Fast track — ArticlesRenal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial
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.
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Study design
As described previously,7 we enrolled participants who were aged 55 years or older with established atherosclerotic vascular disease or with diabetes with endorgan damage. Exclusion criteria included major renal artery stenosis, uncorrected volume or sodium depletion, a serum creatinine concentration above 265 μmol/L, and uncontrolled hypertension (>160 mm Hg systolic or >100 mm Hg diastolic). Before entering the study, 64·1% of participants were taking ACE inhibitors or ARB.7 After a 3-week
Results
At baseline, mean serum creatinine was 93·7 (SD 22·8) μmol/L and mean eGFR 73·6 (19·6) mL/min/1·73 m2; eGFR was less than 60 mL/min/1·73 m2 in 6157 participants (mean 50·7 [7·7]) and 60 mL/min/1·73 m2 or more in 19 394 participants (80·9 [15·6]). There were few participants with an eGFR below 30 mL/min/1·73 m2 (n=263). Creatinine clearances calculated according to the Cockcroft–Gault formula were higher than eGFR by 6–8% (data not shown). During follow-up, eGFR concentrations decreased more
Discussion
The primary renal outcome of dialysis, doubling of serum creatinine, and death was similar for telmisartan and ramipril, but was significantly more frequent with the combination of both drugs than with ramipril alone. The composite of dialysis and doubling of serum creatinine was also more frequent with combination therapy. Surrogate renal endpoints unexpectedly showed contrasting effects, with an adverse effect of combination therapy on typical renal outcomes and on decline in eGFR, but showed
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