#383 Hotcakes: Loop Diuretics for CHF, Time Restricted Eating, Breaks from Sitting, Early FMT for C. diff

February 27, 2023 | By Matthew Watto, MD

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Join us as we review recent practice-changing articles on loop diuretics for heart failure exacerbation (torsemide vs furosemide), time-restricted eating vs small frequent meals for weight loss, how sedentary breaks from sitting effect blood glucose & blood pressure, early FMT for C. diff, and a brief rant on medications for obesity. Fill your brain hole with a delicious stack of hotcakes! Featuring Nora Taranto (@norataranto, The DIGEST), Paul Williams (@PaulNWilliamz), Rahul Ganatra (@rbganatra), and Matt Watto (@doctorwatto).

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Show Segments

• Intro, disclaimer
• Loop diuretics (torsemide vs furosemide) for heart failure exacerbation
• Time-restricted eating vs small frequent meals for weight loss
• Sedentary breaks for lowering blood glucose and blood pressure
• Early fecal microbiota transplant (FMT) for C. diff infection 
• Outro

Hotcake #1: Torsemide vs Furosemide in CHF (Rahul)

Mentz RJ, Anstrom KJ, Eisenstein EL, et al. Effect of torsemide vs furosemide after discharge on all-cause mortality in patients hospitalized with heart failure: the transform-hf randomized clinical trial. JAMA. 2023;329(3):214-223.

What was the research question? Among patients hospitalized with acute heart failure (AHF), does torsemide reduce all-cause mortality (compared with furosemide) by at least 20% within 12 months?

Why is this study important? Laboratory, pharmacologic, and clinical evidence exists to support the hypothesis that torsemide might work better than furosemide by lowering RAAS tone and reducing readmissions and mortality. TRANSFORM-HF is the long-awaited RCT intended to settle this question once and for all.

How was the study done? Randomized, open-label, pragmatic comparative effectiveness trial conducted at 60 hospitals in the US from 2018 to 2022. 2,800 patients hospitalized with CHF were randomized to torsemide or furosemide at discharge, with the dose determined by treating clinicians, and follow-up with their regular cardiologists, in line with the pragmatic design. The primary outcome was time to death from any cause. 

Who were the patients?

• Included: chronic decompensated or acute de novo heart failure, with either EF <40% or an elevated natriuretic peptide level
• Excluded: heart transplant, LVAD, pregnancy, life expectancy <12 months
• Median age 65, 1 in 3 were women, 1 in 3 were black. 

Top-line results: There was no difference in all-cause mortality in this study, with 26% of patients in each group having died over a median of 17 months of follow-up. Results were consistent across subgroups. 

Learning points: 

• A higher-than-expected event rate was observed (only half the planned sample size was needed to achieve the required number of events). I don’t think this makes a false negative more likely – if anything, if there was an effect, here’s our chance to see it! 
• The choice of all-cause mortality as the primary outcome: great in an open-label study (no adjudication required), but tougher to show an effect. 
• This was NOT an underpowered study! You might worry about that given that they were looking for a >20% reduction in all-cause mortality, which is huge, but these results are not equivocal – there was no difference at all. 

Bottom Line / Hotcakes rating: This was a really well-done study that informs a common clinical decision. I interpret these results as giving me license to use whichever loop diuretic the patient and I decide. I give it 4 out of 5 hotcakes. 

Further Reading:

• A small (N=50) open-label RCT in 2003 found that patients with CHF treated with torsemide for 6 months had higher levels of renin & aldosterone, and lower levels of BNP, suggesting that torsemide might block the aldosterone receptor (https://www.jstage.jst.go.jp/article/circj/67/5/67_5_384/_article).
• A small (N=234) open-label RCT in 2001 found that patients with CHF randomized to torsemide had lower readmissions at 1 year compared with furosemide (17% vs 32%) (https://pubmed.ncbi.nlm.nih.gov/11705426/). 
• A great thread from Tony Breu with the above references and more: https://twitter.com/tony_breu/status/1479226309079404552?lang=en 

Hotcake #2: Eating, Sleep Intervals, and Weight Change (Paul)

Zhao D, Guallar E, Woolf TB, Martin L, Lehmann H, Coughlin J, Holzhauer K, Goheer AA, McTigue KM, Lent MR, Hawkins M, Clark JM, Bennett WL. Association of Eating and Sleeping Intervals With Weight Change Over Time: The Daily24 Cohort. J Am Heart Assoc. 2023 Jan 18:e026484. doi: 10.1161/JAHA.122.026484. Epub ahead of print. PMID: 36651320. 

What was the research question? Does time-restricted eating lead to weight loss?

