Discussion
The prognostic significance of NT-pro BNP in patients with HFrEF has been thoroughly established, however, it remains mainly unexplored in patients with HFrEF with ICD. Thus, we performed a meta-analysis evaluating the use of NT-pro BNP to predict all-cause mortality and appropriate ICD shock, which included data from approximately 5000 patients with HFrEF treated with ICD. Several key findings arose from this meta-analysis. To begin, in patients with HFrEF with ICD, a raised NT-pro BNP levels had a nearly twofold increase in the risk of all-cause mortality and appropriate ICD shock as compared with those with a lower NT-pro BNP levels, with a mean duration of follow-up 3.6 years. Second, we discovered a concentration–response relationship between NT-pro BNP and appropriate ICD shock as well as all-cause mortality. However, given its stagnant trends when NT-pro BNP levels reach above the inflection point (3000 pg/mL in both outcomes of interest), it appears that NT-pro BNP has a ceiling effect, which means that an exceedingly high NT-pro BNP value does not necessarily translate into an extremely high risk of composite poor outcomes. Therefore, it justifies the convention that NT-pro BNP should be used as an additional stratification criterion alongside LVEF and NYHA in identifying the most qualified patients with HFrEF in terms of ICD therapy for primary prevention.
The pathophysiological relationship between NT-pro BNP increases and ventricular tachyarrhythmia in HF is poorly understood, but biologically plausible. NT-pro BNP is mostly released from the ventricles in response to increases in intraventricular pressure induced by pooling of the blood inside the ventricle due to left ventricular dysfunction, triggering myocardial stretch. Alterations in ventricular pressure and shape also trigger depolarising cation channels in cardiomyocytes, resulting in electrophysiological changes that may contribute to enhanced arrhythmogenesis, such as dispersed refractoriness and early after depolarisations, which may lead to lethal arrhythmic events.27 28 As the amount of myocardial expansion directly affects the level of NT-pro BNP, and arrhythmogenesis is initiated due to the myocardial dilatation process, measurement of this peptide might conceivably predict the risk of ventricular tachyarrhythmia in patients with HFrEF.29
Despite presenting with satisfying results, it should be emphasised that NT-pro BNP is not only increased with the severity of HFrEF condition, but other cardiac (eg, valvular heart disease, myocarditis, atrial fibrillation and so on) and non-cardiac factors (eg, age, female gender, renal dysfunction, pulmonary embolism, sepsis, severe burns, haemodynamic profile and so on) may also play a role in elevating natriuretic peptide levels.30 31 Regarding these numerous factors that may affect the NT-pro BNP levels, it seems impossible to rule them all out. Moreover, compared with patients with HFrEF with low NT-pro BNP levels, those with high NT-pro BNP levels were older, and tended to have more comorbidities (hypertension, diabetes mellitus, atrial fibrillation, valvular heart disease and kidney dysfunction), as well as presented with lower LVEF, higher NYHA functional class and more HF hospitalisation.12 14 15 18 Fortunately, as most of the included studies were adjusted for several confounding variables and only adjusted HRs were incorporated into the analysis, we can fairly infer that NT-pro BNP was independently correlated with all-cause mortality, thereby reducing the confounding bias.
To the best of our knowledge, no prior study has particularly investigated the predictive value of NT-pro BNP in prognosticating all-cause mortality and appropriate ICD shock in patients with HFrEF eligible for primary prevention therapy of ICD. The fact that a single NT-pro BNP determination was an independent predictor of these composite poor outcomes, the association between NT-pro BNP and all-cause mortality, however, exhibits a moderate-high heterogeneity (figure 2A). Exploration of heterogeneity should ideally be undertaken using meta-regression and subgroup analysis, although this is implausible due to a paucity of research. Hence, the leave-one-out sensitivity analysis was carried out, and it was discovered that two studies14 15 were deemed as the primary contributors to the high inter-study heterogeneity. This can be explained by the fact that Cheng et al and Deng et al investigations have an increased prevalence of hypertension and diabetes, which are conceded as substantial independent risk factors for mortality.32 Though being adjusted in their multivariate analyses, this should be emphasised that hypertension in both studies and diabetes in Deng et al study disclose statistically significant differences amid their interquartile populations, unlike other included studies, by such means contributing to a considerable heterogeneity within the analysis. Nonetheless, the result of our meta-analysis was fairly robust in the leave-one-out sensitivity analysis; removal of any single study did not alter the statistical significance of the pooled estimate, indicating that our results were stable and reliable.
