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


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  • Summary:

    Dr. Jan Basile from the Medical University of South Carolina/Ralph H. Johnson VA Medical Center moderated the topic "Treating Special Populations with Hypertension: Is a Two-Drug or Fixed-Dose Combination Therapy Appropriate Initial Treatment in Hypertension?" with Drs. Alan Gradman from Temple University, Shawna Nesbitt from the University of Texas Southwestern Medical Center, and Dr. Matthew Weir from the University of Maryland Medical Center participating.

    The discussion focused primarily on:
    (1) when to use monotherapy compared to combination therapy in newly diagnosed hypertensive patients;
    (2) the role of baseline blood pressure, age and medical comorbidities as a determinant for monotherapy compared to combination therapy;
    (3) the barriers to combination therapy including education, side effects, insurance coverage;
    (4) the tolerability of combination therapy;
    (5) the use of certain antihypertensives in special populations;
    (6) the use of preferred combination therapies;
    (7) the use of monotherapy compared to combination therapy in elderly patients;
    (8) the use of combination therapy in patients with chronic kidney disease.
    (Med Roundtable Cardiovasc Ed. 2011;2(4):225-234) ©2011 FoxP2 Media, LLC

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DR. BASILE: Over 70 million Americans, and 1 billion people worldwide, have hypertension, classified as a blood pressure (BP) greater than or equal to 140/90 mm Hg. With as many as 50% of adults from Westernized societies projected to have hypertension by 2025, physicians will continue to be challenged with treating this major cardiovascular disease.1

Currently, physicians are utilizing one or more antihypertensive medications, with lifestyle modifications, to get BP controlled to levels below 140/90 mm Hg. Both in clinical practice and in clinical trials a majority of patients may require two or more antihypertensive drugs to be effectively controlled. Thus, the clinician is challenged to determine whether one or more drugs should be started in patients with hypertension, especially in patients who are part of special populations.

I am Jan Basile, from the Medical University of South Carolina and Ralph H. Johnson VA Medical Center in Charleston, South Carolina. With me today are Dr. Shawna Nesbitt, of the University of Texas Southwestern Medical Center in Dallas, Texas; Dr. Matthew Weir of the University of Maryland Medical Center in Baltimore, Maryland; and Dr. Alan Gradman of Temple University School of Medicine in Pittsburgh, Pennsylvania.

While I realize the three of you are often involved in seeing more complicated cases of hypertension and may not often have an opportunity to begin antihypertensive therapy in a newly diagnosed patient, if you were to see a patient with uncomplicated hypertension, how would you decide if a single agent or two or more agents should be utilized when first initiating hypertensive therapy? Let me first start with you, Shawna. How do you approach that?

DR. NESBITT: You know, I really do use the guidelines to help me to make decisions.2,3 These suggest that single drug therapy is appropriate in patients with stage 1 hypertension (BP 140/90 mm Hg–159/99 mm Hg without signification target organ involvement. If stage 2 hypertension is present, (BP 160/100 mm Hg or higher), or significant target organ involvement is identified, then two drug therapy is justified. I think that when we start to look at what is the risk of the patient, what is the BP level, and what am I actually treating, this helps me to make the decision. The consensus statement, as it relates to African-American patients who are at distinctly higher risk for target organ damage associated with elevated BP, takes the approach that we ought to increase aggressiveness in order to get BP under control.

In the International Society of Hypertension in Blacks (ISHIB) document, we have taken the treatment guideline a little bit further.3 We have set the treatment goal from 140/90 mm Hg down to 135/85 mm Hg. For people who have diabetes and renal disease, we’ve kept the goal at 130/80 mm Hg. If the levels are 15 mm Hg systolic or 10 mm Hg diastolic above these goals, we have to decide whether or not we are going to use two-drug therapy to start, which the guidelines recommend.

DR. BASILE: Okay, thank you. Alan, you were the lead author in the American Society of Hypertension (ASH) Position Paper on combination therapy in hypertension.4 Would you comment on the evidence base for both Shawna’s recommendation of treating BPs of 150/95 mm Hg, or 15/10 mm Hg above the minimum goal of 135/85 mm Hg set for Blacks with two drugs,3 in comparison with the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) criteria of 160/100 mm Hg or 20/10 mm Hg in all patients with hypertension?2 How do you approach single-drug therapy or combination therapy?

