Digest 61: January, a time to ADAPT?

January 24, 2025 | By Nora Taranto

Welcome Back to The Curbsiders Digest!

In this issue, we ask whether or not we should ADAPT to New Protocols in Sepsis Care, plus new infrequent zoledronate for fracture prevention, noise exposure and heart disease, weekly insulin, and new treatments for PTSD. Effortlessly absorb important medical news, with our twice monthly newsletter featuring easily digestible analysis of the latest practice-changing articles, and of course…bad puns. 

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Issue 61

01/24/2025

Appetizers (to whet your appetite) 

Palate Cleanser (aka the melon part of the meal) 

The Main Course

A Digestif or two

Appetizers

Brought to you hot off the stove, from a variety of specialties. Delivered in super tasty, bite-sized morsels. 
-Jennifer DeSalvo MD; Laura Glick MD, Alyssa Mancini MD

• Insulin: A New Weekly Option? NEJM recently published the results of a phase 3, parallel-design, open-label, noninferiority trial that randomized 928 insulin-naïve adults with type 2 diabetes to receive efsitora, a once-weekly basal insulin, or degludec, a once-daily basal insulin. At 52 weeks, the mean hemoglobin A1c decreased from 8.21% to 6.97% with efsitora, and 8.24% to 7.05% with degludec–with an estimated treatment difference of -0.09 percentage points, thus satisfying the noninferiority margin of 0.4 percentage points. Noninferiority persisted regardless of GLP-1 receptor agonist use. Participants using efsitora had a time-in-range (glucose 70-180 mg/dL) of 64%, while those using decludec had a time-in-range of 61%.  The rate of clinically significant or severe hypoglycemia was 0.58 events per participant-year of exposure with efsitora and 0.45 with degludec, but there was no severe hypoglycemia reported with efsitora compared to six episodes with degludec. (AM)
• Infrequent zoledronate for fracture prevention in early postmenopausal women? NEJM just published the results of a 10-year, double-blind, randomized, placebo-controlled trial enrolling 1054 early postmenopausal women (mean age 56) with bone density T scores between 0 and -2.5 (non-osteoporotic range) at the lumbar spine, femoral neck, or hip. Participants were randomized to receive an infusion of zoledronate (5 mg) at baseline and 5 years (zoledronate-zoledronate group), zoledronate at baseline and placebo at 5 years (zoledronate-placebo), or placebo at both baseline and 5 years (placebo-placebo). After 10 years of follow-up, a new morphometric fracture  (> 20% change in vertebral height from baseline) occurred in 6.3% of zoledronate-zoledronate group participants, 6.6% in the zoledronate-placebo group, and 11.1% in the placebo-placebo (relative risk 0.56 for zoledronate-zoledronate vs. placebo-placebo [95% CI 0.34 to 0.92, P=0.04], and 0.59 for zoledronate-placebo vs. placebo-placebo [95% CI 0.36-0.97; P=0.08]). (AM)
• Real-world results on DoxyPEP! When using doxycycline post-exposure prophylaxis (doxyPEP), individuals are told to take the antibiotic doxycycline (200 mg) within 72 hours after sex to reduce the risk of sexually transmitted infections (STIs). In mid-2024, the CDC recommended discussing doxyPEP in gay, bisexual, and other men who have sex with men and trangender women with an STI diagnosis in the prior 12 months on the basis of several randomized trials. Now, a retrospective cohort study in JAMA Internal Medicine has looked at real-world effects of doxyPEP on STI incidence, analyzing data from over 11,500 adults (95% male) prescribed HIV preexposure prophylaxis (PrEP) at Kaiser Permanente Northern California between 2022 and 2023 and comparing STI incidence in those dispensed doxyPEP and those who were not–and before/after doxyPEP dispensation.  Of 11,551 HIV PrEP users, 2,253 (19.5%) received doxyPEP. The use of doxyPEP was associated with a significant decrease in the incidence of chlamydia and syphilis (by 79% and 80% respectively) with a modest decrease in gonorrhea (12%). For more on doxyPEP implementation effects, read the accompanying editorial and this time-series analysis comparing STI cases in San Francisco before and after citywide doxyPEP guideline implementation. (LG)
• Combination Therapy for PTSD? In a double-blinded, randomized phase 3 clinical trial recently published in JAMA Psychiatry, 416 adults ages 18-65 years old with a diagnosis of Posttraumatic Stress Disorder (PTSD)–a majority of whom had not received prior PTSD pharmacotherapy–were randomized to receive the atypical antipsychotic brexpiprazole plus sertraline (a selective serotonin reuptake inhibitor) or sertraline plus placebo daily. Symptoms were measured using the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), a validated tool ranking the severity of 20 PTSD symptoms on a scale (0-80), with higher scores indicating worse symptoms. At 10 weeks, the group receiving brexpiprazole/sertraline experienced a statistically significant improvement in CAPS-5 score compared to the sertraline/placebo group (mean change -19.2 vs -13.6 points, P<0.001), with a higher proportion of brexpiprazole/sertraline participants experiencing >30% improvement (68.5% vs 48.2%, P<0.001). The discontinuation rate due to adverse events–which were mostly mild to moderate in severity–was 3.9% with brexpiprazole/sertraline and 10.2% with sertraline/placebo. (LG)
• Jet lag for the heart? JACC recently published a cohort study of 3,635 UK residents living near four major airports who had cardiovascular magnetic resonance (CMR) imaging performed after 2014, using generalized linear models to evaluate the association of aircraft noise levels with cardiac structure and function. Participants exposed to higher nighttime aircraft noise (>45 dB, estimated based on postcode and the Aircraft Noise CONtour model (ANCON-2)) had adverse left ventricular (LV) remodeling (7% greater LV mass and 4%  greater LV wall thickness with a normal septal-to-lateral wall thickness ratio) and worse LV myocardial dynamics (8% lower global circumferential strain)–findings that are associated with a higher risk of major adverse cardiac event (MACE). This association appeared to be partially mediated by hypertension and obesity, suggesting that these factors may have a role in the theorized pathway from noise exposure to adverse remodeling. (JD)

