CMR GUIDE Misses Primary Endpoint, Indicates Possible Cardiac Death Reduction With ICDs

Although it failed to achieve its primary endpoint of reducing sudden cardiovascular death or ventricular arrhythmia in heart failure (HF), the CMR GUIDE trial did indicate a patient population that may benefit more from implantable cardioverter-defibrillators (ICDs).¹

These data were presented at the European Society of Cardiology (ESC) Congress 2026 in Munich, Germany, by Joseph Selvanayagam, MBBS, professor of cardiovascular medicine at Flinders University and director of cardiac imaging at SA Health. In an interview with HCPLive, Selvanayagam discussed the impetus for the trial and the success the investigators found despite the program’s overall failure.¹

“Guidelines currently do not recommend an ICD in patients with EF 36-50%, yet there is a treatment paradox there,” Selvanayagam told HCPLive. “We treat the patients below 35%, who numerically have fewer sudden cardiac deaths, but we don’t treat the ones above 35%, where the numerical events are high. We need better risk stratifiers.”

CMR GUIDE was a multicenter randomized controlled trial investigating the efficacy of ICD implantation in patients with a left ventricular ejection fraction (LVEF) of 36-50% and cardiovascular magnetic resonance (CMR)-identified myocardial scar to reduce sudden cardiac death or hemodynamically significant ventricular arrhythmia (HSVA). Patients were eligible for inclusion if they had an LVEF within the established range attributable to cardiomyopathy and evidence of ventricular scar on CMR. Patients were excluded if they had a history of cardiac arrest, cardiomyopathy related to sarcoidosis, or an established indication for an ICD, among other criteria.^1,2

Eligible patients were randomly assigned in a 1:1 ratio to either a single-chamber ICD or an implantable loop recorder (ILR). The primary outcome was a composite of sudden cardiac death or HSVA – the latter was defined as a ventricular arrhythmia that produced syncope or was associated with hypotension. Prespecified secondary outcomes included the individual components of sudden cardiac death and HSVA, all-cause mortality, cardiovascular mortality, quality of life, and HF-related hospitalization.¹

A total of 352 patients were enrolled and randomized; of these, 159 patients received an ICD and 163 received an ILR. The median age between groups was 65 years (interquartile range [IQR], 57-71 years), and 72% of patients had ischemic etiology. Another 25 patients without myocardial scar were also enrolled in a concurrent observational registry.¹

By the end of the trial, 131 patients in the ICD group and 118 in the ILR group were still alive with active implants. Median follow-up was 6.3 years (IQR, 4.8-7.6 years) – in this time, the primary composite outcome occurred in 14 of 180 patients in the ICD arm and 16 of 173 patients in the ILR arm (unadjusted HR, 0.76; 95% CI, 0.37-1.58; adjusted HR, 0.77; 95% CI, 0.37-1.59). The latter hazard ratio was adjusted for age, sex, cardiomyopathy etiology, and baseline LVEF. Neither endpoint was statistically significant.¹

Sudden cardiac death occurred in 3 ICD recipients and 10 ILR recipients (HR, 0.26; 95% CI, 0.07-0.95), while HSVA occurred in 12 ICD recipients and 6 ILR recipients (HR, 1.77; 95% CI, 0.65-4.81). Rates were similar for all-cause mortality, cardiovascular mortality, and HF-related hospitalization, regardless of the assigned intervention group. Among the enrolled patients, 68% were <70 years old. These patients were less likely to experience the primary outcome (HR, 0.28; 95% CI, 0.09-0.89; P = .01) compared to those ≥70 years (HR, 2.33; 95% CI, 0.75-7.26).¹

Although the primary endpoint was not achieved, Selvanayagam and colleagues noted the potential reduction in sudden cardiac death found in younger patients with low competing risk from other causes of death. Selvanayagam highlighted this in the interview, suggesting future research into this area to corroborate these findings.¹

“This was not an overall neutral trial,” Selvanayagam said. “The primary outcome was neutral, but there were certainly enough signals in the deep dive of the data to suggest that we need to think carefully about the design of future trials. That’s the good news – the more challenging news is that this is going to take a long time, as this is a difficult population to enroll.”

Editors’ Note: Selvanayagam reports disclosures with AstraZeneca, Bayer, Biotronik, Boehringer-Ingelheim, Novartis, Pfizer, and others.

References

1. Selvanayagam JB, Cleland JGF, Hillis GS, et al. Cardiovascular Magnetic Resonance to Guide Defibrillator Implantation for LVEF of 36% to 50%: The CMR GUIDE Randomized Clinical Trial. JAMA. Published online August 28, 2026. doi:10.1001/jama.2026.17078

2. Flinders University. Cardiac Magnetic Resonance GUIDEd Management of Mild-moderate Left Ventricular Systolic Dysfunction (CMR_GUIDE). ClinicalTrials.gov Identifier: NCT01918215. Updated July 8, 2026. Accessed September 18, 2026. https://clinicaltrials.gov/study/NCT01918215?id=NCT01918215&viewType=Card&rank=1