Digest 70: A Hearty Halloween Edition

October 31, 2025 | By Nora Taranto

Welcome Back to The Curbsiders Digest!

In this special Halloween issue, we discuss the latest insights on aspirin + DOAC risk in chronic CAD, interpreting CAC scores in symptomatic patients, cancer genetics in the general population, and so much more! 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 70

10/31/2025

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. 
-Beth Garbitelli MD, Joshua Gilman MD, Laura Glick MD

• Harm from long-term aspirin + oral anticoagulation in high-risk CAD? NEJM recently published the Aquatic Trial, a multi-center, double blind, randomized, placebo-controlled trial comparing aspirin vs placebo in patients with high atherosclerotic risk on baseline anticoagulation (AC). 872 patients with coronary artery disease (CAD) and high atherothrombotic risk, a coronary stent placed  >6 months prior to enrollment, and who were also on oral AC were randomized to aspirin (100mg) or placebo. Patients also continued AC after randomization. High atherothrombotic risk was defined as prior acute coronary syndrome (ACS) requiring stent placement or a percutaneous coronary intervention for non-ACS related reasons with additional risk factors (e.g. diabetes, chronic kidney disease, peripheral artery disease). The trial was stopped early, after a median follow up of 2.2 years, because of excess death from any cause in the aspirin group. The primary outcome (composite of cardiovascular death, myocardial infarction, stroke, systemic embolism, coronary revascularization, or acute limb ischemia) occurred in 16.9% of patients in the aspirin group compared to 12.1% in the placebo group (HR 1.53, 95% CI 1.07-2.18, p=0.02). Death from any cause was higher in the aspirin group (13.4% vs 8.4%; HR 1.72, 95% CI 1.14-2.58, p=0.01), with a >3 fold increase risk of major bleeding in patients with aspirin (10.2% vs 3.4%, HR 3.35, 95% CI 1.87-6.00; p <0.001). (JG) 
• Cancer Gene Prevalence in the US Population. A cross sectional research study just published in JAMA aimed to estimate the population level prevalence of pathogenic or likely pathogenic variants (P/LPVs) in key cancer susceptibility genes in >414,000 US participants in the NIH All of Us Research Program. 3454 unique P/LPVs in 72 genes were identified in 20,968 unique individuals (5.05% of the total population), higher than prior estimates for the general population. There was significant variation in variant prevalence across self-reported racial groups, with the lowest prevalence among Asian participants and the highest (5.72%) among White participants. The three mutations with the highest prevalence were the MUTYH gene (1.33%) the BRCA2 gene (0.42%) and MITF gene (0.37%). There was a significant difference between carriers compared to non-carriers in the prevalence of cancer (26.4% vs 19.7%), age of first cancer diagnosis, and those with one or more family members with a history of cancer. (JG) 
• Acupuncture for Geriatric Back Pain?! Chronic lower back pain in our geriatric patients is an evergreen problem in primary care.  A recent JAMA Open study offers more evidence for multimodality pain control with acupuncture for back pain relief.  Investigators conducted a multi-center, randomized controlled trial with 800 patients randomized to three groups: standard acupuncture, standard acupuncture plus maintenance (an additional 4-6 sessions), or usual care. Response to intervention was measured via standardized disability scoring questionnaires well as pain intensity. Patients who were randomized to the acupuncture groups reported improved scoring on the disability questionnaire as well as improvement in pain intensity. Notably, the pain scale improvements were more pronounced in the maintenance acupuncture group. Both the standard and maintenance approaches had improvements over usual care that were persistent after a year. (BG) 
• High-dose Influenza Vaccine Effectiveness against Hospitalization in Older Adults. A recent NEJM article reported results from DANFLU-2, a large Danish randomized trial of over 330,000 adults aged 65 and older, comparing high-dose versus standard-dose influenza vaccines across three influenza seasons (2022-2025).  The primary outcome—hospitalization for influenza or pneumonia—occurred in 0.68% of high-dose recipients versus 0.73% with standard-dose, a non-significant 5.9% relative vaccine effectiveness (95% CI, — 2.1% to 13.4%; p = 0.14). However, influenza-specific hospitalizations were significantly lower in the high-dose vaccine group (relative vaccine effectiveness ~44%), while hospitalizations for pneumonia, cardiorespiratory disease, all cause, or death were similar between the two groups. Both vaccines were safe, with comparable rates of serious adverse events. (LG) 
• An FDA Approval for MASH. In August 2025, the U.S. Food and Drug Administration (FDA) granted accelerated approval to semaglutide as the first Glucagon-like peptide-1 agonists (GLP-1) for adults with metabolic dysfunction–associated steatohepatitis (MASH) and moderate-to-advanced liver fibrosis (without cirrhosis). The decision was based on interim results from the ongoing Phase 3 ESSENCE trial, which showed that semaglutide significantly improved liver scarring compared with placebo. At week 72, 63% of participants receiving semaglutide had MASH resolution and no worsening of liver scarring, compared to 34% of those receiving placebo (with a parallel improvement in liver scarring in a greater proportion of individuals receiving semaglutide than placebo). The approval is contingent on ongoing trials to confirm long-term benefits on liver-related outcomes and includes that semaglutide should be used with lifestyle modifications including exercise and diet. This marks a major milestone for treating MASH—a common and serious liver disease previously lacking effective medical therapies. This approval comes after an earlier approval in March 2024 of resmetirom for noncirrhotic MASH with fibrosis. (LG)

