GDMT a moving target
Primary-prevention defibrillators entered practice at a time when expected background GDMT consisted of beta-blockers and either ACE inhibitors or ARBs, the current report notes. In practice, many patients receive the devices without both drug classes optimally on board. Moreover, many who otherwise meet guidelines for such ICDs won’t tolerate the kind of maximally tolerated GDMT used in the major primary-prevention device trials.
Yet current guidelines give such devices a class I recommendation, based on the highest level of evidence, in HFrEF patients who remain symptomatic despite quad GDMT, observed Gregg C. Fonarow, MD, University of California Los Angeles Medical Center.
The current analysis “further reinforces the importance of providing all four foundational GDMTs” to all eligible HFrEF patients without contraindications who can tolerate them, he said in an interview. Such quad therapy “is associated with incremental 1-year survival advantages” in patients with primary-prevention devices. And in the major trials, “there were reductions in sudden deaths, as well as progressive heart failure deaths.”
But the current study also suggests that in practice “very few patients can actually get to all four drugs on GDMT,” Roderick Tung, MD, University of Arizona, Phoenix, said in an interview. Optimized GDMT in randomized trials probably represents the best-case scenario. “There is a difference between randomized data and real-world data, which is why we need both.”
And it asserts that “the more GDMT you’re on, the better you do,” he said. “But does that obviate the need for an ICD? I think that’s not clear,” in part because of potential confounding in the analysis. For example, patients who can take all four agents tend to be less sick than those who cannot.
“The ones who can get up to four are preselected, because they’re healthier,” Dr. Tung said. “There are real limitations – such as metabolic disturbances, acute kidney injury and cardiorenal syndrome, and hypotension – that actually make it difficult to initiate and titrate these medications.”
Indeed, the major primary-prevention ICD trials usually excluded the sickest patients with the most comorbidities, Dr. Saba observed, which raises issues about their relevance to clinical practice. But his group’s study controlled for many potential confounders by adjusting for, among other things, Elixhauser comorbidity score, ejection fraction, type of cardiomyopathy, and year of device implantation.
“We tried to level the playing field that way, to see if – despite all of this adjustment – the incremental number of heart failure medicines stills make a difference,” Dr. Saba said. “And our results suggest that yes, they still do.”
GDMT coverage in the real world
The analysis of patients with HFrEF involved 3,210 with ICD-only implants and 1,762 with CRT-D devices for primary prevention at a major medical center from 2010 to 2021. Of the total, 5% had not been prescribed any of the four GDMT agents, 20% had been prescribed only one, 52% were prescribed two, and 23% were prescribed three or four. Only 113 patients had been prescribed SGLT2 inhibitors, which have only recently been indicated for HFrEF.
Adjusted hazard ratios for death from any cause at 2 years for each added GDMT drug (P < .001 in each case), were 0.64 (95% confidence interval, 0.56-0.74) for ICD recipients, 0.70 (95% CI, 0.58-0.86) for those with a CRT-D device, 0.70 (95% CI, 0.60-0.81) for those with ischemic cardiomyopathy, and 0.61 (95% CI, 0.51-0.73) for patients with nonischemic disease.
The results “raise questions rather than answers,” Dr. Saba said. “At some point, someone will need to take patients who are optimized on their heart failure medications and then randomize them to defibrillator versus no defibrillator to see whether there is still an additive impact.”
Current best evidence suggests that primary-prevention ICDs in patients with guideline-based indications confer benefits that far outweigh any risks. But if the major primary-prevention ICD trials were to be repeated in patients on contemporary quad-therapy GDMT, Dr. Tung said, “would the benefit of ICD be attenuated? I think most of us believe it likely would.”
Still, he said, a background of modern GDMT could potentially “optimize” such trials by attenuating mortality from heart failure progression and thereby expanding the proportion of deaths that are arrhythmic, “which the defibrillator can prevent.”
Dr. Saba discloses receiving research support from Boston Scientific and Abbott; and serving on advisory boards for Medtronic and Boston Scientific. The other authors reported no relevant relationships. Dr. Tung has disclosed receiving speaker fees from Abbott and Boston Scientific. Dr. Fonarow has reported receiving personal fees from Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Edwards, Janssen, Medtronic, Merck, and Novartis.
A version of this article first appeared on Medscape.com.