Digest 78 – Is Dig Making A Comeback? Plus negative trials in critical care, deprescribing PPIs, & more

July 31, 2026 | By Nora Taranto

Welcome Back to The Curbsiders Digest!

In this issue we discuss everything from negative trials in critical care, deprescribing PPIs, and much more. Effortlessly absorb important medical news, with our monthly newsletter featuring easily digestible analysis of the latest practice-changing articles, and of course…bad puns. 

Yummy! 

If you or a friend are hungry for more, sign up here.

Menu 

Issue 78

07/31/2026

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.  

Joshua Gilman MD, Laura Glick MD, Alyssa Mancini MD 

• Deprescribing intervention to reduce PPI use.  JAMA Internal Medicine recently published the results of a cluster-randomized clinical trial (DEPRESCRIPP) aiming to address inappropriate PPI use in primary care. Over 34,000 adults with at least 1 year of PPI use from nearly 700 general practitioner (GP) practices in France were included in the study. GP practices were randomized to 3 groups: a patient- and GP-facing deprescribing intervention (a brochure outlining PPI deprescribing sent to patients, and a letter outlining a PPI deprescribing algorithm sent to GPs), a GP-facing intervention only, or usual care. PPI dose reduction (50% or more reduction in PPI use) at 1 year was significantly higher in the patient- and GP-facing intervention group compared with the usual care group (14.9% vs. 7.0%; adjusted absolute risk difference 6.9%; 95% CI 5.7%-8.3%, P < .001) and compared with those in the GP-facing intervention group (14.9% vs. 7.7%). Importantly, gastroesophageal reflux symptom recurrence was not significantly higher in the intervention arm. (AM) 
• In critically ill adults with metabolic acidosis, bicarb may not be beneficial. NEJM recently published the results of a pragmatic, adaptive, double-blind, randomized trial that looked at whether sodium bicarbonate was beneficial in adults with metabolic acidosis who were receiving vasopressors in the ICU. The study included 500 adults in 55 ICUs (across 7 countries) who were randomized to receive either sodium bicarbonate or placebo, infused over < 5 hours. A major adverse kidney event (death, use of renal-replacement therapy, or persistent renal dysfunction, within 30 days) occurred in 40.2% of patients in the sodium bicarbonate group and 39.4% in the placebo group (adjusted difference 1.2 percentage points; 95% CI -7.1 to 9.4; P=0.78). The rates of renal-replacement therapy and in-hospital mortality were similar in both groups. Four patients in the sodium bicarbonate group had an adverse effect, compared to none with placebo. (AM) 
• CLEAR-ing VTE with bempedoic acid. A post hoc analysis of the CLEAR Outcomes randomized clinical trial published in JAMA Cardiology evaluated whether bempedoic acid (180mg/day) reduces the risk of venous thromboembolism (VTE) in 13,970 statin-intolerant patients with or at high risk for atherosclerotic cardiovascular disease (ASCVD) compared to placebo. Over a median follow-up of 40.6 months, treatment with bempedoic acid was associated with a 42% lower risk of VTE compared with placebo (39 vs. 67 events; HR 0.58, 95% CI 0.39–0.86; P = .006). This benefit was consistent for both deep vein thrombosis (DVT) (HR 0.56, 95% CI 0.31–0.996) and pulmonary embolism (PE) (HR 0.61, 95% CI 0.37–0.996). Subgroup analyses showed a consistently lower VTE risk with bempedoic acid, and the effect persisted in a sensitivity analysis censoring VTE events that occurred after a first major adverse cardiovascular event. (LG)
• More or less O2 in the critically ill. The LOGICAL trial, just published in NEJM, randomized 1,840 mechanically ventilated patients after cardiac arrest across 53 ICUs in Australia, New Zealand, and Ireland to either a conservative oxygen strategy (SpO2 ceiling of 95%, weaned toward FiO2 0.2) or a liberal oxygen strategy (no upper SpO2 limit, minimum FiO2 0.3). At 180 days, there was no significant difference between the conservative-oxygen group and the liberal-oxygen group in the primary outcome of survival with favorable functional recovery (38% vs. 40%; RR 0.97, p=0.65). This result held true regardless of how early oxygen titration started after return of circulation or ICU admission. (LG) 
• Persistent atrial fibrillation: is ablation the first move?  The AVANT GUARD trial, recently published in NEJM, randomized 310 patients with persistent atrial fibrillation (lasting >7 days) to receive either pulsed field ablation (PFA) or antiarrhythmic drugs (AAD) as first line therapy. The primary effectiveness endpoint was short term success (procedural success in the PFA group and absence of an ablation by 90 days in the AAD group) and long term success (no recurrence of atrial arrhythmias, no repeat ablation, and freedom from amiodarone or other AADs from months 3-12). At one year, the primary effectiveness endpoint (short and long term success) occurred in 56% of ablation group participants compared to 30% in the AAD group (HR for treatment failure 0.46, 95% CI 0.33-0.65, p<0.001). Most treatment failure was due to recurrence of asymptomatic atrial arrhythmias lasting >60 minutes (30% in PFA group vs 46% in the AAD group). Procedural/device complications occurred in approximately 5% of patients, but serious adverse events were similar in both groups (25% vs 21%). (JG) 

