Abstract
BACKGROUND
Cardiac resynchronization therapy (CRT) has been a major therapeutic advancement for patients with heart failure and electrical dyssynchrony. While CRT improves symptoms, reduces hospitalizations, and enhances survival, the role of implantable cardioverter-defibrillators (ICDs) alongside CRT in patients with non-ischemic cardiomyopathy (NICM) remains controversial. To evaluate and compare the outcomes of CRT with ICD (CRT-D) versus CRT with pacemaker-only (CRT-P) in individuals diagnosed with NICM, with a specific focus on the elderly.
METHODS
A comprehensive search of PubMed, Embase, and the Cochrane Central Register of Controlled Trials was conducted in January 2024. Studies comparing CRT-D and CRT-P in patients with NICM were included, with subgroup analyses focusing on patients aged 75 years and older.
RESULTS
Twelve studies, including two randomized clinical trials, with a total of 62,145 patients and 16,754 pooled death events (9,171 in CRT-D and 7,583 in CRT-P), were analyzed. CRT-D was associated with a significantly lower risk of all-cause mortality compared to CRT-P (pooled OR = 0.72; 95% CI: 0.61–0.85; P < 0.01), with significant heterogeneity (I2 = 83%). RCT subgroup analysis, was not statistically significant (pooled OR = 0.82; 95% CI: 0.64-1.06; P = 0.41; I2 = 0%). In patients older than 75 years, no significant difference in mortality risk was observed (pooled OR 0.96; 95% CI: 0.81–1.15; I2=39%).
CONCLUSION
Our meta-analysis suggests that the addition of ICD therapy to CRT in patients with NICM significantly reduces all-cause mortality. However, this benefit does not extend to cardiovascular mortality, likely due to the primary role of ICDs in preventing sudden cardiac death rather than other causes such as progressive heart failure. The survival advantage of CRT-D is most pronounced in younger patients, with those over 75 years of age deriving less benefit. This highlights the importance of careful patient selection, considering age and comorbidities, when deciding on ICD implantation in NICM patients.
Heart failure (HF) remains a prevalent cardiovascular diagnosis, contributing significantly to global morbidity and mortality.[1] The prevalence of HF is approximately 1%–2% of adults, and it continues to rise primarily due to aging populations.[2] CRT is an established intervention in the management of HF, targeting intraventricular dyssynchrony, which is commonly observed in patients with HF and left ventricular systolic dysfunction.[3] CRT has shown to improve survival in patients with prolonged QRS duration (≥ 130 ms) and reduced left ventricular ejection fraction (LVEF).[4–6]
For patients with LVEF ≤ 35%, CRT is often paired with implantable cardioverter-defibrillators (ICDs), creating a combined approach known as CRT-D. ICDs are intended to reduce sudden cardiac death, a major cause of mortality in this population. However, the survival benefit of CRT-D over CRT with pacemaker-only therapy (CRT-P) is still uncertain, as no large-scale randomized controlled trials (RCTs) have directly compared these two modalities. Additionally, ICD implantation is associated with higher costs and potential risks such as lead failure and inappropriate shocks. In current clinical practice, CRT-P is more frequently used in older patients and those with more comorbidities.[7]
Recently, the etiology of HF has been increasingly emphasized when assessing the potential benefits of CRT-D over CRT-P. Observational studies have suggested that CRT-D reduces all-cause mortality in patients with ischemic cardiomyopathy, while no significant difference in outcomes has been observed in NICM.[8–12] The Defibrillator Implantation in Patients with Non-ischemic Systolic Heart Failure (DANISH) trial found no significant improvement in survival with ICDs in NICM patients,[13] even though the rate of CRT was 58% in both groups. However, long-term follow-up data from DANISH and other studies have shown that ICDs are associated with a reduction in all-cause mortality, cardiovascular death, and sudden cardiac death, particularly in patients aged 70 years or younger.[13] In a large multicenter registry involving more than 50,000 patients, CRT-D was associated with increased survival irrespective of the underlying etiology.[14]
Given these mixed results, the aim of this study is to conduct a systematic review and meta-analysis comparing CRT-D and CRT-P in patients with NICM.
METHODS
Protocol
This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Supplemental Table 1). The study was registered in the PROSPERO database at its inception (Registration number: CRD42023390199).
Literature Search
A systematic literature search was conducted in PubMed, Embase, and the Cochrane Central Register of Controlled Trials databases in January 2024. The search aimed to identify studies comparing CRT-P and CRT-D in patients diagnosed with NICM. There were no restrictions on publication date, but the search was limited to studies in English, Portuguese, or Spanish, and involving human subjects. Additional data were obtained from protocols of RCTs. The complete search strategy is provided in Supplemental Figure 1.
