Digest 47: A stuffed (and nutty) Thanksgiving edition

November 18, 2023 | By Nora Taranto

Welcome Back to The Curbsiders Digest!
In this issue, we feature ACORN and the vanc/pip-tazo debates, blood transfusion thresholds, testosterone replacement and anemia, and CPAP adherence and heart disease.
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Issue 47

11/17/2023

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. 
–Jenifer Desalvo MD, Alyssa Mancini MD, Matthew Watto MD FACP

• Can CPAP decrease cardiovascular risk in patients with cardiovascular disease and OSA? JAMA published a systematic review and individual participant data meta-analysis of 3 randomized controlled trials that included 4186 adults with moderate to severe obstructive sleep apnea (OSA) and established cardiovascular disease (82% men, mean age 61, 50% receiving CPAP treatment). While the intention-to-treat analysis reported no effect of CPAP treatment on the risk of recurrent major adverse cardiac and cerebrovascular events (MACCEs), the on-treatment analysis revealed a reduced risk of MACCEs in “adherent” individuals–with lower risk for those who used CPAP for at least 4 hours daily, compared to those using CPAP less than that (HR 0.69, 95% CI 0.52-0.92). (AM) 
• A new way to TReaT anemia in men with hypogonadism? JAMA Network Open recently published a study nested within the TRAVERSE trial, assessing whether testosterone replacement therapy (TRT) can correct anemia in men with hypogonadism. This was a randomized, placebo-controlled trial enrolling 5204 middle-aged and older men with hypogonadism–of whom 815 had anemia–who received either testosterone gel or placebo gel daily. Anemia corrected in a significantly greater proportion of men treated with testosterone than with placebo as early as 6 months (41.0% vs. 27.5%) and as late as 48 months (44.6% vs. 39.2%). In men without anemia, a smaller proportion developed anemia if they were treated with testosterone, compared to placebo. (AM) 
• TCAs to make it to the fabled ATLANTIS of IBS relief? In the primary care setting, low-dose amitriptyline (10-30 mg daily) outperformed placebo in ATLANTIS, a blinded RCT of 463 patients age 18 or older with longstanding, moderate to severe IBS symptoms despite first-line treatments (dietary changes, fiber, laxatives, antispasmodics, peppermint oil). At baseline in this study, just published in Lancet, IBS-SSS scores were ~270 in both groups (severity worsens as scores increase; max 500 points). At 6 months, IBS-SSS dropped by -99.2 with amitriptyline compared to -68.9 with placebo. While this 27-point between-group difference did not meet the 35-point “minimum clinically important difference”, PCPs might consider a trial of TCAs as second line therapy for IBS. As expected, more anticholinergic side effects were seen with amitriptyline. (MW) 
• Cannabis in Cancer: Is it Common? A recent study, just published in Cancer, looked at rates of cannabis use among patients with cancer. Of the >250 adult patients with cancer who were surveyed, 26% self-reported using cannabis within the past month, commonly for pain, cancer, sleep, anxiety, and nausea/vomiting, with reported relief for many of these symptoms. Participants most commonly used edibles (65%) or smoked (51%). Interestingly, patients who used cannabis reported more severe physical and psychological symptoms than those who did not report cannabis use. Consider screening patients with cancer for cannabis use, including modality of use, and monitoring subsequent symptoms. (JD)
• To transfuse or not to transfuse? That is the question. The MINT trial recently published in NEJM randomized >3,500 adults with myocardial infarction and anemia (hemoglobin <10 g/dL) to a restrictive or liberal transfusion strategy (hemoglobin cutoffs for transfusion 7-8 g/dL vs <10 g/dL, respectively). Although there was no significant difference in incidence of recurrent myocardial infarction and death at 30 days between the two groups, patients in the liberal transfusion strategy had numerically lower rates of the primary endpoint than those receiving restrictive therapy. Meanwhile, new international guidelines published in JAMA recommend a general, restrictive transfusion strategy between 7-8 g/dL in hospitalized adult patients who are hemodynamically stable, after reviewing 45 RCTS with >20,500 patients comparing strategies. (JD) 
• SGLT2 inhibitors were victorious again in the fight against heartbreak, with improved morbidity and mortality in adults with cancer therapy-related cardiac dysfunction. This retrospective cohort study published in JACC analyzed aggregate data from 1,280 adult patients (mean age 68, 42% female, 68% white) with cancer and type 2 diabetes who were diagnosed with non-ischemic cardiomyopathy or heart failure after exposure to potentially cardiotoxic antineoplastic therapy.  Compared to guideline-directed medical therapy (GDMT) alone, patients treated with SGLT2 inhibitors and GDMT together had a significantly reduced risk of heart failure exacerbation, atrial fibrillation/flutter, acute kidney injury, need for renal replacement therapy, all-cause hospitalizations or ED visits, and all-cause mortality. (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.

