#472 DIGEST: cfDNA & cancer in Pregnancy, Vitamin K2 for Leg Cramps, PRN anti-hypertensives, GLP-1 Agonists for AUD, Short-Course Antibiotics

February 24, 2025 | By Nora Taranto

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Join us as we review recent articles and news featured in The DIGEST issues #59-61, including cfDNA and incidental detection of cancer in pregnancy, vitamin K2 for nocturnal leg cramps, the danger of as-needed anti-hypertensive medications in the hospital, GLP-1 agonists for alcohol use disorder, short-course (7 vs 14 days) antibiotics for bacteremia, and patient-collected HPV testing for cervical cancer screening. Fill your brain hole with a fully digestible meal! Featuring Laura Glick MD, Nora Taranto (@norataranto), Paul Williams (@paulnwilliamz), and Matt Watto (@doctorwatto). 

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Show Segments

• 00:00 Introduction and Overview
• 02:57 The IDENTIFY study: Non-Invasive Prenatal Testing and Cancer Detection with cfDNA
• 05:54 Implications of Non-Reportable Results in Prenatal Testing
• 08:51 Vitamin K2: A New Approach to Managing Nocturnal Leg Cramps
• 12:07 Practicality and Future of Vitamin K2 in Clinical Practice
• 23:21 The Dangers of As-Needed Antihypertensives in the hospital
• 32:21 Exploring GLP-1 Agonists for Alcohol Use Disorder
• 40:24 Shorter Antibiotic Courses in Sepsis
• 46:09 Advancements in Patient-Collected HPV Screening for cervical cancer

Disclosures

The Curbsiders report no relevant financial disclosures. 

#1 cfDNA and cancer risk (Nora)

Covered by Jen DeSalvo MD in DIGEST #60

​​Turriff AE, et al. Prenatal cfDNA Sequencing and Incidental Detection of Maternal Cancer. N Engl J Med. 2024 Dec 5;391(22):2123-2132. doi: 10.1056/NEJMoa2401029. PMID: 39774314; PMCID: PMC11711700. 

Recommended Reading: 

• Editorial accompanying the study (Vora, 2024) 

Summary: cfDNA Summary: Prenatal screening for genetic abnormalities is now routinely offered via blood tests that look at circulating cell-free DNA (cfDNA) in the plasma of pregnant individuals. This noninvasive prenatal testing (NIPT) has reduced the need for invasive diagnostic procedures to evaluate for fetal aneuploidy (missing/extra chromosomes in the fetus) such as amniocentesis or chorionic villus sampling.  These noninvasive tests look at free DNA that is floating in the plasma of mothers-to-be, where a relatively small proportion derives from the placenta/fetus and the majority comes from the pregnant individual’s normal blood cells. Tumors, however, can also shed DNA into the blood, and so these tests can theoretically pick up abnormalities from the fetus, normal maternal cells, or maternal tumor cells. Typically, when tumor cfDNA is picked up on one of these screens, the clinical report returns an abnormal or “nonreportable sequencing result” as the fetal status can’t be assessed.  But though there is standard workup if testing reports concern for fetal aneuploidy, there are no guidelines or data about what to do when one gets an abnormal or nonreportable result on a prenatal cfDNA screen in the presence of a normal-appearing fetus/normal fetal karyotype.

