Impact of renin–angiotensin system blocker after aortic valve replacement—a systematic review and meta-analysis

Introduction

Aortic stenosis (AS) is a common valvular heart disease in the aging population, which is always associated with cardiac hypertrophy in response to the increased afterload (1). The activation of renin-angiotensin system (RAS) was considered to accelerate the left ventricular (LV) remodeling in patients with AS (2). Inhibition of RAS was demonstrated to decrease blood pressure, modulate myocardial hypertrophy and improve clinical outcomes in patients having heart failure with reduced left ventricular ejection fraction (LVEF), which made RAS inhibitors (RASi) to be widely used in patients with cardiovascular disease (3,4). While, use of RASi including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) has traditionally been avoided in patients with AS, inasmuch as the concern of deteriorated hemodynamic results and subsequent hypotension (5). In fact, more increasing data demonstrate the safety and even potential beneficial effect of ACEIs/ARBs in patients with AS (6-9).

Aortic valve replacement (AVR) including surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR), was an effective strategy to treating patients with AS. However, if patients with AS were not treated timely, excessive LV hypertrophy and fibrosis would compromise the clinical outcome after AVR (10,11). Numerous data demonstrated that patients with persistence of LV hypertrophy and fibrosis were at high risk for increased long-term mortality after AVR (12,13). However, there is no specific recommendation for the use of ACEIs/ARBs after AVR to attenuate LV hypertrophy and fibrosis, and debate surrounded the impact of ACEIs/ARBs on clinical outcome after AVR. Therefore, we performed the meta-analysis and systematic review to explore the effect of RASi on clinical outcome after AVR including SAVR and TAVR in patients with AS. We reported the present article in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting checklist (available at http://dx.doi.org/10.21037/apm-20-1155).

Methods

Data sources and study selection

A literature search of the PubMed online database was conducted to identify studies reporting the impact of RASi on clinical outcome after AVR on February 9, 2020 (Figure 1). The electronic search terms were as follows: (renin-angiotensin system inhibitor OR ACEI OR ARB OR renin-angiotensin system OR ACE inhibitor OR renin-angiotensin system blockade) AND (surgical aortic valve OR SAVR OR transcatheter aortic valve OR aortic valve replacement OR AVR OR TAVR OR TAVI). Additionally, reference lists of pertinent articles were also screened manually in case of omitting potential relevant citations. All citations were initially identified at the level of title and abstract. And then the full-length articles were assessed further. Two authors checked the citations separately, a discussion was made to achieve consensus once controversies existed.

Figure 1 The process of study selection. AVR, aortic valve replacement.

Inclusion and exclusion criteria

Only articles in English were included. The inclusion criteria were: (I) studies that reported the impact of RASi on mortality after SAVR; (II) studies that reported the impact of RASi on mortality after TAVR; (III) studies that illustrated the particular number of death or survival curve regarding the RASi after AVR. Studies were excluded if one of the following existed: (I) studies were case reports, reviews, abstracts, guidelines, editorials, comments and conference presentations; (II) studies that were not related to human.

Data extraction and quality assessment

Two independent authors (L Zeng and J Li) extracted the data and reached a consensus on all items from eligible studies including author, publication year, research category, type of RASi, sort of AVR, follow-up time and mortality. If mortality or number of death was not presented directly, digitizing software (Engauge Digtizer 4.1) were utilized to acquire relevant data from survival curve (14).

Study quality was evaluated using the Cross-Sectional/Prevalence Study Quality Assessment Form or Newcastle-Ottawa Quality Assessment Scale (NOS) accordingly (15,16).

Data synthesis and statistical analysis

We combined data that reporting the impact of RASi on all-cause mortality and cardiac-cause mortality after AVR. Pooled odds ratios (OR) were gained using the Review Manage 5.3 software. Hazard ratios (HRs) were combined by using generic inverse variance method. Heterogeneity was evaluated by calculating the I² statistic and its P value. Random-effects model was used when the I² statistic was more than 50% and its P value was less than 0.05, otherwise, the fixed-effects model was carried out. Two-sided P values of 0.05 were considered statistically significant.

Publication bias analysis

Publication bias was assessed by visual inspection of the symmetry of the funnel plot. However, if the number of pooled studies was small, publication bias was not performed.