If the thought of “DocGPT” taking over physicians’ jobs in the future gives you acute urticaria, consider reading Aditya Jain’s “Updating the role of doctors in the age of AI.” The author highlights the importance of partnering with AI to revise the physician’s role in medicine. AI could allow for increased focus on providing personalized patient care and advocating for patients through health policy, quality improvement, and research, as AI helps physicians analyze data for improved diagnosis and treatment. The article also calls for redesigning medical education in collaboration with AI to “prioritize knowledge capture, not knowledge retention” and prepare students to “evaluate emerging technologies…as support tools to improve patient outcomes and reduce physician burnout.”
– Jen Desalvo MD

The Main Course

Alexander Chaitoff MD MPH

ACORN, Causal Inference, and the Pip-Tazo Debate (in a nutshell) 

How to answer that eternal question–whether to reach for piperacillin-tazobactam (aka pip-tazo) or cefepime in the sick patient needing pseudomonal coverage–likely depends largely on institutional culture informed by local antibiograms.  But in 2011, observational evidence suggested that patients on vancomycin and pip-tazo together had unexpectedly high rates of kidney injury.  Ultimately, one meta-analysis of 3549 patients across 14 observational studies identified three times the odds of acute kidney injury in those who got vancomycin and pip-tazo compared with those who got vancomycin and another antibiotic. These observational data led many, including high-ranking members of the Infectious Disease Society of America, to suggest avoiding pip-tazo when alternatives were available. 

But is it cause and effect?

An entire branch of science is dedicated to drawing causal inferences from observational data. Philosopher John Stuart Mills suggested three criteria that could imply causality.  First, the independent variable needs to precede the dependent– the cause needs to happen before the effect. Second, the independent and dependent variables must be associated with one another. Third, there cannot be another explanation for the correlation between the two variables (ie. no confounding variables to explain the relationship).  

With vancomycin and pip-tazo, the observational studies did show receipt of drugs before kidney injury, and there was clearly an association between getting them and kidney injury.  But was the association due to the drug itself?  There was no clear mechanism to explain the correlation, raising concerns about confounding. And notably, while numerous studies tried to identify a mechanism behind this proposed synergistic nephrotoxicity with vancomycin and pip-tazo, nothing was found.  Moreover, in clinical practice, physicians choose to administer pip-tazo over alternative antibiotics for particular reasons and indications, leading even the authors of the above observational studies to caution readers about the possibility of confounding by indication.

Then, researchers noted that most studies of vancomycin/pip-tazo defined kidney injury using changes in serum creatinine. Creatinine is subject to both glomerular clearance and tubular secretion, the latter of which is affected by pip-tazo. If serum creatinine rises from less tubular secretion, this clearance change may represent pseudotoxicity, or an elevation of creatinine without other evidence of kidney dysfunction (such as changes in cystatin C, or BUN).  So researchers conducted a prospective cohort study of ICU patients receiving vancomycin/pip-tazo or vancomycin/cefepime and assessed creatinine and cystatin C– whose secretion is not affected by pip-tazo.  Vancomycin/pip-tazo was associated with a greater creatinine increase but not with a change in cystatin C.

Definitive evidence?

Finally, the issue has seemingly been put to bed with the publication of the ACORN trial. In this pragmatic, open-label trial, 2511 adults hospitalized with suspected infection were randomized to either pip-tazo or cefepime, with a majority also receiving vancomycin at enrollment. The primary outcome was the highest stage of acute kidney injury or death by day 14, with secondary outcomes looking at major adverse kidney events and # days alive and free of delirium by day 14.  By day 14, the incidence of major adverse kidney events did not differ between groups (absolute difference, 1.4%, 95% CI −1.0% to 3.8%), nor were there differences in needs for new kidney replacement therapy or death.  And it seemed that the proposed neurotoxicity of cefepime may be real, as those randomized to cefepime experienced fewer days free of delirium and coma than those who received pip-tazo (odds ratio 0.79, 95% CI 0.65-0.95).  There were several trial limitations, including around 20% cross-over in each group, and a relatively short duration of treatment (median 3 days).  But, overall, this trial provides much-needed randomized evidence of no significant difference in kidney injury risk between pip-tazo and cefepime, in a population receiving also vancomycin. And so the pip-tazo versus cefepime debate may ultimately join a long list of others, with medicine misled by observational data, only for trials to set the record straight.

Read The ACORN Trial Results HERE

Digestifs

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

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This week on The Curbsiders: This week, we’re jumping into the deep end, with Episode #415, a phenomenal dive into bipolar disorder with Dr. Kevin Johns. The pearls are a-plenty, with reminders about the different causes of depressive symptoms besides major depressive disorder, the genetics behind bipolar disorder, the Mood Disorder Questionnaire, and so much more.

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The Curbsiders Digest

Issue 47

Editor in Chief: Nora Taranto MD

Banner: Kate Grant  MBChB, DipGUMed

Disclosures:

Alyssa Mancini, Alex Chaitoff, Jennifer DeSalvo, Nora Taranto, and Matt Watto report no disclosures. 

Kate Grant reports no disclosures

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