Review Article

The Timing for Primary Prevention for ICD in the Current Era of Pharmacotherapy

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Abstract

Recent advances in the pharmacological therapy of heart failure with reduced ejection fraction (HFrEF) have significantly impacted the overall survival, heart failure hospitalisations and rates of sudden cardiac death (SCD). In this context, the relevant timing of placing ICDs as primary prevention is a matter of on-going debate. This manuscript provides evidence for an updated view regarding the timing of implanting ICD in eligible patients with HFrEF receiving optimal guideline-directed medical therapy, accounting for the timing to reverse cardiac remodelling (RCR) occurrence and residual SCD risks over time. Clinically significant RCR occurs beyond 3 months of optimal guideline-directed medical therapy, while the residual risks of SCDs remain low for certain HFrEF populations. However, when deciding on ICD implantation, one should always consider individual modulators of RCR and SCD risks, as well as the non-competing risks of death that can affect patients’ overall outcomes. Risk stratification algorithms need to be developed and validated in future pragmatic clinical trials to further define better timing for the use of ICDs in primary prevention.

Keywords

Guideline-directed medical therapy, heart failure with reduced ejection fraction, ICD, primary prevention, residual risk, sudden cardiac death, timing.,

Received:

Accepted:

Published online:

DOI: https://doi.org/10.15420/cfr.2025.05

Disclosure: HS has received honoraria for presentations and advisory board participation from Abbott, AstraZeneca, Boehringer Ingelheim, Novartis, Novo Nordisk, Servier and Vifor. AY has received speaking honoraria and consulting fees from AstraZeneca, Bayer, Bridgebio, Merck, Novo Nordisk and scPharmaceuticals. AS has no conflicts of interest to declare.

Correspondence: Hadi Skouri, Balamand University School of Medicine, Rond Point Saloumeh-Dekouaneh, Beirut, Lebanon, PO Box 55251. E: skourihadi73@gmail.com

Copyright:

© The Author(s). This work is open access and is licensed under CC-BY-NC 4.0. Users may copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Sudden cardiac death (SCD) remains a leading cause of death in patients with heart failure with reduced ejection fraction (HFrEF).1 According to the heart failure (HF) guidelines of international cardiac societies, ICDs for primary prevention should be considered in symptomatic HFrEF patients (New York Heart Association [NYHA] functional class II–III), who have left ventricular ejection fraction (LVEF) <35% despite at least 3 months of medical treatment, independent of the aetiology of the cardiomyopathy, unless patients have had an MI in the prior 40 days.2,3

Since the introduction of primary prevention ICDs in HF guidelines, guideline-directed medical therapy (GDMT) has been redefined to include key Class IA medications: β-blockers, angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin-II receptor blockers (ARBs)/angiotensin receptor–neprilysin inhibitors (ARNI), mineralocorticoid receptor-antagonists (MRAs) and sodium–glucose cotransporter 2 inhibitors (SGLT2Is).2,4 Novel agents, ARNI and SGLT2Is, have significantly improved survival, reducing hospitalisations and the risk of SCD.5,6 Considering a greater number of GDMT components with class I recommendations that exert their effect in a dose-dependent manner over a longer period, some HFrEF patients might require extended time on pharmacotherapy beyond 3 months before withdrawing ICD indications. Thus, advances in HF pharmacotherapy could further influence the urgency of ICD implementation. The rationale for a longer waiting period for preventive ICD implantation has recently been discussed but has not yet impacted the initial conventional approach.7–10

This review discusses the emerging data related to the risk of SCD in the era of contemporary pharmacotherapy and the effects of ARNI and SGLT2Is on preventive ICD indications in HFrEF patients by determining reverse cardiac remodelling (RCR) and SCD rates. It also provides an overview of potential clinical, biochemical and imaging factors that could modify the response to GDMT.

