Digest 64: April Showers (Us in Data)

April 18, 2025 | By Nora Taranto

Welcome Back to The Curbsiders Digest!

In this issue, we discuss lower dose DOACs in cancer-associated VTE prevention, plus steroids in high-CRP CAP, a shingles vaccine to prevent dementia, 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 64

04/18/2025

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. 
-Jennifer DeSalvo MD, Laura Glick MD

• A vaccine to protect against both shingles and dementia? Receiving the zoster vaccine may also lower risk of dementia, according to a recently published article in Nature. This large-scale natural experiment was conducted in Wales based on specific age eligibility cutoffs for the live-attenuated zoster vaccine (with those born before September 2, 1933 always ineligible and those born after that date eligible for at least 1 year for the vaccine starting in 2013). The authors determined birthdate-based vaccine eligibility through electronic health records and assessed the risk of dementia over 7 years of follow up using regression discontinuity.  In addition to reducing the occurrence of shingles, receiving the live-attenuated zoster vaccine reduced the likelihood of a new dementia diagnosis by 3.5% (95% CI 0.6–7.1%, P=0.019), corresponding to a 20% relative reduction (95% CI 6.5-33.4%) over the seven-year follow-up period.  Notably, this study’s follow-up occurred prior to UK availability of the recombinant shingles vaccine (Shingrix). (LG)
• CRP to guide steroids in Community-Acquired Pneumonia (CAP)? In this meta-analysis published in Lancet Respiratory Medicine, researchers compared adjuvant corticosteroid use versus placebo in over 3200 hospitalized patients with CAP from eight randomized controlled trials, with a primary endpoint of 30-day all-cause mortality. Patients were classified by pneumonia severity index and baseline C-reactive protein (CRP) levels (within 0-48 hours of presentation) to assess the heterogeneity of treatment effect from steroids. Patients with elevated baseline CRP levels (CRP >204 mg/L) had a significant mortality reduction with corticosteroid use (6.1% vs. 13.0%; OR 0.43, 95% CI, 0.25–0.76, p-interaction = 0.026), while patients with lower CRP levels (CRP ≤ 204 mg/L) had no significant benefit with steroids (13% in both groups; OR 0.98). (LG)
• Intermittent fasting or daily caloric restriction for weight loss? A randomized trial just published in Annals of Internal Medicine assessed weight loss in 165 overweight/obese adults who were randomly assigned to follow a 4:3 intermittent-fasting diet (reduced caloric intake by 80% on 3 non-consecutive days per week and no restrictions on the other 4 days) or a daily calorie-restricted diet (daily 34% calorie reduction), with a primary outcome of change in body weight at 12 months. Both groups received behavioral support/gym memberships and were encouraged exercise at least 300 minutes weekly.  Ultimately, the 4:3 intermittent fasting group lost an average of 7.6% of their body weight, compared to a 5% decrease in the daily caloric restriction group at 12 months (with a mean difference in weight loss between the two groups of 2.89 kg; 95% CI 5.65-0.14, P = 0.040). (LG)
• FRESH(en)-UP with fluid goals in heart failure. In this multicenter open-label clinical trial recently published in Nature Medicine, outpatients with chronic heart failure (HF) were randomized to receiving advice for liberal fluid intake versus a 1.5 liter fluid restriction, with health status assessed by patient-reported Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS) at 3 months. Among the 504 study participants (mean age 69, 67% male, 52% with HF with reduced ejection fraction), health status was similar in the liberal fluid intake cohort compared to the fluid restricted group, with a mean difference of 2.17 (95% CI -0.06 to 4.39, p=0.06) adjusted for baseline scores. The fluid-restriction group had higher perceived thirst distress, and no significant differences for safety events were observed between groups (including a composite of death, HF and all-cause hospitalizations or intravenous loop diuretic use). These findings call into question the utility (and benefit) of fluid restriction in the outpatient management of patients with chronic HF. (JD)
• Medicine for the SOUL. In SOUL, an international multicenter, double-blind, superiority trial recently published in NEJM, 9650 patients aged >50 years with type 2 diabetes (hemoglobin A1C 6.5-10%) and known atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), or both were randomized to once-daily oral semaglutide (14 mg max dose) or placebo, on top of standard care. Compared to placebo, patients receiving oral semaglutide had significantly fewer major adverse cardiovascular events (a composite of cardiovascular-related death, nonfatal myocardial infarction, or nonfatal stroke) over a mean of 48 months (13.8% in placebo versus 12% with semaglutide, HR 0.86, 95% CI 0.77-0.96, p=0.006), with the greatest difference in rates of nonfatal myocardial infarction (4% with semaglutide versus 5.2% with placebo, HR 0.74). A prespecified analysis at 3 years demonstrated a 2% absolute risk reduction and a number needed to treat (NNT) of 50 to prevent one event. Secondary outcomes were not significantly different between groups, nor was the incidence of serious adverse events. (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.

AI-guided lung ultrasound–Is AI the new expert?
Having difficulty acquiring point-of-care ultrasound (POCUS) images during a rapid response in the hospital for acute respiratory distress? Enter artificial intelligence (AI)-guided lung ultrasound, which could help clinicians with minimal POCUS training obtain high-quality diagnostic images.  In a multicenter validation trial just published in JAMA Cardiology, 176 participants underwent one lung POCUS examination by a trained healthcare professional (THCP) using “Lung Guidance AI”,  in addition to a second examination by an ultrasound-fellowship trained expert.  Most THCPs were registered nurses and medical assistants without any formal training in ultrasound.  Of these, 98% of TCHP-acquired studies obtained with Lung Guidance AI were of sufficient diagnostic quality when evaluated by an independent panel of blinded readers, without a significant difference in image quality compared to expert-acquired studies.  Interestingly, AI-guided POCUS acquisition and interpretation for clinical assessment have also been studied in cardiac POCUS – read more about real world applications of this technology discussed by the authors here!

