Sue Hughes

April 01, 2008

April 1, 2008 (Chicago, IL) – Everyone seems to agree that there is little in the ONTARGET megatrial, presented yesterday at the American College of Cardiology (ACC) 57th Annual Scientific Session, to quibble about and that it shows clear results: doctors now have a choice of an ACE inhibitor or angiotensin receptor blocker (ARB) in high-risk CHD/diabetes patients, but the combination should be avoided.

Lead investigator Dr Salim Yusuf (McMaster University, Hamilton, ON) said: "There have been suggestions that ARBs should be better than ACE inhibitors and other suggestions that they might be worse, but we found they are actually very similar. People can take either one. Physicians now have a choice, and they will have to think about blood-pressure reduction, cost, and tolerability when making that choice.

"The other message is that a combination of ACE inhibitor and ARB should not be used in the ONTARGET type of population," Yusuf added. "Heart failure may be a bit different. We saw some benefit in the CHARM-Added trial from combination therapy, but this trial included patients in severe heart failure despite being on an ACE inhibitor. But there was a strong trend in ONTARGET toward more dialysis in patients in the combination group, and other side effects were also increased, without any benefit. So overall now we can say that, other than in certain heart-failure populations, don't use the combination."

No arguments

And in what comes as a refreshing change when such large trials first report, there appears to be no arguments over the interpretation of these results.

Dr Sanjay Kaul (Cedar Sinai Medical Center, Los Angeles) says this is because the trial was so well designed. Kaul, who has been critical of the design of many trials in the past, commented to heartwire : "This was a great trial. It was large, with a simple design and a rigorous noninferiority margin, so we can definitely say that telmisartan is similarly as effective as ramipril. It asked two specific questions and got two clear answers, in contrast to most clinical trials these days, which try to answer too many questions at the same time and often don't get any clear answers."

In general, there was no surprise about the main result showing similar effectiveness of the ACE inhibitor and ARB. Dr Peter Sleight (Oxford University, UK), who was one of the key players in ONTARGET, told heartwire : "I wasn't expecting the ARB to be better than the ACE inhibitor as the ACE-inhibitor data are fantastic. But this result is what I thought would happen. The ARB is solidly just as good as the ACE inhibitor. And it lays all the ghosts to rest about suggestions of increased risk of MI with ARBs--this trial shows that was all nonsense."

Combination result unexpected

But Sleight said the lack of benefit with the combination was unexpected. "We thought the two together would be beneficial even if was just because of a reduction in blood pressure, but this turned out not to be true at all. We saw no difference in efficacy with the combination and some nasty and worrying side effects--more hypotension, syncope, and renal problems--particularly raised potassium, which in the general-practice population, where you might not monitor electrolytes very much, could be very dangerous."

He added that they haven't analyzed all the renal data yet regarding subgroups with different degrees of albuminuria, but this should be available in a few weeks. "But the message at the moment is that it is better not to be on the combination unless you've got some specific indication like heart failure that isn't controlled on one or the other alone. That is a really important clinical message. And it simplifies life for people in that you don't have to think about giving both."

Several other doctors also expressed disappointment over the lack of benefit seen in the combination arm.

Dr Roger Blumenthal (John Hopkins University, Baltimore, MD) commented to heartwire : "To my mind this was a disappointing study. I was hoping for more impressive results--in particular, an additional benefit in the combination group. This isn't going to change my practice very much."

Dr Harlan Krumholz (Yale University School of Medicine, New Haven, CT) added: "What is particularly intriguing is that the additional blood-pressure lowering did not translate into clinical benefit. Is this signaling to us that the surrogate outcome of blood pressure may not reliably predict what happens to patients? On top of ENHANCE, this study also suggests that we really do need outcomes studies to assess the net benefit of therapeutic strategies."

ACE or ARB: How to make that choice?

The main discussion of the trial revolved around how doctors would choose between an ACE inhibitor and an ARB in this population.

