George Bakris, MD: Hello. I'm Dr. George Bakris, Professor of Medicine and Director of the Hypertensive Diseases Unit at the University of Chicago Pritzker School of Medicine. I'm joined today by Dr. Rajiv Agarwal, who is Professor of Medicine, the Division of Nephrology at Indiana University. Today we really want to talk about the impact of combination therapy and its new role as potentially starting with combination therapy. This is coming from the new guidelines, the National Institute for Health and Clinical Excellence (NICE) guidelines, which are from the United Kingdom.[1] These guidelines are not only read by the United Kingdom but influence European and other guidelines around the world. They're very evidence based, and, in fact, the JNC 8 is going to mirror the process that the NICE guidelines are using, which will be new to many of you.
One of the things being talked about in the brand new guidelines that were just released are initial combination therapy, specifically with a blocker of the renin-angiotensin system and a calcium antagonist, relegating diuretics to third line, which for Americans is relatively new in terms of concept but actually not that new for the rest of the world. So, it really is a new way of going about things and I'm just wondering, Rajiv, what are your thoughts about this? There is an evidence base for it but is it strong enough to be making this as a recommendation?
Rajiv Agarwal, MD: So, George, the NICE guidelines have taken 1 study as the evidence to make this recommendation, and that's the ACCOMPLISH study which looked at a high-risk population of hypertensives and randomized them to a benazepril plus hydrochlorothiazide (HCTZ) combination or to a benazepril, [an angiotensin-converting enzyme inhibitor (ACEI)] plus amlodipine, a calcium channel blocker (CCB), combination.[2] What they found in 11,508 patients was that there were more cardiovascular events, primarily driven by MIs, in the hydrochlorothiazide group. There was a protection in the CCB group. That was strong enough for the NICE guidelines to make the recommendation. So, the data was primarily driven by MIs, and the absolute risk reduction in the composite endpoint in ACCOMPLISH was 2.2%, which is quite remarkable because the number needed to treat is only 50. The NICE guidelines say that you will protect 6 out of a thousand [people from] MIs if you delegated patients to the benazepril/CCB combination.
I think it's all about cost. If this was not a concern, there would be no question. We wouldn't be having this conversation. So, if CCB/ACEI combination was as cheap as the ACEI/thiazide combination, all bets are off. We would be using that combination. So, yesterday I went to the Wal-Mart 10-dollar pharmacy. I looked for the combinations that were available. The CCB/HCTZ was available and CCB/ACEI was not available. In other words, the access to care in people who can afford this therapy would be limited in people who can't afford drugs. If affordability was not a concern, I would certainly use the CCB/ACEI combination over the other. Now, recognize that other studies would show that the ACEI/diuretic combination can improve events in people who are very old, for example the HYVET study,[3] -- and other studies show protection, but there are very few head-to-head trials. Certainly, that would be an appropriate combination to use.
Dr. Bakris: Well, Rajiv, this is very interesting. Let me make a couple of points. First of all, one of the interesting things that happened when ACCOMPLISH was finished was that amlodipine/benazepril (Lotrel®), which at that time was branded, went generic literally the week the trial was announced. So, the one piece of good news is there is a generic ACE/CCB combination that is available out there. It's only available in one dose, 5/20, but you can certainly mix and match that combination to the patient's needs. So, cost is not as big a deal as it would normally be. Certainly with the angiotensin receptor blocker (ARB) combinations -- you are absolutely right -- cost is an issue, but not with the amlodipine/benazepril combination which is generic. So, that's actually a piece of good news.
The other interesting thing is -- and people don't appreciate this -- in the IDNT trial, the nephropathy trial in diabetes,[4] there was an amlodipine alone arm. One of the interesting things is while it was very bad for the kidney it was very good for the heart. In fact, there was a 40% reduction of myocardial infarction and other related cardiovascular events, which admittedly was a by-the-way secondary endpoint, but a number of people when I presented this at the nephrology meetings came up to me and said, "Why are you ignoring this? This is actually very good news for amlodipine. Well, unfortunately in that trial it wasn't paired with an ACE or an ARB, but we know from all the kidney trials that if you have a calcium antagonist and it's married to either an ACE or an ARB, the benefits are seen in both the kidney and the heart, and I think ACCOMPLISH reflects that.