– Jennifer DeSalvo MD

The Main Course

Alyssa Mancini MD

A Low-Dose Approach to Cancer-Related Clots?

Reduced-Dose Apixaban to Prevent Recurrent VTE in Patients with Cancer
Patients with cancer are in a tough spot, when it comes to clots. They’re at higher risk for venous thromboembolism (VTE) than the general population and at higher risk of recurrent events despite anticoagulation–but also at high risk of bleeding complications due to anticoagulation.  Clinical practice guidelines from major medical societies (e.g. ASH, ASCO, CHEST) recommend anticoagulation with a direct oral anticoagulant (DOAC) or low-molecular-weight heparin (LMWH) for an initial period of 6 months after VTE diagnosis in those with active cancer.  These guidelines also suggest continuing long-term anticoagulation in patients with active cancer (e.g. those with metastatic cancer or receiving chemotherapy), simultaneously acknowledging limited evidence to support this approach and the need for clinical judgement to weigh the risks and benefits of anticoagulation.

The data to consider? Well, the 2013 AMPLIFY-EXT study found that extended anticoagulation with apixaban at both full-dose and reduced-dose reduced the risk of recurrent VTE without increasing the rate of major bleeding in the general population. However, data on use in patients with cancer were limited. Enter the API-CAT (Apixaban Cancer Associated Thrombosis) trial, which compared reduced-dose apixaban to full-dose apixaban for the prevention of recurrent VTE in patients with active cancer.

Breaking it down:
The API-CAT trial, results of which were recently published in NEJM, was an international, randomized, double-blind, noninferiority trial that included 1766 patients with active cancer and VTE (either proximal deep-vein thrombosis (DVT) of the lower limb or symptomatic/incidental pulmonary embolism (PE) in a segmental or larger pulmonary artery) who had completed at least 6 months of anticoagulation with LMWH, DOAC, or vitamin K antagonist (VKA). Patients were randomly assigned (1:1) to receive oral apixaban at a reduced dose (2.5 mg) or full dose (5 mg) twice daily for 12 months. The primary efficacy outcome – centrally adjudicated fatal or nonfatal recurrent VTE – was assessed in a noninferiority analysis, with a prespecified noninferiority margin of 2 for the upper boundary of the 95% confidence interval of the subdistribution hazard (a.k.a. subhazard) ratio.

Getting into the statistical weeds – This noninferiority margin was set using the estimated risk of recurrent VTE with full-dose apixaban compared to placebo (7.4%) in AMPLIFY-EXT, with an estimated preservation of 50% of this effect with reduced-dose apixaban, leading to an upper boundary of 1.92 (conservatively rounded to 2). And for those (like me) less familiar with subhazard ratios: they are used to estimate treatment effects in the setting of competing risks (see Fine and Grey methodology and section 3.4.2 of the trial protocol for more)–for example, in the high-risk cancer population, where death can be viewed as a competing risk that prevents assessment of recurrent VTE.

Ultimately, API-CAT patients had a median age of 69 years, 43.4% were men, and most (76%) were being treated for a pulmonary embolism (PE). The most frequent sites of primary cancer were breast (23%), colon or rectum (15%), gynecologic organs (12%), and lung (11%). A majority of patients received DOACs (43.6%) and LMWH (54.8%) for their index VTE event. In the intention-to-treat analysis, recurrent VTE occurred in 2.1% of patients in the reduced-dose group and 2.8% in the full-dose group (adjusted subhazard ratio 0.76, 95% CI 0.41 to 1.41, p=0.001 for noninferiority).  Clinically relevant bleeding occurred in 12.1% of patients in the reduced-dose group and 15.6% in the full-dose group (adjusted subhazard ratio 0.75, 95% CI 0.58 to 0.97, p=0.03 for superiority), most commonly in the gastrointestinal tract. Two fatal major bleeding events occurred in each group.

What does this mean?
In API-CAT, extended anticoagulation with reduced-dose apixaban was noninferior to full-dose apixaban for the prevention of recurrent VTE in patients with active cancer. Furthermore, use of reduced-dose apixaban led to less clinically relevant bleeding (an important clinical endpoint for patients beyond major bleeding) than full-dose apixaban. A strength of this trial is its generalizability – in that the patient population is largely reflective of patients in routine practice who are considered for extended anticoagulation in terms of age, cancer site, and extent of cancer. The study does have limitations – the incidence of recurrent VTE was low in both groups (though this is consistent with previously published data), and efficacy and safety data beyond 12 months of follow-up remain uncertain. But given the results above, reduced-dose anticoagulation for long-term prevention is likely to make its way into guidelines and clinical decision-making.

Read The Study Here!

Digestifs

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This week on The Curbsiders: In Episode #479, Dr. Jessi Gold leads us through the management of treatment-resistant depression. Packed with pearls about how to switch antidepressants, what to consider as adjunctive medications, and what novel therapies exist, this one’s sure to earn a gold star from our listeners!    

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The Curbsiders Digest

Issue 64

Editor in Chief: Nora Taranto MD

Banner: Kate Grant  MBChB, DipGUMed

Jennifer DeSalvo,  Laura Glick, Alyssa Mancini, and Nora Taranto report no disclosures.
Kate Grant reports no disclosures.

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