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: Good question. One thing I would add is that I would re-emphasize indapamide in the list of diuretics where there is evidence of benefit in the elderly. This was the drug that was used in HYVET and, in addition to producing major stroke reduction, there also was a 21% mortality reduction compared to placebo.9,12 It is one of the only hypertension trials to my knowledge that has shown a reduction in overall mortality. I think I would include indapamide in the list of diuretics to be considered.

To get back to your question about chlorthalidone, I would agree with much of what Shawna said. We know that chlorthalidone is a longer acting drug; it’s more potent on a milligram per milligram basis, and I would agree that the use of a low dose is preferable.

I don’t think we have the answer to the question of chlorthalidone compared to HCTZ from an end-point perspective, but there is no question that the body of evidence favors chlorthalidone at this particular point in time, just because it was used in several US trials.

DR. BASILE: Matt, any thoughts on this?

DR. WEIR: I am in complete agreement with the points that Alan made.

DR. BASILE: In the older hypertensive do we have good evidence to start with two drugs or a combination, i.e., has any clinical trial evaluated the 20/10 mm Hg rule that JNC 7 recommended (i.e., two drugs for BPs greater than 160/100 mm Hg). Matt, do you know how many older people there were in ACCOMPLISH?

DR. WEIR: I can tell you the average age in the study was 63.7

DR. WEIR: So that gives you a good clue that many, if not most, of the patients were in their 60s, and obviously a fair number were also into their 70s.

DR. BASILE: Do you think there is an age range or an age where perhaps we shouldn’t use two drugs as initial therapy, even when the pressures are high and it may be difficult for BP to get to goal, Matt?

DR. WEIR: I think it is appropriate for older people. It just gives them a leg-up on the ever-advancing pill counts. It will improve compliance; it will probably reduce the likelihood of missing doses. I am not making an argument from day one to start older patients on a single pill combination, but if they can be carefully titrated to their ideal BP goal, one can then consolidate their medications into fewer pills.

DR. BASILE: Okay, Alan, how do you feel, one drug in the oldest of the old to start with?

DR. GRADMAN: My usual practice is to start with one drug. As per your discussion of the recent consensus document, I don’t think we have very clear evidence for selection of target BP in older patients, particularly in the very elderly, and I don’t think we have clear evidence as to the basis for whether or not to routinely begin combination therapy.

At this point it’s up to the discretion of the physician. I tend to err on the side of caution. It should be noted, however, that if you look at the studies and the literature there has never been an excess of major adverse events in elderly people started on two drugs or combination therapy, so it’s probably safe.

DR. BASILE: Shawna, how do you feel?

DR. NESBITT: I tend to agree with what’s been said. I guess my only concern about the elderly as it relates to clinical trials is that we don’t have combination trials in older patients, meaning over 80. In patients over 80, I have not really started them on combination therapy as the very first step of treatment, although once they are on treatment and are not controlled, I think switching to a combination is appropriate. I think the 140 to 145 mm Hg systolic BP range is probably a reasonable one.

DR. BASILE: That seems reasonable and a practical approach to treating these patients with hypertension. Let me turn last to patients with chronic kidney disease (CKD). Matt, what is your approach to both single- and multi-agent therapy in patients with CKD, and at what estimated glomerular filtration rate (GFR) do you feel that thiazide diuretics may no longer be effective?

DR. WEIR: This is not well studied. My personal opinion is that decisions about diuretic support should be based in part on the physical exam, and the degree of the BP elevation.

As the GFR decreases to 50 ml/min/1.732 or below, my thoughts on which thiazide diuretic to use changes more from HCTZ to chlorthalidone, and then eventually towards loop diuretics. The diuretic action of thiazides diminishes as the GFR drops, since they have to be filtered, and then reabsorbed in order to achieve their activity within the kidney.

Obviously as GFR declines you need a larger dose of a drug to provide the same diuretic effect as in someone with a higher GFR. That being said, we also know that thiazides have peripheral vasodilatory activities. The interesting question is whether thiazide diuretics have antihypertensive properties, which are independent of their effects on volume reduction, in patients with lower GFR. That’s an area where we do not have good clinical data.

It’s an important question, because if thiazides possess antihypertensive activity in lower GFR patients, it may require them to be euvolemic to see the effect, as increased blood volume offsets the antihypertensive properties of all drugs.

DR. BASILE: Do you feel that there is an ideal two-drug combination in patients with CKD?

DR. WEIR: I think a RAS blocking drug is part of the equation for everybody, whether they have kidney disease or not. I think the decision about whether they need a diuretic or a calcium blocker is the next step. This should be based on the degree of renal insufficiency and the assessment of volume.

More often than not, as the GFR decreases, the likelihood of requiring a diuretic goes up substantially. People with kidney disease tend to be salt retainers (although this is not true for all forms of kidney disease).

Decisions about diuretic use need to be individualized. Often people with kidney disease will need three medicines, given the fact that they should be treated to a lower systolic BP goal of about 130 mm Hg.

DR. BASILE: Alan, your thoughts on that?

