Treating Special Populations with Hypertension: Is a Two-Drug or Fixed-Dose Combination Therapy Appropriate Initial Treatment in Hypertension?

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DR. GRADMAN: I think ACCOMPLISH is an important trial. Many of us have believed in the efficacy and safety of CCBs for a long time. However, I don’t consider it definitive in establishing the superiority of calcium blockers over diuretics. If you go back to ALLHAT,8 for example, the diuretic chlorthalidone was equal to amlodipine, the same drug that was used in ACCOMPLISH, at least in terms of primary end-point reduction.

The other thing that we know is that, if you look at some combination therapy studies, there are a significant percentage of patients who require diuretics to achieve BP lowering. Patients who have renal insufficiency of any degree usually require diuretics. In many other patients as well, addressing volume with diuretics also turns out to be critical in terms of controlling BP.

I personally hope that they change the JNC 7 default recommendation for diuretics. On the other hand, I wouldn’t necessarily put diuretics in third place behind CCBs as my preferred combination partner.

DR. NESBITT: I guess the statement here is not to suggest that CCBs are better than diuretics; however, I think that we are looking at which combination might be better. In ACCOMPLISH there was a mortality benefit that existed with the CCB that did not exist with the diuretic.

While a single agent may not necessarily be better as exemplified in ALLHAT,8 when you combine that same agent with another agent, the combination of the two may actually perform better from a mortality standpoint.

I agree with Alan that there are going to be a significant number of patients who clearly need a diuretic, and the recommendation is absolutely that those patients ought to get a diuretic first.

DR. GRADMAN: I do not believe there was a mortality difference in ACCOMPLISH,7 I think it was the overall end-point—the composite endpoint that was 20% different. But there was a significant difference in strokes and myocardial infarctions, et cetera, between the ACE inhibitor/CCB and ACE inhibitor/diuretic groups.

DR. WEIR: It was the composite endpoint.


DR. NESBITT: That’s correct, I’m sorry I misstated, it was the overall end-point.

DR. BASILE: So what I’m hearing is that, rather than specifically recommend a particular initial single agent for most patients with hypertension, there are different times when you will prefer to use either a RAS blocker or a CCB like amlodipine or a thiazide diuretic. At the end of the day these are the three classes of drugs as a single agent that you feel most comfortable with in people without a compelling indication. Would you agree with that, Shawna?



DR. WEIR: Yes.



DR. BASILE: Okay. That’s single-agent therapy, but we’re suggesting early on, depending on the degree of BP elevation, that there are many patients who will require two agents as initial therapy. Let me just turn a little bit to some of these special populations. Shawna has already mentioned the ACCOMPLISH6,7 trial, which compared a fixed dose combination of the ACE inhibitor benazepril with the dihydropyridine CCB amlodipine as initial therapy compared to benazepril with hydrochlorothiazide—no BP difference, but a benefit for the amlodipine combination for the composite outcome.

Let me ask you, Alan: In the ASH position paper,4 you actually recommended one of four therapies as preferred dual agent combination therapy. Can you talk about that?

DR. GRADMAN: We did not recommended them as preferred specifically for initial therapy. We recommended them as being the preferred two-drug combination in general. Also, I would agree if one were going to choose initial therapy, then we would pick from among four drug categories. Again, I think we’ve talked about the reasons that we all prefer RAS blockers in terms of their end-point reduction data in patients with renal disease, in patients with heart failure, and in patients with established vascular disease.

We have also discussed the differences between diuretics and CCBs, in terms of their end-point effects. Beyond that, a positive feature of these combinations relates to the fact that, in addition to having additive effects on BP reduction, they also may improve the tolerability profile of the combination partners.

For example, if you combine a diuretic with either an ACE inhibitor or an angiotensin receptor blocker (ARB), you attenuate the degree of hypokalemia and the frequency with which clinically significant hypokalemia occurs. Maintaining metabolic balance is a very positive feature of these drugs. By the same token, if you combine an ACE or an ARB with a dihydropyridine calcium blocker certainly, you tend to reduce the magnitude of edema, which is the dose limiting side effect of those CCBs.

I think there are many good reasons, in terms of BP reduction, tolerability, and evidence-based end-point reduction, that favors the use of these medications in combination therapy.

DR. BASILE: Matt, how do you feel about that?

DR. WEIR: I think there are pros and cons as to how you choose the mate for the RAS blocker. I’ve already given you some specific insights that I use primarily based on tolerability for the different genders.

As Alan mentioned, the beauty of the RAS blocker is that it attenuates some of the metabolic effects of the thiazide diuretics. They attenuate the pedal edema associated with CCBs. It is fair to say also that any of the two drug combinations are equally effective in terms of their abilities to lower BP with RAS blockers.

I think if you add to the improved tolerability with better BP reduction, in one pill, it is a win-win situation. Which approach you use needs to be individualized, based on tolerability.