Why is this study important? I had a vague sense that intermittent fasting or time-restricted eating might improve outcomes, but also remembered that there was an article in NEJM last year (Liu, 2022) that did not show any real benefit over calorie restriction. 

How was the study done? This is a multi-site, prospective cohort study. Patients were recruited from Johns Hopkins, Geisinger Health Systems, and UPMC. Patients logged their meals, which included timing and size (<500 calories, 500-1000 calories, or >1000 calories) on an app designed by the study team over the course of 6 months.  Weights were collected via the EHR, and the authors evaluated the relationship between each exposure and weight.  The exposures included average sleep and meal-related time intervals and weight trajectories.

Who were the patients? They were over the age of 18, had at least one height and weight measurement in the EHR within two years of enrollment, and were recruited through the patient portal or email.  

Top-line results: Time from first to last meal was not associated with weight change.  Increased frequency of small meals was associated with weight loss.  More frequent, larger meals were associated with weight gain, suggesting that total calories were the driver of weight gain.

Learning points: 

• Lots of potential confounders. 
• Other than the anthropometric data, the data were self-reported. Patients have historically been shown to under-report their caloric intake. 
• The inclusion criteria presupposed a certain degree of access and technological literacy, as well as motivation, so there is potential for some bias here as well.  

Bottom line / Hotcakes rating: Three hotcakes from me.  Glad to have this added to the body of knowledge, but limited in generalizability.

Hotcake #3: Breaking up Prolonged Sitting (Watto)

Duran, Andrea T et al. Breaking Up Prolonged Sitting to Improve Cardiometabolic Risk: Dose-Response Analysis of a Randomized Cross-Over Trial. Medicine & Science in Sports & Exercise ():10.1249/MSS.0000000000003109, January 12, 2023. | DOI: 10.1249/MSS.0000000000003109

Supplement: http://links.lww.com/MSS/C779 

What was the research question? What is the optimal frequency and duration for sedentary breaks to improve blood glucose (primary outcome) and blood pressure (secondary outcome) during an 8-hour period?

Why is this study important? As discussed in the last Hotcakes episode, we have well-established weekly activity targets. Further, “sitting is the new smoking” is now a common statement, and even though it’s not an accurate comparison, we need to try to compensate for sedentary periods. I’m interested in whether or not brief periods of activity improve cardiometabolic risk and mitigate excursions in blood glucose after meals.

How was the study done? This was a randomized cross-over study of eleven healthy adults. Subjects spent five 8-hour days under the supervision of research staff. For sedentary breaks, they ate standardized meals and performed light walking on a treadmill at two mph (0% grade).

Who were the patients? At least 45 years old (mean age 57) and sedentary for >8 hours per day. Exclusions included preexisting cardiometabolic conditions or self-reported exercise 3 or more days/week. 

Top-line results: Breaking up prolonged sitting with light-intensity activity for 1-5 minutes/30-60 minutes significantly reduced systolic blood pressure (3-5 mmHg) and sedentary breaks of 5 minutes/30 minutes reduced blood glucose (lower 1hr peak by 32.9 mg/dL [6.2 vs 39.1 mg/dL] and deeper 3.25hr nadir by 9.2 mg/dL [-14.4 vs -5.2 mg/dL]) compared to unbroken sedentary periods.

Learning points: 

• This small trial was stopped early due to the pandemic and could not complete its enrollment target. Further, it will require a culture and mindset shift to implement/allow 1-5 minutes of light activity in current workplaces. 
• Without a registered study protocol, evaluating the likelihood of a false-positive finding is difficult.

Bottom Line / Hotcakes rating: I give this a 3.5 rating. It’s hypothesis generating and builds on a growing body of evidence to the significant benefits of regular physical activity. Larger trials should be done to confirm the results. I suspect the benefits of breaking up prolonged sitting might be even greater if tested in a higher-risk group.  

Further Reading: We know that sedentary behavior is associated with increased mortality (Park 2020, Patterson 2018, Biddle 2016, Katzmarzyk 2009). One meta-analysis found light or moderate activity interruptions of prolonged sitting reduced post-prandial glycemia and insulin (Quan 2021). Another review and meta-analysis found that prolonged sitting increases blood pressure (Patterson 2022). 

Hotcake #4: Early FMT (Nora)

Baunwall SMD, et al. Faecal microbiota transplantation for first or second Clostridioides difficile infection (EarlyFMT): a randomised, double-blind, placebo-controlled trial. Lancet Gastroenterol Hepatol. 2022 Dec;7(12):1083-1091. doi: 10.1016/S2468-1253(22)00276-X. Epub 2022 Sep 22. PMID: 36152636. 

What was the research question? Does the early use of fecal microbiota transplant during the first or second episode of C. diff infection (CDI) improve the rate of symptom resolution, compared to the standard of care (treatment with Vancomycin)? 

