RAS antagonists associated with lower all-cause mortality in HF with severe renal insufficiency
Association between renin-angiotensin system antagonist use and mortality in heart failure with severe renal insufficiency: a prospective propensity score-matched cohort study.
Edner M, Benson L, Dahlström U, Lund LH
Eur Heart J. 2015 Jun 11. pii: ehv268. [Epub ahead of print]
BackgroundIn patients with heart failure (HF) with reduced ejection fraction (EF), angiotensin-converting enzyme inhibitors (ACEIs) reduce all-cause mortality, and angiotensin receptor blockers (ARBs) lower cardiovascular (CV) mortality and/or HF hospitalisation alone or in combination with ACEI, because of the maladaptive activation of the renin-angiotensin-aldosterone system seen in HF [1-4].
Renal insufficiency is common in patients with HF. It is independently associated with increased all-cause and CV mortality. Renin-angiotensin system (RAS) antagonists like ACEIs and ARBs lower the incidence and progression of renal insufficiency in patients with or at risk of CV disease [5,6]. Patients with HF and renal insufficiency may therefore specifically benefit from treatment with these agents.
Patients with severe renal insufficiency were excluded from RAS antagonist trials [1-4] and guidelines often consider renal insufficiency a contraindication or state that it warrants caution [7,8].
This study assessed the effect of RAS antagonists on all-cause mortality in HF (EF<39%) with severe renal dysfunction, defined according to guidelines as creatinine > 221 μmol/L or creatinine clearance < 30 mL/min (CKD 4 and 5). This study used data from 2410 patients with severe renal insufficiency included in the Swedish Heart Failure Registry (SwedeHF) .
Main results• Crude 1-year survival was 61% (95%CI: 59-63) in treated vs. 42% (95%CI: 39-46) in untreated patients. 3-Year (31 vs. 18%) and 5-year (17 vs. 7%) survival were also higher in treated patients. 403 (95%CI: 380-427) vs. 708 (95%CI: 655-763) deaths per 1000 patient-years were seen, yielding an unadjusted HR was 0.61 (95%CI: 0.56-0.67, P<0.001).
• A propensity score for treatment with RAS antagonists was determined based on 36 variables. In the propensity score matched cohort (n=602 for treated and untreated), 1-year survival was 55% (95%CI: 51-59) in treated vs. 45% (95%CI: 41-49) in untreated patients. 3-year survival was 28 vs. 20% and 5-year survival was 14 vs. 8%.
In this cohort, 475 (95%CI: 432-521) vs. 648 (95%CI: 592-708) deaths per 1000 patient-years were seen, yielding an unadjusted HR was 0.76 (95%CI: 0.67-0.86, P<0.001).
• HR in the overall cohort after adjustment for propensity score was 0.81 (95%CI: 0.73-0.91, P<0.001).
• Making a distinction between mortality <100 days and >100 days, suggests that RAS antagonists are associated with greater benefits during the first 100 days, or that cross-over may have occurred over time (HR: 0.60 vs. HR: 0.86 at >100 days).
• No statistically significant interactions with the effect of RAS antagonism on mortality were seen for clinically relevant subgroups.
• A positive control analysis in over 21000 HF patients without severe renal insufficiency showed greater survival in treated and untreated individuals than in patients with renal insufficiency. Without renal dysfunction, 217 (95%CI: 203-233) vs. 280 (95%CI: 262-298) deaths per 1000 patient-years were seen in the matched cohort, with unadjusted HR: 0.79 (95%CI: 0.72-0.86, P<0.001).
ConclusionIn this large HF registry, 9.9% of patients had severe renal insufficiency. Although not recommended, 66% of those used RAS antagonists. Their benefit had not been established in this patient group, but this study showed that RAS antagonism was associated with reduced all-cause mortality. The lower mortality was similar to that seen in a positive control consistency analysis in patients with HF but without severe renal insufficiency. The observation that RAS antagonists may be beneficial in HF with severe renal insufficiency should be confirmed in a randomized trial, possibly in a registry-randomised clinical trial concept, since RAS antagonists are generic.
Editorial comment Guideline recommendations reflect the lack of evidence in HF patients with moderate to severe renal dysfunction and therefore do not recommend the use of RAS inhibitors in this large patient population. Over time, however, several retrospective analyses had been published showing that RAS inhibition was safe and effective in patients with HF and moderate to severe renal dysfunction. These reports have encouraged many clinicians “to trust our anecdotal experience and cautiously treat these patients with perceived contraindications”. The current analysis by Edner et al of real-life clinical data “demonstrates the power of a large high-quality registry to bring clarity to important clinically relevant issues and generate hypotheses that deserve to be tested prospectively”. (…) “The authors created a matched cohort based on propensity scores for RAS antagonist use and demonstrated that the hazard ratio (HR) for 1-year survival in treated patients was almost identical whether or not severe renal in- sufficiency was present.” (…)
“So do these results from the Swedish Registry have ‘game-changing’ impact? From my vantage point, the answer is yes. Substantial renal dysfunction should not be considered a contraindication to the judicious use of RAS inhibitors in patients with symptomatic HF. However, healthcare professionals have an obligation to confirm that the treatment strategy includes an adequate follow-up plan. “
Find this article online at Eur Heart Journal
1. Results of the Cooperative North Scandinavian Enalapril Survival Study (CON- SENSUS). The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. N Engl J Med 1987;316:1429–1435.
2. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991; 325:293 – 302.
3. McMurray JJ, Ostergren J, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet 2003; 362:767 – 771.
4. Granger CB, McMurray JJ, Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet 2003;362:772 – 776. 5. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861–869.
6. Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 2000;355:253–259.
7. McMurray JJ,Adamopoulos S,Anker SD, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012;33: 1787 – 1847.
8. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2013;128:1810–1852.
9. Lund LH, Benson L, Dahlstrom U, et al. Association between use of beta-blockers and outcomes in patients with heart failure and preserved ejection fraction. JAMA 2014;312:2008 – 2018.
10. Is substantial renal dysfunction in patients with heart failure no longer a contraindication for RAS inhibition? The power of a large, high-quality registry to illuminate major clinical issues. Dickstein K. Eur Heart J 2015 July 22. doi:10.1093/eurheartj/ehv300