Palate Cleanser

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

July has a way of making every physician nostalgic; or at least once you’ve recovered enough to laugh about it. In “The Night I Begin to Become a Physician,” Dr. Mohammad Jay reflects on the journey from overwhelmed intern to confident attending with a sense of candor and humor. He details the unique challenge of trying to build a life as a resident while learning to care for the lives of others, amid the familiar soundtrack of incessant pages, unfinished notes, and the elusive hope of eating lunch. As he transitions from intern to senior resident, he realizes that his newfound confidence stems not from having all the answers, but from his willingness to notice, ask, listen, and care. Reflecting finally as an attending, he reframes the fear that once felt paralyzing as an intern as evidence of how deeply he cared rather than that of inadequacy, with a sense of compassion and grace that many of us reserve only for our patients. Check out his essay for a timely reminder that becoming a physician is a lifelong practice of curiosity, humility, and compassion for our patients and colleagues alike, without forgetting to care for ourselves along the way.

– Jennifer DeSalvo MD 

The Main Course

Joshua Gilman MD 

Digoxin, the comeback kid
Cardiac glycosides have a long history in the world of heart failure (HF) dating back to the late 18th century. They reached their peak use in the late 20th century when digoxin prescription rates approached 80%. Two trials published in 1993, the PROVED and RADIANCE trials, were the basis for this common use. Both trials evaluated discontinuing vs continuing digoxin in patients with HF with reduced ejection fraction (HFrEF) already on the medication. The PROVED trial showed there were more HF events (death, hospitalization or worsening symptoms) in the discontinuation group. In RADIANCE, there was a significantly higher risk of worsening HF in the discontinuation group. Limitations included relatively small sample sizes (< 200 in both), short term follow up (12 weeks in both trials), and the lack of de novo digoxin exposures in either trial (given that at the time digoxin was considered standard of care). 

A long history 
These trials helped solidify digoxin’s 200 year history in the management of HF.  However, disruption came via the infamous 1997 DIG (Digitalis Investigation Group) trial. DIG was the first large scale, randomized controlled trial randomizing 6,800 patients with HFrEF (EF <45%) to receive digoxin or placebo on top of diuretics and ACEi’s (landmark beta blockers trials would not be published until 1999-2001). At a mean follow up of 37 months there was no difference in mortality between the groups (34.8% vs 35.1% p=0.80), the trial’s primary endpoint. Of the secondary outcomes, there was a significantly lower rate of hospitalizations for worsening HF favoring the digoxin group (26.8% vs 34.7%). As expected, there were higher rates of suspected digoxin toxicity in the digoxin arm, with numerically higher rates of all types of arrhythmias. Of note, the DIG trial targeted serum digoxin concentration of 0.5-2.0ng/mL, higher than what is currently recommended by HF guidelines (0.5-0.9ng/mL). A 2009 post-hoc analysis demonstrated that there was likely a drug concentration-dependent benefit – with patients who had low serum concentrations of digoxin (<1ng/mL) experiencing lower rates of both death and hospitalization.