Why is this study important? Having seen many patients during training who had refractory and recurrent CDI–and having seen the efficacy of fecal transplant down the line for these folks when Vancomycin and Fidaxomicin don’t work–it made sense to ask whether using this tool earlier might be more effective. Also, the FDA recently approved the first fecal microbiota product on Nov 30, 2022 (Rebyota, for recurrent CDI, was previously available under the “Investigational New Drug” category). This paper was also discussed in Digest #33 – check it out! 

How was the study done? This was a randomized, double-blind, placebo-controlled trial, ultimately enrolling 42 adults with a first or second C. Difficile infection (>3 watery stools per day and a positive C. Diff PCR) to either fecal microbiota transplant or placebo (21 to each group) after receiving 125 mg oral vancomycin four times daily for 10 days.  Encapsulated fecal transplant or placebo were given twice, on day 1 and sometime between days 3 and 7. Patients were followed for 8 weeks or until C. Diff recurrence. The primary outcome was resolution of C. Diff Associated Diarrhea (CDAD) 8 weeks after the second study treatment. 

Who were the patients? Exclusion criteria included other antibiotic use besides vancomycin, need for proton pump inhibitors, pregnancy, allergy to vancomycin or anaphylaxis to any food groups, and fulminant CDI. Notably, the study included patients with multiple comorbidities, immunocompromised patients, and patients with IBD.

Top-line results: The trial was stopped early, after the interim analysis (initially accrual aimed to include 84 patients), because there was a significantly lower rate of resolution of CDI in the placebo group than the transplant group, with 90% resolution achieved with transplant (19/21, 95% CI 70-99) and 33% in placebo (7/21, 95% CI 15-57), p 0.00031. The absolute risk reduction with fecal transplant compared to placebo was 57% (95% CI 33-81). 

Learning points: 

• More patients in the placebo group (48% vs 33%) were on their second CDI, which might have made them more likely to have CDAD at 8 weeks. 
• Continuous need for PPI was an exclusion criteria, presumably because they may predispose to treatment failure
• Aspects that may favor the treatment arm include the fact that this was a single center, highly regulated transplant product, that the transplant patients got two doses of transplant, and that there were more second infections in the placebo group. 
• Questions that remain include whether one fecal transplant treatment is better than two, and whether all fecal transplant products are the same

Bottom Line / Hotcakes rating: 4.5 hotcakes for me. This data will likely change practice going forward in thinking about fecal transplant earlier, in addition to antibiotics (though the logistics of getting it done may be challenging). 

Further Reading:

• Editorial about the results:  https://www.thelancet.com/journals/langas/article/PIIS2468-1253(22)00301-6/fulltext 

Hot take #1 Do we have agency over obesity? (Watto)

60 Minutes segment on Obesity 1 Jan 2023 (Spotify)

Ozempic Face (Forbes)

AAP CPG on Obesity 2023

Summary: 60 Minutes (allegedly sponsored by Wegovy) recently did a 15-minute segment discussing semaglutide as a chronic treatment for obesity. The show discussed the highly hereditary nature of obesity and characterized it as unavoidable even with optimal diet and exercise during childhood. While it’s true that obesity is a chronic disease and in many cases requires chronic medication (like semaglutide) or metabolic surgery, we need to go upstream and prevent obesity in children and young adults. Our country has a toxic food environment where the right choice is never the easy choice. Highly processed and highly addictive foods filled with salt, sugar, seed oils, preservatives, and refined carbohydrates are ubiquitous, including school lunches, which regularly offer things like french toast sticks, french fries, chocolate milk, and ice cream. Further, the pharmaceutical industry has no incentive to prevent chronic diseases like diabetes and obesity since they benefit from chronic disease treatment. In fact, Novo (maker of semaglutide) has allegedly sponsored 60 Minutes! 

Bottom line: We need to get serious about preventing obesity and diabetes by making the right food choices the easy choices. 

Links

Links are included in the show notes above.

Goals

Listeners will review recent practice-changing articles and medical news.

Learning objectives

After listening to this episode listeners will…

1. Determine whether torsemide provides a mortality benefit versus furosemide for heart failure exacerbations
2. Decide if time-restricted feeding improves weight loss
3. Review the possible benefits of sedentary breaks on blood glucose and blood pressure
4. Explore the benefits of early fecal microbiota transplant for C. diff infection

Disclosures

The Curbsiders report no relevant financial disclosures. 

Citation

Ganatra R, Taranto N, Williams PN, Watto MF. “#383 Hotcakes: Loop Diuretics for CHF, Time Restricted Eating, Breaks from Sitting, Early FMT”. The Curbsiders Internal Medicine Podcast. https://thecurbsiders.com/episode-list Final publishing date, February 27, 2023.