DR. BASILE: Okay. I want to talk a little bit about the elderly patient with hypertension because I think we’re changing some of our thoughts on how to approach these patients. Evidence is available to suggest that they be treated regardless of their age, as in the Hypertension in the Very Elderly Trial (HYVET),9 where the oldest of the old (mean 84 years of age) benefited with a reduction in mortality when compared to placebo therapy.

Many clinicians are reluctant to start two drugs in elderly patients with hypertension. Alan, let me start with you and ask, are there situations where you might start with two drugs in an elderly patient with hypertension?

DR. GRADMAN: There are situations in which treatment should be initiated with a combination. Remember, however, that the majority of elderly patients with hypertension have isolated systolic hypertension. The target BP in this population is not quite as clear as perhaps JNC 72 would indicate. There are some people who state that there is no proven advantage to lowering systolic pressure below 160 mm Hg. HYVET,9 which enrolled patients over the age of 80, used 150 mm Hg systolic as the target BP.

This is just a lead-in to the fact that the standard approach that we use in younger patients with combined systolic-diastolic BP elevations may not necessarily apply to people who have isolated systolic hypertension with low or normal diastolic BPs. Some data suggest that too low a diastolic BP may be associated with an increased risk of cardiovascular events in patients who have coronary disease. For these reasons I think there is some reluctance to use aggressive initial combination therapy, particularly in very elderly patients who have isolated systolic hypertension.

Now, if you talk about patients who have combined systolic-diastolic hypertension then I believe those patients can be started on two drugs or combination therapy using the same criteria that we previously discussed for other patient subgroups.

DR. BASILE: Matt, should elderly patients be started on two drugs?

DR. WEIR: Well, let me first go on record and say I object to the word “elderly.” I think what is more appropriate is “older,” because that terminology in all of us is changing as we get older ourselves.

It is a question of where you are with the patient and where you hope to be. I am not against using two medicines in an older patient. Let’s say, for example, if they are higher than 25 or 30 mm Hg systolic BP from goal—in other words, with a systolic BP of more than 165 or 170 mm Hg. I am always more cautious in older patients, and I always carefully monitor them for positional changes in BP. As we age, the baroreceptors are not as responsive as they once were, and this increases the risk for orthostatic symptoms, which obviously can be substantial in an older patient who may be infirm, not have as good balance, or neuropathy, et cetera.

As for the medications I would use, I think we have good supportive evidence for the use of thiazide diuretics, CCBs, and drugs that block the RAS. We’ve already discussed some of the different trials that have supported the use of these medicines, so I would be using those three as treatment considerations.

I would be a little bit more careful about beta-blockers, unless the patient had known heart failure or coronary artery disease, in large part because we know the beta blockers also tend to predispose to some degree of orthostasis, and we also know they tend not to be as protective against incident stroke compared to other drugs like calcium blockers, thiazide diuretics, and RAS-blocking drugs.

DR. BASILE: Yes, the most recent recommendations by the consensus document on the older hypertension patient is that systolic BP values of less than 140 mm Hg are appropriate goals for most patients who are less than 80 years of age, but for those 80 and older, as in the HYVET, 140 to 144 mm Hg, if tolerated, can be acceptable.10

The report went on to highlight HCTZ, chlorthalidone, bendroflumethiazide, and indapamide, a thiazide-like diuretic used predominantly in Europe, as diuretics of choice. Based on this recommendation I would like to follow up on the use of chlorthalidone specifically in the elderly.

DR. WEIR: Older!

DR. BASILE: Excuse me, in the older patient. And I guess this recommendation is based on both the ALLHAT8 and the Systolic Hypertension in the Elderly (SHEP) trials,11 which reported definite outcome benefits in older patients with chlorthalidone. What are your thoughts on this?

Let’s start with you, Shawna, as you already mentioned the ACCOMPLISH trial, which used HCTZ and found it to be a less effective partner with a RAS blocker than the CCB, amlodipine. What are your thoughts on chlorthalidone compared to HCTZ?

DR. NESBITT: You know, it’s an interesting debate, and it’s one that we don’t have a clear answer to, except that we know that chlorthalidone compared to HCTZ, pharmacologically speaking, is more potent. We know it’s longer acting, and we know it will lower BP more effectively.

My concerns for older patients, however, are that I worry about giving high dose diuretics to any older patient because of the concern about low sodium, which I do see reasonably frequently in my little old ladies and I worry about low potassium.

Because chlorthalidone is more potent there is a likelihood of seeing those complications even more frequently in that population, although in SHEP and ALLHAT this did not seem to occur. Although I think you can use it, you certainly need to be more vigilant about using a more potent diuretic in this population, where the side effects, like a hip fracture, will be more dangerous. Hip fractures were, however, not more common in the SHEP diuretic-treated cohort compared to placebo.

DR. BASILE: Your points are well taken. We may be guilty of telling our older patients to restrict sodium and they end up taking in a lot of free water, which can result in hyponatremia as well as hypokalemia. So when using a thiazide diuretic, especially in the older patient, sodium as well as potassium has to be followed.

Alan, what are your thoughts on the chlorthalidone dilemma? Should it be the preferred thiazide in the older patient, where the evidence is greatest for its use?