#540 Hotcakes: Varenicline by mail for smoking cessation, anticoagulation for intermediate risk AF, CAC score plus PREVENT, blood testing for CRC, oral PCSK9 inhibitors, and more

September 28, 2026 | By Rahul Ganatra

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Join us as we review recent practice-changing articles on Varenicline by mail for smoking cessation, anticoagulation for intermediate risk AF, CAC scores plus PREVENT for ASCVD risk stratification, blood testing for CRC, a new oral PCSK9 inhibitor, and more. Fill your brain hole with a delicious stack of hotcakes! Featuring Paul Williams (@PaulNWilliamz), Rahul Ganatra (@rbganatra), and Matt Watto (@doctorwatto).

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Show Segments

• Intro, disclaimer
• Varenicline by mail for smoking cessation
• Anticoagulation for intermediate-risk AF
• CAC scores added to PREVENT for ASCVD
• Blood testing for colorectal cancer
• Oral PCSK9 inhibitor, negative results for pelacarsan and ziltivekimab 
• Outro

Hotcake #1 Good luck with the varenicline! (Paul)

Carpenter MJ et al. Medication samples and smoking cessation among adults: A randomized clinical trial.  JAMA Network Open. 2026; 9(5):e2611418.

What was the research question? Does the provision of varenicline samples by mail, with minimal guidance or instruction, facilitate smoking cessation among adults who smoke?

Why is this study important? 29 million adults in the United States smoke cigarettes – a major, reversible cause of morbidity and mortality. Varenicline, the most effective pharmacotherapy for tobacco cessation, is underprescribed. Whether providing access to this safe prescription medicine to adults who smoke improves cessation rates is unknown. 

How was the study done? Participants were recruited via advertisement on social media.  After informed consent was obtained, participants were screened for exclusions (e.g. acute psychiatric conditions, pregnancy, and others). Participants were randomized in a 2:1:1 ratio to receive a 4-week sample of varenicline, nicotine replacement therapy (NRT; 14 mg patch + 4 mg lozenges), or referral to a phone-based smoking quitline. All medications were provided by mail with limited instructions on dose titration. Outcomes were assessed at 2, 4, 8, 12, and 24 weeks by self-reported surveys; exhaled carbon monoxide was also measured.

Who were the patients? 651 adults (mean age, 52; 66% female) residing in South Carolina who smoked >5 cigarettes per day for >1 years were included. Patients with significant psychiatric contraindications or seizures were excluded. Initially, access to a primary care physician was an inclusion criteria, but this was removed because of high rates of screening failure (834 screen failures within 4 months).  

Top-line results: This was a positive trial: compared with the quitline group, participants receiving varenicline reported higher point prevalence abstinence at month 6 (10% vs 17%, P=0.048), floating abstinence throughout follow up (34% vs 20%, P=0.0033) and greater incidence of 50% reduction in cigarettes per day at week 8, but not at 6 months. Varenicline sampling was also superior to NRT sampling for 6-month reported self-abstinence and floating abstinence through 6 months. 

Learning points & limitations: This is kind of a wild study. There are a few factors here that I would expect to bias towards the null. First, the recommended treatment duration for varenicline is 12 weeks; patients in this study were provided with 4, and many patients did not have a PCP to continue prescribing it. Second, the average participant reported smoking 18 cigarettes per day, meaning the 14 mg nicotine patch was effectively underdosed. Also, although self-reported outcomes were positive, there was no difference in exhaled CO-confirmed abstinence (though this comparison was limited because very few people provided this data).  

Bottom line: I am all for lower barriers to treatment for tobacco use. Based on the above limitations, I’m surprised this moved the needle at all. The fact that it did reaffirms my belief that we should redouble efforts to prescribe effective medications for smoking cessation.  

Hotcakes rating: 4 / 5  

Further reading:

• Cruz Lopes L et al.Varenicline for Tobacco-Dependent Adults Who Are Not Ready to Discontinue Use: A Systematic Review and Meta-Analysis.  Annals of the American Thoracic Society. 2022; 19(12): 2077-2086.