Palate Cleanser

The melon part. To get rid of the taste of those pesky apps.  And to fill your brain with some fun facts.

Have you thought about your “why medicine” recently? While waiting for a groundhog to tell us how many weeks are left in this season of short, wintry days, reflecting on the “why” is how one author transformed her personal tragedy into motivation to help others. In her article, Leeolou describes the healing and liberating powers of ballet while struggling with psoriasis since childhood; however, the development of psoriatic arthritis forced her to abandon her ballet career. She extended her love of ballet into a passion for medicine given her desire to share her experience as a patient and help others heal and “find their own strength, their own grace to carry forward.” Check out her moving piece, “Extension,” recently published in JAMA!

– Jennifer DeSalvo MD

The Main Course

Cyrus Askin, MD
Pulmonary & Critical Care Medicine

Should we be ADAPTing to New Protocols in Sepsis Care?

Introduction

Sepsis remains a global challenge, with timely and appropriate antimicrobial therapy forming the cornerstone of treatment. However, optimizing the duration of antibiotics is critical to preventing antibiotic resistance, minimizing adverse effects, and improving patient outcomes. Enter the ADAPT-Sepsis trial—a multicenter, randomized study assessing whether biomarker-guided protocols, specifically daily procalcitonin (PCT) and C-reactive protein (CRP) measurements, can safely reduce antibiotic duration in critically ill patients with suspected sepsis.

Breaking It Down

The ADAPT-Sepsis trial, published in December 2024 in JAMA,  randomized 2,760 patients across 41 UK intensive care units into three groups: daily PCT-guided protocols, daily CRP-guided protocols, and standard care. The primary goals were twofold—to evaluate reductions in antibiotic duration (effectiveness) and assess all-cause mortality at 28 days (safety) across the three groups.  

