Hamilton, ON - A new, prespecified analysis of renal outcomes in the large ONTARGET study has shown that those taking a combination of the angiotensin receptor blocker (ARB) telmisartan and ACE inhibitor ramipril fared worse than those taking either drug alone [1]. Dr Johannes FE Mann (McMaster University, Hamilton, ON) and colleagues report their findings in the August 16, 2008 issue of the Lancet.

But nephrologists Dr Pantelis A Sarafidis (AHEPA Hospital, Thessaloniki, Greece) and Dr George Bakris (Pritzker School of Medicine, Chicago, IL) warn in an accompanying editorial that the findings need very careful interpretation, given the diverse cohort studied and the way in which the renal end-point data were collected [2]. They agree that the ARB/ACE-inhibitor combination should be avoided in the vast majority of patients in ONTARGET; this was also the general conclusion when the main results of ONTARGET were reported at ACC meeting earlier this year.

But these findings should not be misinterpreted to mean that the combination should never be prescribed, Sarafidis explained to heartwire. This ARB/ACE-inhibitor option is useful for around 5% of the patients that nephrologists see, the very sick with overt nephropathy and albumin excretion >1 g/day, and there were only a few hundred of these patients out of 25 000 in ONTARGET, he notes. In terms of these patients, "ONTARGET doesn't help us at all, and if the message that comes out from this is, don't use this combination for this particular group of people, that would be dangerous," he says.

ONTARGET doesn't help us at all, and if the message that comes out from this is, don't use this combination for [overt nephropathy patients], that would be dangerous.

The presentation of the main results of ONTARGET at the ACC meeting showed that telmisartan was "noninferior" to ramipril in the ONTARGET population—25 620 patients with coronary heart disease or diabetes plus additional risk factors who were over the age of 55 but did not have evidence of heart failure. In fact, the combination of the two drugs was associated with more adverse events, without an increase in benefit.

At the time of the presentation of the main results, there was unequivocal agreement that doctors now have a choice of an ACE inhibitor or ARB in high-risk CHD/diabetes patients but that the combination should be avoided.

In the new analysis, a composite primary renal end point of dialysis, doubling of serum creatinine, and death was used, and the outcome was similar for telmisartan or ramipril alone but was significantly more frequent with combination therapy; the same was true for the secondary outcome of dialysis or doubling of creatinine.

But other surrogate renal end points "unexpectedly showed contrasting effects,"' Mann et al note, "with an adverse effect of combination therapy on typical renal outcomes and on decline in estimated glomerular filtration rate (eGFR), but . . . beneficial effects on proteinuria."

The ONTARGET investigators point out that nearly 3500 primary renal events were recorded, and their numbers for specific renal outcomes—162 cases of dialysis and 461 participants with a doubling of creatinine—are similar to the numbers seen in some of the largest randomized renal trials to date.

The theory has been that the benefit of combined ARB/ACE-inhibitor therapy is strongest in protecting the kidney, but this paper shows that that is not true, and that if anything it's harmful.

Senior author Dr Salim Yusuf (McMaster University) told heartwire: "This finding is important because the theory has been that the benefit of combined ARB/ACE-inhibitor therapy is strongest in protecting the kidney, but this paper shows that that is not true, and that if anything it's harmful. A lot of nephrologists use this combination therapy, so this paper has a lot of implications."

But the researchers also concede that ONTARGET was not specifically powered to detect differences of major renal outcomes and that death was the most common component of the composite primary outcome.

Nevertheless, they did look at patients at substantial renal risk—ie, those with diabetic nephropathy, of whom there were around 700 out of 25 000. The results "do show in favor of combination therapy for the primary outcome [in this group], with a relative risk reduction of 8%, but this was not significant," they point out.

"Therefore, there is no evidence to support the use of combination therapy in any subgroup of patients included in ONTARGET beyond lowering of urinary albumin excretion," they conclude.

But Mann told heartwire that, in general, he agrees with the conclusions of Sarafidis. "Our results are applicable to those with protein excretion <1 g/day but not to those with excretion >1 g/day, ie, the very sickest patients, of whom there were only a couple of hundred in ONTARGET."

Sarafidis does not disagree that the ARB/ACE-inhibitor combination should be avoided in the vast majority of patients in ONTARGET. "A third of the patients were normotensive, and when you give a combination of these blockers to these patients, it could be potentially harmful, and as we saw, it was associated with more hypotension—which was the main side effect—and more syncope," he notes.

Because of the diverse population, you have a few people who might benefit [from the combination], but many more people in danger.

The same scenario is true when viewed from a renal standpoint, he says. "You get many more acute renal-failure episodes with the combination, but the difference is in acute renal failure, not in chronic renal failure, chronic dialysis, and doubling of creatinine—among these end points we saw very minor differences in this analysis," he continues.

"Because of the diverse population, you have a few people who might benefit [from the combination], but many more people in danger, because they were not hypertensive, and many of them had atherosclerotic vascular disease in the renal arteries. They were the people who would have developed acute renal failure being on the combination," Sarafidis added.

Sarafidis says that nephrologists should continue to give those with overt nephropathy a combination of ARB/ACE inhibitor, although he concedes that a prospective trial would be nice, as there were only the couple of hundred patients with such overt nephropathy in ONTARGET, he says.

"A properly done prospective trial of patients with advanced proteinuric chronic kidney disease is still needed to answer definitively the question about the efficacy of combination therapy to block the renin angiotensin system [RAS] on progression of chronic kidney disease," he and Bakris conclude.

Also, the decision to prescribe the combination in overt nephropathy patients is based on the findings of the COOPERATE study, published in 2003, Sarafidis said. And there have been some criticisms of this study, which he says he agrees with, "although there is also evidence from meta-analyses of smaller studies on this kind of population to support the conclusion."

For his part, he believes the combination is "basic science" for these very sick patients. "This is the end of the natural history of this disease, and in these people we do want to block the RAS to make their 'engine' work at a smaller rate to preserve the low function."

Mann agrees that an outcomes trial is needed with the combination of ARB/ACE inhibitor in this specific subgroup of overt nephropathy patients and admitted that the new renal analysis of ONTARGET was "not particularly helpful" when it comes to this group of patients.