Everyone seems to agree that there is little in the ONTARGET megatrial, presented 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."
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 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 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, said that, "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."
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.
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.
Yusuf was 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. 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
Presented at the AmericanCollege of Cardiology (ACC) 57th Annual Scientific Session, April 2008