Digest 76: The Battle To Conquer Stroke Treatment.

April 24, 2026 | By Nora Taranto

Welcome Back to The Curbsiders Digest!

In this issue we discuss the battle to conquer stroke treatment, plus lower lipid targets, a new treatment for pancreatic cancer, and much more.  Effortlessly absorb important medical news, with our monthly newsletter featuring easily digestible analysis of the latest practice-changing articles, and of course…bad puns. 

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Issue 76

04/24/2026

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.  

Joshua Gilman MD, Laura Glick MD, Alyssa Mancini MD

• Is a lower LDL better? Yes, it seems! The EZ-Pave trial, just published in NEJM, provides outcome data comparing LDL cholesterol (LDL-C) treatment goals in patients with atherosclerotic cardiovascular disease (ASCVD). This multi-center, open label, superiority trial conducted in South Korea randomized 3048 patients with known ASCVD to a target LDL-C of <55mg/dL (intensive group) or <70mg/dL (conventional group). At  3-year follow-up, median LDL-C was 56mg/dL in the intensive group compared to 66mg/dL in the conventional group, with a consistent between-group difference throughout the trial. Patients in the intensive group were more likely to be on a high-intensity statin (48% vs 32%) as well as ezetimibe (67% vs 57%). The use of PCSK9 inhibitors was overall low (2.3% vs 0.9%). There was a reduction in the primary outcome (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, any revascularization, or hospitalization for unstable angina) favoring the intensive group (6.6% vs 9.7%, hazard ratio [HR] 0.67, confidence interval [CI] 0.52-0.86, p=0.002) with significant reductions in non-fatal myocardial infarctions and need for revascularization. There were no major differences in safety outcomes. (JG) 
• Consider stopping low-dose levothyroxine in adults 60 years or older. JAMA recently published the results of an open-label, single-group, prospective study designed to determine the percentage of middle-aged to older adults who can successfully discontinue levothyroxine. The study included 370 community-dwelling adults aged 60 years or older (median age 70 years, 80% female) who were taking a stable dose of levothyroxine for at least 1 year and had a TSH <10 mIU/L (median levothyroxine dose 50 mcg daily, median TSH 2.2 mIU/L). Importantly, adults were excluded if they were taking high doses of levothyroxine (>150 mcg daily); had a history of thyroidectomy, radioactive iodine treatment, neck irradiation, congenital hypothyroidism, or secondary hypothyroidism; were taking medications that can affect thyroid function (e.g. amiodarone, lithium, thionamides); or had NYHA class IV heart failure, dementia, or a life expectancy < 6 months. A protocol-driven stepwise dose reduction was employed, with thyroid function testing at least 6 weeks after each dose reduction. At 1 year, 26% of participants discontinued levothyroxine while maintaining a TSH <10 mIU/L (median TSH 5.03 mIU/L) and a free T4 within reference range. Among the 88 participants who were taking levothyroxine 50 mcg daily or lower, 64% successfully discontinued treatment at 1 year. Furthermore, thyroid-related quality of life showed no clinically relevant change from baseline to 1 year. (AM) 
• Daraxonrasib Shows Significant OS Benefit in Metastatic Pancreatic Cancer. In RASolute 302, a global, randomized phase 3 trial, the once-daily oral RAS(ON) inhibitor daraxonrasib significantly improved outcomes compared with standard chemotherapy in patients with previously treated metastatic pancreatic ductal adenocarcinoma. According to a recent press release from Revolution Medicines, the median overall survival with daraxonrasib was 13.2 months versus 6.7 months with standard chemotherapy (HR 0.40; p <0.0001), nearly doubling survival and meeting the primary endpoint of the study. Results also showed statistically significant improvements in progression-free survival. The benefit was observed across a broad population, including patients with diverse RAS mutations, consistent with the drug’s mechanism as a multi-selective RAS(ON) inhibitor, targeting a pathway altered in the majority of pancreatic cancers. Treatment was generally well tolerated with a manageable safety profile (including rash and diarrhea). (LG) 
• Holding vs. Continuing GLP-1/GIP Agonists Before Upper Endoscopy. Just published in JAMA Internal Medicine, the OCULUS trial randomized patients on GLP-1 or GLP-1/GIP agonists who were undergoing elective upper endoscopy to continuing therapy versus holding therapy. Investigators found that continuing therapy prior to the procedure significantly increased clinically relevant residual gastric volume (RGV) compared with holding one dose (25.0% vs 3.1%; absolute difference 21.9%, 90% CI 7%-36.7%, P=0.003), leading to early trial termination after crossing a prespecified safety boundary. Clinically significant RGV—defined as retained gastric contents that precluded or interrupted endoscopy or required escalation of care—was markedly higher in the continuation group, particularly among patients undergoing EGD alone without bowel preparation (46.7% vs 5.0%, absolute difference 41.7%). Interestingly, no events occurred in those who also underwent colonoscopy and followed a clear liquid diet the day prior, suggesting that a preprocedural clear liquid diet may mitigate the risk regardless of medication status. (LG) 
• Aspirin versus Clopidogrel for chronic maintenance monotherapy after percutaneous coronary intervention. In the 10-year follow-up of the HOST-EXAM trial, just published in Lancet, clopidogrel monotherapy after PCI was linked to a lower risk of the composite endpont—including all-cause mortality, myocardial infarction, stroke, acute coronary syndrome readmission, and major bleeding—compared with aspirin. The study randomized over 5,000 patients (who had completed 6–18 months of dual antiplatelet therapy without events after stent placement) to clopidogrel 75 mg daily or aspirin 100 mg daily. After a median follow-up of 10.5 years, the primary composite endpoint occurred less frequently in the clopidogrel group (25.4% vs 28.5%; HR 0.86). Clopidogrel was also associated with fewer thrombotic events and a lower incidence of bleeding (17.3% vs 20.0% and 9.1% vs 10.8%, respectively) than aspirin, while overall mortality was similar between groups. (LG)