IDENTIFY is an ongoing “natural history” study conducted by the National Institutes of Health that enrolled pregnant/postpartum individuals without a known cancer diagnosis who have “unexpected results” on cfDNA sequencing (NIPT) performed as part of routine obstetric care.  107 individuals with abnormal results on clinical NIPT (majority from genomewide, not targeted, sequencing) were enrolled and underwent cancer screening with whole-body MRI, blood tests (including normal labs and tumor markers), fecal occult blood test, and physical exam.  Mean age was 33, and 89/107 were pregnant at the time of cancer screening, with a mean gestational age of 22 weeks.  Cancer was found in 52 / 107 (48.6%) participants–including lymphoma in 31 individuals (Hodgkin’s in 20), and 20 with solid cancers including colorectal and breast cancers. Among those with solid tumor diagnoses, 13/20 were eligible for potentially curative treatment. Whole-body MRI was able to reliably detect occult cancers in these individuals with a high sensitivity, specificity, and negative predictive value (98%, 88.5%, and 98%, respectively), but other cancer screening approaches (e.g. physical exam and labs, including tumor markers) had a significantly lower sensitivity / NPV to detect occult cancer.  Research sequencing that divided sequencing patterns into 6 categories demonstrated that almost all individuals with copy-number gains AND losses had a diagnosis of cancer (47/49 individuals, 96%). The other sequencing patterns were found in individuals with evidence of other non-malignant conditions such as with fibroids or confined placental mosaicism. 

Bottom line (Is this practice changing?):  Not yet, but it does raise an as-yet unanswered and important question – what should one do with abnormal prenatal cfDNA results? While cfDNA is offered as part of routine prenatal care to screen for fetal aneuploidy, there are a variety of products available for this assessment (with varying cost and coverage), with no specific guidelines yet about how to handle these abnormal test results.  Not to mention that full-body MRI even for this indication is not standardly covered by insurance (see Editorial).  We need specific guidelines–which will lead to infrastructure being built to provide these individuals with the proper, timely workup and management–to follow up with patients who have nonreportable results, as these individuals appear to be at a high risk of having a cancer that requires treatment. 

#2  – Vitamin K(2)ramp relief (Watto)

Covered by Hannah Smith MD in DIGEST #59

Tan J, et al. Vitamin K2 in Managing Nocturnal Leg Cramps: A Randomized Clinical Trial. JAMA Intern Med. 2024 Dec 1;184(12):1443-1447. doi: 10.1001/jamainternmed.2024.5726. PMID: 39466236; PMCID: PMC11581596. 

Recommended Reading:

• Pilot of K2 for leg cramps in patients on dialysis (Xu, 2022)
• The PICCLES RCT (Tapper, 2022)

Summary: This multicenter, randomized, double blind, placebo-controlled trial from China examined whether one daily capsule of vitamin K2 (menaquinone-7 (MK-7), 180 μg) taken at night could reduce nocturnal leg cramps (NLCs) in adults 65 and over with at least two NLC during 2 weeks of screening. The primary outcome was mean number of NLCs per week.  Secondary outcomes included duration (minutes) and severity of cramps (analog scale of 1-10).  Among the 310 participants, 111 were excluded (over 35%). The 199 participants had a mean age of 72 years with 103 receiving K2 group and 96 receiving placebo.  Mean baseline weekly NLCs was 2.6-2.71. Over the 8 week intervention, in intention-to-treat analysis, the K2 group saw a reduction to 0.96  mean weekly NLCs while placebo saw an increase to 3.63 weekly NLCs, with a between-group difference of -2.67.  Severity was reduced in the K2 group by 2.55 compared to a reduction of 1.24 with placebo (between-group difference of 1.31). The K2 group had a greater mean reduction in duration vs placebo–56 seconds vs 19 seconds respectively (between group difference of 37 seconds). Notably, we don’t know why this works, but the authors speculate it might have to do with an anti-contraction effect by blocking voltage-dependent calcium channels.  

Participants generally had a low overall frequency of nocturnal leg cramps (~2.5 per week), and the study also excluded individuals on vitamin K antagonists (and patients with cramps from a variety of metabolic causes as well as those on diuretics). No adverse events were identified from K2–and it is generally thought to be a well-tolerated vitamin formulation without significant toxicities. 

Bottom line (Is this practice changing?): Yes. This low-risk intervention (which has both a low cost and apparent low risk of adverse effects) can be tried in patients with bothersome leg cramps.  But future studies should include patients with more severe/frequent leg cramps, those with specific metabolic causes, and those receiving diuretics.  

