Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial

Summary

Background

Angiotensin receptor blockers (ARB) and angiotensin converting enzyme (ACE) inhibitors are known to reduce proteinuria. Their combination might be more effective than either treatment alone, but long-term data for comparative changes in renal function are not available. We investigated the renal effects of ramipril (an ACE inhibitor), telmisartan (an ARB), and their combination in patients aged 55 years or older with established atherosclerotic vascular disease or with diabetes with end-organ damage.

Methods

The trial ran from 2001 to 2007. After a 3-week run-in period, 25 620 participants were randomly assigned to ramipril 10 mg a day (n=8576), telmisartan 80 mg a day (n=8542), or to a combination of both drugs (n=8502; median follow-up was 56 months), and renal function and proteinuria were measured. The primary renal outcome was a composite of dialysis, doubling of serum creatinine, and death. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00153101.

Findings

784 patients permanently discontinued randomised therapy during the trial because of hypotensive symptoms (406 on combination therapy, 149 on ramipril, and 229 on telmisartan). The number of events for the composite primary outcome was similar for telmisartan (n=1147 [13·4%]) and ramipril (1150 [13·5%]; hazard ratio [HR] 1·00, 95% CI 0·92–1·09), but was increased with combination therapy (1233 [14.5%]; HR 1·09, 1·01–1·18, p=0·037). The secondary renal outcome, dialysis or doubling of serum creatinine, was similar with telmisartan (189 [2·21%]) and ramipril (174 [2·03%]; HR 1·09, 0·89–1·34) and more frequent with combination therapy (212 [2·49%]: HR 1·24, 1·01–1·51, p=0·038). Estimated glomerular filtration rate (eGFR) declined least with ramipril compared with telmisartan (−2·82 [SD 17·2] mL/min/1·73 m² vs −4·12 [17·4], p<0·0001) or combination therapy (−6·11 [17·9], p<0·0001). The increase in urinary albumin excretion was less with telmisartan (p=0·004) or with combination therapy (p=0·001) than with ramipril.

Interpretation

In people at high vascular risk, telmisartan's effects on major renal outcomes are similar to ramipril. Although combination therapy reduces proteinuria to a greater extent than monotherapy, overall it worsens major renal outcomes.

Funding

Boehringer-Ingelheim.

Introduction

Clinical trials of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) have shown that these drugs reduce albuminuria, as well as renal risk—ie, loss of glomerular filtration rate (GFR) and need for dialysis in those with advanced renal disease.¹ Whether a combination of these classes of drugs further reduces renal risk, and whether the effects of ARB and ACE inhibitors are equivalent, is unknown. A recent meta-analysis indicated that the combination of an ACE inhibitor and an ARB reduces proteinuria to a greater extent than either drug alone,² but the total number of patients in each trial was less than 30 on average, the duration of therapy rarely exceeded 1 year, and the effects on major renal outcomes, such as GFR changes or occurrence of dialysis, was not reported. Proteinuria has been suggested not only as a marker but also as a cause of progressive renal insufficiency.³ Further reduction of proteinuria by combined ACE inhibitor and ARB therapy could theoretically protect the kidney from chronic kidney failure compared with either agent alone.³ Proteinuria has also been linked with increased cardiovascular morbidity.⁴

Combining ACE inhibitors with an ARB might also lead to more frequent adverse events than monotherapy,⁵ including acute renal failure and hyperkalaemia. Assessment of the net balance of benefits and risks of ACE inhibitors and ARB alone and in combination requires direct comparisons in large randomised controlled trials. Although most trials of renal disease progression include participants with pre-existing advanced renal disease, these patients constitute only a small number of patients who are eligible to receive ACE inhibitors and ARB.

As part of the prespecified analyses of the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) study,⁶ we examined the effects of telmisartan, (an ARB), ramipril (an ACE inhibitor), and their combination used at full doses, on renal outcomes in a large population at high cardiovascular risk. We specifically report: the frequency of the primary composite renal outcome of dialysis, doubling of serum creatinine, and death, and each component; and changes in surrogate markers such as estimated GFR (eGFR) and proteinuria.