Inclusion Criteria
To be included in this study, the selected trials had to meet the following criteria: (1) patients aged ≥ 18 years with NICM; (2) patients diagnosed with NICM and with class I indication for CRT implantation; and (3) studies comparing CRT-D and CRT-P with all-cause mortality as the primary outcome.
Exclusion Criteria
Studies were excluded if: (1) patients aged < 18 years; (2) studies not published in English, Spanish or Portuguese; (3) case–control studies, reviews, dissertations, editorials, guidelines, commentaries, and letters; (4) studies lacking absolute numbers of events or sufficient data for meta-analysis; (5) duplicate publications (longest follow-up was included in the analysis).
Primary and Secondary Outcomes
The primary endpoint of this meta-analysis was all-cause mortality. Secondary endpoints included cardiovascular death, periprocedural complications, and sudden cardiac death. Subgroup analyses were conducted based on study type (RCTs, observational studies), propensity score-matched cohorts, and age.
Data Collection and Management
Two independent reviewers (GC and VN) screened the titles and abstracts of the retrieved publications to identify studies meeting the inclusion criteria. Full texts of eligible studies were then reviewed to confirm their eligibility. Data extracted from the studies included baseline clinical characteristics, interventions, and key outcomes (Table 1). Where multiple publications of the same study were identified, the most recent and complete data were used to avoid duplication.
Table 1. Study characteristics.
| Name | Study Group | Single vs. multicenter/country | Study design | Randomized vs cohort | Publication | Year | NICM CRT-D | NICM CRT-P | Follow-up (months) | Outcomes | Adjustments made |
| ACEI: inhibitor indicates angiotensin-converting enzyme inhibitor; AF: atrial fibrillation; AM: all-cause mortality; COPD: chronic obstructive pulmonary disease; CRT: cardiac resynchronization therapy; CRT-D: CRT defibrillator; CRT-P: CRT pacemaker; CV: cardiovascular; CVD: cerebrovascular disease; HF: heart failure; UK: United Kingdom; US: United States; LVEF: left ventricular ejection fraction; MACE: major adverse; SCD: sudden cardiac death; NYHA: New York Heart Association Functional Classification for Heart Failure. | |||||||||||
| Kutyifa, et al. [9] |
N/A | Single center/Hungary | Retrospective | Cohort | Eur Hear J HF | 2014 | 209 | 458 | 28 | AM, LVEF improvement | Age and sex |
| Marijon et al [10] |
CeRtiTuDe trial | Multicenter/Europe | Prospective | Cohort | Eur Hear J | 2015 | 571 | 245 | 24 | AM | Propensity score |
| Witt, et al.[15] |
N/A | Single center/Denmark | Retrospective | Cohort | EP Europace | 2016 | 122 | 305 | 48 | AM | Apriori confounders |
| Kober, et al.[12] |
DANISH trial | Multicenter/Danish | RCT | RCT | N. Eng. J. Med | 2016 | 322 | 323 | 67.6 | AM; device infection | Time-to-event methods |
| Barra, et al.[11] |
French-UK-Sweden CRT Network | Multicenter/European | Retrospective | Cohort | JACC | 2017 | 1943 | 682 | 41.4 | AM | Propensity score |
| Drozd, et al.[16] |
N/A | Single center/UK | Prospective | Cohort | J Cardiova Med | 2017 | 25 | 240 | 35.2 | AM | Propensity score |
| Leyva, et al.[8] |
N/A | Multicenter/UK | Retrospective | Cohort | EP Europace | 2018 | 114 | 116 | 56.4 | AM, HF, MACE, cardiac mortality, SCD, VT/VF | Propensity score |
| Wang, et al.[17] |
N/A | Single center/US | Retrospective | Cohort | Indian Pacing | 2019 | 93 | 42 | 46 | AM | LVEF. ACE inhibitor use |
| Saba, et al. [18] |
N/A | Multicenter/US | Retrospective | Cohort | Heart Rhythm | 2019 | 4359 | 1236 | 60 | AM, medical costs | Cox proportional hazard |
| Gras, et al. [19] |
N/A | Multicenter/French | Retrospective | Cohort | Europace | 2020 | 9129 | 8176 | 30.4 | AM, cardiovascular and noncardiovascular death | Propensity score |
| Liang, et al. [20] |
N/A | Single center/China | Retrospective | Cohort | J CARDIOL | 2020 | 202 | 117 | 36 | AM | Propensity score |
| Doran, et al.[21] |
COMPANION trial | Multicenter/US | RCT | RCT | JACC HF | 2021 | 270 | 285 | 17.1 | AM, SCD, HF | Cox propensity hazards models |