The Mechanism of Sudden Cardiac Death in Heart Failure

The mechanism of SCD in HFrEF is complex and mainly includes two main pathways: ventricular tachyarrhythmias (VTs) and bradyarrhythmia/electromechanical dissociations.11 The VT pathway is triggered by MI, catecholamine surge and electrolyte imbalance. It can be prevented by ICDs, which do not affect the substrate of arrhythmia. Bradyarrhythmia/electromechanical dissociations develop as a result of adverse ventricular remodelling, which occurs because of cardiomyocyte loss and myocardial fibrosis accumulation in settings of maladaptive neurohormonal system activity.11 GDMT interferes with this pathway by significantly reducing the extension of cardiac remodelling over time.

The synergistic effect of ICDs and conventional GDMT is evident and has been confirmed in clinical trials and real-world studies. Survival benefits are repeatedly demonstrated in prophylactic ICD recipients treated with triple GDMT. EU-CERT-ICD, a prospective observational study conducted in 44 centres across Europe including 2,327 well-treated HFrEF patients (β-blockers/ACEIs/ARBs ~90%, MRA ~80%) with guideline indications for prophylactic ICD showed a 27% reduction in mortality during a mean follow up period of 2.4 ± 1.1 years in the ICD group.12 Similarly, a SwedHF database analysis reported 27% and 22% all-cause mortality risk reduction with ICD at 1 and 5 years, respectively.13 Conversely, in ICD carriers, GDMT optimisation is associated with marked mortality benefits. In a study of 4,972 recipients of primary prevention ICD, in which 5%, 20%, 52%, and 23% of patients were prescribed none, one, two, or three to four GDMT medications, respectively, each additional GDMT conferred a reduction in the risk of death by 36% (HR 0.64; p<0.001).14

Trends in Sudden Cardiac Death Rates and Heart Failure

Over the last two decades, there has been a decline in the annual rates of SCD in HFrEF from 6.5% to 3.3% per 100 patient-years; this has occurred in parallel with the improvement of pharmacological therapy for HF.6 Recent findings from registry-based studies reported similar or lower SCD incidence rates worldwide. The long-term EORP HF registry indicated SCD incidence rates of 3.4% per 100 patient-years in the HFrEF cohort.15 A multicentre observational cohort study, the IMAC-2 study, showed an SCD risk of 1.9% in patients with recent onset non-ischaemic cardiomyopathy (NICM).16 In a cohort of 140,204 post-MI patients included in the PROFID project, the SCD rates in non-ICD individuals with LVEF <35% were 1.84% and 3.41% at 12 and 36 months, respectively.17 Of note, the aforementioned data were obtained before the widespread use of SGLTIs and ARNI. With that, can novel HFrEF pharmacological agents still impact the rate of risk of SCD?

Sudden Cardiac Death in Contemporary Heart Failure Therapy

In PARADIGM-HF, the annual risk of SCD was 2.7% per 100 patient-years in the ARNI arm, which was significantly lower than the control arm (3.3% per 100 patient-years).18,19 In the randomised groups combined, the cumulative incidences of SCD at 3–6−12, 24 and 36 months were 1.0, 95% CI [0.8–1.3]; 2.0, 95% CI [1.7–2.3], 3.7, 95% CI [3.3–4.2] and 8.8, 95% CI [8.0–9.5], respectively.6

In the DAPA-HF trial, the annual risk of SCD in the dapagliflozin arm was 2.7%, significantly lower than in controls (3.3% per 100 patient-years).20 Of note, only 11% of those individuals received ARNI. Also of note, the effect of both SGLT2Is and ARNI on SCD risk reduction was more pronounced beyond 3 months of therapy.19,20

A post hoc analysis of DAPA-HF showed that, in the dapagliflozin arm, HFrEF patients had a 21% lower risk of the composite of serious ventricular arrhythmia (VA), resuscitated cardiac arrest or SCD compared with patients who received conventional therapy (HR 0.79; 95% CI [0.63–0.99]; p=0.03).21 This significant role of ARNI and SGLT2Is in the reduction of sustained VT, non-sustained VTs (NSVT), ICD shocks and SCD risks has been further confirmed in several meta-analyses.21–23

Importantly, simultaneous administration of ARNI, β-blockers, MRA and SGLT2Is is associated with the greatest reduction of all-cause mortality, cardiovascular (CV) death or first hospital admission for HF compared with conventional strategies, providing an additional 8.3 life years.5,6 It is possible that further reductions in SCD rates may be expected when quadritherapy is implemented.

