Individualized Treatment Effects of Oxygen Targets in Mechanically Ventilated Critically Ill Adults

Buell, Kevin G.; Spicer, Alexandra B.; Casey, Jonathan D.; Seitz, Kevin P.; Qian, Edward T.; Graham Linck, Emma J.; Self, Wesley H.; Rice, Todd W.; Sinha, Pratik; Young, Paul J.; Semler, Matthew W.; Churpek, Matthew M.

doi:10.1001/jama.2024.2933

Cited by 21 publications

(1 citation statement)

References 38 publications

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“…Prior studies have shown that risk-based models can effectively measure variation in treatment effect. 38,39 This study suggests that, when possible, both risk-based and effect-based approaches should be tested when determining if an intervention should be targeted to a subset of individuals.…”

Section: Discussionmentioning

confidence: 99%

Identifying a Heterogeneous Effect of Atrial Fibrillation Screening in Older Adults: A Secondary Analysis of the VITAL-AF Trial

Shah,

Iyer,

Agha

et al. 2024

Preprint

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Background: One-time screening trials for atrial fibrillation (AF) have produced mixed results; however, it is unclear if there is a subset of individuals for whom screening would be effective. Identifying such a subgroup would support targeted screening. Methods: We conducted a secondary analysis of VITAL-AF, a randomized trial of one-time, single-lead ECG screening during primary care visits. We tested two approaches to identify heterogeneous screening effects. First, we developed an effect-based model for heterogeneous screening effects using a potential outcomes framework. Specifically, we predicted the likelihood of AF diagnosis under both screening and usual care conditions using LASSO, a penalized regression method. The difference between these probabilities was the predicted screening effect. Second, we used the CHARGE-AF score, a validated AF risk model, to test for a heterogeneous screening effect. We used interaction testing to determine if observed AF diagnosis rates in the screening and control groups differed when stratified by decile of the predicted screening effect and predicted AF risk. Results: Baseline characteristics were similar between the screening (n=15187) and usual care (n=15078) groups (mean age 74 years, 59% female). On average, screening did not significantly increase the AF diagnosis rate (2.55 vs. 2.30 per 100 person-years, rate difference 0.24, 95%CI -0.18 to 0.67). In the effect-based analysis, in the highest decile of predicted screening efficacy (n=3026), AF diagnosis rates were higher in the screening group (6.5 vs. 3.06 per 100 person-years, rate difference 3.45, 95%CI 1.62 to 5.28, interaction p-value 0.003). In this group, the mean age was 84 years, 68% were female, and 55% had vascular disease. The risk-based analysis did not identify a subgroup where screening was more effective. Predicted screening effectiveness and predicted baseline AF risk were poorly correlated and demonstrated a U-shaped relationship (Spearman coefficient 0.13). Conclusions: In a secondary analysis of the VITAL-AF trial, we identified a small subgroup where one-time screening was associated with increased AF diagnoses using an effect-based approach. In this study, predicted AF risk was a poor proxy for predicted screening efficacy. These data caution against the assumption that high AF risk is necessarily correlated with high screening efficacy.

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Section: Discussionmentioning

confidence: 99%

Identifying a Heterogeneous Effect of Atrial Fibrillation Screening in Older Adults: A Secondary Analysis of the VITAL-AF Trial

