#506 DIGEST-Hotcakes: PSA Screening, Acetaminophen and Autism, COVID19 Vaccines and Cancer, Aspirin and Anticoagulation in Coronary Artery Disease

December 2, 2025 | By Rahul Ganatra

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Join us as we review recent articles and news featured in The DIGEST #70, including PSA screening, acetaminophen and autism, COVID19 vaccines and cancer, and aspirin and anticoagulation in coronary artery disease. Fill your brain hole with a delicious stack of hotcakes! Featuring Drs. Paul Williams (@PaulNWilliamz), Nora Taranto (@norataranto), Rahul Ganatra (@rbganatra), Laura Glick (@lauraglick) and Matt Watto (@doctorwatto).

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Show Segments

• Intro, disclaimer
• Prostate Cancer Screening
• Acetaminophen and Autism
• COVID19 vaccines and cancer risk
• Aspirin and anticoagulation in coronary artery disease
• Outro

This show is based on articles and news featured in The DIGEST #70, #71 (to come!), as well as some material covered nowhere else!

Hot take #1 PSA Screening (Nora)

Covered by Dr. Beth Garbitelli in Digest #71

Roobol MJ et al; European Study of Prostate Cancer Screening – 23-year follow up. N Engl J Med. 2025 Oct 29; 393:1669-1680. DOI: 10.1056/NEJMoa2503223 

Additional/Recommended Reading:

• NEJM Editorial by Andrew Vickers

Background and Significance:  Prostate cancer, if caught early, remains a curable disease – but exactly how to screen for prostate cancer using the prostate-specific antigen (PSA) has long been a subject of debate. Two other large randomized trials have evaluated prostate cancer screening: the UK CAP study compared a single invitation to PSA screening or standard care, while the US PLCO study compared PSA screening for 6 years (+ digital rectal exams for 4 years) to control. While the CAP study found lower prostate-cancer related deaths at 15 years in the screening arm, the PLCO did not (though almost 90% of men in the control arm received PSA testing). Now, the European Randomized Study of Screening for Prostate Cancer (ERSPC) has published its 23-year (final) follow-up. 

Summary and Appraisal: This was a positive study. At a median follow-up of 23 years, prostate cancer mortality was 13% lower in the screening group than in the control group (Rate Ratio 0.87, 95% CI 0.8-0.95), with an absolute risk reduction of 0.22% (95% CI 0.1 – 0.34%). At 23 years of follow-up, 1 death from prostate cancer was prevented for every 456 men who were invited for screening, and one death was prevented for every 12 men who were diagnosed. 83% of patients in the screening group underwent at least one screening, and there was high compliance with prostate biopsies after a positive result. The excess incidence of prostate cancer diagnoses was 27 cases of prostate cancer per 1,000 men (95% CI 23 – 30). 

Bottom line (Is this practice changing?): This study reassures me that screening is beneficial, but repeat testing and decades of follow-up are needed to realize that benefit. Even though mortality is not the only important outcome, overdiagnosis and overtreatment remain real problems. Improvements in diagnostic testing, including more sensitive tests and MRI guidance for biopsies, can hopefully limit the harms of overdiagnosis until we determine the best screening strategy. 

Hot take #2 Acetaminophen and Autism (Rahul)

Not previously covered in a digest (does that make it indigestible)?

Prada D, Ritz B, Bauer AZ, Baccarelli AA. Evaluation of the evidence on acetaminophen use and neurodevelopmental disorders using the Navigation Guide methodology. Environmental Health. 2025;24(1):56.    

Additional/Recommended Reading:

• Sheikh J, Allotey J, Sobhy S, et al. Maternal paracetamol (Acetaminophen) use during pregnancy and risk of autism spectrum disorder and attention deficit/hyperactivity disorder in offspring: umbrella review of systematic reviews. BMJ. 2025;391:e088141.
• https://thehill.com/policy/healthcare/5582061-kennedy-trump-tylenol-autism/

Background and Significance: Recently, concern has been raised about the possible role of maternal acetaminophen (APAP) use in the pathogenesis of autism spectrum disorders. This systematic review sought to answer whether APAP use during pregnancy is associated with subsequent diagnoses of autism, ADHD, or other neurodevelopmental disorders (NDDs) in children. This study formed the basis for the US FDA’s September 2025 label change to APAP and letter to physicians about the risks of APAP during pregnancy. Independent of those actions, clinicians with a stake in promoting maternal and child health will face questions about the safety of APAP in pregnancy.

Summary and Appraisal: This systematic review (without a meta-analysis) included 46 observational studies, the majority of which had at least some risk of bias in exposure assessment. The authors concluded that maternal APAP use is associated with NDDs, and that pregnant women should limit their exposure to it. However, there are at least four threats to this conclusion. First, maternal fever may influence autism risk, creating confounding by indication in the relationship between APAP use and autism (see the directed acyclic graph below). Second, genetic factors are thought to account for ~80% of the risk of autism, meaning APAP lacks specificity as a putative cause. Third, studies that addressed unmeasured confounding using sibling-controlled analyses found no association. Finally, the effect sizes found in studies reporting an association were generally small, which is itself a threat to causal inference in observational studies where confounding could completely explain modest associations.