Subgroup analysis

Several subgroup analyses were performed including the impact of RASi on all-cause mortality within 30 days, 1 year and beyond 1 year, the impact of RASi on cardiac mortality beyond 1 year. The effect of RASi after SAVR and TAVR were carried out respectively. And, the influence of RASi on all-cause mortality after AVR based on the baseline LVEF was also performed. Besides, the impact of ACEI versus ARB after AVR was also conducted.

Results

Studies selection

The process of study selection was presented in Figure 1. A total of 126 potential relevant citations were identified after initial search from PubMed database. After careful review of the title and abstract, 114 studies were excluded. There were 9 (17-25) articles incorporating 33,063 patients were eligible after reading full text. A summary of included studies is illustrated in Table 1.

Table 1 Characteristics of included studies
Full table

Quality assessment

The quality of included single-arm studies were assessed using Cross-Sectional/Prevalence Study Quality, while the quality of eligible cohort studies was evaluated by using the NOS scale. Overall quality of these included studies was good.

Impact of RASi on all-cause mortality after AVR

A total of 6 (17,19,21,22,24,25), 6 (18,19,21,22,24,25), 6 (17-19,21,24,25) studies recruiting 27,435, 22,864 and 9,753 patients reported the effect of RASi after AVR, which revealed that patients taking RASi had a significant lower risk for mortality at 30 days (OR, 0.80, 95% CI, 0.69 to 0.94, I²=0%, Figure 2), 1 year (OR, 0.75, 95% CI, 0.69 to 0.81, I²=77%, Figure 3) and beyond 1 year (OR, 0.52, 95% CI, 0.38 to 0.73, I²=86%, Figure 4) after AVR respectively, compared to those patients without RASi.

Figure 2 The impact of RASi on 30-day all-cause mortality after AVR. RASi, renin-angiotensin system inhibitor; SAVR, surgical aortic valve replacement; TAVR, transcatheter aortic valve replacement.

Figure 3 The impact of RASi on mortality within 1 year after AVR. RASi, renin-angiotensin system inhibitor; SAVR, surgical aortic valve replacement; TAVR, transcatheter aortic valve replacement.

Figure 4 The impact of RASi on all-cause mortality beyond 1 year after AVR. RASi, renin-angiotensin system inhibitor; SAVR, surgical aortic valve replacement; TAVR, transcatheter aortic valve replacement.

Impact of RASi on all-cause mortality after TAVR

Consistently, there were 4 (17,21,22,25), 4 (18,21,22,25), and 4 (17,18,21,25) studies reporting that patients who took RASi had lower mortality at 30 days (OR, 0.76, 95% CI, 0.63 to 0.92, I²=0%, Figure 2), 1 year (OR, 0.76, 95% CI, 0.70 to 0.95, I²=86%, Figure 3) and beyond 1 year (OR, 0.65, 95% CI, 0.45 to 0.94, I²=80%, Figure 4) on the basis of incorporating 22,829, 20,604 and 7,493 patients separately.

Impact of RASi on all-cause mortality after SAVR

While, pooled studies displayed that patients having the description of RASi was associated with lower mortality at 1-year (OR, 0.53, 95% CI, 0.29 to 0.95, I²=41%, Figure 3) and beyond 1-year (OR, 0.39, 95% CI, 0.25 to 0.61, I²=73%, Figure 4) mortality, but not at 30-day (OR, 0.90, 95% CI, 0.68 to 1.19, I²=48%, Figure 2), based on 2 (19,24), 2 (19,24) and 2 (19,24) studies including 2,260, 2,260 and 4,606 patients.

Impact of RASi on all-cause mortality after AVR by using univariate and multivariate analysis

In order to exclude the influence of confounders on outcome, we also pooled studies that reported the HR of RASi after AVR. We found that patients taking RASi was associated with reduced mortality beyond 1 year compared to those did not take RASi after AVR (HR, 0.84, 95% CI, 0.77 to 0.91, I²=82%, Figure S1) by using univariate analysis based on the combination of 7 (17-19,22-25) studies. In line with pooled univariate analysis, combined multivariate analysis also revealed a significant improvement of long-term survival in patients with RASi after AVR (HR, 0.87, 95% CI, 0.84 to 0.91, I²=0%, Figure S2) on the basis of pooling 5 (18-20,24,25) studies.