Shah,

Iyer,

Agha

et al. 2024

Preprint

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Your Mileage May Vary

Angus

2024

JAMA

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When car makers tout standard emission tests to demonstrate their car's fuel efficiency, they must disclose that the results are just estimates and that a prospective buyer's experience may differ. 1 The phrase. "your mileage may vary" is used to acknowledge that the average result from a standard test may not reflect an individual user's experience. This phrase is now so ubiquitously understood that the phrase appears on more than 70 million web pages and is routinely shortened to YMMV in online reviews of topics far beyond fuel efficiency.In medicine, things are different. The standard test is the randomized clinical trial (RCT), which also generates an average, not an individual, effect. Treatment guidelines acknowledge physician judgment is needed to determine if RCT results apply to their patient. However, guidelines typically recommend that physicians prescribe to all patients those interventions that worked in applicable populations and withhold those that do not. Quality improvement efforts further rely on the average effect when they set compliance targets. In other words, the emphasis is on the average effect and not the possibility that your mileage may vary.Using the average effect as a guide for everyone works in many situations. If all that varies for a therapy with an average beneficial effect is the magnitude of the benefit, one could start that therapy at a low dose and adjust as needed, particularly if there were no downsides to titrating slowly and cessation of the therapy quickly resolved any untoward adverse effects. But, what if an intervention, even in applicable populations, helped some patients but hurt others? And what if, once one approach was selected, an alternative was no longer possible? In this issue of JAMA, Buell et al 2 consider such a potential situation: supplemental oxygen support for patients requiring mechanical ventilation in the intensive care unit (ICU).Supplemental oxygen, listed as an essential medicine by the World Health Organization, 3 is used to avert lifethreatening tissue hypoxia in many conditions, and may be the world's most prescribed therapy. Oxygen is provided to every patient receiving mechanical ventilation, set as a fraction of inspired gas. The fraction is adjusted to maintain an arterial oxygen saturation target, typically measured by continuous pulse oximetry (with or without intermittent arterial blood gas estimation). The challenge comes in choosing the target. One can set a target close to 100%, thereby giving lots of oxygen and providing the best chance of avoiding vital organ tissue hypoxia (a liberal oxygen approach). Alternatively, one can give just enough oxygen (a conservative oxygen approach) to avoid arterial hypoxemia (below 90%), thereby minimizing the like-

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Dapagliflozin for Critically Ill Patients With Acute Organ Dysfunction

Tavares,

Azevedo,

Rea-Neto

et al. 2024

JAMA

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ImportanceSodium-glucose cotransporter 2 (SGLT-2) inhibitors improve outcomes in patients with type 2 diabetes, heart failure, and chronic kidney disease, but their effect on outcomes of critically ill patients with organ failure is unknown.ObjectiveTo determine whether the addition of dapagliflozin, an SGLT-2 inhibitor, to standard intensive care unit (ICU) care improves outcomes in a critically ill population with acute organ dysfunction.Design, Setting, and ParticipantsMulticenter, randomized, open-label, clinical trial conducted at 22 ICUs in Brazil. Participants with unplanned ICU admission and presenting with at least 1 organ dysfunction (respiratory, cardiovascular, or kidney) were enrolled between November 22, 2022, and August 30, 2023, with follow-up through September 27, 2023.InterventionParticipants were randomized to 10 mg of dapagliflozin (intervention, n = 248) plus standard care or to standard care alone (control, n = 259) for up to 14 days or until ICU discharge, whichever occurred first.Main Outcomes and MeasuresThe primary outcome was a hierarchical composite of hospital mortality, initiation of kidney replacement therapy, and ICU length of stay through 28 days, analyzed using the win ratio method. Secondary outcomes included the individual components of the hierarchical outcome, duration of organ support–free days, ICU, and hospital stay, assessed using bayesian regression models.ResultsAmong 507 randomized participants (mean age, 63.9 [SD, 15] years; 46.9%, women), 39.6% had an ICU admission due to suspected infection. The median time from ICU admission to randomization was 1 day (IQR, 0-1). The win ratio for dapagliflozin for the primary outcome was 1.01 (95% CI, 0.90 to 1.13; P = .89). Among all secondary outcomes, the highest probability of benefit found was 0.90 for dapagliflozin regarding use of kidney replacement therapy among 27 patients (10.9%) in the dapagliflozin group vs 39 (15.1%) in the control group.Conclusion and RelevanceThe addition of dapagliflozin to standard care for critically ill patients and acute organ dysfunction did not improve clinical outcomes; however, confidence intervals were wide and could not exclude relevant benefits or harms for dapagliflozin.Trial RegistrationClinicalTrials.gov Identifier: NCT05558098

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Individualized Treatment Effects of Oxygen Targets in Mechanically Ventilated Critically Ill Adults

Cited by 21 publications

References 38 publications

Identifying a Heterogeneous Effect of Atrial Fibrillation Screening in Older Adults: A Secondary Analysis of the VITAL-AF Trial

Identifying a Heterogeneous Effect of Atrial Fibrillation Screening in Older Adults: A Secondary Analysis of the VITAL-AF Trial

Your Mileage May Vary

Dapagliflozin for Critically Ill Patients With Acute Organ Dysfunction

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