Bottom line (Is this practice changing?): There is a dearth of high-quality information available to help pregnant women decide whether the risks of APAP use during pregnancy outweigh the benefits. That said, there are clear harms to alternatives like NSAIDs and aspirin which APAP does not have, and there are also clear harms (including maternal suffering) of fever in pregnancy. The APAP label already says to ask a healthcare professional before use, a position supported by professional societies like ACOG. So, no, I don’t think this is practice-changing.  

Hot take #3 COVID19 Vaccines and Cancer Risk (Adam Cifu)

Also indigestible…

1-year risks of cancers associated with COVID-19 vaccination: a large population-based cohort study in South Korea

Additional/Recommended Reading: 

• Blue After-Visit Summaries, COVID Vaccines, and Cancer

Background and Significance: Despite their effectiveness in preventing hospitalization and death, COVID vaccines have been the target of misinformation and disinformation. This article, purporting to show an association between COVID19 vaccines and elevated risk of cancer diagnoses, has received attention from those skeptical of COVID19 vaccines. However, it contains several analytical errors that prevent a causal interpretation and provide a good opportunity to practice critical appraisal skills.

Summary and Appraisal: This retrospective cohort study, which used propensity matching to compare 2.4 million South Korean adults who received a COVID vaccine between 2021 and 2023 with 600,000 who did not, was positive: the authors found that six cancer types (breast, stomach, prostate, colon, thyroid, and lung) were more common in the vaccine group (hazard ratios ranging from 1.2 for breast cancer to 1.7 for prostate cancer). However, there are at least three threats to this finding. First and foremost, the six cancers identified as being associated with COVID19 vaccination are routinely screened for in Korea at doctors’ appointments or after a referral. Second, in the cumulative incidence curve, the lines separate immediately, continue separating for about 6 months, and then run parallel. This implies that oncogenesis happens within months, which is implausibly fast, even for things that are known to cause cancer, like ionizing radiation (the damage takes years to manifest). Third, the authors performed multiple comparisons (they examined rates of 30 different cancers), raising the risk of false positive findings.

Bottom line (Is this practice changing?): No. The most likely interpretation is that we are not detecting an effect of a COVID vaccine, but we are detecting the effect of going to a doctor and getting screened for cancer, while at the same time receiving a COVID vaccine. These findings lack a clear mechanistic basis and don’t stand up to scrutiny: residual confounding from unmeasured care-seeking propensity completely explains the purported association. This is a manifestation of healthy user bias, a type of selection bias: people who are more likely to take preventative health measures (like getting a COVID vaccine) are also more likely to see their doctors and undergo recommended cancer screenings 

Hot take #4 Aspirin and anticoagulation in CAD (Laura)

Originally covered by Dr. Joshua Gilman in Digest #70

Lemesle G, Didier R, Steg PG, et al. Aspirin in patients with chronic coronary syndrome receiving oral anticoagulation. N Engl J Med. 2025;393(16):1578-1588.

Additional/Recommended reading:

• The AFIRE trial: https://www.nejm.org/doi/full/10.1056/NEJMoa1904143
• The EPIC-CAD trial: https://www.nejm.org/doi/abs/10.1056/NEJMoa2407362

Background and Significance: Patients with coronary artery disease (called “chronic coronary syndrome” in the paper) who require long-term oral anticoagulation are at risk for both atherothrombotic and bleeding events. It is unclear whether adding low-dose aspirin to oral anticoagulation improves outcomes in this population. Several randomized trials have previously shown adding an antiplatelet agent to oral anticoagulation increased the risk of bleeding without a clear benefit, but those trials were open-label, conducted in Asian populations, and included low-risk populations CAD (i,.e. not all patients had undergone PCI). The AQUATIC trial was designed to assess the safety and efficacy of dual therapy with aspirin and anticoagulation in patients with high-risk CAD.

Summary and Appraisal: This was a positive trial: AQUATIC was stopped early after a median follow-up of 2.2 years because of harm: the primary outcome (composite of cardiovascular death, myocardial infarction, stroke, systemic embolism, coronary revascularization, or acute limb ischemia) occurred in 17% of patients in the aspirin group and 12% in the placebo group (a ~5% absolute increase, or a ~50% relative increase). Similarly, all-cause death was about 5% higher in the aspirin group (13% vs 8%; HR 1.72), and the bleeding risk was tripled (10% vs 3%, HR 3.35). This was a well-done randomized trial without major threats to the authors’ conclusions, and it expands upon prior results from the AFIRE and EPIC-CAD trials. 

Bottom line (is this practice changing?): Yes, it absolutely should be! The takeaway from the AQUATIC trial is clear: combination therapy with an oral anticoagulant and aspirin leads to more harm than good. As Dr. Cifu would say, we have a medical reversal on our hands. 

Links

Links are included in the show notes 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. Describe the benefits of prostate cancer screening
2. List some problems with the claim that maternal acetaminophen use causes autism
3. Apply the findings of the AQUATIC trial to clinical practice

Disclosures

The Curbsiders report no relevant financial disclosures. 

Citation

Taranto N, Ganatra RB, Cifu A, Glick LR, Williams PN, Watto MF. “#506 DIGEST-Hotcakes: PSA Screening, Acetaminophen and Autism, COVID19 Vaccines and Cancer, Aspirin and Anticoagulation in Coronary Artery Disease”. The Curbsiders Internal Medicine Podcast. https://thecurbsiders.com/episode-list Final publishing date, 01 December 2025.