By Van Selby, MD
Assistant Professor of Medicine,
UCSF Cardiology Division,
Advanced Heart Failure Section

Dr. Selby reports no financial relationships relevant to this field of study. This article appeared in the April 2015 issue of Clinical Cardiology Alert.

SOURCE: Kiernan MS, et al. Early and late effects of high- versus low-dose angiotensin receptor blockade on renal function and outcomes in patients with chronic heart failure. JACC Heart Failure 2015;3:214-223.

Renin-angiotensin-aldosterone (RAAS) blockade is an important component of guideline-recommended therapy for heart failure with reduced ejection fraction (HFrEF). ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) often cause a reduction in the glomerular filtration rate (GFR). The relationship between ACEI or ARB dose and changes in renal function and the long-term implications of these changes is not well-described. To address this issue, Kiernan and colleagues performed a secondary analysis of the Heart Failure Endpoint evaluation of Angiotensin II Antagonist Losartan (HEAAL) study. HEAAL randomized 3834 patients with HFrEF to either 150 mg or 50 mg losartan daily. Patients with serum creatinine > 2.49 mg/dL, potassium > 5.7 mmol/L, or renal artery stenosis were excluded.

Compared to the 50 mg dose, patients receiving 150 mg losartan had a greater reduction in GFR over time (mean difference -3.79 mL/min/1.73 m2, P < 0.0001). The difference was driven by early worsening renal function (WRF), defined as an increase in creatinine > 0.3 mg/dL. After the first 4 months of therapy, there was no significant difference in GFR between the two doses (P = 0.016). WRF in the first 4 months was not associated with an increased risk of death or hospitalization for heart failure (HF) (HR [hazard ratio], 1.09, P = 0.20). Overall, losartan 150 mg was associated with reduced risk of death or hospitalization for HF (HR, 0.85, P < 0.0001). Among patients with chronic kidney disease (CKD) at baseline, there was no significant difference in change in GFR between the two doses. The authors concluded that compared with 50 mg losartan, 150 mg losartan is associated with an increased risk of early WRF, but this appears to be a benign event. Losartan 150 mg daily retains its net clinical benefit and is associated with reduced risk of death or hospitalization for HF in patients with HFrEF.

COMMENTARY

It is well known that initiation of ACEI or ARBs can cause a rise in serum creatinine, and WRF is a common reason for ACEI/ARB discontinuation or dose reduction. Although WRF, in general, has been associated with adverse outcomes, the clinical significance of this early WRF, following ACE or ARB initiation, is less clear. This is among the first studies to examine the dose effect of ACEI or ARB therapy on renal function in patients with HFrEF, as well as the association with long-term outcomes.

The acute rise in serum creatinine following ARB initiation is likely related to alterations in hemodynamics, related to the role angiotensin II plays in regulating renal blood flow. Longer-term declines in renal function, on the other hand, generally reflect disease progression, and not surprisingly are associated with worse outcomes. Thus, when patients with HFrEF develop WRF, it is crucial the clinician carefully evaluate the cause of the decline before adjusting the patient’s medication. Current ACC/AHA guidelines recommend an angiotensin receptor blocker for patients with HFrEF who cannot tolerate ACE inhibitors. For losartan, the target dose is 150 mg daily, and given the clear long-term benefit associated with this higher dose, it is important to consider whether dose modification or discontinuation is truly necessary when patients develop WRF.

The findings among patients with baseline CKD are important to note. In the HEAAL study, patients with baseline mild-to-moderate CKD saw smaller average changes in GFR following ARB initiation compared to patients without baseline CKD. Prior studies have shown that CKD patients are less likely to receive target doses of RAAS inhibitors compared to patients with HFrEF and normal renal function, likely related to concern for WRF. These findings support the same target dose of 150 mg in patients with mild-to-moderate CKD (remember that patients with serum creatinine > 2.49 mg/dL were excluded from HEAAL). Of course it is critical that patients be monitored closely for worsening renal failure or hyperkalemia after ACEI or ARB initiation.

This was a retrospective, secondary analysis with important limitations. Study investigators were not blind to changes in renal function, and it is possible that treatments were modified in response to changes in serum creatinine or potassium. The study also was not powered to detect differences in clinical events according to presence of WRF. The authors could not determine what was considered a “safe” increase in creatinine following ARB initiation, and what degree of early WRF should prompt drug discontinuation.

Despite these limitations, the findings suggest the early decline in GFR associated with initiation of high-dose losartan does not increase adverse outcomes, and the net clinical benefit favors targeting the 150 mg dose in patients with HFrEF. It is important to consider the cause of WRF in all HF patients, and strive to maintain the guideline-recommended dose of ACEI or ARBs whenever possible, rather than discontinuing or reducing the dose as an automatic reaction to a rise in serum creatinine.