Sudden Cardiac Death and Ventricular Arrhythmias: The Role of ARNI and SGLT2Is

The favourable effect of ARNI and SGLT2Is on SCD reduction is mediated – at least partially – through the drug effect on RCR. The association between RCR and life-threatening VAs has been previously reported in CRT studies, which justified the unique role of RCR in SCD development. The study demonstrated a 55% lower risk of life-threatening VA episodes in those HFrEF patients whose reduced left ventricular end-diastolic volumes (LVEDV) were >25% post CRT implantation compared with those with a lower degree of LVEDV change (HR 0.45; 95% CI [0.31–0.66]; p<0.001).24 Such associations were also confirmed in pharmacotherapy studies. Minami et al. showed that, in patients with new-onset HFrEF treated with conventional HF medications, every 1% increase in LVEF was associated with a 22% decrease in the odds of SCD (OR per 1% increase 0.78; 95% CI [0.65–0.93]).25 Martens et al. found a significant reduction of NSVT episodes within a year following switching from ACEI/ARB to ARNI, with a greater decrease in VA episodes in those with pronounced left ventricular reverse remodelling.26 A post hoc analysis of DAPA-HF reported a 14% risk reduction of composite serious VA, resuscitated cardiac arrest, or SCD with every 5% increase in LVEF (HR 0.86; 95% CI [0.78–0.94]; p=0.001).20

Reverse Cardiac Remodelling: The Role of ARNI and SGLTIs

ARNIs have demonstrated a pronounced effect on RCR (Table 1). The PROVE-HF study, which assessed the changes in cardiac structure and function after ACEI substitution with ARNI in HFrEF, showed an LVEF improvement of 5.2% and 9.4% and indexed LVEDV reduction of 6.65 (~8%) and 12.3 (~15%) ml/m2 at 6 and 12 months respectively.27 Guerra et al. further demonstrated a 3.9% LVEF increase after 6 months of ARNI therapy.28 Martens et al. proved that 44% of patients had >5% of LVEF improvement by 12 months following a switch to ARNI.26

HFrEF patients treated with empagliflozin in the placebo-controlled EMPA-TROPISM trial had 6% LVEF improvement and a 12% LVEDV reduction29 compared with control arms at 6 months of treatment with empagliflozin. However, the SUGAR-DM-HF study did not find an LVEF increase in HFrEF patients treated with empagliflozin after 9 months, but a significant reduction in LVEDDi of 8% in the empagliflozin group was reported.30 The discrepancies in the findings between these two studies could be explained, at least partially, by the differences in GDMT (Table 1). A recent meta-analysis of 555 HFrEF patients in six SGLT2I trials reported mean changes in LVEF of +2.7% and a reduction in LVEDV by 17.07 ml after 12–36 weeks of SGLT2I treatment.31

Timing of Reverse Cardiac Remodelling

It is crucial to understand the timeframe within which RCR occurs in HFrEF patients after GDMT initiation and optimisation to select the ICD candidates properly. It is important to exclude those who might soon not be indicated for ICD implantation. In a cohort of the PROVE-HF study, which included HFrEF individuals with long-term HF and LVEF below 35%, 32% and 62% of patients improved LVEF to over 35% after 6 and 12 months of ARNI therapy and, thus, did not meet the criteria for ICD implantation (Table 1).27 Similar findings were reported by Guerra et al.28 The recent prospective observational HF-OPT study of 598 patients with de novo HFrEF and LVEF <35%, to whom GDMT was initiated in index admission (ACEI/ARBs ~68%, ARNI ~25%, β-blockers ~95%, MRA ~60%) showed a progressive increase in the proportion of patients with improved LVEF over 35% on therapy over time.32 At 3 months the proportion was 46% of patients, reaching 68% at 6 months and 77% at 12 months of therapy. It was noted that target doses of GDMT at 3 months were achieved in only approximately 50% of patients, while at 6 months, the target doses were achieved in 75% of patients. Among those on target doses of GDMT, 72% increased their LVEF above 35%. Remarkably, until 90 days, sustained VTs were observed only in 1.8% of, while after 90 days, no sustained VT in wearable cardioverter defibrillator (WCD) carriers occurred. Summarising the findings, it is worth noting that LVEF improves further in substantial proportions of HFrEF patients beyond 3 months of GDMT when target doses are achieved.

