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Combination Therapy Reduces Proteinuria More Than Single Drugs but causes More Kidney Damage (ONTARGET STUDY)

LONDON, Aug. 15, 2008--Combination therapy using angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) reduces the levels of excess protein in the urine (proteinuria) more than either therapy alone in patients at high vascular risk, but also causes more kidney damage. These are the conclusions of authors of an Article in this week’s Cardiology Special Issue of The Lancet.

Proteinuria can be a sign of kidney damage, as malfunctioning kidneys allow proteins into the urine. Diabetes is the most common cause of proteinuria, although a range of other conditions can cause it. Both ACE inhibitors and ARBs have been shown to reduce proteinuria,but data comparing the two, or both combined, on long-term effects on the kidneys has not been available. Dr Johannes Mann, McMaster University and Hamilton General Hospital, Hamilton, Ontario, Canada, and Munich General Hospitals, Germany, and colleagues did the ONTARGET study to assess the effects of the ACE inhibitor ramipril and the ARB telmisartan, and their combination in patients aged over 55 years with established vascular disease or diabetes in which organ damage had occurred.

The trial took place between 2001 and 2007, and after a three week run-in period, 25620 participants were randomly assigned to ramipril 10mg daily (8576 patients), telmisartan 80mg daily (8542) or both combined (8502). The primary end point of the trial was composite of the proportions of patients that had to have kidney dialysis, that doubled their levels of serum creatinine* or died, as well their effect on proteinuria.

The researchers found that 784 patients had to discontinue treatment due to symptoms of low blood pressure (hypotension) (406 combination, 149 ramipril and 229 telmisartan). The number of events for the composite primary outcome was similar for telmisartan (1147 events) and ramipril (1150), but increased with combination therapy (1233); and of these events, there were 989 deaths in the telmisartan group, compared with 1014 in the ramipril group and 1065 in the combination group. For the secondary renal outcome, dialysis or doubling of serum creatine, 189 events were recorded in the telmisartan group, compared with 174 in the ramipril group, but 212 in the combination group. The estimated glomerular filtration rate (a more precise measure of kidney function than serum creatinine) declined more with combination therapy than either drug alone. Urine protein excretion was least with combination therapy and highest with ramipril.

The authors conclude: “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.”

In an accompanying Comment, Dr Pantelis Sarafidis, American Hellenic Educational Progressive Association Hospital, University of Thessaloniki, Greece, and Dr George Bakris, University of Chicago and Pritzker School of Medicine, Chicago, USA, say: “The findings of ONTARGET support previous guidelines that propose use of drugs to block the renin-angiotensin system as part of an antihypertensive regimen to lower blood pressure and urinary protein in chronic kidney disease. These data should not lead to guideline modifications...Combined with previous studies, ONTARGET supports the notion that use of single agents to block the renin-angiotensin system is well tolerated.”

Dr Johannes Mann, McMaster University and Hamilton General Hospital, Hamilton, Ontario, Canada. T) +49 89 3068 2386,

Comment Dr George Bakris, University of Chicago and Pritzker School of Medicine, Chicago, USA. T) +1 773-702-7936 / +1 312-208-9113,

Note to Editors
Creatinine is a waste product of muscle cells, and is excreted via the kidney. Thus high levels indicate kidney damage, ie, less waste removal. Telephone: +44 (0)20 7424 4949/4249

Posted: August 2008