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SOURCES: Damman K, et al. Worsening renal function and outcome in heart failure patients with preserved ejection fraction and the impact of angiotensin receptor blocker treatment. J Am Coll Cardiol 2014;64:1106-1113. Metra M, Lombardi C. Renin-angiotensin system blockade and worsening renal function in heart failure: An unfinished story. J Am Coll Cardiol 2014;64:1114-1116.
In patients with reduced left ventricular (LV) systolic function and heart failure, worsening renal function is associated with poor outcomes. However, worsening renal function after beginning renin angiotensin aldosterone system (RAAS) blockers has not been associated with worse outcomes in clinical trials, yet it is prognostic in the placebo group. There are few data on the importance of worsening renal function in patients with heart failure with preserved LV function. Nor is there information in this group regarding the effect of RAAS inhibition. Thus, these issues were explored in an analysis of the Irbesartan in Heart Failure With Preserved Ejection Fraction (I-PRESERVE) study. In this study, changes in estimated glomerular filtration rate (eGFR) and their association with clinical outcomes and randomized treatment (placebo or irbesartan) were examined. Patients with a baseline creatinine > 2.5 mg/dL were excluded from the study. Treatment was titrated from 75 mg daily to 300 mg daily if tolerated. All those with a creatinine level measured at 8 weeks were included in this analysis. Follow-up continued for 30 months. Worsening renal function was defined as an increase in creatinine of 0.3 mg/dL or more, along with an absolute difference between baseline and the 8-week creatinine of 25% or more. The primary outcome was cardiovascular death or the first occurrence of hospitalization for heart failure. Secondary outcomes included all-cause mortality and all-cause cardiovascular hospitalization. Outcomes were adjudicated by an independent committee.
Among the 3595 patients who met the entry criteria, eGFR decreased by 5 mL/min/1.73 m2 at 30 months compared to baseline. eGFR decreased more in the irbesartan-treated patients (-7.2 vs -3.4, P < 0.001), and the decrease was initially more rapid in the irbesartan group. Worsening renal function at 8 weeks developed in 8.4% of the irbesartan group and 4.3% of the placebo group (odds ratio, 2.0; 95% confidence interval [CI], 1.6-2.8; P < 0.001). The primary outcome of cardiovascular death or first hospitalization for heart failure occurred more commonly in those with worsening renal function (37% vs 24%; hazard ratio [HR], 1.75; 95% CI, 1.4-2.2; P < 0.001), and irbesartan treatment was also associated with poorer outcomes (HR 1.66; 95% CI, 1.2-2.3; P = 0.002). However, after multivariate adjustments, the treatment allocation and worsening heart failure association was no longer significantly related to the primary outcome, but it remained predictive of all-cause mortality and heart failure hospitalization. The authors concluded that the incidence of worsening renal failure in patients with heart failure and preserved LV function is similar to that of patients with heart failure due to reduced LV function and is more frequent with irbesartan therapy.
Although this is a retrospective analysis of a completed clinical trial, it raises the concern that angiotensin receptor blockers (ARBs) may cause harm in patients with heart failure with preserved LV function. The I-PRESERVE study did not demonstrate any benefit for irbesartan in this subgroup of heart failure patients and this analysis shows that worsening renal function in these patients is more common with ARB therapy and is associated with worse clinical outcomes. This finding is different from what has been observed in patients with heart failure due to reduced LV function. In these patients, worsening renal function may be due to aggressive diuresis or transient hypotension, but once these issues have resolved, long-term outcomes are often better. In patients with baseline low GFRs and heart failure with reduced LV function, worsening renal function associated with ARB therapy can lead to worse outcomes, but not in those with baseline normal GFR. So, the outcomes associated with reductions in GFR in stable patients with reduced LV function depend on the situation in which it is observed.
In this study, the incidence of worsening renal function was 6-14% depending on your definition. This is similar to that observed with heart failure with reduced LV function (6-10%). However, in heart failure with reduced LV function, the hemodynamic changes associated with ARB treatment usually counterbalance any negative effects of worsening renal function such that initial reductions in GFR are clinically irrelevant. The worsening renal function in this study was not related to changes in mineralocorticoid receptor antagonist use or dosage adjustments, nor the use of loop diuretics. However, the worsening renal function in the irbesartan group was associated with greater reductions in mean arterial pressure compared to those without renal function deterioration (-7 vs -4 mmHg, P = 0.003). In the placebo group, worsening renal function was not associated with blood pressure changes. So, one explanation why worsening renal function in heart failure with preserved LV function patients leads to poor outcomes is that it is a marker for adverse effects of ARBs such as hypotension. Another potential explanation is that preserved LV-function patients are more sensitive to reduced GFR. Perhaps the most attractive explanation is that there are no positive counterbalancing effects of ARBs in these patients.
The bottom line for patients with heart failure and preserved LV function is that there is currently no proven therapy that will improve long-term outcomes, but ARBs may actually do harm. This observation may extend to other renin angiotensin system blockers such as angiotensin converting enzyme inhibitors.