DR. GRADMAN: Certainly I agree with most of what Matt said. Of course you don’t get much additive BP-lowering effect when you combine most beta-blockers with RAS inhibiting drugs. Basically I would agree with Matt. I do think that you need loop diuretics in patients who have significant renal insufficiency—that there may be some advantage to using longer acting loop diuretics like torsemide, for example, as compared to furosemide, and that treating volume is a necessity in patients who have renal insufficiency. Even if they’re not constantly volume overloaded, the time course of sodium excretion is changed even in patients with mild renal insufficiency and it’s important to avoid transient increases in blood volume, which may adversely affect BP control.

DR. BASILE: Shawna, anything else you’d like to add?

DR. NESBITT: Well, I think, going back to the ISHIB consensus statement, these are the patients that you would want to start with a RAS blockade and a diuretic, rather than the RAS plus the CCB agent, as an initial consideration for combination therapy.

Frequently three agents are needed, and in these cases probably the CCB as the third agent would be the alternative in order to get them to the goal. Again, I think Alan mentioned that with a GFR of less than 30 or so they probably will need a loop diuretic in order to get volume control.

DR. BASILE: Well, we’ve covered a lot of ground. Let me try to summarize what we have said. I think there has been some agreement that we’re not quite sure that there is a best initial antihypertensive medication in patients without a compelling indication, although there may be some favorites in some special populations.

I heard you all suggest using either a RAS blocker, a CCB—preferably of the dihydropyridines type, mentioning amlodipine—or a thiazide diuretic (preferably chlorthalidone) as possible initial therapy in patients with hypertension. There was less enthusiasm, especially in the older patient, for the use of a beta-blocker unless there is a compelling indication for their use, and there was no mention of a direct renin inhibitor (DRI) as initial therapy in hypertension.

We didn’t have time to discuss other medications, such as mineralocorticoid receptor antagonists, like spironolactone or eplerenone, that are more often used in those with resistant hypertension. However, I will ask you all, if you do use a drug like a spironolactone in therapy before these three main classes: RAS blockade, thiazide diuretic, and CCB.

I heard a lot of agreement on the use of initial two drug combinations when there was a larger burden to get to goal BP, either a 15/10 mm Hg as in the ISHIB guideline elevation above goal (greater than 150/95 mm Hg), or a 20/10 mm Hg elevation as in the JNC 7 goal (greater than 160/100 mm Hg). Alan pointed out that the recent Simplified Therapeutic Intervention to Control Hypertension (STITCH) trial suggested that even in stage one hypertension where there is less than a 20/10 elevation in BP that either an ACE/diuretic or an ARB/diuretic as initial therapy allowed patients to get to goal more effectively over six months of treatment without any more side effects.5

Finally, which is the best two-drug combination is debatable. Shawna suggested that a CCB and RAS blocker, based on one study, ACCOMPLISH, was better than HCTZand a RAS blocker despite equal BP reduction. Others pointed out the differences in chlorthalidone and HCTZ, especially in the older patient.

Alan mentioned indapamide, another evidence-based thiazide-type diuretic not often thought about in this country that has been used in clinical trials that often originated overseas.

There is always controversy in treating patients with hypertension. Does anyone have any final comments before we wrap it up? Shawna?

DR. NESBITT: Just to clarify points made earlier, I would say that I’m not sure that I intended to suggest that DRIs would be considered that much differently than RAS blockade in my mind. I probably would use them in some patients as an initial agent for the treatment of hypertension.

DR. BASILE: Alan and Matt, do you agree with that?

DR. WEIR: Yes, absolutely, compared to an ACE or an ARB. I consider them therapeutically equivalent, and equally well tolerated for lowering blood pressure.

DR. GRADMAN: Yes, I would agree with that—the only caveat would be that in patients who have specific indications, for example, patients who have type II diabetes with proteinuria in which there are specific Food and Drug Administration indications for ARBs, for example, I would prefer the ARB, but generally speaking I agree with including a DRI in the RAS blocker category.

DR. BASILE: Let me add that I don’t know of any clinical trial where the DRIs have been used as initial therapy. We have no outcomes; although they certainly do lower BP and are Food and Drug Administration-approved for hypertension. I would prefer an ACE or an ARB with the outcomes that we have before I’d start with a DRI.

I appreciate what Alan said about adding a DRI to an ARB in nephropathy, et cetera. I think JNC 8 will have a similar approach to this class of antihypertensive agent.

DR. GRADMAN: The only thing is that these are general recommendations, and comorbidities often alter our drug selection. You mentioned diabetic nephropathy in patients with proteinuria. There a combination of an ARB and a DRI might be an appropriate initial treatment. In cardiology we see lots of patients who have coronary disease and heart failure in whom beta-blockers are a very important component of therapy and I don’t think we should forget about them. These agents still have a large place in the treatment of hypertension. I think it’s very important to pay careful attention to comorbidities.

DR. WEIR: I still think, with a lifelong, progressive, largely asymptomatic disease process, that tolerability of medication is a major concern. Simplicity is important, and our best opportunities to facilitate compliance will require us to pay attention to strategies to consolidate pill counts with well tolerated medications. This will help us get more patients to what we feel is an appropriate goal BP.

DR. BASILE: I want to thank each of you for your expertise and your time.