So, I think if you are talking about people who are on Medicaid or who clearly can't afford any kind of medication, then yes you are limited, but if you are talking about people that have any type of insurance or that have even Medicare, I think an ACE/CCB combination, at least Lotrel in its generic form, is very affordable. I use it all the time and have never gotten any pushback from anybody. So, I think it is something to think about because of the benefits.
The one thing I would say is that both benazepril and amlodipine have unique effects on nitric oxide release and they both have been shown to increase nitric oxide release. In fact, that was one of the hypotheses of ACCOMPLISH. For full disclosure since we're talking about this, I am on the executive committee of that trial and I was one of the people that designed the trial, but I thought it was important to note. Frankly, I thought NICE went a little too far -- I agree with you -- using that 1 trial to make a sweeping recommendation, but they have a number of other studies that are blood pressure driven that show the same thing. There are actually 4 of those studies that I know of. They are blood pressure [driven], not outcomes. For a guideline that advertises as being outcome based, I thought it was a bit much. I don't think that JNC 8 is going to pick up anywhere near this level of importance, but I do know they're going to have to give lip service to it. So, I don't know what your thoughts are about that.
Dr. Agarwal: Well, what is very interesting in the ACCOMPLISH trial is that there was a large ambulatory blood pressure monitoring sub-study of more than 500 patients. I know that you and Dr. Jamerson wrote a letter to the editor to The New England Journal of Medicine[5] pointing out that there was absolutely no difference between groups in the year two of the study in the systolic blood pressure/diastolic blood pressure whether you take the 24-hour daytime or nighttime. That's very important. The benefits of the CCB were realized despite blood pressure that somewhat favored hydrochlorothiazide.
What is even more interesting is that the hydrochlorothiazide and chlorthalidone has been compared head-to-head in an ambulatory blood pressure study. When we're looking at the 2 drugs, chlorthalidone certainly wins. The chlorthalidone wins because it has almost twice the blood pressure reduction at night compared to hydrochlorothiazide. Even though the 24-hour blood pressure control is superior in chlorthalidone, it's really the nocturnal blood pressure. In that study, they did not find any difference between the 2 drugs in terms of clinic blood pressure. So, these drugs have important differences, and when we are talking thiazides, not all thiazides are created alike. Chlorthalidone has been tested in the ALLHAT trial,[6] and indapamide, which is a diuretic probably more used in Europe than in the United States, has minimal metabolic side effects and was part of the PROGRESS trial,[7] which reduced strokes quite dramatically. Those 2 would be more favorable diuretics.
Dr. Bakris: Right.
Dr. Agarwal: Coming back to the affordability issue, if you look at the cost effectiveness, the NICE guidelines say amlodipine needs to be priced at 94 pounds to be cost effective. That's 150 dollars per year of amlodipine. When I looked at it online I couldn't find many places where I could buy a year's supply of amlodipine for 150 bucks. So, it depends on which healthcare system you are in, whether you're on Medicare, Medicaid, or self-pay, but the important thing is to get the blood pressure down.
Dr. Bakris: Rajiv, thank you very much. I think this was a very illuminating discussion. You clarified very nicely the role of chlorthalidone vs hydrochlorothiazide and certainly put into context the cost issue about diuretics versus nondiuretics. So, it's very much appreciated. I think the audience is better be prepared because JNC 8 is going to be talking about -- as you noted -- chlorthalidone and indapamide as the diuretics with the evidence base and not hydrochlorothiazide. In fact, a new ARB is going to have chlorthalidone paired with it. One of the reasons that chlorthalidone hasn't gotten a lot of airplay is because there are not many mixed combinations using chlorthalidone. That is going to start changing. So, I think in the next era here we'd better be familiar with these diuretics. Thank you very much for your comments, Rajiv. Thank you to all for joining us and we hope you have a good day.
Dr. Agarwal: Thank you.
Medscape Nephrology © 2011
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Cite this: George Bakris, Rajiv Agarwal. The Right Antihypertensives at the Best Price - Medscape - Nov 03, 2011.
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