Digoxin use subsequently declined, with one analysis showing prescription rates dropping from 30% in 2005 to 10% in 2014. Additionally, both the American College of Cardiology (ACC) / American Heart Association (AHA) and the European Society of Cardiology (ESC) guidelines on the management of HF reduced their level of recommendation for digoxin, with the most recent 2022 ACC/AHA and the 2021 ESC guidelines both giving cardiac glycosides a class 2b level of recommendation.  But the story doesn’t end there. Given DIG’s secondary endpoints and the post-hoc analysis findings, subsequent studies aimed to further assess the role of cardiac glycosides at lower doses (and on top of more modern guideline-directed medical therapy (GDMT)).

Making DECISIONs
The 2025 DIGIT-HF (Digitoxin to Improve Outcomes in Patients with Advanced Chronic HF) trial evaluated the use of digitoxin, a cardiac glycoside available outside the US. Digitoxin is similar to digoxin but with a more stable and renally safe pharmacokinetic profile – including increased protein binding, a longer half life, and both renal and enterohepatic excretion. The trial, published in the NEJM (and briefly covered in Digest 69) was an international, double-blind placebo controlled trial that randomized 1,212 patients with HFrEF (EF <40%) to low dose digitoxin vs placebo on top of contemporary GDMT. At a median follow up of 36 months, there was a reduction in the primary endpoint of all-cause mortality or first hospitalization for HF favoring the digitoxin group (39.5% vs 44.1%, hazard ratio [HR] 0.82, 95% CI 0.69-0.98, p=0.03). There were low rates of adverse reactions in both arms (4.7% vs 2.8%). 

The 2026 DECISION (Digoxin Evaluation in Chronic HF: Investigational Study in Outpatients in the Netherlands) trial, published in Nature Medicine also renewed interest in digoxin. This double-blind, placebo controlled trial randomized 1,001 patients with symptomatic chronic HFrEF (EF <50%) to low-dose digoxin (concentration target of 0.5-0.9ng/mL) or placebo on top of GDMT. Over a median follow up of 36.5 months, there was a non-significant but numerical reduction in the the primary composite outcome of worsening HF events and cardiovascular (CV) mortality with digoxin (15.7 vs 19.3 events per 100 patient years; rate ratio 0.81, 95% CI 0.61-1.07, p=0.133). There was a high rate of drug discontinuation in both arms (24% with digoxin, 21% with placebo) – attributed to the COVID pandemic. An as-treated sensitivity analysis showed a reduction in the primary outcome favoring digoxin (10.6 vs 16.1 events per patient years, rate ratio 0.66, 95% CI 0.47-0.92, p=0.015). There were no significant differences in adverse events.

Tying it all together
A 2026 study-level meta-analysis, published in JAMA, combined data from the 9,013 patients included in the DIG, DIGIT-HF and DECISION trials. The analysis found a 15% relative risk reduction in the composite outcome of CV death or first worsening HF event favoring cardiac glycosides (pooled HR 0.85, 95% CI 0.80-0.91, p<0.001). Of the secondary outcomes, cardiac glycosides were associated with lower rates of first worsening HF events (26% vs 33%, HR 0.75, p<0.001) but no difference in CV mortality or all-cause mortality. A sensitivity analysis showed no significant heterogeneity between trials based on background GDMT.

While less effective than the current 4 pillars of GDMT, the efficacy of cardiac glycosides appears similar to other accepted add-on HF therapies such as ivabradine or vericiguat. The most recent guideline recommendations were written before DIGIT-HF and DECISION were published, and both trials have now addressed the question of their benefit in the current GDMT era. Whether the next guideline updates will upgrade cardiac glycosides to a stronger recommendation remains to be seen, but at pennies per pill, this old drug class may be poised for a comeback.

Read the meta-analysis HERE!

Digestifs

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

Consolidate your learning with a Quiz!  

This week on The Curbsiders:  Episode #534 is perhaps the highest yield as they come, given how often patients ask about herbs and supplements – Dr. Paul Wurtz joins the Curbsiders to tackle the data around supplements in primary care. 

Comments for the Chef

We want to hear from you!

Please share your feedback and ideas in this Survey!

Thanks so much for joining us this week.

Until next time, keep that brain hole digesting! 

The Curbsiders Digest

Issue 78
Editor in Chief: Nora Taranto MD
Banner: Kate Grant  MBChB, DipGUMed

Jennifer DeSalvo, Joshua Gilman, Laura Glick, Alyssa Mancini, and Nora Taranto report no disclosures.

Join our PATREON!

Bundle & Save with our CME Tier (Annual Subscription Only)