Hotcake #2 Anticoagulation in intermediate-risk AF (Rahul)

Kim D, Lee YS, Shim J, et al. Anticoagulation for atrial fibrillation with intermediate stroke risk. N Engl J Med. Published online August 28, 2026:NEJMoa2607978 

What was the research question? Does anticoagulation with a DOAC reduce adverse events in patients with intermediate-risk atrial fibrillation (that is, CHADS2VASc score of 1 for men or 2 for women)?

Why is this study important? Anticoagulation in patients with intermediate-risk AF gets a grade IIa recommendation from the ACC/AHA and the ESC, but this is based on observational data only. Data from randomized trials informing whether these patients really benefit are lacking.

How was the study done? This was an open-label superiority trial conducted in 19 centers in South Korea from 2020-2023. Patients were eligible if they had a C2V of 1 for men or 2 for women, and ineligible if they had Cr >3.5 or CrCl <30, active hepatitis, cirrhosis, another indication for anticoagulation, or significant structural heart disease. Patients were randomized 1:1 to receive a DOAC (which could be apixaban or rivaroxaban) or no anticoagulation. Antiplatelets were allowed but not recommended. Patients were followed for 24 months.

Who were the patients? 1,800 patients (mean age of 60, ~75% men, ~75% with paroxysmal AF) were enrolled. Only ~10% had diabetes, ~10% had CHF, and the median HAS-BLED score was 0 in both groups. Two-thirds of patients in the DOAC group received apixaban. Antiplatelets were used in one-third of the no anticoagulation group, and essentially nobody in the DOAC group. 

Top-line results: This was a positive trial: at 24 months, treatment with a DOAC led to a ~1% absolute (and a ~70% relative) reduction in composite of cardiovascular death, stroke, systemic embolism, or major bleeding compared with no anticoagulation. The benefit was driven by fewer strokes in the anticoagulation group.

Learning points & Limitations: Some aspects that strengthen our acceptance of the results are that randomization was reasonably effective, crossover was rare (~5%), and loss to follow-up was minimal. Some things that threaten our acceptance are that we don’t know how many people were screened for enrollment, the primary outcome effect estimate based on very few events (4 vs 13) in a homogenous population at very low bleeding risk, and the imbalance in antiplatelet use (with more people in the no treatment group using antiplatelets) could obscure a real difference in bleeding risk. 

Bottom line: I’m not rushing to put all my parents with low C2Vs on a DOAC without taking into account their bleeding risk, since this trial population was all people at very low risk of bleeding. Individual decision-making will be needed.

Hotcakes rating: 3.5 / 5

Further reading:

• 2024 ESC Guidelines for the management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS)
• Joglar JA, Chung MK, Armbruster AL, et al. 2023 acc/aha/accp/hrs guideline for the diagnosis and management of atrial fibrillation: a report of the american college of cardiology/american heart association joint committee on clinical practice guidelines. Circulation. 2024;149(1). doi:10.1161/CIR.0000000000001193 

Hotcake #3 PREVENT plus CAC score (Watto)

Huang X et al. Predictive Utility of Coronary Artery Calcium Score Added to the PREVENT Atherosclerotic Cardiovascular Disease Equations. JAMA. 2026 Aug 26. doi: 10.1001/jama.2026.13233. Epub ahead of print. PMID: 42647022. 

What was the research question? In US adults aged 45–79 without clinical ASCVD, does adding CAC to PREVENT-ASCVD improve 10-year risk prediction?

Why is this study important? The 2026 ACC/AHA dyslipidemia guidelines recommend selective CAC testing in people at borderline or intermediate ASCVD risk via the PREVENT risk calculator. Clinicians need to know whether CAC actually adds useful information beyond PREVENT on its own. CAC scores add cost, radiation, and subject patients to incidental findings.

