Digest 48: Hefty Holiday Highlights Edition

December 23, 2023 | By

The Curbsiders Digest

Welcome Back to The Curbsiders Digest!

In this issue, we feature  Subclinical AFib and AC, COVID Viral Rebound, Cannabis in Pregnancy, GLP1 adverse events, and ADCs for Bladder Cancer– plus Picks of the Year from Matt, Paul, and Rahul. 
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 48


Appetizers (to whet your appetite) 

Palate Cleanser (aka the melon part of the meal) 

The Main Course

A Digestif or two


Brought to you hot off the stove, from a variety of specialties. Delivered in super tasty, bite-sized morsels. 
Beth Garbitelli MD, Alyssa Mancini MD, Hannah Smith MD 

  • The Covid Strikes BackA recent observational cohort study in Annals IM evaluated the frequency of viral rebound in 127 outpatients with acute COVID-19, and the association with nirmatrelvir-ritonavir (aka Paxlovid). Virologic rebound was defined as a positive Covid culture after a negative test, or sustained, elevated viral load above a certain threshold after an initial decrease. The patients receiving nirmatrelvir–ritonavir were (unsurprisingly) older and more immunosuppressed. However, even accounting for these factors in multivariate analysis, only nirmatrelvir–ritonavir use was associated with virologic rebound, occurring in 21% of those taking the drug and 2% of those without treatment. Rebound Covid occurred more in those who started therapy within 2 days of symptom onset. Alarmingly, patients with viral rebound likely have prolonged transmission risk, with a median 14 days of viral shedding!  (BG) 
  •  Treating advanced bladder cancer, made EV Peasy? Maybe not quite, but on December 15, the FDA announced approval for combination therapy enfortumab vedotin-ejfv (EV) and pembrolizumab for locally advanced or metastatic urothelial cancer.  EV is an antibody-drug conjugate (ADC) that delivers an anti-tumor drug, MMAE, to cells (like bladder cancer cells) expressing Nectin-4 on their surface. The FDA reviewed an open-label study (EV-302) of 886 patients with advanced urothelial cancer and no prior systemic treatment, randomized to enfortumab vedotin-ejfv with pembrolizumab (EV +Pembro), or gemcitabine with cisplatin or carboplatin. Overall survival in the EV+Pembro trial arm was twice as long as with standard-of-care (31.5 months vs. 16.1 months), with longer progression free survival and higher overall response rates. More common serious side effects with EV+Pembro included rash, peripheral neuropathy, and hyperglycemia. (BG)
  • Decolonization for all, and for all (nursing home residents) …a lower risk of hospitalization from infection? NEJM recently published a cluster-randomized trial at 28 nursing homes (including nearly 29,000 residents) looking at decolonization versus routine-care bathing. Nursing homes were randomized to universal decolonization (chlorhexidine for routine bathing and nasal povidone-iodine twice daily for 5 days every other week) or routine-care bathing, with 18-month baseline and 18-month intervention periods.  There was a decreased risk of hospital transfer because of infection in the decolonization group (difference in risk ratio of 16.6% compared to routine care). With decolonization, 35.5% experienced hospital transfers for any reason during baseline, down to 32.4% during the intervention (RR 0.92), with a risk ratio difference of 14.6% versus routine care. Overall, the number-needed-to-treat (NNT) to prevent one infection-related hospitalization was 9.7, and 8.9 to prevent one hospitalization for any reason. (AM) Cannabis and Adverse Pregnancy Outcomes. JAMA recently published an analysis of the multicenter cohort study nu-MoM2b looking at cannabis exposure and a primary composite outcome of adverse pregnancy outcomes (small-for-gestational-age birth, medically indicated preterm birth, stillbirth, or hypertensive disorders of pregnancy). Of 9257 participants analyzed, 6.6% were exposed to cannabis during pregnancy (of whom 32% had first trimester exposure only), as confirmed by urine assay.  After adjusting for confounders, the primary composite outcome occurred in 25.9% with cannabis exposure vs. 17.4% without exposure (adjusted RR 1.27, 95% CI 1.1-1.5). Using a 3-category cannabis exposure model (no exposure vs. first trimester exposure vs. ongoing exposure), cannabis use only during the first trimester was not associated with the primary composite outcome, but ongoing use was. (AM) 
  • GI Problems with GLP1s? This cohort study published in JAMA assessed the incidence of gastrointestinal adverse events in >5,400 patients prescribed GLP-1 agonists (liraglutide or semaglutide) or a non-GLP-1 medication (bupropion-naltrexone) for weight loss.  Most patients in this random sample from a national claims database were prescribed liraglutide, and all had a diagnosis of obesity but no diagnosis of diabetes. There was a significantly increased risk of pancreatitis, bowel obstruction, and gastroparesis in those prescribed GLP1 agonists compared to bupropion-naltrexone–with hazard ratios of 9.1, 4.2, and 3.7, respectively.  Among the 4144 patients prescribed liraglutide, the incidence rates of pancreatitis and bowel obstruction were ~8/1000 person-years, compared to 1-2/1000 with bupropion-naltrexone. There was no significant difference in biliary disease incidence. (HS)