Table 1: Reverse Cardiac Remodelling in Patients Receiving Angiotensin Receptor– Neprilysin Inhibitors and/or Sodium–Glucose Cotransporter 2 Inhibitors

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Modifiers of Reverse Cardiac Remodelling

The extension of RCR in response to GDMT can be modified by several factors. Early responders with a greater increase in LVEF are mainly those with newly diagnosed HFrEF, naïve to renin–angiotensin–aldosterone system inhibitors and β-blockers, with shorter HF durations and NICM.33–35 Initiation of triple HF therapy in newly diagnosed HFrEF patients with LVEF ≤35% reduced the proportion of those who may require ICD by twofold at 3 months and by threefold in 6 months.31 On the contrary, advanced age (>70–75 years), chronic obstructive pulmonary disease and AF were associated with poor LVEF recovery and a lower probability of an absolute increase of >5% in LVEF in ejection fraction at 6–12 months. Several studies have confirmed that myocardial scar burden is associated with a greater decline in LVEF and is the strongest determinant of LVEF trajectory in ICM patients.36

Rationale for the Development of Personalised Approaches in Defining Optimal Guideline-directed Medical Therapy Timing before Preventive ICD

In addition to RCR modifiers, there are other factors that influence the risk of SCD that should be taken into account when deciding on preventive ICD implantation. These include specific cardiomyopathies, high arrhythmia burden and high myocardial scar burden, among others (Figure 1). Several proposed scoring systems have evaluated the probability of ICD benefit in specific cardiomyopathies (arrhythmogenic right ventricular cardiomyopathy, phospholamban cardiomyopathy, lamin A/C cardiomyopathies, etc.), which are discussed elsewhere.37 For the HFrEF cohort, scores were developed using clinical characteristics from pivotal primary prevention ICD trials, including the SCD-HEeFT and MADIT-II trials: MADIT-ICD benefit score and Seattle Proportional Risk Models.38–41 Although both scores demonstrated promising results, we still lack a relevant SCD prediction model in clinical practice to reliably distinguish between high- and low-risk patients.

Figure 1: Algorithm for Decision-making for Primary Prevention ICD Implantation in Patients with Heart Failure with Reduced Ejection Fraction

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In the search for relevant and reliable predictors of SCD, recent studies have reported the role of the sizeable myocardial scar on cardiac MRI (CMR) in predicting serious VA or SCD. Marco et al., in a retrospective analysis of 1,165 NICM patients, demonstrated that late-gadolinium enhancement (LGE) was an independent and robust predictor of the arrhythmic endpoints, including appropriate ICD therapies, sustained VT, resuscitated cardiac arrest and SCD.42 A meta-analysis of seven studies, including 1,827 NICM patients over a mean follow-up duration of 36.1 ± 19.3 months, showed the presence of mid-wall LGE was a significant independent predictor of SCD irrespective of LVEF.43 Trials designed to establish the efficacy of CMR-guided ICD strategies are on-going (CMR-GUIDE [NCT01918215]; CMR-ICD [NCT04558723]; and BRITISH [NCT05568069]).

Therefore, the development of a personalised approach, which would help clinicians to determine the urgency of ICD implementations, is required and should weigh up the probability of RCR against individual risks of SCD.

Importantly, when considering indications for primary preventive ICD, a competing risk of non-arrhythmic cardiac death or non-CV causes should be taken into consideration. According to the Frankenstein et al. study, conducted in a cohort of advanced HF patients defined as LVEF ≤20% and pVO2 ≤14 ml/kg/min, those individuals had no benefit from ICD implantation.44 Therefore, high-risk features summarised by the acronym “I NEED HELP” should be used to identify and exclude those at risk of pump failure.4