Palate Cleanser

There are few certainties in life as a clinician: death, taxes, and the annual pilgrimage through manual training modules. Dr. Michael Gottlieb recently published an editorial in JAMA imploring the reassessment of mandatory training modules that often consist of passive transfer of information from years-old minimally interactive slide decks whose educational yield often feels inversely proportional to the number of clicks required to complete them. Furthermore, these modules come with high opportunity costs of lost time devoted to patient care, teaching, research, or quality improvement, subsequent economic implications, and contribution to burnout given loss of clinician autonomy. Instead, he suggests these modules be reassessed to determine which are truly mandatory and how those could be tailored to role and specialty. Additionally, modules could be redesigned to include an option to test out, as well as interactive cases and spaced repetition with short quizzes based on adult learning theory. If you’ve ever questioned whether the time spent clicking through these modules could be better invested elsewhere, Dr. Gottlieb’s thoughtful and pragmatic call for reform is well worth your attention.

– Jennifer DeSalvo MD

The Main Course

Jennifer DeSalvo MD

Emerging Therapy in Secondary Stroke Prevention
Patients who have suffered from a stroke or transient ischemic attack (TIA) are at increased risk of stroke recurrence and cardiovascular atherosclerotic morbidity/mortality, despite use of antiplatelet therapies for secondary prevention.  Recently, studies have evaluated whether antithrombotic regimens (i.e. anticoagulants) can further reduce risk in addition to, or in replacement of, anti-platelet agents such as aspirin or clopidogrel. But to this point, such studies testing direct oral anticoagulants (e.g. rivaroxaban) in this setting have either failed to significantly reduce stroke risk and/or led to increased bleeding risk.

Enter Factor XI. Prior research has shown that inherited deficiencies in Factor XI, a coagulation factor within the intrinsic coagulation cascade, are associated with a reduced risk of ischemic stroke without an increase in major bleeding, and that increased levels of Factor XI are associated with a higher risk of ischemic stroke.  Factor XI inhibitors have thus emerged as a potential therapeutic agent to reduce risk of ischemic stroke without significant bleeding risk. Two phase 2 trials investigated short-term use of Factor XIa inhibitors (Asundexian in the PACIFIC-Stroke trial and Milvexian in the AXIOMATIC-SSP trial) in combination with antiplatelet therapy, without a significant increase in bleeding risk.  The phase 3 trial, Oral Factor Eleven A Inhibitor Asundexian as Novel Anti-thrombotic Stroke (OCEANIC-STROKE), now published in NEJM, looked at longer term outcomes with Asundexian. 

