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MedWire News: Combined treatment with the angiotensin receptor blocker (ARB) telmisartan and ACE inhibitor ramipril is associated with worse renal outcomes relative to monotherapy with these drugs in patients at high cardiovascular risk, according to a prespecified secondary analysis of ONTARGET.
The results, provisionally presented at the European Society of Hypertension annual conference, are published in The Lancet.
ONTARGET (the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) included 25,620 patients with established atherosclerotic disease or diabetes with end-organ damage. As reported by MedWire News, the main results showed that combination treatment failed to provide any additional reduction in cardiovascular outcomes compared with either drug alone, and was associated with an increase in adverse events.
The present analysis was done to look at whether dual renin-angiotensin-system (RAS) blockade would reduce renal risk further than a single RAS inhibitor.
Over a median follow-up of 56 months, the composite primary outcome of dialysis, doubling of serum creatinine, and death occurred in 13.4% of patients taking telmisartan alone, 13.5% of those on ramipril, and 14.5% of those on the combination therapy. This translated as a significant 9% increase in the hazard for this outcome among combination-treated patients relative to the ramipril group (p=0.037).
Similarly, the secondary endpoint of dialysis or doubling of serum creatinine occurred at similar frequency with telmisartan (2.21%) and ramipril (2.03%) but was more common with the combination (2.49%, hazard ratio=1.24 versus ramipril group; p=0.038).
Johannes Mann (Ludwig Maximilians University, Munich, Germany) and fellow ONTARGET investigators note that a substantial proportion of dialysis cases were acute (61 of 161) and that acute dialysis was more common with the combination than the other drugs, whereas chronic dialysis occurred at similar frequency among treatment groups.
Further analysis revealed contrasting effects of combination therapy on the surrogate renal endpoints estimated glomerular filtration rate (eGFR) and proteinuria.
eGFR declined least in patients taking ramipril, by 2.82 ml/min/1.73m2, compared with a reduction of 4.12 ml/min/1.73m2 among patients on telmisartan (p<0.0001) and 6.11 ml/min/1.73m2 with the combination therapy (p<0.0001).
Meanwhile urinary albumin excretion increased least with the combination: the mean ratio of urine albumin to creatine increased by 21% in this group compared with 24% in the telmisartan group and 31% in the ramipril group (p<0.001 for combination and p<0.004 for telmisartan versus ramipril).
"Our data suggest that proteinuria by itself cannot be taken as a definitive marker of improved renal function, and that the benefits of any treatment, including combination blockade of the RAS on major renal outcomes, remain to be shown," the authors comment.
They note that, "although ONTARGET was not specifically powered to detect differences of major renal outcomes, nearly 3500 primary renal events were recorded."
However, George Bakris (University of Chicago, Illinois, USA) and Pantelis Sarafidis (Aristotle University of Thessaloniki, Greece) said in a related Commentary that the results do not exclude the possibility that the combination may benefit patients with advanced nephropathy, since this group was under-represented.