How was the study done? This study used data from the longitudinal MESA cohort, which enrolled patients at 6 US sites from 2000 – 2002. All patients underwent CAC scans at the time of cohort enrollment and were followed for the occurrence of ASCVD events for up to 10 years. The performance of PREVENT alone and PREVENT + CAC to predict ASCVD events was compared by examining differences in discrimination and calibration, as well as estimating the net reclassification resulting from adding CAC scores to PREVENT. 

Who were the patients? 6,098 adults aged 45–79 without baseline clinical ASCVD were included; mean age was 61 years, about half were female. In total, 366 ASCVD events occurred during 10 years of follow-up.  

Top-line results: Adding CAC to PREVENT only minimally increased discrimination from 0.73 to 0.75 (indicating slightly better discrimination), and decreased the calibration slope from 1.09 to 0.92 (indicating slightly more spread out risk estimates). In terms of reclassification, among the 366 people who had an ASCVD event during follow-up, adding CAC to PREVENT correctly reclassified 4.9% of people (that is, into a higher risk category), but incorrectly classified 10.7% of people (that is, into a lower risk category). Among the 5,732 people who did not have an ASCVD event, adding CAC to PREVENT correctly reclassified 19.1% (that is, into a lower risk category) and incorrectly reclassified 3.9% (that is, into a higher risk category).

Learning points & Limitations: Across the entire spectrum of risk, CAC adds little predictive value, but does correctly reclassify some people with borderline-to-intermediate PREVENT risk. Also, the CAC scans were done at cohort entry (more than 20 years ago), raising the possibility that modern CT technology may lead to better discrimination. In this study, only adults aged 45–79 years were assessed; younger populations (e.g. 30–44 years old) were not included – a population who often ask about the value of CAC scans, e.g, in the setting of strong family history. Finally, reclassification is a surrogate for downstream benefit; this study does not inform whether adding a CAC score to the PREVENT calculator reduces MACE. 

Bottom line: CAC scoring has a role in borderline patients when the results might change management. However, I will discourage my patients with high risk and low risk PREVENT classification from pursuing CAC scoring as it is unlikely to improve discrimination or correctly reclassify their risk. 

Hotcakes rating: 3 / 5

Further reading:

• Blumenthal RS, Morris PB, et al. 2026 acc  / aha / aacvpr / abc / acpm / ada / ags / apha / aspc / nla / pcna guideline on the management of dyslipidemia: a report of the american college of cardiology/american heart association joint committee on clinical practice guidelines. Circulation. 2026;153(17). doi:10.1161/CIR.0000000000001423 

Hot take #1 Blood test for colorectal cancer screening (Rahul)

Wolf AMD, Hoffman RM, Walter LC, et al. Colorectal cancer screening: An update to the American Cancer Society guideline, 2026. CA A Cancer J Clinicians. 2026;76(3):e70083

Summary: Recently updated guidelines for colorectal cancer screening contain recommendations on the use of blood tests for screening. Currently, only one test has FDA approval, a cell-free DNA (cfDNA) assay marketed as Shield. In a 2024 validation study, cfDNA was only 88% sensitive for cancer, and 13% sensitive for advanced adenomas. An important caveat of this test, in addition to its low sensitivity for adenomas, is that it sacrifices the opportunity to remove advanced adenomas afforded by colonoscopy and flexible sigmoidoscopy. The optimal screening interval is not known, but the manufacturer suggests every 3 years.

Bottom line: While it is great to have more options for the one-third of eligible patients who are not up to date with CRC screening, the relatively poor performance of this test means it should be reserved only for patients who opt out of a “preferred” screening test, which includes direct visualization (colonoscopy, CT colonography, or flex sig) and stool-based tests (Fecal IHC, hemoccult, or multitarget DNA testing), or possibly in combination with other tests.

