Is therapy of people with chronic kidney disease ONTARGET?

The results of the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) study were unexpected, demonstrating no cardiovascular or renal benefit but substantial adverse effects of adding an angiotensin II receptor blocker (ARB), telmisartan 80 mg/day, to an angiotensin-converting enzyme (ACE) inhibitor, ramipril 10 mg/day (‘dual therapy’) vs ramipril alone [1,2]. Those results stirred up a number of commentaries especially from the nephrological community and in most major nephrological journals [3–11]. In this journal, Dr. Abutaleb [10] brings up a number of concerns related to the design and the renal results of ONTARGET, and we will reply to those concerns in the following. From the beginning, we would like to stress that ONTARGET is the only reliable outcome trial at present to build our judgment on dual therapy outside heart failure and one flawed renal study [13,14]. All other evidence comes from randomized controlled studies with only surrogate endpoints and from inferences of experimental studies. It is important to ponder strengths and weaknesses of that singular major trial. ONTARGET did not test different levels of blood pressure but tested more or less complete blockade of the renin– angiotensin system. The hypothesis was that more complete blockade of the renin–angiotensin system with the increase in bradykinin from the ACE inhibitors would result in less cardiovascular and renal outcomes. Blood pressure was lower with dual therapy by 2.4/1.4 mmHg compared to monotherapy with ACE inhibitors in people with a mean blood pressure of 142/82 mmHg at inclusion. Current guidelines for people with renal disease propose that we should aim for target blood pressure <130/80 mmHg and <125/75 in those with substantial proteinuria. Therefore, we can safely state that antihypertensive treatment in ONTARGET was not inappropriate or un-indicated but in accordance with accepted strategies of patient management. The latter is underlined by the findings of the HOPE study, a placebo-controlled trial with lower baseline blood pressure than in ONTARGET and inclusion of 50% normotensive participants, where ramipril 10 mg/day demonstrated cardiovascular and renal benefits [15–17] and a lower blood pressure than placebo. In contrast to Dr. Abutaleb’s assumption, there was no difference in mortality between randomized groups in ONTARGET and very few dropouts (study discontinuation <0.5%). However, there were more people discontinuing randomized therapy, more in the dual therapy group (about 29% vs 23% with monotherapy), but of those 29%, 22% discontinued both drugs, and 7% discontinued only one drug. Discontinuation of study medication occurred at some time during the study, was in part intermittent and was in the range of other major trials. There is no easy way to choose the right dose of drugs in clinical outcome trials. Ideally, one would like to do dose–response curves, as with experimental studies, but in the case of the ONTARGET study that would require five to 10 times the number of participants, this is an impossible undertaking. When asking whether more inhibition is better than less inhibition of the renin–angiotensin system, it is unreasonable to compare moderate doses of dual therapy with moderate doses of monotherapy. Thus, ONTARGET choose to compare the addition of a high dose of an ARB to the highest recommended dose of ramipril, namely 10 mg/day. There are other studies showing a dose–response for major outcomes of ramipril from 1.25 to 10 mg/day in patients [15,18,19]. Unknown renal artery stenosis in people with vascular disease is a problem in any outcome study that includes participants with vascular disease such as in ONTARGET. To our knowledge, there is no good clinical data that addition of an ARB to high dose ACE inhibitors increases renal risks associated with inhibition of the renin–angiotensin system in people with renal artery stenosis. Incidentally, observational data suggest that such inhibition proffers substantial cardiovascular benefits in people with renal artery stenosis at the cost of a lower glomerular filtration rate (GFR) and the risk of acute kidney injury. Estimated GFR values above 60 ml/min are often far from true GFR. However, unpublished data of ONTARGET show that the small but significantly greater decrease in eGFR with dual therapy than with ramipril was driven by