    A Few (Extra) Highlights from 2023, from Rahul, Matt, and Paul: 
  • A Major Milestone in Gene Therapy. The first gene therapies for sickle cell disease just received FDA approval! Both therapies involve myeloablative chemotherapy and an autologous transplant of a patient’s own genetically modified hematopoietic stem cells, but differ in how they treat the disease. Exagamglogene autotemcel, or “exa-cel,” (Casvegy™) uses the CRISPR/Cas9 gene editing system to disable the patient’s “off” switch for fetal hemoglobin production, leading to increased hemoglobin F levels. Meanwhile, lovotibeglogene autotemcel, or “lovo-cel,” (Lyfgenia™) uses a lentiviral vector to restore functional copies of the beta globin gene, allowing production of a genetically modified hemoglobin A. Both appear highly effective: 29/31 (94%) patients in the single-arm exa-cel trial experienced no vaso-occlusive crises in the year following administration (from a baseline of 3.5 crises / year), and 28/32 (88%) patients in the single-arm lova-cel trial experienced complete remission of vaso-occlusive crises 6-18 months after administration. While we await long-term safety data, we can be sure that the population impact of these exciting new therapies will hinge on access, and therefore, price. (Rahul Ganatra MD MPH)

  • Cough it up. Despite limited evidence, over-the-counter (OTC) cough and cold medicines are a >$10 billion/year industry (per Statista) featuring combinations of antihistamines, antitussives, analgesics, and decongestants.  Phenylephrine, the decongestant found in most OTC products in the US, has poor oral bioavailability (inactivated by the gut & liver) and does not affect nasal congestion when taken orally (Kanfer, 1993; Hatton, 2007; Meltzer, 2015).  An FDA advisory committee therefore recently recommended that oral phenylephrine be removed from the OTC monograph of drugs “generally regarded as safe and effective”–opening the door to a possible removal from the market. The Bottom line? Prescribe topical therapies for nasal congestion instead of oral phenylephrine and recognize that the evidence is limited for most other OTC remedies (guaifenesin, benzonatate, etc.). This piece by C&EN nicely summarizes things. (Matt Watto MD FACP) 

