Renin–angiotensin blockade after aortic valve replacement: A review based on current literature

Aortic stenosis is the most common valvular heart disease and is known to augment the risk of cardiovascular morbidity and mortality. Aortic valve replacement (AVR), either surgical (SAVR) or transcatheter (TAVR), is the only treatment that has consistently shown improved survival in these patients.¹ From 2009 to 2015, there was a 123% increase in the number of AVR procedures in Medicare beneficiaries.² This number is expected to further increase with the improving technological advancement and broader utilization of TAVR. Nearly two-thirds of post-SAVR patients die within 10 years,³ and half of the post-TAVR patients die within five years of the procedure.⁴ Renin–angiotensin system (RAS) blockade with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) has been associated with improved survival in patients with aortic stenosis.⁵ Currently, there are no recommendations regarding the use of RAS blockers post-AVR. Owing to the increasing number of these patients and the need for improved long-term outcomes in this population, we sought to systematically review the literature to investigate the benefits of RAS blockers in the patients who had undergone SAVR and TAVR.

We performed a search of PubMed, Embase, and Cochrane central utilizing the keywords ‘Renin–Angiotensin Inhibitor’ OR ‘angiotensin receptor blocker’ OR ‘angiotensin-converting enzyme inhibitor’ AND ‘aortic valve replacement’ including transcatheter or surgical in all combinations, with limits of humans activated. No restriction for language or publication year was used. Once identified, full manuscripts were extracted to assess against a priori inclusion criteria. The articles were considered for inclusion if they had the comparative data available for with or without the use of ACE or ARB in aortic stenosis patients who underwent AVR. The outcome of interest was all-cause mortality. Due to a significantly high heterogeneity noted in the meta-analysis, we are reporting our findings only as a systemic review.

Our initial search yielded 336 articles. After careful screening, we ended up with five articles.^6,,,–10 All the included studies were observational retrospective cohort studies. Our results showed that the use of RAS blockers after AVR was significantly and consistently associated with a reduction in mortality; see Table 1 for the details. The effect size in the form of odds ratio ranged from 17% to 69% reduction in all-cause mortality with the RAS blockade. Our result shows that RAS blocker therapy is associated with a statistically significant improvement in survival in patients after AVR.

Table 1.

Studies showing effects of renin–angiotensin blockage post TAVR.

	Design	Type of AVR	Adjustment	Odds ratio	Overall effect	Level of evidence	GRADE recommendation
Inohara 2018	Retrospective cohort study	TAVR	Propensity score matching	0.82 (0.75–0.90)	Reduction in mortality	III	C
Ochiai 2018	Retrospective cohort study	TAVR	Multivariable analysis	0.45 (0.22–0.91)	Reduction in mortality	III
Magne 2018	Retrospective cohort study	SAVR	Propensity score and multivariate	0.31 (0.20–0.47)	Reduction in mortality	III
Goel 2014	Retrospective cohort study	SAVR	Propensity score matched	0.58 (0.44–0.75)	Reduction in mortality	III
Lassnigg 2013	Retrospective cohort study	SAVR	Multivariate Cox regression survival analysis	0.83 (0.69–0.99)	Reduction in mortality	III

AVR: aortic valve replacement; GRADE: Grading of Recommendations Assessment, Development and Evaluation; TAVR: transcatheter AVR; SAVR: surgical AVR.

Previous recommendations for secondary prevention postoperatively in patients with AVR have consisted of supervised exercise, diet education, and stress and depression management that has resulted in improvement in functional status and quality-of-life.^11,12 Our literature review is the first one to show mortality benefit consistently seen across the studies.

Left ventricular (LV) dysfunction and myocardial hypertrophy is a consequence of long-standing pressure overload due to aortic stenosis. Due to their antihypertensive effects; RAS blockers have been shown to regress LV hypertrophy in hypertensive patients. Similarly, AVR is expected to reduce LV afterload, which should regress LV hypertrophy. In a randomized study of 12 months, RAS blockade has also been found to be an independent predictor of regression in LV mass index in a multivariate-adjusted model.¹³ This suggests that the cardiovascular remodelling benefits of RAS blockade are over and above the benefits observed due to a reduction in blood pressure and afterload. Furthermore, RAS blockers may reduce the comorbidity burden by reducing post-cardioversion recurrence of atrial fibrillation in patients with AVR.

RAS blockers are routinely used in patients with compelling indications such as hypertension, decreased LV systolic function, myocardial infarction, and diabetic nephropathy. In the RIAS (Ramipril in Aortic Stenosis) trial, RAS blockers were shown to reverse myocardial hypertrophy in aortic stenosis patients with preserved ejection fraction.¹⁴ Despite increasing evidence from the studies above and our analysis, there are no current recommendations for pharmacological therapy addressing myocardial remodelling after AVR. Our findings suggest that RAS blockers should be considered after AVR as their use has shown to reduce all-cause mortality, likely by optimizing myocardial remodelling.

This review has several limitations related to the observational nature of the included studies with inherent biases of observational designs. The results should be interpreted with caution as they cannot confer causality because of the lack of randomization. Despite propensity score matching and covariate adjustment, there may be some unmeasurable residual confounders, including the presence or absence of other pharmacological agents, that might have attributed lower mortality risk to the patients on RAS blockers. Additionally, we are not sure why the patients were given RAS blockers in the first place, whether it was because they had concomitant comorbidities, including hypertension, LV dysfunction, or diabetic kidney disease. However, in all the trials, we used the adjusted effects estimate to account for the confounding.

Moreover, the possibility of concomitant comorbidities makes our findings more robust, considering a higher comorbidity burden is associated with an increased risk of mortality. Also, these analyses lack information regarding RAS blocker dosage and adherence. Furthermore, we did not have detailed information regarding individual RAS blockers, and we have pooled different RAS blockers together assuming a class effect. We should note that the LV ejection fraction was not reported for two studies, which limited our ability to assess the effects of ARB based on the ejection fraction. Finally, the risk of publication bias remains important as studies showing significant findings are more likely to get published. However, these findings are significant, and the current analysis is based upon the best available evidence. Moreover, all included studies were of good quality and were population-based.

To date, no randomized studies have evaluated the clinical outcomes due to RAS blockade in the patients after aortic valve surgery. As a result, there is a lack of explicit pharmacological guidance for this increasing number of patients. Our findings, based on observational studies, indicate that RAS blockade post-AVR is associated with a significant reduction in all-cause mortality. Results of the Renin–angiotensin System Blockade Benefits in Clinical Evolution and Ventricular Remodeling after Transcatheter Aortic Valve Implantation study should clarify the role of RAS blockers.¹⁵

Author contribution

AM contributed to the conception or design of the work. AM, SY also contributed to acquisition analysis or interpretation as well including the initial draft. SS and RE contributed to the acquisition, analysis, or interpretation of data for the work; and drafted the manuscript. All authors critically revised the manuscript. All gave final approval and agree to be accountable for all aspects of work ensuring integrity and accuracy.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.