RAS Inhibitors After TAVR Improve 1-Year Outcomes in Retrospective Cohort Study

Surprisingly, biggest effect seen in patients with preserved LVEF

Prescribing a renin-angiotensin system (RAS) inhibitor at hospital discharge following transcatheter aortic valve replacement (TAVR) is associated with significant reductions in death and in hospitalization for heart failure one year after the procedure. That’s the finding of a large registry-based retrospective cohort study recently published in JAMA (2018;320:2231-2241).

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The study, which confirms prior observational studies suggesting a prognostic benefit from RAS inhibition in patients with aortic stenosis, is the strongest evidence of such benefit to date, says co-author Samir Kapadia, MD, Section Head of Invasive and Interventional Cardiology at Cleveland Clinic. He adds, however, that the evidence is still too preliminary to change practice recommendations: “These are encouraging findings from a large contemporary cohort of TAVR patients, but they are retrospective and must be viewed as hypothesis-generating until confirmed in a large randomized trial.”

Such a trial might also help clarify one of the study’s unanticipated findings — namely, that the outcomes benefit observed with RAS inhibitors was most pronounced among patients with preserved left ventricular ejection fraction (LVEF). “This result surprised us,” Dr. Kapadia says. “In the setting of heart failure, the benefits of RAS inhibitors have been greatest among patients with reduced LVEF. This suggests a possible difference in mechanism of RAS inhibition between heart failure and aortic stenosis.”

Building on findings in SAVR

The study helps address a dearth of data on the role of RAS inhibitors — i.e., ACE inhibitors and angiotensin-receptor blockers (ARBs) — in patients with aortic stenosis undergoing TAVR. A potential role has been proposed in view of these agents’ modulation of adverse left ventricular remodeling and regression of myocardial hypertrophy.

Some of the first clinical data to support such a role came from a large retrospective Cleveland Clinic study (Ann Intern Med. 2014;161:699-710) showing that RAS inhibitor therapy was associated with increased survival in patients undergoing surgical aortic valve replacement (SAVR) for severe aortic stenosis. “Our earlier findings in SAVR patients, which showed benefit even in patients with normal ejection fraction, prompted this new analysis in TAVR patients,” explains Dr. Kapadia.

Drawing on the TVT Registry

He and colleagues from several other institutions analyzed data from consecutive Medicare enrollees who underwent TAVR between July 2014 and January 2016. The data were drawn from the Society of Thoracic Surgeons (STS)/American College of Cardiology Transcatheter Valve Therapies (TVT) Registry.

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Among 21,312 TAVR patients at 417 U.S. sites who met inclusion criteria, 8,468 patients (39.7 percent) were prescribed a RAS inhibitor at discharge. Patients prescribed a RAS inhibitor were more likely to have atherosclerotic comorbidities, lower LVEF, a concomitant beta-blocker prescription and a lower STS Predicted Risk of Mortality score.

To assess the effect of RAS inhibitor therapy on outcomes, the investigators matched these patients with similar TAVR patients from the registry who had no RAS inhibitor prescription at discharge, using propensity scoring to account for potential confounding variables. The result was a final study cohort of 15,896 patients — 7,948 with a RAS inhibitor prescription and 7,948 without a prescription. Mean age was 82.4 years, and 48 percent of patients were women.

Reductions in death and HF hospitalizations

The primary end points were mortality and hospitalization for heart failure in the year after TAVR. Comparison of the groups with and without a RAS inhibitor prescription revealed the following:

  • One-year mortality was lower in patients prescribed a RAS inhibitor (12.5 vs. 14.9 percent; hazard ratio [HR] = 0.82 [95% CI, 0.76 to 0.90]).
  • Rates of hospitalization for heart failure were also lower in those prescribed a RAS inhibitor (12.0 vs. 13.8 percent; HR = 0.86 [95% CI, 0.79 to 0.95]).
  • Improvement in health status (as measured by the Kansas City Cardiomyopathy Questionnaire) was statistically significantly greater in the RAS inhibitor group, but the effect size was deemed not clinically meaningful.

When mortality outcomes were stratified by patients’ LVEF, RAS inhibitor therapy was associated with significantly reduced mortality among patients with preserved LVEF (> 40 percent) (HR = 0.78; 95% CI, 0.71 to 0.86) but not among those with reduced LVEF (≤ 40 percent) (HR = 0.95; 95% CI, 0.81 to 1.12).

“The latter finding contrasts with current guidelines recommending RAS inhibitor therapy only for patients with reduced LVEF in the context of heart failure,” observes Dr. Kapadia. “This warrants further investigation.”

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RAS inhibition may loom large in low-risk TAVR

“This is the first study we know of to demonstrate that prescribing a RAS inhibitor at discharge after TAVR is associated with significant reductions in both mortality and heart failure admissions,” Dr. Kapadia points out. He says the next step is a prospective randomized trial to confirm these findings, adding that some additional insights may come from the ongoing RASTAVI trial of ramipril after TAVR.

He notes that the potential utility of RAS inhibitor therapy after TAVR will only expand if TAVR gains regulatory approval for use in patients with aortic stenosis at low surgical risk. “If RAS inhibition is found to promote survival in TAVR patients, it could hold particular appeal in younger patients at low surgical risk,” he says.

A potential new standard

“This is a very important study that expands our understanding of the current therapy of aortic stenosis,” adds Cleveland Clinic cardiothoracic surgeon Douglas Johnston, MD, who was not involved in the analysis. “Much of the focus for RAS inhibition has been in the population with low ejection fraction, but patients with normal ejection fraction and aortic stenosis go through an important period of reverse remodeling after surgery, which has significant implications for their long-term survival and function. If RAS inhibition has the potential to modulate that process, as the study suggests, this may represent a new standard for treating patients with aortic stenosis after surgical or transcatheter AVR.”