Impact of RASi on all-cause mortality after TAVR by using univariate and multivariate analysis

A total of 5 (17,18,22,23,25) studies found that patients taking RASi had lower risk for mortality beyond 1 year than those patients without RASi after TAVR (HR, 0.89, 95% CI, 0.82 to 0.96, I²=71%, Figure S1) by using univariate analysis. Consistently, combined multivariate analysis also figured out that patients with RASi after TAVR were associated with significant reduced mortality beyond 1 year (HR, 0.87, 95% CI, 0.84 to 0.91, I²=0%, Figure S2) by pooling 2 (18,25) studies.

Impact of RASi on all-cause mortality after SAVR by using univariate and multivariate analysis

Except for the impact of RASi after TAVR, we also pooled studies that reported the impact of RASi after SAVR by using univariate and multivariate analysis. There were 2 (19,24) and 3 (19,20,24) studies displaying that patients taking RASi were associated lower mortality beyond 1 year compared to those patients without RASi after SAVR by using univariate analysis (HR, 0.73, 95% CI, 0.56 to 0.96, I²=88%, Figure S1) and multivariate analysis (HR, 0.89, 95% CI, 0.84 to 0.93, I²=0%, Figure S2) respectively.

Impact of RASi on all-cause mortality regarding the baseline LVEF

Combined results (22,25) found that patients with reduced LVEF, taking RASi were associated with numerically lower mortality (HR, 0.91, 95% CI, 0.77 to 1.07, I²=76%, Figure S3). While, interestingly, patients with preserved LVEF (22,25), having a prescription of RASi had significant lower mortality (HR, 0.90, 95% CI, 0.87 to 0.94, I²=0%, Figure S3) than those patients without RASi. Besides, Goel et al. (24) also found that the favorable effect of RASi after SAVR was consistent across patients with reduced (P<0.05) and preserved LVEF (P<0.05).

Impact of RASi on all-cause mortality regarding the type of RASi

Magne et al. (19) described the relationship between the type of RASi and mortality, reporting that ARB had the best long-term survival, ACEI had the intermediate survival as compared with those patients without RASi (8-year survival, ARB vs. ACEI vs. no-RASi, 87% vs. 79% vs. 52%, P<0.0001). Besides, after multivariable adjustment, they also demonstrated that patients with ARB was associated with lower risk for long-term all-cause mortality after SAVR (HR, 0.66, 95%, 0.48 to 0.93), compared to those patients with ACEI.

We also pooled studies that reported the impact of ACEI and ARB on all-cause mortality beyond 1 year in patients undergoing TAVR. The combined results showed that both ARB (22,25) (HR, 0.89, 95% CI, 0.85 to 0.94, I²=0%, Figure S4) and ACEI (22,25) (HR, 0.89, 95% CI, 0.81 to 0.99, I²=79%, Figure S4) had lower all-cause mortality than those patients without RASi. Furthermore, there was no significant difference between patients taking ARB and ACEI after TAVR beyond 1 year (22,25) (ARB vs. ACEI, HR, 0.98, 95% CI, 0.89 to 1.09, I²=62%, Figure S4).

Impact of RASi on cardiovascular mortality after TAVR

In addition to all-cause mortality, we also performed analysis to investigate the effect of RASi on cardiovascular mortality after TAVR. Pooled studies demonstrated that patients with RASi had lower cardiovascular mortality than those patients without RASi after TAVR [30 days (17,25), OR, 0.63, 95% CI, 0.44 to 0.90, I²=22%; 1 year (17,25), OR, 0.60, 95% CI, 0.50 to 0.73, I²=0%; beyond 1 year (17,25), OR, 0.63, 95% CI, 0.54 to 0.74, I²=0%,Figure S5].

Consistently, pooled univariate (17,25) (HR, 0.83, 95% CI, 0.78 to 0.89, I²=0%, Figure S6) and multivariate (17,25) (HR, 0.84, 95% CI, 0.78 to 0.91, I²=0%, Figure S6) analyses showed that patients taking RASi after TAVR were correlated with reduced cardiovascular mortality beyond 1-year follow-up, compared to those patients who did not take RASi.

Discussion

The main results of the present study were as follows: (I) patients with RASi had lower all-cause mortality at 30 days (OR, 0.80, 95% CI, 0.69 to 0.94), 1 year (OR, 0.75, 95% CI, 0.69 to 0.81) and beyond 1 year (OR, 0.52, 95% CI, 0.38 to 0.73) after AVR; (II) the combined results showed that both ARB (HR, 0.89, 95% CI, 0.85 to 0.94) and ACEI (HR, 0.89, 95% CI, 0.81 to 0.99) had lower all-cause mortality after TAVR, compared to those without RASi; (III) patients with preserved LVEF having a prescription of RASi were associated with reduced mortality (HR, 0.90, 95% CI, 0.87 to 0.94) TAVR; (IV) pooled multivariable analysis also revealed that patients taking RASi after TAVR was associated with lower risk for cardiovascular mortality (HR, 0.84, 95% CI, 0.78 to 0.91).

