Don't Miss a Beat: CARDIO-TTRansform and New HF Guidelines at ESC 2026

Welcome back to Don't Miss a Beat!

Stephen Greene, MD, an advanced heart failure specialist at Duke University School of Medicine, and Muthiah Vaduganathan, MD, MPH, a cardiologist at Brigham and Women's Hospital, recorded this episode on site at the 2026 European Society of Cardiology (ESC) Congress in Munich, Germany. The hosts walk through the headline neutral result of CARDIO-TTRansform, the largest transthyretin amyloid cardiomyopathy (ATTR-CM) trial to date, and the major structural changes in the newly released 2026 ESC heart failure guidelines.

CARDIO-TTRansform: Eplontersen Misses Its Primary Endpoint in ATTR-CM

Vaduganathan opens by noting Hotline Session 1 shifted focus toward specific cardiomyopathies, including CARDIO-TTRansform, which tested eplontersen, a transthyretin gene silencer, against placebo in more than 1400 patients with ATTR-CM across 20 countries.¹ Greene frames the trial against the three approved disease-modifying ATTR-CM therapies to date: TTR stabilizers tafamidis and acoramidis, and vutrisiran, another silencer meeting its primary endpoint in HELIOS-B.

For the composite primary endpoint of cardiovascular death or recurrent cardiovascular events, CARDIO-TTRansform was neutral, with a rate ratio of 0.89. Greene highlights a detail he found notable despite the neutral topline: all-cause mortality showed a nominally significant 20% relative risk reduction, echoing a pattern the hosts previously discussed with the VICTOR trial.

Background Stabilizer Use Complicates the Combination Therapy Question

Vaduganathan explains why background TTR stabilizer therapy is central to interpreting the results. Unlike HELIOS-B, where stabilizer use was modest at baseline, 57% of CARDIO-TTRansform participants were already on a stabilizer at enrollment. Another 24% started one during follow-up, leaving roughly 80% exposed to stabilizer therapy at some point in the trial.

A prespecified subgroup analysis suggested benefit with eplontersen monotherapy but no apparent effect among patients already on a stabilizer. Vaduganathan points to a meta-analysis of CARDIO-TTRansform and HELIOS-B published alongside the trial in JAMA, finding clinical benefit concentrated in patients not previously treated with a stabilizer.²

A similar signal appeared in 6-minute walk distance and Kansas City Cardiomyopathy Questionnaire scores. Greene calls the finding hypothesis-generating rather than definitive, noting the central open question in ATTR-CM is now whether and when to combine mechanisms rather than assuming additive benefit by default.

The 2026 ESC Heart Failure Guidelines Replace GDMT With FMT and AMT

Turning to the newly released 2026 ESC heart failure guidelines, Greene highlights 2 structural changes. First, the guidelines adopt the Universal Definition of Heart Failure's 2-category approach, eliminating heart failure with mildly reduced ejection fraction and defining HFrEF as an ejection fraction below 50%. Second, the familiar term guideline-directed medical therapy is replaced with foundational medical therapy (FMT), tracking with class I recommendations, alongside additional medical therapies (AMT) and a new guideline-directed interventional therapy (GDIT) category for procedures.³

A New Two-Pillar Approach for HFpEF, With Some Loss of Nuance

Vaduganathan explains FMT now includes SGLT2 inhibitors and mineralocorticoid receptor antagonists (MRAs) for all patients with heart failure regardless of ejection fraction. ACE inhibitors, angiotensin receptor-neprilysin inhibitors or angiotensin receptor blockers, and beta-blockers are added for HFrEF.

Greene welcomes explicit guideline text discouraging overthinking sequencing, alongside a new class I recommendation for in-hospital initiation of SGLT2 inhibitors. Vaduganathan cautions the simplified 2-pillar framework introduces some loss of nuance at the drug level.

The guidelines recommend steroidal MRAs in HFrEF but permit either steroidal or nonsteroidal MRAs in HFpEF, a designation Vaduganathan calls imperfectly aligned with the trial evidence. FINEARTS-HF enrolled patients with an ejection fraction of 40% or higher, and spironolactone now carries a class I recommendation in HFpEF despite never being studied in this population in TOPCAT. Greene adds clinicians still need to know a patient's exact ejection fraction, since decisions about AMTs and devices continue to depend on it.

The hosts close by noting the new ESC cardiovascular disease and chronic kidney disease guideline, released the same day, recommends MRA use in a way diverging from the heart failure guideline. Vaduganathan's point: guidelines require clinical judgment grounded in the underlying trial evidence, not uncritical adoption.

Relevant disclosures for Vaduganathan include Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Cytokinetics, Lexicon, and others. Relevant disclosures for Greene include Amgen, AstraZeneca, Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals, Cytokinetics, and others.

References

1. Fontana M, Masri A, Solomon SD, et al; CARDIO-TTRansform Investigators. Eplontersen for transthyretin amyloid cardiomyopathy. N Engl J Med. Published online August 28, 2026. doi:10.1056/NEJMoa2608510

2. Gillmore JD, Hamatani Y, Fontana M, et al. Gene silencer therapy in transthyretin amyloid cardiomyopathy: a meta-analysis of outcomes trials. JAMA. Published online August 30, 2026. doi:10.1001/jama.2026.17246

3. Køber L, Adamo M, Ruwald A, et al. 2026 ESC Guidelines for the management of heart failure. Eur Heart J. 2026;ehag100. doi:10.1093/eurheartj/ehag100