DR. GRADMAN: Generally the level of BP at baseline is the primary determinant of whether two-drug therapy or single-drug therapy is initiated. There is evidence that even in patients with stage one hypertension, initiating patients with two drug therapy results in more rapid goal attainment, as well as a higher percentage of patients who achieve target BPs.5

So, even though the current standard of practice is to use baseline BP as the primary determinant, an argument can be made to treat even more patients with initial two-drug or combination therapy than are recommended by various guidelines.

With regard to the evidence base, which was your question, the question is what evidence are you talking about? In terms of end-point reduction I’m not sure that there is much evidence basis to support initiation of two-drug therapy. However, in terms of BP reduction and target BP attainment there is a great deal of information that documents that initiating multiple drug therapy gives you more BP reduction and faster attainment of target BP.5

DR. BASILE: Matt, what are your thoughts?

DR. WEIR: Basically, my decisions about using two-drug or combination therapy in patients is based on their current BP and how far they are from the goal. First, I establish what I feel would be the most appropriate goal BP for them based on their age, medical comorbidities, et cetera, and then I estimate how far they are from that goal. My general rule of thumb is that it is probably going to take one medication for every 10 mm Hg of systolic BP reduction.

If they are more than 20 mm Hg from goal, i.e., 160 mm Hg systolic BP or higher, I would start them on a single pill combination, especially if their prescription program would allow this. Obviously, if their program precluded that, I would be left with using two separate medications.

My philosophy for using a combination of two medications is simply grounded on the fact that hypertension is just only one disease treatment process, and patients will often require other medications. I prefer to keep the pill burden to a minimum in order to help compliance.

I would preferably use a single pill combination including a renin-angiotensin system (RAS) blocking drug and either a thiazide diuretic or a calcium channel blocker (CCB), depending on which I thought would be better tolerated.

DR. BASILE: What do you think are some of the obstacles that do not allow clinicians to use two drugs as initial therapy? Alan, let’s start with you.

DR. GRADMAN: Well, one of the obstacles may be the education of physicians who, in some cases—and I think this applies more to older physicians—have been taught that it’s better from a safety standpoint to initiate one drug and be able to determine its specific effects and side effects. I think that is one barrier. The other barrier is one that Matt just mentioned: Insurance coverage may dictate initiation of a single drug rather than initiation of two drug therapy. These are the two main barriers, I believe to the use of combination therapy.

DR. BASILE: To get around that second one they could use two single pills that may be less expensive if they cannot get a single-dose combination as part of their prescription plan.

DR. GRADMAN: That’s another option, yes. I would add, however, that I believe we, as clinicians, must insist on our prerogative to select antihypertensive therapy on the basis of optimal efficacy, and not allow others to obtain our consent to utilize inferior treatments.

DR. BASILE: Shawna, in the population that you often see in Texas, what do you think some of the obstacles are?

DR. NESBITT: I would agree with what’s already been stated about the major obstacles—physicians’ understanding for the need for multiple drug therapy and the consideration for side effects. Some of the problems may be experience-based and a failure to understand that there is synergy in some combinations that may make management easier.

In fact, there may be contraindications to some of the combinations of antihypertensives. All antihypertensives are not the same. While they all lower BP, the mechanisms of two or more agents given together don’t necessarily fit. I think that education for physicians and other providers could go a long way in helping to make better choices in how we put medications together.

Then the other part of it really speaks to how well we can get the system to support improving our outcomes by helping to financially support patients to be more compliant with one pill if this is necessary for treatment.

DR. BASILE: Matt, anything else to add?

DR. WEIR: I would add that the major decision process I use for choosing medications is largely based on tolerability. I have a firm belief that the vast majority of people should be treated with a RAS-blocking drug, in large part because they are so well tolerated. They certainly work well with thiazide diuretics and CCBs in lowering BP.