  • A REPRIEVE from CAD. One of the most exciting studies in 2023 was the REPRIEVE trial, published in August in NEJM.  While HIV infection is recognized as a risk factor for cardiovascular disease, data on long-term cardiovascular outcomes are limited, and the Pooled Cohort Equation, recommended to estimate ASCVD risk, actually underestimates this risk, with HIV regarded as a “risk-enhancer” in major guidelines. To better understand underlying ASCVD risk and the benefit of statins in this setting, REPRIEVE randomized 7769 persons living with HIV (PLWH) on antiretroviral therapy (ART) and low-to-moderate risk for atherosclerotic cardiovascular disease (ASCVD) to either pitavastatin 4 mg or placebo. The trial was stopped early due to efficacy after a median follow up of 5.1 years, as the patients in the pitavastatin arm had a significantly lower risk of the primary outcome of major cardiovascular event (4.81 per 1000 person-years in the pitavastatin group and 7.32 per 1000 person-years in the placebo group (hazard ratio, 0.65; 95% confidence interval [CI], 0.48 to 0.90; P = 0.002). Incident diabetes and muscle-related symptoms were more common with pitavastatin.  I suspect that this landmark trial will fundamentally change the way we manage primary prevention in persons living with HIV, and may lead to major guideline recommendations for statin therapy in all adults living with HIV as they’re recommended for patients with diabetes. It is very exciting to see this evidence gap addressed in such a concrete, well-done, and public way. (Paul Williams MD FACP) 

Palate Cleanser

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

It’s baking season! What are we whipping up at The Digest? 

Jammy Thumbprints – Beth Garbitelli

Cardamom Babka (These are my favorite babka doughs – Breads Bakery, Smitten Kitchen) and for the cardamom filling – mix up ½ cup of white sugar, ½ cup (1 stick) of butter, ¼ cup of brown sugar, 1 tablespoon of cardamom, coat with simple syrup as directed after baking. And be sure to line your loaf pan with parchment paper) – Beth Garbitelli

Somali Cake – Sent in by Asha Mohamud, by way of Beth Garbitelli   

Cornmeal Lime Shortbread Fans  – Beth Garbitelli 

Cinnamon Stars (Zimtsterne) These are my favorite absolute holiday cookies, and will have everyone around you eating one after the next. – Nora Taranto 

Confetti Cookies (Smitten Kitchen) – Nora Taranto

The Main Course

Jennifer DeSalvo MD  

To Anticoagulate or No:

Ongoing Dilemmas in Device-Detected Atrial Fibrillation 
Stroke risk with atrial fibrillation–and recommendations for anticoagulation–may seem like old news.  But the advent of devices that detect transient atrial fibrillation (often asymptomatically) has created a new category of “device-detected” events of unclear clinical significance.  These device-detected atrial fibrillation (AF) or atrial high-rate episodes (AHRE) events increase the risk of atrial fibrillation recurrence, with a recent matched cohort study in Annals IM demonstrating that 1 in 3 hospitalized patients found to have transient new-onset AF had monitor-detected or clinical recurrence at 1 year.  Patients with device-detected AF/AHRE also have a higher risk of stroke than those without detected episodes–but this risk depends on episode duration and other clinical risk factors, with short episodes < 5 minutes not associated with events, and episodes > 24 hours associated with higher stroke risk (and uncertainty between those two extremes).  The benefit of oral anticoagulation in this population has not yet been well-established.   

The updated 2023 ACC/AHA guidelines address stroke risk and anticoagulation in device-detected AF/AHRE. For those with a CHA2DS2-VASc score ≥2 and device-detected AHRE ≥ 24 hours, they give a 2A recommendation, stating it is reasonable to initiate anticoagulation, using shared-decision making to account for individual patient risk. For shorter episodes (5 minutes – 24 hours) and patients with a higher CHA2DS2-VASc score (>3), they give a less-strong 2B recommendation, stating it may be reasonable to anticoagulate, using shared-decision making–with no benefit to anticoagulation in those with device-detected AHRE <5 minutes. All recommendations were based on level B (nonrandomized) evidence– with acknowledgement that the ARTESIA and NOAH-AFNET 6 trials were actively assessing oral anticoagulation in subclinical AF/AHRE < 24 hours. 