| Schrage, et al. [22] | N/A | Multicenter/Sweden | Retrospective | Cohort | EP Europe | 2022 | 1108 | 880 | 28.2 | AM | Propensity score |
| Farouq, et al.[23] |
N/A | Multicenter/Sweden | Retrospective | Cohort | EP Europe | 2023 | 2693 | 2334 | 51.6 | AM | AF, Hypertension, LBBB, CKD, COPD, Malignancy, Age, Sex, CVD |
Assessment of Risk of Bias and Certainty of Evidence
The risk of bias for RCTs was independently assessed by two authors (GC and VN) using the Cochrane risk of bias tool (Supplemental Table 2), evaluating biases in random sequence generation, allocation concealment, blinding of participants and personnel, outcome assessment, incomplete outcome data, selective reporting, and other potential sources of bias. Non-randomized studies were assessed using the Newcastle-Ottawa Scale (NOS) (Supplemental Table 3), which evaluates cohort selection (0–4 points), cohort comparability (0–2 points), and outcome assessment (0–3 points). The results of the quality assessments are presented in supplemental material. The certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluations (GRADE) framework (Supplemental Table 4).
Statistical Analysis
Dichotomous, non-adjusted data were pooled using odds ratios (ORs) to describe effect sizes, applying the Mantel-Haenszel method in a random effects model. The meta-analysis was conducted using Review Manager (RevMan) version 5.4.1. Funnel plots were used to assess heterogeneity and potential publication bias. Results were considered statistically significant if the 95% CI for the effect size did not include zero. Heterogeneity was measured using the I2 statistic, with values exceeding 50% considered indicative of substantial heterogeneity.
RESULTS
Search Results
Our literature search yielded 7,246 relevant records. After removing duplicates and excluding studies that did not meet our predefined inclusion and exclusion criteria, a total of 13 studies were included in the final analysis (Figure 1). These studies comprised 62,700 patients, with 35,836 in the CRT-D group and 26,002 in the CRT-P group. Some relevant studies comparing CRT-D and CRT-P were excluded as they did not specify event numbers according to etiology.
Figure 1.
PRISMA flow diagram.
The overall study characteristics are provided in Table 1. The studies represented data from various regions: one from China, three from the United States, and ten from Europe. Seven of the studies used propensity score-matched analysis. There was no reported difference in implantation complications. Patients in the CRT-P group were generally older and had a lower proportion of males compared to those in the CRT-D group.
All-Cause Mortality
In the primary analysis, CRT-D was associated with a significantly lower risk of all-cause mortality compared to CRT-P (pooled OR = 0.72; 95% CI: 0.61–0.85; P < 0.01) (Figure 2). However, there was significant heterogeneity among the studies (I2 = 83%). In the RCT subgroup analysis, the difference between CRT-D and CRT-P was not statistically significant (pooled OR = 0.82; 95% CI: 0.64-1.06; P = 0.41; I2 = 0%).
Figure 2.
Forest plot of all studies pooled in meta-analysis for the risk of all-cause mortality in NICM.
CRT-D: cardiac resynchronization therapy with cardioverter-defibrillators; CRT-P: cardiac resynchronization therapy with pacemaker-only; M-H: Mantel Haenszel; NICM: non-ischemic cardiomyopathy.
Subgroup analysis focusing on propensity score-matched studies yielded consistent results. The pooled OR for all-cause mortality in this subgroup was 0.82 (95% CI: 0.77–0.87; P < 0.01) (Figure 3), with no observed heterogeneity (I2 = 0%). Additionally, subgroup analysis for patients older than 75 years showed no significant difference in all-cause mortality between CRT-D and CRT-P (pooled OR = 0.96; 95% CI: 0.81–1.15; P = 0.58) (Figure 4), with high heterogeneity (I2 = 0%).
Figure 3.
Forest plot for subgroup analysis for all-cause mortality in propensity score-matched studies.
CRT-D: cardiac resynchronization therapy with cardioverter-defibrillators; CRT-P: cardiac resynchronization therapy with pacemaker-only; M-H: Mantel Haenszel.
Figure 4.
Forest plot for subgroup analysis for all-cause mortality risk in patients older than 75 years old with NICM.