As a matter of concern, various HF aetiologies within our study population also warrant a further discussion. In contrast to ischaemic cardiomyopathy (ICM), primary preventive ICD therapy in patients with non-ischaemic cardiomyopathy (NICM) is still in a moot point. The AHA and the ESC were unable to reach an agreement regarding this matter. According to the AHA guideline, patients with NICM still receive recommendation class I for ICD treatment for primary prevention.2 In contrast, the recent ESC guideline has degraded its recommendation to class IIa.1 The basis for this contentious issue is that the recent The Danish Study to Assess the Efficacy of Implantable Cardioverter-Defibrillators in Patients with Non-ischemic Systolic Heart Failure on Mortality trial revealed that ICD implantation for primary prevention did not substantially reduce all-cause mortality risk in patients with NICM after a median follow-up of 9.5 years.33 Aside from the previously stated stretch-induced arrhythmia mechanism, scar formation resulting from a prior myocardial infarction can also result in ventricular tachyarrhythmias in patients with HF, implying that NT-pro BNP as a parameter of ventricular dilatation may not be solely correlated with appropriate ICD shock in patients with ICM.34 Hence, it is reasonable to discriminate the study population into two distinct HF entities (ICM and NICM) to ascertain whether NT-pro BNP can assist LVEF in stratifying for primary SCD prevention, especially in NICM population. However, a large cohort study conducted by Deng et al suggests that HF aetiology (ICM and NICM) had no effect on the significant correlation between NT-pro BNP and appropriate ICD shock in patients with HF based on their multivariate analysis.15 Unfortunately, since the majority of our included studies recruited the whole HF population, subgroup analysis was not possible in this meta-analysis.11 13–18
In regard to addressing the aforementioned dispute, Mirelis et al conducted a cohort study in which they demonstrated that the combination of late gadolinium enhancement from cardiac magnetic resonance (CMR) and positive genotype was useful in predicting SCD risk in patients with NICM and thus capable of stratifying the most qualified patients who benefit the most from primary prevention ICD therapy in this population. However, because CMR and genetic laboratories are time-consuming and hardly available in most healthcare institutions, as well as the restricted usage of gadolinium contrast in patients with end-stage renal disease, NT-pro BNP is still preferable to be used.17 35 Thus, more cohort studies evaluating the predictive efficacy of NT-pro BNP in ICM and NICM are highly needed to better understand the role of NT-pro BNP in stratifying patients with HFrEF who would benefit the most from ICD implantation for primary prevention.
Additionally, as ventricular arrhythmias were deemed as the primary mode of death in patients with HFrEF, several studies are being pursued with fervour to identify a pharmaceutical strategy for lowering the incidence of SCD in such population. Therefore, several novel HF drugs, namely sodium-glucose cotransporter 2 inhibitor (SGLT2i) and angiotensin receptor neprilysin inhibitor (ARNI) were proposed into various tenable hypotheses to likely reduce the risk of this lethal arrhythmic events.1 2 36 37 Although ARNI usage was opted in Deng et al study,15 the association between these two variables failed to reach statistical significance, despite the fact that none of our included studies involved SGLT2i into their analysis given to the novelty of this drug. Thus, we also recommend further large cohort studies addressing patients with HFrEF who receive these state-of-the-art medications to thoroughly evaluate the relationship between NT-pro BNP and SCD in patients with HFrEF with ICD implantation under the influence of these treatments.
Several limitations still warrant consideration in this meta-analysis. First, four of nine included studies were retrospective cohorts; hence, it increases the likelihood of recall and selection bias. Second, several confounding factors that alter NT-pro BNP levels are not entirely excluded by all included studies, thereby increasing the possibility of bias. Third, the dynamic variations in NT-pro BNP caused by several aforementioned factors, which represent the variability of ventricular dilatation degree, might increase the risk of ventricular arrhythmic events over time. However, our analysis was confined to investigating the prognostic value of baseline NT-pro BNP. As a result, it may overestimate or underestimate the likelihood of our outcomes of interest. Lastly, several observational studies that studied the connection between NT-pro BNP along with all-cause mortality and appropriate ICD shock in patients with ICM and NICM separately are utmost important in light of this debatable subject about the indication of primary preventive ICD treatment in NICM population.