The markers of a high risk of dying from non-CV causes include advanced age (>70 years), multiple comorbidities and frailty.45 In a prespecified subgroup analysis of the DANISH study, younger patients (<70 years) had higher SCD rates and benefited the most from ICD implantation compared with the older subgroup (>70 years), in whom non-CV mortality prevailed.46 On the contrary, the SwedHF registry did not demonstrate any benefit from ICDs between different age subgroups.14 A recent sub-analysis of the SCD-HeFT trial revealed that age-related is modulated by frailty. The analysis showed that patients with lower frailty burden at baseline were more likely to benefit from ICD therapy regardless of age. In contrast, no benefits were seen in HFrEF individuals aged ≥65 years with a high frailty burden (median Frailty Index [FI], 0.54).45 Therefore, frailty status, rather than physiological age, influences the effect of primary preventive ICD on all-cause mortality in HFrEF. The findings from the retrospective EU-CERT-ICD registry projects and other studies have reported no survival benefit from ICD implantation in people with diabetes.13,47

Importantly, when considering ICD for primary prevention, all therapeutic options should be considered if available in eligible HFrEF patients, including WCD and prophylactic catheter ablation of the arrhythmic ventricular substrate.48,49

It is also worth noting that ICD therapy is associated with several adverse events, including device infections, lead displacement and lead-induced tricuspid regurgitation deterioration, which occur in approximately 1.5%, 3.1%, and 9.4% of cases, respectively.50,51 Another issue is that ICD implantation implies the risk of inappropriate shock, the rate of which accounts for 0.49 per 100 person-years.52 This potential risk of ICD-related adverse events should be considered when decision is made and weighed up against the benefit in every patient.

Future Directions

More research is needed on the effect of the combined foundational therapy on residual risks of SCD and cardiac remodelling among patients with HFrEF. Currently, there are several on-going and registered clinical trials that aim to investigate the efficacy of ICD for primary prevention in HFrEF of both ischaemic and non-ischaemic origin in the settings of contemporary HF GDMT. These include BRITISH, CMR GUIDE DCM, CMR-ICD; SPANISH-1, personalised risk stratification for SCD prevention after MI and PROFID.7 These randomised controlled trials examine different stages for SCD risk stratification, including genetic testing, CMR and electrophysiology studies. They will increase our knowledge and will facilitate the development of personalised approaches in decision-making on ICD implantation for primary prevention.

Moreover, further studies are required to investigate whether emerging HF agents such as vericiguat and omecamtiv mecarbil could influence RCR and the waiting time window. The thresholds for prognostically significant annual SCD rates in HFrEF patients must be defined with further development of individual SCD risk prediction scores and algorithms. An individualised approach to risk estimation will become more common as our knowledge advances with more artificial intelligence projects. Algorithms using ECG-based learning to predict SCD and non-SCD have proven efficacy.53 A considerable European effort towards personalised prediction and prevention of SCD after MI funded by the EU – the PROFID project – that includes over 3,900 patients, will provide a better understanding of a personalised approach using digitalisation.54

Conclusion

This article provides evidence for an updated view on SCD and RCR in the new era of contemporary GDMT. The waiting time window for primary preventive ICD implantation should be determined in ICD-eligible HFrEF patients, considering both timing to RCR occurrence and residual SCD risks. Six months from the Optimal medical therapy timeframe is a potential time period in which to decide on preventive primary ICD. However, individual modulators of RCR and SCD risks and the probability of dying from other causes should be considered individually. The approach provided may be used to analyse large HF registries and in pragmatic trials to further define the timing and benefit of primary prevention ICD.