#3 PRN Meds for HTN (Paul)

Covered by Dr. Jen DeSalvo in DIGEST #62

Canales MT, Yang S, Westanmo A, Wang X, Hadley D, Ishani A, Mohandas R, Shorr R, Lo-Ciganic W. As-Needed Blood Pressure Medication and Adverse Outcomes in VA Hospitals. JAMA Intern Med. 2025 Jan 1;185(1):52-60. doi: 10.1001/jamainternmed.2024.6213. PMID: 39585709; PMCID: PMC11589853. 

Recommended Reading: 

• Neph Madness Episode #144 

Summary: Asymptomatic elevated blood pressure is common in hospitalized patients, even in those without a diagnosis of hypertension.  It remains common practice to treat these elevations with as needed blood pressure medications, although previous studies have suggested this can actually lead to worse outcomes (though remember that most of these prior studies excluded cardiovascular admissions).  This current study examined the association of as-needed blood pressure treatment with the development of acute kidney injury (and other clinical outcomes) among veterans admitted to a non-ICU VA hospital setting between 2015 and 2020.  This study used a trial emulation design in a retrospective cohort of veterans, comparing use of as-needed antihypertensives and non-use of as-needed antihypertensives (control arm).  Inpatient hypertension was defined as at least one systolic blood pressure > 140 mm Hg.  Veterans were assigned to the as-needed group if they received at least one as-needed blood pressure medication.  The primary outcome was time to first acute kidney injury event, defined as an increase in serum creatinine by 0.3 mg/dL from baseline within 48 hours or 50% increase over 7 days.  The observation period began after receipt of first dose.  Secondary outcomes included rapid drop in blood pressure (>25% decrease in systolic BP within 3 hours) and the composite outcome of myocardial infarction, stroke, and death (defined based on discharge diagnosis code).

130,771 veterans were included in the AKI analysis, 20% of whom received as-needed blood pressure medications.  18% received IV only, 66% received oral meds only, and 15% received both.  Before propensity score matching, patients who received as-needed BP meds were more likely to be Black, with higher admission blood pressures, and higher frequency of cardiovascular admissions.  AKI was 23% more likely to occur among veterans who received at least one as-needed BP medication.  AKI was more pronounced among those who received IV only medications (64% increased risk).  Veterans who received as-needed medications were 1.5 times more likely to have a rapid drop in BP in 3 hours and 1.7 times more likely to have the composite outcome of MI, stroke, and death.

Bottom line (Is this practice changing?):  I guess? But this is something we’ve talked about for a while.  We had a NephMadness episode in 2019 (see link above) where we discussed the hazards of IV hydralazine.  Three different studies came out in 2021 that underscored these concerns.  Hopefully this adds to the culture change that seems to slowly be happening. 

#4 GLP1 agonists for AUD (Laura)

Covered by Laura Glick MD in DIGEST #60

Lähteenvuo M, Tiihonen J, Solismaa A, Tanskanen A, Mittendorfer-Rutz E, Taipale H. Repurposing Semaglutide and Liraglutide for Alcohol Use Disorder. JAMA Psychiatry. 2025 Jan 1;82(1):94-98. doi: 10.1001/jamapsychiatry.2024.3599. PMID: 39535805; PMCID: PMC11561716.

Recommended Reading:

• The role of glucagon-like peptide 1 (GLP-1) in addictive disorders. (Klausen 2022) 

Summary:  GLP-1 agonists are widely prescribed for diabetes and obesity, but recent studies have shown promise for the use of GLP-1 agonists in patients with alcohol use disorder (AUD). In a cohort study published in JAMA Psychiatry, researchers used a within-individual design to study the risk of hospitalization due to alcohol use disorder during the use of GLP-1 agonists compared to periods of non-use for the same individual.  Secondary outcomes included any substance use disorder-related hospitalization, somatic hospitalization and suicide attempt. This observational study analyzed data from a national registry in Sweden between 2006 and 2023 and included over 227,000 patients (ages 16-64) with a diagnosis of alcohol use disorder. The majority of the cohort (63.5%) were male with a mean age of 40 years old and a median follow-up time of 9 years. 

