Effect of Mineralocorticoid Receptor Antagonists on the Prognosis of Patients with Ventricular Tachyarrhythmias

Introduction: The study sought to assess the effect of treatment with mineralocorticoid receptor antagonists (MRAs) on long-term prognosis of patients with systolic heart failure (HF) surviving index episodes of ventricular tachyarrhythmias. Methods: A large retrospective registry was used including consecutive HF patients with left ventricular ejection fraction <45% and index episodes of ventricular tachyarrhythmias from 2002 to 2015. The primary endpoint was all-cause mortality at 3 years and secondary endpoints were rehospitalization, as well as the composite endpoint consisting of recurrent ventricular tachyarrhythmias, sudden cardiac death and appropriate implantabe cardioverter defibrillator (ICD) therapies at 3 years. Results: 748 patients were included, 20% treated with MRA and 80% without. At 3 years, treatment with MRA was not associated with improved all-cause mortality (22% vs. 24%, log-rank p = 0.968; hazard ratio (HR) = 1.008; 95% CI 0.690–1.472; p = 0.968). Accordingly, risk of the composite endpoint (28% vs. 27%; HR = 1.131; 95% CI 0.806–1.589; p = 0.476) and first cardiac rehospitalization (24% vs. 22%; HR = 1.139; 95% CI 0.788–1.648; p = 0.489) were not affected by treatment with MRA. Conclusion: In patients with ventricular tachyarrhythmias, treatment with MRA was not associated with improved all-cause mortality at 3 years. The therapeutic effect of MRA treatment in patients with ventricular tachyarrhythmias needs to be reinvestigated within further randomized controlled trials.


Introduction
Almost 2 decades have passed since the publication of the EPHESUS-trial ("Eplerenone Post -Acute Myocardial Infarction Heart Failure Efficacy and Survival Study") that demonstrated improved survival in patients treated with mineralocorticoid receptor antagonists (MRAs) presenting with systolic heart failure (HF) with severely reduced left ventricular ejection fraction (LVEF ≤40%) following acute myocardial infarction (AMI) [1]. Although improved survival was already seen at 30 days of follow-up, which may be related to reduced cardiac fibrosis in the initial phase of AMI, MRAs are withheld from many patients with systolic HF [2]. This may be related to the rather small amount of randomized controlled trials in the field of MRA treatment in comparison to pharmacological treatment with betablockers or angiotensin-converting enzyme inhibitors (ACEi) or receptor blockers (ARBs) [3][4][5][6]. In line, characteristics and treatment strategies for underling cardiac disease (including nationwide health-care supply, improving revascularization strategies, possibility to implant cardiac devices such as an implantable cardioverter defibrillator (ICD), or cardiac resynchronization therapy) demand the need to re-evaluate these pharmacotherapies within the 21th century [7]. Therefore, the therapeutic effect of MRA treatment on the prognosis of todays' patients remains unclear. Even though a reduction of sudden cardiac death (SCD) by 23% within patients treated with MRA was suggested in HF patients, the benefit of MRA may further decrease in patients with concomitant multi-pharmacological treatment including the guideline-recommended therapies of betablocker and ACEi/ARB [8]. Even less data are available focusing on patients presenting with ventricular tachyarrhythmias [7]. Therefore, this study evaluates the effect of MRA treatment on the primary endpoint of all-cause mortality at 3 years, as well as on secondary endpoints (i.e., composite endpoint of recurrent ventricular tachyarrhythmias, sudden cardiac death and appropriate ICD therapies and cardiac rehospitalization) in HF patients surviving index episodes of ventricular tachyarrhythmias. Furthermore, patients treated with spironolactone were compared to patients treated with eplerenone. Finally, a time trend analysis was performed regarding MRA prescription rates during the study period (i.e., from 2002 to 2015).

Data Collection and Documentation
The present study included retrospectively all consecutive patients surviving index episodes of ventricular tachyarrhythmias (i.e., ventricular tachycardia [VT] or ventricular fibrillation [VF]) on admission from 2002 to 2015 at our institution as recently published [9]. The present study is derived from an analysis of the "Registry of Malignant Arrhythmias and Sudden Cardiac Death -Influence of Diagnostics and Interventions," a single-center registry including consecutive patients presenting with ventricular tachyarrhythmias and aborted cardiac arrest being acutely admitted to the University Medical Center Mannheim, Germany (clinicaltrials.gov identifier: NCT02982473). The study was carried out according to the principles of the Declaration of Helsinki and was approved by the Medical Ethics Committee II of the Medical Faculty Mannheim, the University of Heidelberg, Germany.