The Trial Data 
The double-blind, randomized, placebo-controlled NOAH-AFNET 6 trial, published in NEJM in September 2023, enrolled >2500 patients with subclinical, device-detected AHRE lasting >6 minutes, who were  ≥65 years old and who had either >1 additional CHA2DS2-VASc risk factor (except sex) or were over 75 years old. Patients were randomized to edoxaban or placebo (with 54% of the placebo arm receiving aspirin). The trial was terminated early, at 21 months median follow-up, given a higher incidence of the composite of death or major bleeding with edoxaban versus placebo (5.9% vs. 4.5% per patient-year, HR 1.31 95% CI 1.02 – 1.67)–without a significant reduction in the incidence of cardiovascular death, stroke, or systemic embolism.   Meanwhile, the ARTESIA trial, published in NEJM in November 2023, randomized >4000 patients > 55 years old, with a CHA2DS2-VASc score ≥3 and subclinical AF on monitoring devices (6 minutes – 24 hours) to apixaban or aspirin.  Over mean follow-up of 3.5 years, those randomized to apixaban had a lower risk of stroke or systemic embolism compared to aspirin (0.78% vs 1.24% per patient-year; HR 0.63; 95% CI 0.45-0.88) but also had a higher risk of major bleeding (1.71% vs 0.94% per patient-year; HR 1.8; 95% CI 1.26-2.57).  A meta-analysis published in Circulation combining these trial data further confirmed the decreased stroke/increased bleeding risk with oral anticoagulation in this setting.

So Where Do We Go From Here? 
We finally have trial data to consider in the higher-risk stroke population with transient, device-detected AF/AHRE. While the incidence of ischemic stroke with subclinical AF/AHRE appears quite low (around 1% per patient-year), the risk of disabling/fatal strokes was halved in those treated with apixaban compared to aspirin–at the cost of major bleeding (primarily GI).  Future subanalyses are needed to understand whether particular subgroups might benefit from (or be harmed by) anticoagulation in this setting, the duration of therapy needed to provide benefit, and how to screen for progression to sustained AF.  But for now, we may ultimately come back to the guidelines, and shared-decision making, with additional emphasis on stroke and bleeding risk factor modification–regardless of the decision to anticoagulate. 

 Read The AHA Guidelines HERE



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

Consolidate your learning with a Quiz!  

This week on The Curbsiders: We had a break this week from new episode content, but make sure you didn’t miss Episode #419 in the Rapid Response Series, a great primer on recognizing and treating sepsis with Dr. Mohleen Kang (@KangMohleen).  

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Until next time, keep that brain hole digesting! 

The Curbsiders Digest

Issue 48

Editor in Chief: Nora Taranto MD

Banner: Kate Grant  MBChB, DipGUMed


Beth Garbitelli,, Jennifer DeSalvo,  Alyssa Mancini, Hannah Smith, Nora Taranto, Matt Watto, and  Paul Williams report no disclosures. 

Rahul Ganatra reports equity in Abbott Labs; AbbVie Inc.; Becton Dickinson; Bristol Myers Squibb; Dexcom Inc.; Eli Lilly and Co.; Intuitive Surgical Inc.; Medtronic; Stryker Corp.; UnitedHealth Group Inc.; Thermo Fisher Scientific Inc.; Johnson & Johnson; Merck and Co. Inc.; Alcon SA; Cigna Corp.; Elevance Health Inc.; Zoetis Inc.

Kate Grant reports no disclosures


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Episode Credits

The Curbsiders Digest

Issue 48

Editor in Chief: Nora Taranto MD

Banner: Kate Grant  MBChB, DipGUMed

Disclosures: Beth Garbitelli,, Jennifer DeSalvo, Alyssa Mancini, Hannah Smith, Nora Taranto, Matt Watto, and Paul Williams report no disclosures. Rahul Ganatra reports equity in Abbott Labs; AbbVie Inc.; Becton Dickinson; Bristol Myers Squibb; Dexcom Inc.; Eli Lilly and Co.; Intuitive Surgical Inc.; Medtronic; Stryker Corp.; UnitedHealth Group Inc.; Thermo Fisher Scientific Inc.; Johnson & Johnson; Merck and Co. Inc.; Alcon SA; Cigna Corp.; Elevance Health Inc.; Zoetis Inc.

Kate Grant reports no disclosures

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