References

  1. Leyva F, Israel CW, Singh J. Declining risk of sudden cardiac death in heart failure: fact or myth? Circulation 2023;147:759–67. 
    Crossref | PubMed
  2. McDonagh TA, Metra M, Adamo M, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021;42:3599–726. 
    Crossref | PubMed
  3. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol 2022;79:e263–421. 
    Crossref | PubMed
  4. Writing Committee Members, ACC/AHA Joint Committee Members. 2022 AHA/ACC/HFSA guideline for the management of heart failure. J Card Fail 2022;28:e1–167. 
    Crossref | PubMed
  5. Tromp J, Ouwerkerk W, van Veldhuisen DJ, et al. A systematic review and network meta-analysis of pharmacological treatment of heart failure with reduced ejection fraction. JACC Heart Fail 2022;10:73–84. 
    Crossref | PubMed
  6. Shen L, Jhund PS, Petrie MC, et al. Declining risk of sudden death in heart failure. N Engl J Med 2017;377:41–51. 
    Crossref | PubMed
  7. Yehya A, Davis JD, Sauer AJ, Ibrahim NE. Is it time to revisit ICD indications? Heart Fail Rev 2022;27:2177–9. 
    Crossref | PubMed
  8. DeFilippis EM, Butler J, Vaduganathan M. Waiting period before implantable cardioverter-defibrillator implantation in newly diagnosed heart failure with reduced ejection fraction: a window of opportunity. Circ Heart Fail 2017;10:e004478. 
    Crossref | PubMed
  9. Patel RB, Nohria A, Butler J, Vaduganathan M. Dying is not what it used to be! Impact of evolving epidemiology and treatment on mode of death in heart failure. Eur J Heart Fail 2019;21:1267–9. 
    Crossref | PubMed
  10. Yehya A, Lopez J, Sauer AJ, et al. Revisiting ICD therapy for primary prevention in patients with heart failure and reduced ejection fraction. JACC Heart Fail 2025;13:1–13. 
    Crossref | PubMed
  11. Packer M. What causes sudden death in patients with chronic heart failure and a reduced ejection fraction? Eur Heart J 2020;41:1757–63. 
    Crossref | PubMed
  12. Zabel M, Willems R, Lubinski A, et al. Clinical effectiveness of primary prevention implantable cardioverter-defibrillators: results of the EU-CERT-ICD controlled multicentre cohort study. Eur Heart J 2020;41:3437–47. 
    Crossref | PubMed
  13. Schrage B, Uijl A, Benson L, et al. Association between use of primary-prevention implantable cardioverter-defibrillators and mortality in patients with heart failure: a prospective propensity score-matched analysis from the Swedish Heart Failure registry. Circulation 2019;140:1530–9. 
    Crossref | PubMed
  14. Dhande M, Rangavajla G, Canterbury A, et al. Guideline-directed medical therapy and the risk of death in primary prevention defibrillator recipients. JACC Clin Electrophysiol 2022;8:1024–30. 
    Crossref | PubMed
  15. Kapłon-Cieślicka A, Benson L, Chioncel O, et al. A comprehensive characterization of acute heart failure with preserved versus mildly reduced versus reduced ejection fraction – insights from the ESC-HFA EORP Heart Failure Long-Term Registry. Eur J Heart Fail 2022;24:335–50. 
    Crossref | PubMed
  16. Sheppard R, Mather PJ, Alexis JD, et al. Implantable cardiac defibrillators and sudden death in recent onset nonischemic cardiomyopathy: results from IMAC2. J Card Fail 2012;18:675–81. 
    Crossref | PubMed
  17. Peek N, Hindricks G, Akbarov A, et al. Sudden cardiac death after myocardial infarction: individual participant data from pooled cohorts. Eur Heart J 2024;45:4616–26. 
    Crossref | PubMed
  18. Rohde LE, Chatterjee NA, Vaduganathan M, et al. Sacubitril/valsartan and sudden cardiac death according to implantable cardioverter-defibrillator use and heart failure cause: a PARADIGM-HF analysis. JACC Heart Fail 2020;8:844–55. 
    Crossref | PubMed
  19. Desai AS, McMurray JJV, Packer M, et al. Effect of the angiotensin-receptor-neprilysin inhibitor LCZ696 compared with enalapril on mode of death in heart failure patients. Eur Heart J 2015;36:1990–7. 
    Crossref | PubMed