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 you’ve managed to escape a pickleball-related injury thus far, you may be one of the lucky few – according to a recent article published in JAMA Ophthalmology, pickleball-related eye injuries are spiking faster than a drop shot, with a significant estimated increase in incidence by approximately 405 cases annually from 2021 to 2024 (95% CI 288-522 cases; P=0.004). Adults aged 50 and up are taking the biggest hit—quite literally—with nearly a 39% higher incidence compared to younger players (95% CI 6–65%; P = 0.03). Reported injuries range from hyphema and globe trauma to orbital fractures and retinal detachment, all courtesy of rogue balls and paddles and the occasional graceless fall. As the pickleball craze continues, consider adding some eye protection to your courtside ensemble.

– Jennifer DeSalvo MD

The Main Course

Calcium –A New Cardiac Biomarker? 
The late twentieth century witnessed the birth of quantitative coronary artery calcium (CAC) scoring as a noninvasive method to measure the calcified atherosclerotic plaque burden.   Multiple studies have demonstrated that higher CAC scores–which can be calculated based on measurements taken from a computed tomography (CT) scan of the heart–correlate with a greater extent of angiographic coronary artery disease and increased risk of atherosclerotic cardiovascular disease (ASCVD) including myocardial infarction, strokes, cardiovascular-related death, and all-cause mortality. Over the last decade, the American College of Cardiology (ACC) and American Heart Association (AHA) have published multiple guidelines (including the 2018 guidelines and the 2022 ACC/AHA Expert Consensus) recommending CAC scoring to help refine atherosclerotic cardiovascular disease (ASCVD) risk estimates beyond traditional risk factors for primary prevention statin therapy.  Specifically, the 2018 Guideline on the Management of Blood Cholesterol suggests consideration of CAC scoring in asymptomatic adults (40-75 years old) without diabetes who have an LDL of 70-189 mg/dL and a 10-year ASCVD risk of 7.5% to <20% to determine which patients would most benefit from initiation of statin therapy for primary prevention.  Other international guideline recommendations take a generally similar approach, using CAC scores to stratify patient risk and to define treatment thresholds for primary prevention.