Sleight said he thought most would start on an ACE inhibitor because it was cheaper. "But around 20% of people will not tolerate ACE inhibitors because of cough. And in the long term, if you're talking about treating someone for life, tolerability becomes more important," he added. He explained that the difference in tolerability between the two drugs in ONTARGET was not so large because there had been a run-in period where those who had side effects were filtered out. "So if they got a cough in the run-in, they didn't get randomized," Sleight said. "Also, we tried very hard to keep people on the same medication throughout the trial, and if they got a cough we would retry them on the same drug, which might not happen in real life. So the compliance rates were better than would be expected in real life. The New England Journal of Medicine didn't want us to emphasize the better tolerance of the ARB, as they thought the data weren't so clear on that, but the data in this trial were on somewhat of an artificial population in this regard," he added.

Kaul suggested that the incidence of cough with ACE inhibitors may not be as high as 20%. "I personally feel that cough with ACE inhibitors has been overplayed. My experience is that 5% to 7% of patients cannot tolerate ACE inhibitors, but this figure can be higher in certain ethnic groups such as those from the Indian subcontinent," he told heartwire . Dr John Cleland (University of Hull, UK) added that ARBs may be preferable for first-line use in women, who are also at an increased risk of cough with ACE inhibitors.

Cost issues will be key

The choice of ACE inhibitor or ARB and then which individual drug within each class dominated the discussion at the ACC press conference on the ONTARGET trial.

Yusuf said he would still start with an ACE inhibitor but would make the switch to an ARB sooner now if there were any problems. "Before these results, if a patient could not tolerate ramipril initially, I would make them persevere for a while before switching, but now I would switch them earlier to telmisartan. But telmisartan is four times the price of ramipril in Canada, so I would still start with ramipril," he commented. But he added: "I'm told that family-practice doctors might now prefer to start with telmisartan as it lowers blood pressure to a slightly greater extent and is better tolerated, and so patients are less likely to come back and are more likely to be compliant. Many of the investigators in ONTARGET who were family practitioners thought it was great result because now they can use an ARB with confidence."

Yusuf noted that the driving force in making the decision between an ACE inhibitor and an ARB when starting treatment was probably cost and the ability to pay. "I've been told that in some countries telmisartan and ramipril are the same price, in which case you would probably go with telmisartan to avoid the cough. If the costs are widely different, as is the case in most places, I think the right thing to do is to start with an ACE inhibitor and move to the ARB if you run into problems."

Class effect?

Yusuf was also insistent that doctors should choose the individual drug shown to give benefit rather than a different member of the same class. "I would say that if you have chosen an ARB it should be telmisartan, and if you have chosen an ACE inhibitor, it should be ramipril, because those two have the best data. Yes, some of the effect is bound to be a class effect, but we don't know for sure if other ACE inhibitors/ARBs would do the same thing. I advocate an evidence-based approach, so I use the drug that has shown the benefit in the trial at the dosage used in that trial."

But other panel members at the press conference pointed out that ramipril was still on patent in the US, which made it much more expensive than some other ACE inhibitors. Yusuf engaged in some lighthearted banter over this with Dr Steve Nissen (Cleveland Clinic), who said that because of this price difference, generic lisinopril would be his first choice. Yusuf countered that this may not be wise, as it had not been proven to give the same benefit as ramipril.

Nissen disagreed on this point: "Most of us think that there is nothing special about ramipril and that the ACE inhibitors are all interchangeable. Some generic ACE inhibitors are dirt cheap, and my own view is that you would use one of these first because of the cost advantage to patients, and you save the expensive ARB for people who cough." But Yusuf shot back: "I won't quarrel with Dr Nissen. His opinions are always strong. In this case he may well be right, but he may not be. In any case, ramipril is about to come off patent in the US and the price will come down, so why would you use a different one then?"

Nissen conceded that if ramipril were the same price as lisinopril it would be a fine choice. "This argument does not dim the importance of this trial, which tells us that if patients can't tolerate an ACE inhibitor, you can switch to an ARB and get similar results, and that is great, but cost is an issue, and we want to use the least expensive drug that will get the job done," he added.

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