Myocardial hypertrophy was common in patients with AS, secondary to LV outflow obstruction and increased afterload (26). Progressive myocardial hypertrophy would yield fibrosis and subsequent LV dysfunction (26). More evidence found that RAS contributed to the occurrence of myocardial hypertrophy and fibrosis, RASi could reverse myocardial fibrosis to some extent (2). However, in the past, taking RASi in patients with AS was considered to be unsafe because the vasodilation effect in the presence of LV outflow obstruction would cause hypotension (5). In fact, patients with AS taking RASi was not only safe but also engendered favorable effect on survival, LV regression and even AS progression (6,7).

Existing data reported that patients with LV hypertrophy and fibrosis undergoing AVR was associated with increased mortality, and irreversible LV hypertrophy as well as fibrosis after AVR was not rare which also affected long-term mortality (10,11,13). However, no specific recommendations were provoked to take optimal medication following AVR to enhance the outcome of AVR including SAVR and TAVR. Therefore, there was still a gap regarding the optimal medication after AVR that could improve long-term prognosis.

Although several studies reported the impact of RASi on mortality after AVR, their results were controversy (18,23-25). The present study found that patients receiving RASi who underwent AVR were associated with reduced all-cause mortality at 30 days, 1 year and beyond 1 year, as compared with those patients without RASi, which is in consistence with previous propensity score-matched population studies (17,22,25). The combined results were still positive after adjusting confounders independent of the type of RASi including ACEI and ARB. The beneficial effect of RASi on all-cause mortality may be attributed to the decreased cardiovascular mortality in patients with RASi as the present study also revealed that patients undergoing TAVR with RASi had lower cardiovascular mortality than those patients without RASi. This might be account for the potential role of RASi in further attenuation of LV hypertrophy and fibrosis after AVR, since incompletely reversed LV hypertrophy and fibrosis after AVR were correlated with increased mortality (17,18,24,27).

Increasing evidence demonstrated the significant benefit of RASi in patients with reduced ejection fraction, while the impact of RASi on clinical outcome in patients with preserved ejection fraction was negative (28). However, we found that the beneficial effect of RASi after TAVR was independent of LVEF which is in line with prior study incorporating patients after SAVR described by Goel et al. (24). This might be related to the different pathophysiological mechanism for preserved ejection fraction in patients with AS and other cardiovascular diseases (29). A randomized clinical trial (RCT) containing 114 patients with preserved ejection fraction undergoing SAVR demonstrated that description of candesartan was associated with increased reverse LV remodeling as compared to those patients without RASi, which also might be suggestive of positive effect in patients with TAVR (27). Since the effect of RASi in patients following AVR primarily based on retrospective analysis, RCTs are warranted to evaluate the impact of RASi on mortality after AVR including SAVR and TAVR. Fortunately, RASTAVI, an ongoing RCT, could provide more information to determine the use of RASi (30).

Limitation

Firstly, all the included studies are not RCTs, which might have selection bias. Patients receiving RASi might be more stable and healthier that could tolerate the treatment of RASi. However, the present study found that patients having description of RASi was associated with reduced long-term mortality even after adjustment of confounders; Secondly, several combined results were based on fewer studies with considerable heterogeneity, which needed more studies to confirm these hypothesis-generating findings.

Conclusions

Patients with RASi had reduced short-term and long-term all-cause mortality after AVR than those without RASi. Description of RASi was associated with lower risk for cardiovascular mortality in patients undergoing TAVR. Further studies were needed to confirm these findings.

Acknowledgments

We acknowledged Dr. JiaYu Tsauo for helping check and edit language.

Funding: This work was supported by Post-Doctor Research Project, West China Hospital, Sichuan University (2018HXBH083), National Natural Science Foundation of China (81900348, 81970325); Key Science and Technology Department of Sichuan Science and Technology Department (2019YFS0299); West China Hospital “1·3·5” Discipline of Excellence Project-Percutaneous aortic valve implantation.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at http://dx.doi.org/10.21037/apm-20-1155

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/apm-20-1155). The authors have no conflicts of interest to declare

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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