Comparing FOLFOX delivery in trial and real-world populations using longitudinal cumulative dose.

1521 Background: Patterns of chemotherapy delivery are likely to differ between trial and real-world populations. Typical measures used to compare these patterns are calculated at treatment completion, potentially missing key differences in the timing and trajectory of delays and dose reductions. We used a new measure, longitudinal cumulative dose (LCD), to compare treatment delivery over time in trial and real-world populations. Methods: We compared chemotherapy delivery in patients with stage II-III colon cancer enrolled in the MOSAIC trial of 5-fluorouracil (5FU) vs oxaliplatin + 5FU (FOLFOX4) to patients treated from 2008-2019 in the US Oncology Network with FOLFOX4, FOLFOX6, or mFOLFOX6. For each patient, we computed oxaliplatin LCD as the cumulative oxaliplatin dose received at a given timepoint (t) divided by the final standard oxaliplatin dose. We then estimated the median and 25th and 75th percentiles for oxaliplatin LCD within each regimen at day 68 (before the standard timing of the 7th dose), 168 (two weeks after the standard end of treatment), and 250. Results: The table shows the number of patients receiving each treatment regimen and the median and interquartile range for oxaliplatin LCD at each time. Higher LCDs in the trial show delivery closer to standard treatment, meaning fewer delays, dose reductions, and discontinuations. Differences between the medians, 25th percentiles, and 75th percentiles of LCD in each regimen were small at day 68 but grew considerably by days 168 and 250. Conclusions: Divergence from the standard dosing schedule was larger in real-world versus trial settings and varied by oxaliplatin regimen. LCD, as a longitudinal measure, showed that differences in delivery between trial and real-world populations grew substantially over time (even after 168 days and the standard end of treatment) possibly as real-world patients experienced more side effects and barriers to treatment than trial participants. These discrepancies in LCD may cause poorer outcomes in real-world settings than expected based on randomized trials.[Table: see text]

Prognosis of Claims‐ Versus Trial‐Based Ischemic and Bleeding Events Beyond 1 Year After Coronary Stenting

Background It is unknown whether clinical events identified with administrative claims have similar prognosis compared with trial‐adjudicated events in cardiovascular clinical trials. We compared the prognostic significance of claims‐based end points in context of trial‐adjudicated end points in the DAPT (Dual Antiplatelet Therapy) study. Methods and Results We matched 1336 patients aged ≥65 years who received percutaneous coronary intervention in the DAPT study with the CathPCI registry linked to Medicare claims. We compared death at 21 months post‐randomization using Cox proportional hazards models among patients with ischemic events (myocardial infarction or stroke) and bleeding events identified by: (1) both trial adjudication and claims; (2) trial adjudication only; and (3) claims only. A total of 47 patients (3.5%) had ischemic events identified by both trial adjudication and claims, 24 (1.8%) in trial adjudication only, 15 (1.1%) in claims only, and 1250 (93.6%) had no ischemic events, with annualized unadjusted mortality rates of 12.8, 5.5, 14.9, and 1.26 per 100 person‐years, respectively. A total of 44 patients (3.3%) had bleeding events identified with both trial adjudication and claims, 13 (1.0%) in trial adjudication only, 65 (4.9%) in claims only, and 1214 (90.9%) had no bleeding events, with annualized unadjusted mortality rates of 11.0, 16.8, 10.7, and 0.95 per 100 person‐years, respectively. Among patients with no trial‐adjudicated events, patients with events in claims only had a high subsequent adjusted mortality risk (hazard ratio (HR) ischemic events: 31.5; 95% CI, 8.9‒111.9; HR bleeding events 23.9; 95% CI, 10.7‒53.2). Conclusions In addition to trial‐adjudicated events, claims identified additional clinically meaningful ischemic and bleeding events that were prognostically significant for death.

Caffeine increases peripheral fatigue in low- but not in high-performing cyclists

The influence of cyclists’ performance levels on caffeine-induced increases in neuromuscular fatigue after a 4-km cycling time trial (TT) was investigated. Nineteen cyclists performed a 4-km cycling TT 1 h after ingesting caffeine (5 mg·kg−1) or placebo (cellulose). Changes from baseline to after exercise in voluntary activation (VA) and potentiated 1 Hz force twitch (Qtw,pot) were used as markers of central and peripheral fatigue, respectively. Participants were classified as “high performing” (HP, n = 8) or “low performing” (LP, n = 8) in accordance with their performance in a placebo trial. Compared with placebo, caffeine increased the power, anaerobic mechanical power, and anaerobic work, reducing the time to complete the trial in both groups (p < 0.05). There was a group versus supplement and a group versus supplement versus trial interaction for Qtw,pot, in which the postexercise reduction was greater after caffeine compared with placebo in the LP group (Qtw,pot = −34% ± 17% vs. −21% ± 11%, p = 0.02) but not in the HP group (Qtw,pot = −22% ± 8% vs. −23% ± 10%, p = 0.64). There was no effect of caffeine on VA, but there was a group versus trial interaction with lower postexercise values in the LP group than in the HP group (p = 0.03). Caffeine-induced improvement in 4-km cycling TT performance seems to come at the expense of greater locomotor muscle fatigue in LP but not in HP cyclists. Novelty Caffeine improves exercise performance at the expense of a greater end-exercise peripheral fatigue in low-performing athletes. Caffeine-induced improvement in exercise performance does not affect end-exercise peripheral fatigue in high-performing athletes. High-performing athletes seem to have augmented tolerance to central fatigue during a high-intensity time trial.