Contemporary guidelines highly recommend patients with heart failure with reduced ejection fraction (HFrEF) be on all four drug classes that together have shown clinical clout, including improved survival, in major randomized trials.
Although many such patients don't receive all four drug classes, the more that are prescribed to those with primary prevention implantable defibrillators (ICD), the better their odds of survival, a new analysis suggests.
The cohort study of almost 5000 patients with HFrEF and such devices saw their all-cause mortality risk improve stepwise with each additional prescription they were given toward the full quadruple drug combo at the core of modern HFrEF guideline-directed medical therapy (GDMT). The four classes are SGLT2 inhibitors, beta blockers, mineralocorticoid receptor antagonists (MRA), and renin-angiotensin system (RAS) inhibitors.
That inverse relation between risk and number of GDMT meds held whether patients had solo-ICD or defibrillating cardiac resynchronization therapy (CRT-D) implants; independently of device-implantation year and comorbidities; and regardless of HFrEF etiology.
"If anybody had doubts about really pushing forward as much of these guideline-directed medical therapies as the patient tolerates, these data confirm that by doing so, we definitely do better than with two medications or one medication," Samir Saba, MD, University of Pittsburgh Medical Center, Pennsylvania, told theheart.org | Medscape Cardiology.
The analysis begs an old and challenging question: Do primary prevention ICDs confer clinically important survival gains over those provided by increasingly life-preserving recommended HFrEF medical therapy?
Given the study's incremental survival bumps with each added GDMT med, "one ought to consider whether ICD therapy can still have an impact on overall survival in this population," proposes a report published online July 27 in JACC Clinical Electrophysiology, with Saba as senior author and Mehak Dhande, MD, also from University of Pittsburgh Medical Center, as lead author.
In the adjusted analysis, the 2-year risk for death from any cause in HFrEF patients with primary prevention devices fell 36% in those with ICDs and 30% in those with CRT-D devices for each added prescribed GDMT drug, from none up to either three or four such agents (P < .001 in both cases).
Only so much can be made of nonrandomized study results, Saba observed in an interview. But they are enough to justify asking whether primary prevention ICDs are "still valuable" in HFrEF given today's GDMT. One interpretation of the study, the published report notes, is that contemporary GDMT improves HFrEF survival so much that it eclipses any such benefit from a primary prevention ICD.
Both defibrillators and the four core drug therapies boost survival in such cases, "so the fundamental question is, are they additive. Do we save more lives by having a defibrillator on top of the medications, or is it overlapping?" Saba asked. "We don't know the answer."
For now, at least, the findings could reassure clinicians as they consider whether to recommended a primary prevention ICD when there might be reasons not to, as long there is full GDMT on board, "especially what we today define as quadruple guideline-directed medical therapy."
Recently announced North American guidelines defining an HFrEF quadruple regimen prefer — beyond a beta blocker, MRA, and SGLT2 inhibitor — that the selected RAS inhibitor be sacubitril/valsartan (Entresto, Novartis), with ACE inhibitors or angiotensin-receptor blockers (ARBs) as a substitute, if needed.
Nearly identical European guidelines on HFrEF quad therapy, unveiled last year, include but do not necessarily prefer sacubitril/valsartan over ACE inhibitors as the RAS inhibitor of choice.
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 told theheart.org | Medscape Cardiology. Such quad therapy, he said, "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," said Roderick Tung, MD, University of Arizona College of Medicine, Phoenix. Optimized GDMT in randomized trials probably represents the best-case scenario, he told theheart.org | Medscape Cardiology. "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," 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, 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," Saba said. "And our results suggest that yes, they still do."
GDMT Coverage in the Real World
The analysis of patients with HFrEF involved 3210 with ICD-only implants and 1762 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% CI, 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
0.61 (95% CI, 0.51 - 0.73) for patients with nonischemic disease
The results "raise questions rather than answers," 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, 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."
Saba discloses receiving research support from Boston Scientific and Abbott; and serving on advisory boards for Medtronic and Boston Scientific. The other authors report they have no relevant relationships. Tung has disclosed receiving speaker fees from Abbott and Boston Scientific. Fonarow has reported receiving personal fees from Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Edwards, Janssen, Medtronic, Merck, and Novartis.
JJ Am Coll Cardiol EP. Published online July 27, 2022. Abstract
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Cite this: Do ICDs Still 'Work' in Primary Prevention Given Today's Recommended HF Meds? - Medscape - Jul 29, 2022.