Introducing Asundexian: A rare antithrombotic win?
OCEANIC-STROKE was a multi-center, double-blind trial randomizing patients with noncardioembolic ischemic stroke or TIA to either Asundexian or placebo. Approximately 12,327 patients (mean age 68 years, 95% with ischemic stroke, 5% with TIA, 63% planned for dual antiplatelet therapy with aspirin and P2Y12 inhibitor) were randomized within 72 hours of index noncardioembolic ischemic stroke or TIA to receive oral Asundexian 50 mg once daily vs placebo, in addition to antiplatelet agent(s), over a median follow-up of approximately 1.5 years. 20% received thrombolytic agents, and 3-4% received mechanical thrombectomy. Patients in the Asundexian group had a lower incidence of the primary outcome of recurrent ischemic stroke (6.2% vs. 8.4%, HR 0.74, 95% CI 0.65 to 0.84, P<0.001), with a number needed to treat of 53 patients to prevent recurrence of one ischemic stroke per year.  There was a significantly lower incidence of any stroke (6.6% vs. 8.8%), or a composite of death from cardiovascular cause, myocardial infarction, or stroke (9.2% vs. 11.1%) with Asundexian than with placebo. This effect was consistent across subgroups. The incidence of major bleeding adverse events was similar among both groups (Asundexian group 1.9% and placebo 1.7%, HR 1.10, 95% CI 0.85 to 1.44). 

Beyond 90-days: The Long Game of Factor XI Inhibition
Is this novel XI inhibitor–and antithrombotic therapy on top of antiplatelet therapy–ready for primetime? Maybe not quite yet – but these OCEANIC-STROKE results hold great potential. An accompanying editorial inNEJM helps to put this novel agent into perspective. The benefit in stroke reduction appeared similar across those both with coexisting atherosclerotic disease (who are at particularly high clinical risk) and those without. And while there wasn’t a significant difference in the risk of ischemic stroke within the first 90 days in the Asundexian group compared to placebo, this shouldn’t be surprising, given that the risk of recurrent stroke increases over time.  Extended (5+ year) follow-up of OCEANIC-STROKE and the phase 3 LIBREXIA-STROKE trial—investigating Milvexian in addition to antiplatelet therapy versus placebo in patients following index ischemic stroke or TIA— will be crucial in defining the longer term effects of Factor XI inhibition. An additional challenge to consider with this agent is the lack of a reversal agent–though it does have a short half-life (<24h). Lastly, a retrospective cohort study just published inStroke suggested apparent benefit to early anticoagulant (as opposed to antiplatelet) therapy initiation after cryptogenic stroke in patients who also had left ventricular (LV) dysfunction (LVEF of 20-40% and regional wall motion abnormality). These findings suggest that some patient populations may particularly benefit from therapy beyond antiplatelet therapy alone in preventing recurrent strokes while minimizing major bleeding adverse events. Whether and how Factor XI inhibitors in particular may be useful in this particular population–and how they are useful in larger populations after stroke– remains to be seen. 

Read the full article HERE!

Digestifs

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This week on The Curbsiders: Learn to Age with Grace. In Episode #522 with Dr. Elizabeth Eckstrom, tackle the challenges of healthy aging with Dr. Eckstrom’s pearls – covering tai chi, the mediterranean diet, and much more. 

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The Curbsiders Digest

Issue 76
Editor in Chief: Nora Taranto MD
Banner: Kate Grant  MBChB, DipGUMed

Jennifer DeSalvo,  Joshua Gilman,  Laura Glick, Alyssa Mancini,  and Nora Taranto report no disclosures.

Kate Grant reports no disclosures.  

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