  20. Curtain JP, Docherty KF, Jhund PS, et al. Effect of dapagliflozin on ventricular arrhythmias, resuscitated cardiac arrest, or sudden death in DAPA-HF. Eur Heart J 2021;42:3727–38. 
    Crossref | PubMed
  21. Wang R, Ye H, Ma L, et al. Effect of sacubitril/valsartan on reducing the risk of arrhythmia: a systematic review and meta-analysis of randomized controlled trials. Front Cardiovasc Med 2022;9:890481. 
    Crossref | PubMed
  22. Pozzi A, Abete R, Tavano E, et al. Sacubitril/valsartan and arrhythmic burden in patients with heart failure and reduced ejection fraction: a systematic review and meta-analysis. Heart Fail Rev 2023;28:1395–403. 
    Crossref | PubMed
  23. Li HL, Lip GYH, Feng Q, et al. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and cardiac arrhythmias: a systematic review and meta-analysis. Cardiovasc Diabetol 2021;20:100. 
    Crossref | PubMed
  24. Barsheshet A, Wang PJ, Moss AJ, et al. Reverse remodeling and the risk of ventricular tachyarrhythmias in the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy). J Am Coll Cardiol 2011;57:2416–23. 
    Crossref | PubMed
  25. Minami Y, Kikuchi N, Shiga T, et al. Incidence and predictors of early and late sudden cardiac death in hospitalized Japanese patients with new-onset systolic heart failure. J Arrhythm 2021;37:1148–55. 
    Crossref | PubMed
  26. Martens P, Nuyens D, Rivero-Ayerza M, et al. Sacubitril/valsartan reduces ventricular arrhythmias in parallel with left ventricular reverse remodeling in heart failure with reduced ejection fraction. Clin Res Cardiol 2019;108:1074–82. 
    Crossref | PubMed
  27. Januzzi JL Jr, Prescott MF, Butler J, et al. Association of change in N-terminal pro-B-type natriuretic peptide following initiation of sacubitril-valsartan treatment with cardiac structure and function in patients with heart failure with reduced ejection fraction. JAMA 2019;322:1085–95. 
    Crossref | PubMed
  28. Guerra F, Ammendola E, Ziacchi M, et al. Effect of sacubitril/valsartan on left ventricular ejection fraction and on the potential indication for implantable cardioverter defibrillator in primary prevention: the SAVE-ICD study. Eur J Clin Pharmacol 2021;77:1835–42. 
    Crossref | PubMed
  29. Santos-Gallego CG, Vargas-Delgado AP, Requena-Ibanez JA, et al. Randomized trial of empagliflozin in nondiabetic patients with heart failure and reduced ejection fraction. J Am Coll Cardiol 2021;77:243–55. 
    Crossref | PubMed
  30. Lee MMY, Brooksbank KJM, Wetherall K, et al. Effect of empagliflozin on left ventricular volumes in patients with type 2 diabetes, or prediabetes, and heart failure with reduced ejection fraction (SUGAR-DM-HF). Circulation 2021;143:516–25. 
    Crossref | PubMed
  31. Usman MS, Januzzi JL, Anker SD, et al. The effect of sodium-glucose cotransporter 2 inhibitors on left cardiac remodelling in heart failure with reduced ejection fraction: systematic review and meta-analysis. Eur J Heart Fail 2024;26:373–82. 
    Crossref | PubMed
  32. Veltmann C, Duncker D, Doering M, et al. Therapy duration and improvement of ventricular function in de novo heart failure: the Heart Failure Optimization study. Eur Heart J 2024;45:2771–81. 
    Crossref | PubMed
  33. Zecchin M, Merlo M, Pivetta A, et al. How can optimization of medical treatment avoid unnecessary implantable cardioverter-defibrillator implantations in patients with idiopathic dilated cardiomyopathy presenting with “SCD-HeFT criteria?” Am J Cardiol 2012;109:729–35. 
    Crossref | PubMed
  34. Lupón J, Gavidia-Bovadilla G, Ferrer E, et al. Dynamic trajectories of left ventricular ejection fraction in heart failure. J Am Coll Cardiol 2018;72:591–601. 
    Crossref | PubMed
  35. Duncker D, König T, Hohmann S, et al. Avoiding untimely implantable cardioverter/defibrillator implantation by intensified heart failure therapy optimization supported by the wearable cardioverter/defibrillator – the PROLONG study. J Am Heart Assoc 2017;6:e004512. 