Inclusion and Exclusion Criteria
For the present study, risk stratification was based on the presence or absence of MRA treatment at index hospital discharge. Therefore, patients with in-hospital death were excluded from the present study ( Fig. 1; flow-chart). Since current European guidelines recommend MRA treatment in patients with symptomatic HF and LVEF <40%, all patients with preserved LVEF (i.e., >45%) were excluded from the present study [10]. In line, patients with severe hyperkalemia (i.e., serum potassium level >5.5 mmol/L) were excluded from this analysis. The decision to treat patients with MRA was based on the discretion of the cardiologists during routine care according to European guidelines [7, 10-12].

Definition of Case and Control Groups
The case group (MRA group) comprised all patients with MRA at discharge. Both spironolactone and eplerenone were allowed. The control group (non-MRA group) comprised all patients without treatment with MRA at discharge. All other medical therapies apart from MRA were allowed.

Primary and Secondary Endpoints
The follow-up period was set at 3 years for all outcomes. The primary prognostic endpoint was all-cause mortality. Secondary endpoints were a composite endpoint (i.e., recurrence of ventricular tachyarrhythmias, sudden cardiac death and appropriate ICD therapies) and first cardiac rehospitalization. Cardiac reshospitalization comprised rehospitalization due to recurrent VT, recurrent VF, AMI, acute heart failure, and inappropriate ICD therapies.

Statistical Methods
Quantitative data are presented as mean ± standard error of mean, median and interquartile range, and ranges depending on the distribution of the data and were compared using the Student's t test for normally distributed data or the Mann-Whitney U test for nonparametric data. Deviations from a Gaussian distribution were tested by the Kolmogorov-Smirnov test. Spearman's rank correlation for nonparametric data was used to test univariate correlations. Qualitative data are presented as absolute and relative frequencies and compared using the χ 2 test or Fisher's exact test, as appropriate. First, the univariable Kaplan-Meier method was applied to evaluate prognostic differences within the entire cohort. Hazard ratios (HRs) are given together with 95% confidence intervals. Second, multivariable Cox regression models were developed using the "forward selection" option, where only statistically significant variables (p < 0.05) were included and analyzed simultaneously. Predefined variables being used for multivariable Cox-regressions included age, sex, chronic kidney disease, diabetes mellitus, AMI, presence of an ICD, cardiopulmonary resuscitation, coronary artery disease, LVEF <35%, and MRA treatment. Cox regression analyses were applied for the endpoint all-cause mortality as well as for secondary endpoints. Thereafter, prognosis of patients treated with spironolactone was compared to patients treated with eplerenone using the Kaplan-Meier method.

Study Population
From 2002 to 2015, a total of 1,707 patients survived index episodes of ventricular tachyarryhtmias. Of those, 954 patients were not eligible for MRA therapy due to preserved LVEF (i.e., LVEF >45%) and 5 patients for hyperkalaemia with serum potassium levels >5.5 mmol/L ( Fig. 1; flowchart). The final study cohort comprised 748 consecutive patients with systolic HF (i.e., LVEF <45%). All patients survived an index episode of ventricular tachyarrhythmias and were discharged with or without MRA (non-MRA 80% vs. MRA 20%; p = 0.001). Target dosages of MRA were reached already at discharge, as seen for spironolactone in 60% (mean dosage 34 mg per day) and for eplerenone in 40% (mean dosage 27 mg per day) ( Table 1).

Time Trend Analysis
Finally, we investigated a time trend analysis regarding the prescription of MRA during the study period. From 2002 to 2015, treatment with MRA has significantly increased from 13.8% in 2002 to 45.2% in 2015 (p = 0.001 for the trend) (Fig. 4).