Further reading:

• Updates on Colorectal Cancer Screening from the ACS | NEJM Clinician 
• A Cell-free DNA Blood-Based Test for Colorectal Cancer Screening | New England Journal of Medicine 

Hot take #2 An Oral PCSK9 inhibitor is now available (Watto)

Catapano AL, Mikhailova E, Navar AM, et al. Oral pcsk9 inhibitor enlicitide versus oral nonstatin therapies: a phase 3 randomized clinical trial. J Am Coll Cardiol. 2026;88(3):340-352. doi:10.1016/j.jacc.2026.03.036

Summary: Enlicitide is an oral PCSK9 inhibitor that recently gained FDA approval. It lowers LDL cholesterol by about 60% when added to statin therapy. Enlicitide is an oral macrocyclic peptide that blocks PCSK9 binding to the LDL receptor (similar to how the injectable monoclonal antibodies evolocumab and alirocumab work), reducing LDL receptor degradation and enhancing LDL-C clearance. We don’t yet have clinical outcomes from randomized controlled trials, but given its mechanism of action and what we learned from our soon-to-be-released interview with Dr. Dan Edmundowicz, (Cardiologist at Temple University), we expect it will lower MACE. 

Bottom line: Enlicitide is an FDA-approved oral PCSK9 inhibitor that has been shown to reduce LDL cholesterol by about 60% when added to statins. 

Further reading:

• Coral-Reef Lipids (Navar, 2026) 
• Coral-Reef AddOn (Catapano, 2026)
• Merck Press Release (July 16, 2026)

Hot take #3 You Have To Test A Hypothesis (Watto)

ZEUS And Lp(a)HORIZON: Biomarkers Vs. Cardiovascular Outcomes

Summary: Dr. Robert Glattner, writing for Forbes.com, recently published an article detailing trials of two cardiology drugs that did not meet their endpoints despite a plausible mechanism of action and treatment target. (@drrobertglatter X post from 6 Sep 2026). The Lp(a)HORIZON trial used pelacarsen to lower lipoprotein(a), but this lowering did not reduce cardiovascular events. The ZEUS trial used ziltivekimab, a monoclonal IL-6 inhibitor, to target inflammation by lowering hsCRP, but this lowering also failed to reduce heart attacks or strokes. Novartis dropped a press release on Friday 4 September 2026 alerting the public that pelacarsen is now the first of the Lp(a) lowering drugs to miss its clinical endpoint. 

Bottom line: Be careful about prematurely celebrating reductions in biomarkers – data showing real-world impact on clinical endpoints are definitely needed!

Further reading:

• Design and Rationale of Lp(a)HORIZON Trial: Assessing the Effect of Lipoprotein(a) Lowering With Pelacarsen on Major Cardiovascular Events in Patients With CVD and Elevated Lp(a) – PubMed 
• Study Details | NCT04023552 | Assessing the Impact of Lipoprotein (a) Lowering With Pelacarsen (TQJ230) on Major Cardiovascular Events in Patients With CVD | ClinicalTrials.gov 
• Rationale, Design, and Baseline Clinical Characteristics of the Ziltivekimab Cardiovascular Outcomes Trial: Interleukin-6 Inhibition and Atherosclerotic Event Rate Reduction – PubMed 
• NCT05021835 | ZEUS – A Research Study to Look at How Ziltivekimab Works Compared to Placebo in People With Cardiovascular Disease, Chronic Kidney Disease and Inflammation | ClinicalTrials.gov

Links

Links are included in the show notes above.

Goals

Listeners will review recent practice-changing articles and medical news.

Learning objectives

After listening to this episode listeners will…

1. Evaluate the effectiveness of mailed varenicline samples for smoking cessation
2. Determine which patients with intermediate-risk atrial fibrillation may benefit from anticoagulation
3. Apply CAC scores to improve ASCVD risk stratification

Disclosures

The Curbsiders report no relevant financial disclosures. 

Citation

Ganatra RB, Williams PN, Watto MF. “#540 Hotcakes: Varenicline by mail for smoking cessation, anticoagulation for intermediate risk AF, CAC score plus PREVENT, blood testing for CRC, oral PCSK9 inhibitors, and more”. The Curbsiders Internal Medicine Podcast. https://thecurbsiders.com/episode-list Final publishing date, September 28, 2026.