Clinical and Echo Outcomes After TAVR May Improve on RAS Inhibiting Meds

August 05, 2019

Putting patients on renin-angiotensin system (RAS) inhibiting drugs after transcatheter aortic-valve replacement (TAVR) may reverse some of their ventricular damage and cut long-term risks for atrial fibrillation (AF) and other clinical outcomes, an observational study suggests.

The analysis isn't enough to outright recommend long-term RAS inhibitor therapy after TAVR, "but I think it's pointing in that direction," Ignacio J. Amat-Santos, MD, PhD, told | Medscape Cardiology.

"And if the patient has an indication for antihypertensive treatment, then probably the initial choice should be a RAS inhibitor, according to our results," said Amat-Santos, from Hospital Clínico Universitario de Valladolid, Spain.

The adjusted risk for cardiovascular (CV) death fell by 41% over 3 years (P = .003) for TAVR patients prescribed RAS inhibitors at discharge, compared with those not prescribed the drugs, in the analysis of more than 2700 patients seen at 10 centers in Spain over a recent 10-year period. Risks for cerebrovascular events and readmissions also fell significantly.

RAS inhibitors in the analysis included ACE inhibitors, angiotensin-receptor blockers (ARBs), and the aldosterone inhibitors spironolactone and eplerenone. The newer sacubitril/valsartan (Entresto, Novartis) was prescribed to only eight patients, Amat-Santos said.

Of note, the 1622 patients given RAS inhibitors showed significant reverse remodeling, including shrinkage of left ventricular (LV) volumes and septal hypertrophy over 3 years by echocardiography, compared with the 1163 who didn't get the drugs.

Those improvements were most pronounced in patients with the most severe cardiomyopathy prior to TAVR, but were not associated with degree of aortic stenosis.

"If there was more hypertrophy, there was more regression in the group of patients who received RAS inhibitors," Amat-Santos said. "So it seems like there is a synergistic effect of TAVR and RAS inhibitors in those patients with more diseased ventricles."

Amat-Santos is senior author on the retrospective study published in the August 6 issue of the Journal of the American College of Cardiology, with lead author Tania Rodriguez-Gabella, MD, Hospital Clínico Universitario de Valladolid.

The various findings seem consistent with each other and make intuitive sense given the known benefits of RAS inhibitors in other forms of cardiomyopathy. There's no real randomized trial support for prescribing the drugs after TAVR in the absence of other indications, but previous observational data have shown some survival benefits.

The current analysis goes further by showing broader clinical benefit and echocardiographic improvement in a fairly old and sick TAVR cohort, Amat-Santos said.

"We had some concerns about the use of these drugs, because they might present with more episodes of hypotension or renal failure. We weren't sure they would have the same result as in younger aortic-stenosis patients. So this is reassuring."

Patients who were or were not discharged on RAS inhibitors had been at similar surgical risk, but those prescribed the drugs had more CV risk factors, coronary disease, and previous myocardial infarction, the report notes.

Multivariate analysis adjusted for such differences in the total cohort of 2785 patients, but there was also a secondary analysis that propensity-matched 695 patients in each group, with largely consistent results over the median follow-up of 479 days.

The current study isn't the first to show that post-TAVR RAS inhibitor therapy may improve clinical outcomes, but it's new in finding reduced CV mortality as a benefit, observes an accompanying editorial from Russell J. Everett, MD, PhD, and Marc R. Dweck, MD, PhD, University of Edinburgh, United Kingdom.

"In addition, this study has confirmed more extensive LV reverse remodeling in patients with RAS inhibition, providing a plausible mechanism for this beneficial effect," they write.

All-cause mortality was statistically similar after 1 year in the overall population, at 8.6% for those on and 9.1% for those not on RAS inhibitors. But 1-year CV mortality was lower in the RAS inhibitor group (3.5% vs 5.8%; P = .003).

The survival differences held at 3 years, at which time patients on RAS inhibitors also showed lower rates of incident AF, cerebrovascular events, and hospital readmission.

Clinical Outcomes at 3 Years by Discharge RAS Prescription Status in Propensity-Matched* Cohorts
End Point RAS Inhibitors, % (n = 695) No RAS Inhibitors, % (n = 695) P Value
New-onset AF 23.2 32.0 .002
Cerebrovascular events 1.4 5.9 <.001
Readmission 42.8 51.9 .017
Cardiovascular mortality 7.2 11.3 .006
All-cause mortality 18.4 19.6 .567
*Matched for chronic kidney disease, chronic obstructive pulmonary disease, coronary artery disease, diabetes, dyslipidemia, hypertension, LVEF, and NYHA heart failure functional class.

In multivariate analysis of the matched cohorts, the hazard ratio (HR) for CV mortality in patients discharged on RAS inhibitors was 0.59 (95% CI, 0.41 - 0.87; P = .007). In contrast, CV mortality HRs were significantly increased among patients with previous percutaneous coronary revascularization (PCI), chronic obstructive pulmonary disease, and moderate or severe aortic regurgitation.

Among the 85% of patients in whom echocardiography was performed at the 3-year follow-up, those in the total population and the propensity-matched cohorts both showed associations between RAS inhibitor therapy and significant improvements in LV end-systolic and end-diastolic volumes and septal hypertrophy.

Mean Changes in Echocardiographic Measures of Ventricular Remodeling by Discharge RAS Inhibitor Status in Propensity-Matched* Cohorts
Parameter RAS Inhibitors (n = 695) No RAS Inhibitors (n = 695) P Value
LV ejection fraction, % 0 +2 .076
Aortic valve area, cm² +0.90 +1.0 .008
End-diastolic volume, mL –10 +4 <.001
End-systolic volume, mL +1 +4 <.001
Septal thickness, mm –3 0 <.001
*Matched for chronic kidney disease, chronic obstructive pulmonary disease, coronary artery disease, diabetes, dyslipidemia, hypertension, LV ejection fraction, and NYHA heart failure class.

Limitations of the study, the editorialists and the report's authors note, include the inability to adjust for other potential confounders, both unknown and known, an inability to account for contraindications to RAS inhibitor therapy, and the absence of blood pressure in the propensity matching.

"Indeed, the inclusion of hypertension and chronic kidney disease as binary rather than continuous variables may further influence the validity of the results," write Everett and Dweck.

"Moreover, we do not know the effects of RAS inhibition on myocardial fibrosis, which may be an important mechanism of its apparent efficacy."

That question is a major focus on the ongoing randomized Renin-Angiotensin System Blockade Benefits in Clinical Evolution and Ventricular Remodeling After Transcatheter Aortic Valve Implantation (RASTAVI) trial, Amat-Santos said. It's following 336 patients and assessing whether they were discharged after TAVR with RAS inhibitor prescriptions.

Whether the drugs induce "regression of fibrosis, or only of hypertrophy" after TAVR would help clarify the patients' long-term prognosis, he said. RASTAVI is using cardiac magnetic resonance imaging to track myocardial responses to RAS inhibition, including any changes in amount of fibrosis.

Amat-Santos, Rodriguez-Gabella, their coauthors, and Everett and Dweck report that they have no relevant conflicts.

J Am Coll Cardiol. 2019;74:631-641, 642-644. Abstract, Editorial

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