Discussion
The present study evaluates the effect of MRA treatment on the primary endpoint of all-cause mortality, as well as on secondary endpoints, such as a composite endpoint (i.e., recurrence of ventricular tachyarrhythmias and sudden cardiac death) and cardiac rehospitalization in HF patients with LVEF <45% surviving index episodes of ventricular tachyarrhythmias. In this cohort of HF patients with ventricular tachyarrhythmias, only 20% of patients were treated with MRA at hospital discharge; however, treatment rates with MRA have significantly increased from 13.8% to 45.2% during the study period. These data suggest no prognostic impact of MRA therapy on long-term prognosis in patients with ventricular tachyarrhythmias. Finally, prognosis of patients treated with spironolactone did not differ from that of those treated with eplerenone.
Despite the class IA indication in European guidelines for chronic HF patients [10], treatment with MRA is often withheld from a large group of HF patients [13]. This may be related to the rather small number of randomized studies investigating the potential role of MRA in comparison to other HF pharmacotherapies (such as betablockers or ACEi), an overestimation of potential side effects (i.e., hyperkalaemia and arterial hypotension with low-output resulting in impaired renal function), and the strategy to initiate MRA treatment after up-titration of concomitant beta-blocker and ACEi/ARB treatment [14]. Subsequently, MRA treatment was applied in only 67% of eligible patients within the ESC Heart Failure Long-Term Registry, whereas at least 92% of the patients were treated with beta -blockers and ACEi/ARB, respectively [15]. In line, only 22% of MRA eligible patients were treated with MRA within a recently published study by Wong et al. [2], including 317 patients with AMI with systolic HF. In line, in <10% of all patients without MRA treatment at index hospital discharge, MRA was initiated with the following 3 months [2, 16]. However, endpoint-related data were not provided within the study by Wong et al. [2]. Thus, rather low prescription rates of MRA (i.e., only 20% of MRA eligible patients) in the present study underline the need to further improve guideline adherence for MRA treatment, although a significant trend to improvement to guideline adherence was observed. Of note, this trend may also explain the shorter follow-up duration of MRA patients within the present study, since a large group of MRA patients were included at the end of the study period.
Besides investigating the association of MRA treatment and ventricular tachyarrhythmias, many studies focus on the potential role of MRA on atrial fibrillation [17]. A recently published meta-analysis including 5 studies (3 randomized trials and 2 observational studies) and 1,337 patients demonstrated 31% lower risk of atrial fibrillation in patients treated with MRA as compared to patients without. In contrast, the present study did not identify MRA to improve survival and reduce the risk of the composite arrhythmic endpoint. Moreover, the meta-analysis by Liu et al. [17] investigated the prognostic value of spironolactone compared to eplerenone, demonstrating decreased risk of atrial fibrillation in patients treated with spironolactone only. However, in patients with ventricular tachyarrhythmias on admission, pa-log rank p = 0.991 tients treated with spironolactone and eplerenone were associated with comparable long-term outcomes in the present study.

Months of survival
In line, a recently published study by Hasin et al. [18] investigated the prognostic value of HF therapies in 186 HF patients with primary preventive ICD or cardiac resynchronization therapy-D devices. Thus, it was demonstrated that treatment with beta-blockers or ACEi/ ARB, or MRA treatment did not affect the risk of ventricular tachyarrhythmias. This study confirms the findings by Hasin et al. [18] for "secondary prevention" of sudden cardiac death, suggesting no additional impact of MRA treatment on the combined arrhythmic endpoint. These findings are in line with the randomized SPIRIT trial that demonstrated no prognostic impact of spironolactone (25 mg daily) on the incidence of VT/VF, as well as on appropriate ICD therapies within 90 ICD recipients at moderate to high risk for VT/VF [19].
Even though the present study did not identify MRA treatment associated with improved long-term outcomes in this "all-comers" study, there may be some subgroups of patients where MRA treatment could be more effective. In line, a recently published study by Cohen et al. [20] investigated the prognosis of specific HF phenotypes, as well as the prognostic value of MRA treatment in these patients, including over 3,000 patients from the "TOPCAT" (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial) study. Thus, especially obese patients suffering from diabetes mellitus showed better response to MRA treatment than other phenotypes [20]. Of note, this may especially be related to the so-called diabetic cardiomyopathy [21]. Diabetic cardiomyopathy is related to reactive oxygen species, inflammation, and activation of the renin-angiotensin-aldosterone system, leading to functional myocardial changes and subsequently to left ventricular hypertrophy and adverse remodeling. The prognostic benefit of eplerenone treatment for diabetic cardiomyopathy was already investigated within various studies, suggesting improved long-term outcomes, but increased risk of hyperkalemia in patients treated with MRA [22,23]. It will therefore be of major interest to re-evaluate the impact of MRA treatment in patients with ventricular tachyarrhythmias, as well as on arrhythmic endpoints, within prespecified subgroups (such as patients with diabetic cardiomyopathy) to identify the subgroup of patients that benefit from MRA treatment. In conclusion, rather low subscription rates of MRA (20%) were observed in the present study including consecutive patients with HF and ventricular tachyarrhythmias, which have increased from 13.8% to 45.2% during the study period. It was demonstrated that MRAs were not associated with long-term prognostic endpoints (i.e., all-cause mortality, composite endpoint and cardiac rehospitalization) at 3 years. Finally, prognosis of patients treated with spironolactone or eplerenone was comparable.