CRT-D: cardiac resynchronization therapy with cardioverter-defibrillators; CRT-P: cardiac resynchronization therapy with pacemaker-only; M-H: Mantel Haenszel; NICM non-ischemic cardiomyopathy.
Secondary Outcomes
Cardiovascular death was defined as a death resulting from a primary cardiovascular cause, including acute myocardial infarction, sudden cardiac death, heart failure, stroke, cardiovascular procedures, cardiovascular hemorrhage, or other cardiovascular causes. In this analysis, no significant risk reduction in cardiovascular mortality was observed with CRT-D compared to CRT-P (pooled OR = 0.70; 95% CI: 0.49–1.0; P = 0.06; I2 = 92%), although with substantial heterogeneity (Figure 5).
Figure 5.
Forest plot of all studies for cardiovascular mortality risk in patients with NICM.
CRT-D: cardiac resynchronization therapy with cardioverter-defibrillators; CRT-P: cardiac resynchronization therapy with pacemaker-only; NICM non-ischemic cardiomyopathy.
Data on periprocedural complications and sudden cardiac death were not available for analysis due to insufficient reporting across the included studies. Periprocedural complications were defined as any of the following events: pneumothorax, hematoma, vascular injury, lead dislodgment, cardiac tamponade, endocarditis, infection, or inappropriate shocks. Sudden cardiac death was defined as an unexpected death caused by a sudden loss of cardiac function, occurring within one hour of symptom onset in witnessed cases or within 24 h of the individual being last seen alive in unwitnessed cases.
Risk of Bias and Certainty of the Evidence
Overall, the observational studies included in this analysis exhibited a low to moderate risk of bias. In RCT bias assessment, due to the nature of the intervention, there was a high risk of bias related to blinding of participants and personnel. Given these limitations and the risk of bias, the certainty of evidence for both primary and secondary outcomes was deemed low (Supplementary Table 2).
DISCUSSION
Our study suggests that adding an ICD leading to CRT in patients with NICM is associated with a significant reduction in all-cause mortality. However, this benefit was not observed in the RCTs included in our analysis, where the difference between CRT-D and CRT-P did not reach statistical significance. This discrepancy highlights important considerations regarding the timing of these trials and advancements in heart failure therapy.
Predicting sudden cardiac death in NICM remains challenging due to the heterogeneous nature of the disease. ICDs are highly effective at preventing life-threatening ventricular arrhythmias, which are the primary cause of sudden cardiac death. However, ICD implantation is not without risks, particularly when compared to pacing leads, and these risks can be more pronounced in elderly patients. These risks include higher rates of lead fracture or insulation failure, an increased risk of lead dislodgment, inappropriate shocks, and perforation. Additionally, ICD leads are associated with increased mechanical stress, which may lead to complications such as tricuspid regurgitation. Other drawbacks include reduced device longevity, the need for a larger generator, and the potential for oversensing or undersensing of electrical activity.[23,24] These risks must be weighed against the potential benefits, particularly in older patients with multiple comorbidities, through a shared decision-making process that considers factors such as age and overall health status.[25]
NICM is a complex condition with a diverse etiology that includes genetic and acquired causes.[26] Direct contributors may involve pathogenic gene variants, infections, autoimmune diseases, storage diseases, and tachyarrhythmias. Furthermore, interactions between polygenic risk variants and epigenetic or acquired modifiers may significantly influence disease progression.[27,28,29] Certain genetic mutations have been associated with a higher incidence of life-threatening arrhythmias, regardless of LVEF.[30,31] Therefore, while an LVEF ≤ 35% is commonly used as a threshold for CRT-D eligibility, it may not fully capture the subset of patients who stand to benefit the most from ICD therapy. This discrepancy may explain some of the heterogeneity observed in our primary outcome analysis. Current cardiomyopathy guidelines recommend genetic risk assessment in patients with NICM, even those without LVEF ≤ 35%.[32] Specific high-risk genes, such as those encoding nuclear envelope proteins, desmosomes, and cytoskeletal elements, are associated with a higher incidence of SCD. Risk prediction models for these genetic variants have been developed to assist clinicians in determining the appropriate use of CRT-D versus CRT-P.[33,34] Additionally, guidelines suggest evaluating other risk factors, such as unexplained syncope or late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging. LGE is present in 25%–45% of patients with NICM and is a strong predictor of both all-cause mortality and ventricular arrhythmias.[35] For patients with unexplained syncope, programmed electrical stimulation may help identify the underlying cause and clarify the need for ICD implantation.[36]