Semaglutide and liraglutide (but not other GLP-1 agonist) use were associated with a significant decrease in alcohol use-related hospitalizations (aHR 0.64; 95% CI 0.50-0.83 for semaglutide; aHR 0.72; 95% CI 0.57-0.92 for liraglutide). GLP1-agonist use was also associated with a significant decrease in substance use disorder-related hospitalizations and somatic hospitalizations. Medications approved for AUD (including disulfiram, acamprosate, and naltrexone) were associated with only a modest decrease in AUD-related hospitalizations (aHR 0.98; 95% CI 0.96-1.00). The use of GLP-1 agonists was not associated with a significant change in risk of a suicide attempt.

While the results of this study are promising, there are limitations worth noting. This was an observational study so it cannot establish causality.  It also used a within-individual model, meaning that each individual acts as their own control over time, as opposed to comparing two fully distinct populations (always users and always non-users). 

Bottom line (Is this practice changing?):  Not yet, but it does offer hope. While there will likely be a role for GLP-1s to complement existing treatments for AUD, it is too early to tell in what capacity. I do think it is worthwhile considering these results when treating patients with alcohol use disorder PLUS obesity or diabetes, as these medications are approved for those indications WITH the potential added benefit of helping with alcohol use disorder. If a patient does not have obesity or diabetes, I would personally stick with the medications that are FDA approved. All in all, the study has some promising associations but until we have randomized clinical trials across a broader population, it will not be practice changing.

#5 BALANCE trial and shorter antibiotic courses (Nora)

Covered by Dr. Laura Glick in DIGEST #60

BALANCE Investigators. Antibiotic Treatment for 7 versus 14 Days in Patients with Bloodstream Infections. N Engl J Med. 2024 Nov 20. doi: 10.1056/NEJMoa2404991. Epub ahead of print. PMID: 39565030. 

Recommended Reading:

• Other trials looking at shorter courses of antibiotics for bacteremia include Yahav et al. (2019, Uncomplicated Gram Negative Bacteremia), von Dach et al. (2020, Uncomplicated Gram Negative Bacteremia), and Molina et al. (2022, Enterobacterales) 

Summary: Bloodstream infections can be lethal, but it remains unclear what the optimal duration of antibiotic treatment is for these infections. There has historically been concern about insufficient duration of treatment with shorter courses of antibiotics resulting in relapse of infection and development of resistance. At the same time, infectious disease experts worry about the excessive duration of antibiotics causing C. diff infections, adverse events, and the development of resistance. Recently, there’s been a trend towards shorter courses of antibiotics for pneumonia, cellulitis, and intra-abdominal infections, but it remains unclear how these source-specific studies can be generalized to patients with bloodstream infections, or bacteremia.

BALANCE was a randomized clinical trial testing the noninferiority of 7 days of antibiotics compared to 14 days, which is the median duration currently used to treat bacteremia according to a number of historical studies. The authors compared 7 versus 14 days of antibiotics using a non-inferiority margin of 4% for their primary outcome of death from any cause at 90 days. They found in their intention-to-treat analysis that 7 days of antibiotics was noninferior to 14 days of antibiotics (14.5% had died in the 7-day treatment arm compared to 16.1% in the 14-day arm). Their per-protocol and modified ITT analysis supported this conclusion of the non-inferiority of 7 days as well. There were no significant differences in secondary outcomes such as C. diff infection, antimicrobial-related adverse outcomes, or secondary infection with antibiotic-resistant organisms. 

