels. On-treatment AFP response and control rates were higher with cabozantinib than placebo, and were associated with longer OS and PFS with cabozantinib.