While our meta-analysis included three RCTs, the benefits of ICD implantation in NICM were not clear in this subgroup analysis, probably inherent to their study design. The COMPANION trial was the only RCT that directly compared CRT-D and CRT-P, although it was originally designed to assess CRT versus optimal medical therapy.[37] In this trial, CRT significantly reduced the combined risk of death from any cause or first hospitalization. When CRT was paired with an ICD, mortality was further reduced in both ischemic and non-ischemic cardiomyopathy patients.[37] Subsequent analyses using Cox proportional hazards models stratified by heart failure etiology confirmed that CRT-D was associated with lower all-cause mortality in NICM patients.[21] In contrast, the DANISH trial found no significant reduction in long-term mortality from ICD implantation in NICM patients. Importantly, the DANISH trial was not specifically designed for CRT patients, although a substantial proportion (58%) of patients in both the ICD and control arms received CRT, making the trial’s results hard to interpret concerning ICD vs. medical therapy only.[12]
It is also worth noting that both COMPANION and DANISH trials were conducted prior to the widespread adoption of newer heart failure therapies, such as sacubitril/valsartan and sodium-glucose cotransporter-2 inhibitors. These pharmacologic advances could potentially impact the relative benefits of CRT-D and CRT-P, warranting further investigation and raising questions about the relevance of older RCTs in current clinical practice.
One of the paradoxical findings in our analysis is that CRT-D significantly reduced all-cause mortality without a corresponding reduction in cardiovascular mortality. This can be explained by the mechanism of ICDs, which are specifically designed to prevent sudden cardiac death caused by ventricular arrhythmias. While this substantially lowers overall death rates, it does not address other forms of cardiovascular death, such as those resulting from progressive heart failure or non-arrhythmic events, particularly high in advanced ages. Moreover, the population receiving CRT-D may be inherently healthier and younger than those receiving CRT-P, leading to a lower incidence of non-cardiovascular deaths, such as those from infections or other comorbidities, further contributing to the observed reduction in all-cause mortality. This highlights the need for careful patient selection, as the benefits of CRT-D may be more pronounced in younger, healthier patients at higher risk for arrhythmia-related death, whereas older patients or those with advanced heart failure may not derive the same survival advantage.
Subgroup analysis in patients over 75 years of age demonstrated no significant reduction in all-cause mortality with CRT-D. This suggests that older patients may not derive the same survival benefits from ICD implantation as younger patients. The extended follow-up of the DANISH trial, published in 2021, confirmed that ICD implantation was associated with a significant reduction in all-cause mortality, cardiovascular death, and sudden cardiac death in patients aged 70 years or younger.[12] Similar findings were reported by Gras, et al.,[19] who noted that the mortality benefit of CRT-D was limited to patients younger than 75 years.
Limitations
Our study has several limitations. Despite a sufficient number of included studies, only three were RCTs, which may limit the robustness of our findings. The high heterogeneity observed in the analysis of all-cause mortality suggests variability in study populations and designs. Although propensity-matched analyses were performed, they may not fully account for residual confounding factors, even when no heterogeneity was detected. Additionally, we were unable to gather sufficient data on important secondary outcomes such as periprocedural complications and sudden cardiac death, limiting the comprehensiveness of our analysis.
Conclusions
Our meta-analysis suggests that the addition of ICD therapy to CRT in patients NICM leads to a significant reduction in all-cause mortality. However, this benefit does not extend to cardiovascular mortality, likely due to the primary action of ICDs in preventing sudden cardiac death rather than other cardiovascular causes such as progressive heart failure. Importantly, the survival advantage of CRT-D is most apparent in younger patients, with those over 75 years of age deriving less benefit, underscoring the need for careful patient selection based on age and comorbidities.
These findings emphasize the need for personalized, shared decision-making when determining the optimal device therapy for NICM patients. While CRT-D offers clear benefits for certain patient populations, particularly younger individuals at high risk of arrhythmic death, it may not be necessary in older patients or those with significant comorbidities. Further randomized controlled trials are needed to refine the criteria for selecting CRT-D over CRT-P, particularly in the context of evolving heart failure therapies.
DISCLOSURE
SUPPLEMENTARY DATA
Supplementary data to this article can be found online.
Conflict of Interest
None.
Data Availability
All studies used in our analysis are available to the general public.
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Associated Data
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Supplementary Materials
Supplementary data to this article can be found online.
Data Availability Statement
All studies used in our analysis are available to the general public.