    Crossref | PubMed
  36. Aboul Enein F, Allaaboun S, Khayyat S, et al. Association between myocardial scar burden and left ventricular ejection fraction in ischemic cardiomyopathy. Cureus 2020;12:e12110. 
    Crossref | PubMed
  37. Arbelo E, Protonotarios A, Gimeno JR, et al. 2023 ESC guidelines for the management of cardiomyopathies. Eur Heart J 2023;44:3503–626. 
    Crossref | PubMed
  38. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005;352:225–37. 
    Crossref | PubMed
  39. Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002;346:877–83. 
    Crossref | PubMed
  40. Younis A, Goldberger JJ, Kutyifa V, et al. Predicted benefit of an implantable cardioverter-defibrillator: the MADIT-ICD benefit score. Eur Heart J 2021;42:1676–84. 
    Crossref | PubMed
  41. Shadman R, Poole JE, Dardas TF, et al. A novel method to predict the proportional risk of sudden cardiac death in heart failure: derivation of the Seattle Proportional Risk Model. Heart Rhythm 2015;12:2069–77. 
    Crossref | PubMed
  42. Di Marco A, Brown PF, Bradley J, et al. Improved risk stratification for ventricular arrhythmias and sudden death in patients with nonischemic dilated cardiomyopathy. J Am Coll Cardiol 2021;77:2890–905. 
    Crossref | PubMed
  43. Wang J, Yang F, Wan K, et al. Left ventricular midwall fibrosis as a predictor of sudden cardiac death in non-ischaemic dilated cardiomyopathy: a meta-analysis. ESC Heart Fail 2020;7:2184–92. 
    Crossref | PubMed
  44. Frankenstein L, Zugck C, Nelles M, et al. Primary ICD-therapy in patients with advanced heart failure: selection strategies and future trials. Clin Res Cardiol 2008;97:594–600. 
    Crossref | PubMed
  45. Segar MW, Keshvani N, Singh S, et al. Frailty status modifies the efficacy of ICD therapy for primary prevention among patients with HF. JACC Heart Fail 2024;12:757–67. 
    Crossref | PubMed
  46. Elming MB, Nielsen JC, Haarbo J, et al. Age and outcomes of primary prevention implantable cardioverter-defibrillators in patients with nonischemic systolic heart failure. Circulation 2017;136:1772–80. 
    Crossref | PubMed
  47. Sharma A, Al-Khatib SM, Ezekowitz JA, et al. Implantable cardioverter-defibrillators in heart failure patients with reduced ejection fraction and diabetes. Eur J Heart Fail 2018;20:1031–8. 
    Crossref | PubMed
  48. Reddy VY, Reynolds MR, Neuzil P, et al. Prophylactic catheter ablation for the prevention of defibrillator therapy. N Engl J Med 2007;357:2657–65. 
    Crossref | PubMed
  49. Žižek D, Mrak M, Jan M, et al. Impact of preventive substrate catheter ablation on implantable cardioverter-defibrillator interventions in patients with ischaemic cardiomyopathy and infarct-related coronary chronic total occlusion. Europace 2024;26:euae109. 
    Crossref | PubMed
  50. Ezzat VA, Lee V, Ahsan S, et al. A systematic review of ICD complications in randomised controlled trials versus registries: is our ‘real-world’ data an underestimation? Open Heart 2015;2:e000198. 
    Crossref | PubMed
  51. Zhang XX, Wei M, Xiang R, et al. Incidence, risk factors, and prognosis of tricuspid regurgitation after cardiac implantable electronic device implantation: a systematic review and meta-analysis. J Cardiothorac Vasc Anesth 2022;36:1741–55. 
    Crossref | PubMed
  52. Frodi DM, Diederichsen SZ, Xing LY, et al. Incidence and risk factors for first and recurrent ICD shock therapy in patients with an implantable cardioverter defibrillator. J Interv Card Electrophysiol 2025;68:125–39. 
    Crossref | PubMed
  53. Shiraishi Y, Goto S, Niimi N, et al. Improved prediction of sudden cardiac death in patients with heart failure through digital processing of electrocardiography. Europace 2023;25:922–30. 
    Crossref | PubMed
  54. Dagres N, Peek N, Leclercq C, Hindricks G. The PROFID project. Eur Heart J 2020;41:3781–2. 
    Crossref | PubMed
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