Bottom line (Is this practice changing?):  Yes, I suspect it should be practice-changing or affirming (and builds on smaller trials that have had the same conclusions) as it was a large study that included patients in the ICU and on the floors, and had a relatively narrow non-inferiority margin for mortality.  But it does have some important limitations to keep in mind in applying it. The study excluded those with severe immunocompromise (such as neutropenia or those receiving immunosuppression after organ or bone marrow transplant), those with Staph aureus bacteremia, and those with prosthetic valves or foci requiring prolonged treatment (e.g. septic arthritis, undrained abscesses, osteomyelitis, endocarditis).  The results can’t be extrapolated to these specific populations. 

#6 Patient-Collected HPV Screening (Watto)

Covered by Alyssa Mancini MD in DIGEST #60

Cervical Cancer Screening Draft Recommend from USPSTF site accessed February 1, 2025.

Recommended Reading:

• Opinion piece by Emma McKim Mitchell from STAT accessed February 3, 2025.

Summary:  Society guidelines have evolved to incorporate HPV testing over the last decade or so. The American Cancer Society has recommended primary HPV testing every 5 years as the preferred screening strategy in those aged 25 to 65 since 2020. The American College of Obstetricians and Gynecologists (ACOG) and the American Academy of Family Physicians (AAFP) endorsed the 2018 USPSTF guidelines on cervical cancer screening, which recommended cytology for those aged 21-29 and any of the following options for women aged 30-65: cytology every 3 years, HPV testing alone every 5 years, or co-testing every 5 years. The USPSTF’s 2024 updated draft recommendations now emphasize primary HPV screening every 5 years for those aged 30-65, with alternative options including cervical cytology every 3 years or co-testing every 5 years. In these new recommendations, importantly, HPV primary screening can be either “clinician- or patient-collected.” 

What’s the Data on Self-Collection?
The USPSTF did a deep dive into patient self-collection of HPV specimens, particularly the agreement and test accuracy of self-collected HPV screening specimens compared with clinician-collected specimens to detect precancer. The pooled sensitivity of self-collected samples to detect CIN2+ (cervical intraepithelial neoplasia (CIN) 2 or worse) was 0.86 (95% CI 0.78-0.93), and the pooled specificity was 0.81 (95% CI 0.71-0.91). Agreement between self-collected vaginal and clinician-collected cervical samples was high, similar proportions screened positive, and the relative accuracy of self-collected vaginal samples to detect CIN2+ compared with clinician-collected samples was high.  Furthermore, offering self-collected vaginal HPV tests increased cervical cancer screening rates in 40/42 participation trials, especially among traditionally under-screened groups.  

These draft recommendations reflect new testing approvals by the FDA and concerted efforts by the National Cancer Institute (NCI) to improve access to cervical cancer screening. In May 2024, the FDA approved two HPV tests for self-collection (for now, only in the in-clinic setting)–the result of efforts by the NCI’s “Last Mile” Initiative to improve cervical cancer screening uptake. 

Bottom line (Is this practice changing?): Yes! Patient-collected HPV testing is a patient-centered approach that will no doubt increase cervical cancer screening rates. For now, it’s just approved for self-collection in healthcare settings, but we hope that in-home testing will be approved soon to lower access barriers for patients. 

Links

Links are included above.

Goals

Listeners will review recent practice-changing articles and medical news featured in The DIGEST.

Learning objectives

After listening to this episode listeners will…

1. Recognize that cfDNA can detect cancer in pregnancy
2. Discuss the use of vitamin K2 for nocturnal leg cramps
3. Recognize harm from as-needed anti-hypertensives in the hospital
4. Decide when short-course antibiotics are appropriate for bacteremia
5. Utilize patient-collected HPV tests for cervical cancer screening

Citation

Taranto N, Glick L, Williams PN, Watto MF. “#472 DIGEST: Cancer in Pregnancy, Vitamin K2 for Leg Cramps, PRN anti-hypertensives, GLP-1 Agonists for AUD, Short Course Antibiotics”. The Curbsiders Internal Medicine Podcast. thecurbsiders.com/category/curbsiders-podcast February 24, 2025.