Interpretation of CAC Scores and The “Down-Risk” Approach 
The 2018 ACC/AHA guidelines have defined specific thresholds for treatment based on thresholds of 0 and 100 (and this is paralleled in other international guidelines). A CAC score of 0 suggests no detectable, calcified plaque and implies a lower short-term risk of ASCVD events (a.k.a. the “power of zero”) – with recommendations to consider withholding or delaying statin initiation in favor of lifestyle modifications in those without additional risk factors.  In the guidelines, this de-escalation approach for individuals (who would otherwise qualify for a statin based on 10-year ASCVD risk) based on a CAC score of 0 is termed “down-risk”-ing.  Meanwhile, a CAC score of 1-99 indicates mild calcification and implies low-to-moderate ASCVD risk. The guidelines favor initiation of statin therapy in this cohort, especially if age ≥55 years old (though those <55 years may consider lifestyle changes). And a CAC score ≥100 or ≥75 percentile for age/sex indicates moderate calcification and implies intermediate to high ASCVD risk, with recommendations to consider upgrading individual risk and a strong recommendation for initiation of statin therapy to a target goal LDL-C<70 mg/dL.   

But patient selection is key in down-risking patients based on a CAC score of zero.  The guidelines reiterate that this approach should not apply to those with risk factors such as smoking, diabetes, a strong family history, or those with chronic inflammatory conditions. This is because CAC scoring measures calcified plaque, or chronic, generally stable atherosclerotic lesions. CAC scoring does NOT account for early non-calcified soft plaque–which may be vulnerable to rupture and lead to acute coronary syndrome. 

The Power of Zero in Symptomatic Patients? 
Several studies have brought the challenge of interpreting CAC scores of zero–in particular in symptomatic patients–to light over the last few months. The first study, just published in AJR, looked at patients in the prospective observational registry CONFIRM who had clinical symptoms and therefore underwent coronary CTAs, and were then followed for coronary events over ~3 years of follow-up. The investigators compared 108 patients who ultimately developed Acute Coronary Syndrome (ACS) to 108 who did not, and found that nearly a quarter  (23%) of patients who developed ACS had a CAC score of zero. Patients with a CAC of zero and ACS had a significant burden of noncalcified fibrous, fibrofatty, and necrotic-core plaque, compared to control patients without ACS.  Meanwhile, another cohort study in Eur Heart J followed 22,777 patients with a CAC score of 0 who underwent coronary CT for symptoms between 2008 and 2021. Non-calcified plaques were identified in 11% of patients in this cohort, and patients were followed for a median of 7.1  years. Elevated LDL-C was associated with a higher risk of having a non-calcified plaque (aOR 1.21 of having non-calcified plaque for every 1 mmol/L higher LDL-C, 95% CI 1.15-1.27) and with higher relative risk of future events in this cohort (aHR of 1.28, 95% CI 1.13-1.46).  This risk was most pronounced in individuals aged  ≤45 years, emphasizing the importance of lipid-lower therapies even in younger individuals with a CAC of zero. 

These studies raise an important point about the limitations of CAC score interpretation in symptomatic patients–in addition to patients with risk factors or chronic inflammatory conditions that might increase the risk of having non-calcified plaque.  Several articles have raised additional questions about the value of zero in younger patients and women, and whether using CAC scores of zero to down-risk asymptomatic patients actually may lead to worse lifestyle modification and modifiable risk reduction.  But for now, these studies serve as a cautious reminder about how to use (or not use) the CAC score to estimate risk in symptomatic individuals. 

Read The 2018 Guidelines HERE!

Digestifs

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

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This week on The Curbsiders: Episode #502 will get you up to speed on Inflammatory Bowel Disease. This episode, with Dr. Aline Charabarty, covers the workup, the differences between Ulcerative Colitis and Crohn’s Disease, the basics of management, and the preventive health to be aware of in these patients. 

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The Curbsiders Digest

Issue 70

Editor in Chief: Nora Taranto MD

Banner: Kate Grant  MBChB, DipGUMed

Jennifer DeSalvo,  Josh Gilman,  Laura Glick, and Nora Taranto report no disclosures.

Kate Grant reports no disclosures.

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