Numerous studies have shown that monotherapy with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) reduces proteinuria in patients with diabetic and non-diabetic nephropathy.1,2,3 As a result, it has been proposed that complete blockade of the RAS system might further reduce proteinuria, possibly leading to increased nephroprotective effects.4,5 It has been questioned, however, whether the use of combination therapy with an ACE Inhibitor and an ARB for this purpose is safe and effective. The ONTARGET (Renal Outcomes With Telmisartan, Ramipril, or Both, in People at High Vascular Risk) study provides new data that suggests that combination therapy leads to worsening renal outcomes, with the exception of proteinuria.6
The ONTARGET study was a multi-center, randomized, double-blind, controlled trial that included 25,620 participants who were followed for a period of approximately 56 months. Participants were randomly assigned to receive either ramipril 10 mg daily (n=8,576), telmisartan 80 mg daily (8,542), or the combination of both drugs (8,502). Participants enrolled were 55 years or older with known atherosclerotic vascular disease, or with diabetes with end-organ damage. Patients were excluded if they had major renal artery stenosis, uncorrected volume or sodium depletion, a serum creatinine concentration above 3 mg/dL, or hypertension (>160 mm Hg systolic or >100 mm Hg diastolic).
The primary renal outcome was a composite of dialysis, doubling of serum creatinine, and death. Secondary renal outcomes included each component of the composite outcome alone, the composite of dialysis and doubling of serum creatinine, and surrogate endpoints to include changes in estimated GFR (eGFR), using the MDRD formula, and progression of proteinuria.
Results showed that the frequency of the composite endpoint was similar with telmisartan (13.4%) and ramipril (13.5%), but increased with combination therapy (14.5%; p=0.037 vs ramipril alone). The secondary renal endpoint of dialysis or doubling of serum creatinine also showed no difference among the telmisartan (2.21%) and ramipril (2.03%) groups, but increased in frequency in the combination group (2.49%). The incidence of acute dialysis was more frequent with combination therapy than with ramipril; however the incidence of chronic dialysis was similar between groups. In all subgroups, including the 700 patients with overt diabetic nephropathy (≥300 mg/g creatinine), combination therapy had no clear benefit in terms of the primary renal outcome.
Looking at surrogate markers, urinary albumin:creatinine ratio increased to a lesser extent with combination therapy (+21%) than with telmisartan (+24%) or ramipril (+31%, p=0.0028 vs ramipril). Likewise, the risk of developing new microalbuminuria, macroalbuminuria, or both, was similar with ramipril and telmisartan, but was decreased with combination therapy. Estimated GFR, however, although expected to decline initially after the initiation of an ACE inhibitor or ARB, continued to decline more quickly with the combination group than with ramipril alone.
Importantly, participants were significantly more likely to have renal abnormalities and hypotensive symptoms necessitating discontinuation of the study medication if they were taking combination therapy versus ramipril or telmisartan. In total, 4.8% of patients on combination therapy discontinued treatment due to hypotension, compared to ...