Clinical Context

The management of heart failure with reduced ejection fraction (HFrEF) has come a long way in the past 2 decades, with treatment with a combination of 4 classes of drugs improving patient outcomes. A study using modeling based on the results of randomized controlled trials found that the number needed to treat with the combination of angiotensin receptor neprilysin inhibitors (ARNI), beta-blockers, sodium-glucose cotransporter 2 inhibitors (SGLT2i), and aldosterone antagonists over the course of 2 years to prevent 1 additional case of mortality in cases of HFrEF was just 3.9.^[1]

The authors of this review provided an analysis of the efficacy of different drug classes for HFrEF against mortality, as follows:

Does guideline-directed medical therapy (GDMT) for HFrEF have the same effect in improving mortality among patients who received an implantable cardioverter-defibrillator (ICD)? The current study provides an answer.

Study Synopsis and Perspective

Contemporary guidelines highly recommend that patients with HFrEF receive all 4 drug classes that together have shown clinical clout, including improved survival, in major randomized trials.^[2]

Although many such patients do not receive all 4 drug classes, the more drug classes 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 GDMT.

That inverse relation between risk and number of GDMT medications held whether patients had solo-ICD or defibrillating cardiac resynchronization therapy (CRT-D) implants, independent 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 2 medications or one medication," Samir Saba, MD, from the 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 medication, "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 Dr Saba as senior author and Mehak Dhande, MD, also from University of Pittsburgh Medical Center, as lead author.^[3]

In the adjusted analysis, the 2-year risk for death from any cause in patients with HFrEF 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 3 or 4 such agents (P<.001 in both cases).

Only so much can be made of nonrandomized study results, Dr 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. 

Both defibrillators and the 4 core drug therapies boost survival in such cases, so, for now, at least, the findings could reassure clinicians as they consider whether to [recommend] a primary prevention ICD when there might be reasons not to, as long there is full GDMT on board.

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 with ACEi or angiotensin-receptor blockers (ARBs) as a substitute, if needed.^[4]

Nearly identical European guidelines on HFrEF quad therapy, unveiled last year, include but do not necessarily prefer sacubitril/valsartan over ACEi as the RAS inhibitor of choice.^[5]

GDMT a Moving Target

Primary prevention defibrillators entered practice at a time when expected background GDMT consisted of beta blockers and either ACEi 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 will not 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 patients with HFrEF who remain symptomatic despite quad GDMT, observed Gregg C. Fonarow, MD, from the University of California Los Angeles Medical Center.

The current analysis "further reinforces the importance of providing all 4 foundational GDMTs" to all eligible patients with HFrEF 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 4 drugs on GDMT," said Roderick Tung, MD, from the University of Arizona College of Medicine, Phoenix. Optimized GDMT in randomized trials probably represents the best-case scenario, he told theheart.org | Medscape Cardiology. 

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 receive all 4 agents tend to be less sick than those who cannot.

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.

GDMT Coverage in the Real World

The analysis of patients with HFrEF involved 3210 patients 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 4 GDMT agents, 20% had been prescribed only 1, 52% were prescribed 2, and 23% were prescribed 3 or 4. 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 [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," 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. 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 have disclosed no relevant financial 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.

Clinical Implications

• A previous study examined the efficacy of GDMT for HFrEF, with efficacy against mortality ranging from 16% to 34% for individual agents. Combined, these agents reduced mortality by 73%, resulting in a number needed to treat of less than 4.
• The current study demonstrates the mortality benefit of GDMT in patients with ICD or CRT-D for primary prevention, regardless of the etiology of cardiomyopathy. There was a 34% lower risk of mortality with each GDMT drug added.
• Implications for the healthcare team: The healthcare team should provide education on and emphasize adherence to the maximum number of GDMT drugs tolerated in cases of HFrEF, regardless of ICD status.

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