First, a bit about the methods of this intervention-blinded study. Individuals had to be admitted to a critical care unit, with IV antibiotics started within 24 hours and anticipated continuation for at least 72 hours for suspected sepsis. Patients in all groups had daily research labs collected starting within 24 hours of antibiotics, with treating teams blinded to group assignment. CRP could be collected outside the protocol if deemed necessary by the clinician (other than to guide antibiotic duration), but PCT could not.  Reports, based on the research labs, returned to the treating team; in the PCT-guided protocol, a threshold of PCT < 0.25 µg/l returned a written “Protocol STRONGLY SUPPORTS stopping antibiotics” to the team, with a fall by > 80% from baseline or PCT between 0.25 and 0.50 µg/l returning a “Protocol SUPPORTS stopping antibiotics,” and otherwise a message stating “Protocol supports standard care.” Similar messages went out in the CRP group based on thresholds of CRP < 25 mg/l and CRP fall by >50% from baseline, respectively. In the standard care group, there was no test performed, and the treating team received a message stating “Protocol supports standard care” daily.

The PCT-guided protocol reduced antibiotic duration compared to standard care (10.7 days in standard care and 9.8 days in the PCT-guided group, with a mean difference of 0.88 days [95% CI 0.19 to 1.58, p=0.01]). The CRP-guided protocol failed to achieve significant reductions in antibiotic duration (10.6 days).  Regarding safety, PCT-guided protocols demonstrated noninferiority for 28-day mortality, with mortality rates of 20.9% in the PCT-group compared to 19.4% in the standard care (absolute difference of 1.57% [95% CI -2.18 to 5.32, p=0.02]), within the non-inferiority margin of 5.4% and with similar results in adjusted and sensitivity analyses. Mortality analysis comparing the CRP-guided protocol to standard care was inconclusive. Other endpoints, including hospital length of stay and infection relapse rates, showed no significant differences.

PCT’s dynamic tracking of bacterial inflammation likely accounts for its superior performance compared to CRP. While imperfect and occasionally maligned, PCT is a somewhat unique biomarker given its ability to track bacterial inflammation dynamics—rising early and normalizing rapidly. This is in contrast to CRP, which is notoriously non-specific.

What’s It All Mean?

The ADAPT-Sepsis trial suggests that daily PCT-guided protocols may be able to reduce antibiotic duration in critically ill patients with suspected sepsis–but also raises interesting questions about non-inferiority study designs.  While the reduction in antibiotic duration (<1 day) seen with PCT-guided protocols may seem modest, even this could potentially help antimicrobial stewardship in a population vulnerable to the consequences of overuse. Furthermore, even a single dose reduction reduces risks for adverse effects and lowers the incidence of drug interactions. The study does, however, have limitations. These include the possibility of crossover with CRP testing in standard care guiding treatment decision-making, challenges with messaging and its influence on decision-making in a study like this (Does the phrase “Protocol supports standard care” suggest one should continue current treatment?) and the relatively wide non-inferiority margin used for the primary safety endpoint. This question comes up often in thinking about non-inferiority trials–what is the right width for a non-inferiority margin, in particular when it comes to mortality? Was 5.4% the right margin for this? How–if at all–does one clinically interpret the 1.5% absolute difference in mortality between the PCT and standard care groups–which fell within that prespecified non-inferiority margin?

While questions remain, this study does lend some credence to a practice which already has established footing among many intensive care clinicians–using PCT to guide decision-making about antibiotics–in particular when it comes to de-escalation without an infectious source. But whether this data will influence current guidelines on the use of PCT in critically ill patients remains unclear–and the results cannot be generalized to patients outside of the ICU.

Read The ADAPT-Sepsis Trial Results Here!

Digestifs

Before you go….
we’ve got a few nibbles!

Consolidate your learning with a Quiz!  

This week on The Curbsiders: In Episode #467, Unintentional Weight Loss with Dr. Eva Szymanski, learn all the geriatrician’s secret tips about how to work up and manage weight loss in older adults. Harness the age-friendly “5Ms” in your workup after listening to this high-yield episode.

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Until next time, keep that brain hole digesting! 

The Curbsiders Digest

Issue 61

Editor in Chief: Nora Taranto MD

Banner: Kate Grant  MBChB, DipGUMed

Cyrus Askin, Jennifer DeSalvo,  Laura Glick, Alyssa Mancini, and Nora Taranto report no disclosures.

Kate Grant reports no disclosures.  

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