GDMT and Risk of Death With Primary Prevention ICDs

Quick Takes

  • In patients with HFrEF receiving primary prevention ICDs, incremental addition of heart failure guideline-directed medical therapy (GDMT) is independently associated with lower rates of all-cause mortality.
  • These findings were consistent when stratifying outcomes by type of device (ICD alone or CRT-D) and cause of cardiomyopathy (ischemic or nonischemic).
  • Future studies examining benefit of primary prevention ICDs in the current era of HF GDMT should be considered.

Study Questions:

For patients with heart failure with reduced ejection fraction (HFrEF) and a primary prevention implantable cardioverter-defibrillator (ICD), what is the impact of number of HFrEF guideline-directed medical therapy (GDMT) medications on all-cause mortality?


This was a retrospective, single health system study examining consecutive HFrEF patients undergoing primary prevention ICD implant, with or without cardiac resynchronization therapy (CRT) from January 2010–July 2021. Baseline demographic variables, clinical data, and cardiac medication information were collected. The primary endpoint for the study was rate of all-cause mortality at 2 years following ICD implant. Outcomes were assessed separately for patients with ICD alone (no CRT) and cardiac resynchronization therapy-defibrillator (CRT-D). Association between outcomes and number of HFrEF GDMT medications prescribed were made. GDMT medication classes included angiotensin-converting enzyme inhibitors (ACEi) or angiotensin-receptor blockers (ARB), or angiotensin-receptor neprilysin inhibitors (ARNI), HF-specific beta-blockers, aldosterone antagonists, and sodium-glucose cotransporter 2 inhibitors (SGLT2i). Additionally, time to death, cause of death, total defibrillations, and appropriate defibrillations were examined.


A total of 4,972 patients received primary prevention ICD therapy during the study period. Of these, 3,210 received ICD alone and 1,762 received CRT-D. Overall, 5%, 20%, 52%, and 23% of patients were prescribed 0, 1, 2, or 3-4 HFrEF GDMT medications, respectively. After 2 years of follow-up, 656 patients (13%) died. There was a nearly 4-fold decrease in risk of death when comparing patients on no GDMT to 3-4 GDMT medications (ICD alone: 26% risk on no GDMT vs. 7% on 3-4 GDMT medications, p < 0.001; CRT-D: 30% risk on no GDMT vs. 8% on 3-4 GDMT medications, p < 0.001). In examining time to death and cumulative survival, after risk adjustment, each additional GDMT medication was independently associated with a 36% lower risk of death in patients receiving ICD alone (adjusted hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.56-0.74; p < 0.001) and 30% lower risk in patients receiving CRT-D (adjusted HR, 0.70; 95% CI, 0.58-0.86; p < 0.001). Similar findings were seen when results were stratified by ischemic and nonischemic causes of cardiomyopathy.

For the newer HFrEF therapies, it was noted that 395 patients (7.9%) were prescribed an ARNI, 113 patients (2.3%) were prescribed an SGLT2i, and 468 (9.4%) were prescribed one or both medications. Use of either medication was associated with a 40% reduction in the risk of death at 2 years (unadjusted HR, 0.60; 95% CI, 0.41-0.88; p < 0.008). After risk adjustment, a non-statistically significant trend in risk reduction was noted (HR, 0.73; 95% CI, 0.50-1.07; p < 0.11).

For the 656 patients that died, cause of death was determined in 390 cases (59%). Of these deaths, 202 (52%) were from cardiac causes. Of the cardiac deaths, 51 (25%) were due to arrhythmia. With respect to defibrillations, 215 of 4,972 patients (4.3%) received an ICD shock, though appropriate shocks were noted only in 112 patients (2.3%).


In patients with HFrEF receiving primary prevention ICDs, a higher number of GDMT medications prescribed was independently associated with a lower rate of all-cause mortality at 2 years of follow-up.


Medical therapy for HFrEF has significantly changed and expanded over the last several years, leading to further reductions in morbidity and mortality in patients able to tolerate “quadruple” GDMT. Coupled with trends in decreasing mortality and rates of appropriate ICD shocks for patients with primary prevention ICDs, this brings forth the question of the value of ICD therapy in the current era of HF management. This study adds to this growing body of evidence and highlights two important points. First, it confirms that more GDMT is associated with improved survival in a large cohort of real-world patients, even when considering subgroups with ICD alone, CRT-D, ischemic cardiomyopathy, and nonischemic cardiomyopathy. Second, data were available for some patients on cause of death and ICD shocks, demonstrating low rates of death due to arrhythmia and appropriate ICD shocks. These findings add to the ongoing debate about the risks and benefits of ICD therapy in the current era. Future studies will be needed to address this clinical dilemma but provides more insight when participating in shared decision making with patients.

Clinical Topics: Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Prevention, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Angiotensin Receptor Antagonists, Angiotensin-Converting Enzyme Inhibitors, Angiotensins, Arrhythmias, Cardiac, Cardiac Resynchronization Therapy, Cardiomyopathies, Defibrillators, Implantable, Heart Failure, Ischemia, Mineralocorticoid Receptor Antagonists, Neprilysin, Primary Prevention, Risk Adjustment, Sodium-Glucose Transporter 2 Inhibitors, Stroke Volume

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