Renin–angiotensin system inhibition is not associated with increased sudden cardiac death, cardiovascular mortality or all-cause mortality in patients with aortic stenosis

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Abstract

Background

Renin–angiotensin system inhibition (RASI) is frequently avoided in aortic stenosis (AS) patients because of fear of hypotension. We evaluated if RASI with angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) increased mortality in patients with mild to moderate AS.

Methods

All patients (n = 1873) from the Simvastatin and Ezetimibe in Aortic Stenosis study: asymptomatic patients with AS and preserved left ventricular (LV) ejection fraction were included. Risks of sudden cardiac death (SCD), cardiovascular death and all-cause mortality according to RASI treatment were analyzed by multivariable time-varying Cox models and propensity score matched analyses.

Results

769 (41%) patients received RASI. During a median follow-up of 4.3 ± 0.9 years, 678 patients were categorized as having severe AS, 545 underwent aortic valve replacement, 40 SCDs, 103 cardiovascular and 205 all-cause deaths occurred. RASI was not associated with SCD (HR: 1.19 [95%CI: 0.50–2.83], p = 0.694), cardiovascular (HR: 1.05 [95%CI: 0.62–1.77], p = 0.854) or all-cause mortality (HR: 0.81 [95%CI: 0.55–1.20], p = 0.281). This was confirmed in propensity matched analysis (all p > 0.05). In separate analyses, RASI was associated with larger reduction in systolic blood pressure (p = 0.001) and less progression of LV mass (p = 0.040).

Conclusions

RASI was not associated with SCD, cardiovascular or all-cause mortality in asymptomatic AS patients. However, RASI was associated with a potentially beneficial decrease in blood pressure and reduced LV mass progression.

Introduction

Aortic stenosis (AS) has become the most common form of valvular heart disease in the western world. The prevalence increases exponentially with age, and AS now affects 2% to 7% of adults older than 65 years [1]. Even in its early stages (aortic sclerosis), AS is associated with increased cardiovascular morbidity and mortality [2], [3]. Considerable effort has therefore been put in to better understanding and ultimately finding a way to retard AS progression [2]. Albeit, the paradigm for AS treatment remains careful monitoring and arbitrary timing of aortic valve replacement (AVR). However, as the latter carries significant risks, any medical treatment that retards progression of AS would potentially be of great importance [4].

In traditional teaching, renin–angiotensin system inhibition (RASI) with angiotensin-converting enzyme (ACE) and/or angiotensin receptor blockade (ARB) has been considered relatively contraindicated. This was in large due to a theoretical concern that reduction of peripheral resistance in the setting of AS, could lead to decreased coronary perfusion and hypotensive systemic reactions [5]. Recently more data have become available on the safety of RASI in AS, and there is now mounting evidence to suggest that RASI might increase survival and lower risk of cardiovascular events in these patients [6]. This is particularly encouraging since hypertension is very common in AS, and might be associated with faster progression or earlier need for AVR due to compounding effect of hypertension and AS on LV [7]. Therefore, by lowering systemic vascular resistance, RASI has a potential role for lowering global systolic load in AS patients over other antihypertensive drugs [8], [9].

However, published literature on the effects of RASI in AS are all biased by small sample sizes [5], [10], [11], [12]. To elucidate this further, this study therefore sought to investigate the impact of RASI with ACEI and ARBs on risk of sudden cardiac death (SCD), cardiovascular and all-cause mortality during long-time follow-up of a large cohort of asymptomatic patients with initially asymptomatic mild-to-moderate AS.

Section snippets

Methods

All data origin from the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study, a randomized, multicenter, double-blind, placebo-controlled study investigating whether intensive lipid-lowering with simvastatin plus ezetimibe combination vs. placebo in 1873 patients (45 to 85 years of age) with asymptomatic AS (defined as echocardiographic aortic valve thickening accompanied by Doppler-measured aortic peak flow velocity between 2.5 and 4.0 m/s, normal left ventricular (LV) systolic function,

Baseline characteristics

Among the 1873 patients included in the SEAS study, 769 (445 [57.9%] ACE and 324 RAS [42.1%]) patients received RASI once or more during a mean follow-up of 4.3 ± 0.9 years. Indication for prescribing the ACE or RAS inhibitors are shown in Supplemental Table 1.

545 patients underwent AVR, 101 (54 in patients without vs. 47 in patients with RASI, p = 0.144) had severe AS at baseline and 678 (412 in patients without vs. 266 in patients with RASI, p = 0.799) progressed to severe AS before death or end of

Discussion

This study is the largest secondary analysis of a randomized controlled study in asymptomatic AS and has 2 new findings. First, RASI therapy was not associated with SCD, cardiovascular or all-cause mortality during follow-up in patients with mild to moderate asymptomatic AS, even after adjustment to potential confounders. These findings were further supported in 3 different sensitivity analyses including propensity-matched analyses as well as exclusive analyses of those with severe AS. Second,

Limitations

This study is limited by lack of randomization to the RASI and patients included primarily had mild to moderate AS. Thus, the data cannot be generalized to those with severe AS who may be at highest risk when exposed to RASI. This study does not allow for recommendations regarding in-patient or outpatient initiation of RASI in AS patients. In our opinion, RASI should be started with caution, although increasing evidence suggests that RASI does not produce acute cardiovascular deterioration even

Conclusions

In this large retrospective study with exact measuring of treatment days, RASI with ACEIs and ARBs was associated with a larger decrease of BP and less LVMI progression among AS patients with normal systolic function and no coronary heart disease or congestive heart failure. However, this was not associated with more incidence SCD or all-cause mortality in AS patients. However, there was a weak trend of cardiovascular death among the RASI treated patients. A large prospective study is warranted

Source of funding

This work was supported by The Danish Heart Association Grant number: 10-04-R78-A2962-22582. The SEAS study was funded by Merck & Co., Inc., Whitehouse station, NJ.

Conflict of interest

Drs. Boman, Nienaber, Ray, Rossebø, and Wachtell were on the SEAS steering committee and received honoraria from Merck & Co, Inc., the funding sponsor of the SEAS study. The SEAS study was funded by an unrestricted grant from Merck & Co., Inc.

Disclosures

Drs. Boman, Nienaber, Ray, Rossebø, and Wachtell were on the SEAS steering committee and received honoraria from Merck & Co, Inc., the funding sponsor of the SEAS study. The SEAS study was funded by an unrestricted grant from Merck & Co., Inc. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the manuscript, and its final contents. The remaining authors report no conflicts.

Acknowledgments

We thank the SEAS study investigators [14]. The 1st author who is independent of any commercial funder has full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. This work was supported by The Danish Heart Association Grant number: 10-04-R78-A2962-22582, as well as the Interreg IVa program, a European Union Regional fund.

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