Chen S, Redfors B, Nazif T, et al. Impact of renin-angiotensin system inhibitors on clinical outcomes in patients with severe aortic stenosis undergoing transcatheter aortic valve replacement: an analysis of from the PARTNER 2 trial and registries. Eur Heart J. 2020 Feb 21;41(8):943-954. doi: 10.1093/eurheartj/ehz769.
Pablo Avanzas, MD, PhD, FESC
Professor of Medicine, University of Oviedo, Oviedo, Spain
Left ventricular pressure overload is associated with activation of the cardiac renin–angiotensin system, which may contribute to myocardial fibrosis and worse clinical outcomes. The authors of this article assessed the association between treatment with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) at baseline and clinical outcomes in patients with symptomatic, severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR) in the PARTNER 2 trial and registries.
A total of 3979 intermediate, high, or prohibitive risk patients who underwent TAVR in the PARTNER 2 trial and registries (excluding the valve in valve registry) were included in the study. Clinical outcomes at 2 years were compared according to baseline ACEI/ARB treatment status using Kaplan–Meier event rates and study-stratified multivariable Cox proportional hazards regression models. Sensitivity analysis was conducted using propensity score matching. Of 3979 patients who were included in the current analysis, 1736 (43.6%) were treated and 2243 (56.4%) were not treated with ACEI/ARB at baseline. Treatment with ACEI/ARB was associated with lower 2-year all-cause mortality (18.6% vs. 27.5%, P < 0.0001), cardiovascular mortality (12.3% vs. 17.9%, P < 0.0001), and non-cardiovascular mortality (7.2% vs. 11.7%, P < 0.0001). Angiotensin-converting enzyme inhibitor/ARB treatment at baseline remained independently associated with a lower hazard of 2-year all-cause and cardiovascular mortality after multivariable adjustment, and propensity score matching.
The major finding from this analysis is that among patients with severe symptomatic AS, treatment with ACEI/ARB at baseline was independently associated with decreased 2-year risks of all-cause and cardiovascular mortality after TAVR. The current study is the largest retrospective analysis examining the effect of pre-TAVR treatment with ACEI/ARB in patients with symptomatic severe AS. The data used in the current study was collected prospectively and comprehensively, echocardiographic and electrocardiographic data was analysed by a central core laboratory, allowing adequate adjustment to minimize the inherent risk of confounding. In addition, all events were adjudicated, including type of death (Cardiovascular vs. non-cardiovascular), allowing examination of the effect on specific outcome (cardiovascular death) and reducing the risk of confounding.
In the current study, treatment of patients with severe symptomatic AS, with ACEI/ARB was not only safe but also associated with lower mortality rates after TAVR. One can speculate that these results are confounded due to a selection bias, i.e. that more stable, healthier patients can be expected to be more likely to be treated with ACEI/ARB than sicker, less stable patients for whom these drugs may be withheld. However, although patients who were treated with ACEI/ARB were slightly younger, had slightly lower STS score and were less likely to have renal disease than patients without ACEI/ARB, they had similar rates of NYHA class III or IV symptoms, and higher rates of CAD and cardiovascular risk factors including diabetes. More importantly, the association between ACEI/ARB treatment and lower risk of all-cause and cardiovascular mortality persisted after multivariable adjustment, and propensity score matching. Moreover, treatment with beta-blockers was included in the multivariable models. Beta-blockers are also usually given to relatively stable patients and avoided in decompensated and unstable patients, and would therefore be expected to be associated with the same residual confounding as ACEI/ARB treatment. In contrast to ACEI/ARB treatment, which remained significantly associated with all-cause and cardiovascular mortality after inclusion of beta-blocker treatment in the multivariable model, treatment with beta-blocker was not significantly associated with either all-cause or cardiovascular mortality.
Despite these impressive findings, the absence of randomization precludes the recommendation of routine ACEI/ARB use in TAVR recipients, but raises a hypothesis that must be tested prospectively. Fortunately, this question is being addressed in the ongoing RASTAVI trial, which is assessing clinical outcomes and LV remodelling in 336 TAVR recipients randomized to ramipril vs. standard therapy post-TAVR, with an anticipated follow-up of 3 years. This study is designed with a most optimistic treatment effect (anticipated relative risk reduction of 0.55 for all-cause death) and therefore the limited sample size may render it underpowered to detect more conservative though clinically relevant differences in its primary endpoint of mortality, heart failure hospitalization, and stroke.