Plus, I am impressed with the quarter of a century of data that we have, which demonstrates that RAS blockers provide an approximate 20% relative risk reduction benefit in people with evidence of heart disease and kidney disease. Although we lack data on the benefit of these drugs on disease progression early in the disease process, their tolerability plays a role in my choosing them as a first-line therapy.

I prefer using thiazide diuretics with RAS blockers for women, in large part because women prefer being more svelte and really don’t have as many problems with gouty arthropathy or libido problems as men might have with thiazides.

For men, I prefer using calcium blockers, in large part because they don’t affect libido, and if there are problems with ankle edema it’s less of an issue than it is in women because men wear more comfortable shoes and long pants.

Lastly, I think thiazides offer the advantage of an anti-calciuric effect so that women will tend to retain calcium, which has been demonstrated to facilitate bone mineralization with older age.

DR. BASILE: Let’s go through some of these special populations. Matt, you’ve already brought up women. Alan, let me turn to you; in women without a compelling indication for a particular class of antihypertensive drug, what do you use, or how do you approach initial single-agent therapy in women? Do you pretty much agree with Matt?

DR. GRADMAN: For the most part, yes. I tend to prefer RAS drugs as first step treatment and I don’t think there is any difference in terms of BP response between men and women. I avoid the use of these agents, however, in women of childbearing age who wish to become pregnant. In such patients, low dose diuretics and CCBs are suitable alternatives.

If I’m using monotherapy it tends to be one of those drugs, although certainly diuretics and CCBs have equal evidence basis in terms of long term end-point reduction and they’re all well tolerated agents. But, on balance, I prefer the RAS drugs because they have no dose-dependent side effects and because of their overall tolerability and efficacy.

DR. BASILE: JNC 8 is being put together; what do you think they will say about women? Matt suggested that perhaps for the bone mineral density effects that he uses a thiazide diuretic in women, certainly women at risk for osteoporosis. Do you think that based on gender there is any particular evidence for different classes of drugs as initial therapy?

DR. GRADMAN: Not really. The only thing that I would mention is that there is a high percentage of hypertensive women and men who are obese and of course those patients tend to have abnormalities of glucose metabolism. One can throw the other side of the metabolic effects of diuretics into the equation. They may improve calcium metabolism, but they may worsen glucose metabolism and I think that’s another feature that needs to be kept in mind.

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

DR. NESBITT: Well, in the ISHIB consensus statement we opted for the RAS/CCB combination as a preferred agent unless there is a compelling indication for a diuretic because of volume.3 In the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial,6 which compared the RAS/CCB combination to a RAS agent plus a diuretic, it distinctly showed that even with identical BP control there was a 20% mortality benefit to the RAS/CCB combination. I think that while we don’t have a clear explanation for the results, I think it says a lot about what we should be recommending in terms of not just getting BP under control for a patient.7

When the data were examined, specifically with respect to the African-American population, which was sizable for a clinical trial in this day and age, we saw the same effect. When you then look at the data with 24-hour ambulatory BP recordings—because some of the suggestions have been, “Could this be because the BP control was not achieved as well on a 24 hour basis?”—there was no difference between the angiotensin-converting enzyme (ACE) inhibitor/CCB and the ACE inhibitor/diuretic groups. I think that it’s warranted to suggest that we ought to go for mortality benefit because it’s not just about BP control. This is really about target organ damage.

On the other hand, I think there are a number of patients who have volume concerns, and as Matt points out, that the edema from the CCB is unbearable, and in those patients, the diuretic combination is better, but I’d start with a RAS/CCB as my basis for therapy.

DR. BASILE: So from what you said, Shawna, you’re pretty much putting the thiazides as a third step agent. But remember, ACCOMPLISH is only one study, and there have been several where thiazide diuretics proved to be effective in reducing morbidity and mortality.

DR. NESBITT: As a third line after RAS/CCB, if a patient is not controlled, but if a patient is not a candidate for the RAS/CCB then they would be on RAS/diuretic, so it would be second step in that case.

DR. BASILE: What would not make them a candidate for the RAS/CCB?

DR. NESBITT: If someone is volume overloaded, as in patients with kidney disease or who are edematous, I think that patient probably needs a diuretic as part of their therapy.

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

DR. WEIR: I am a firm believer in the ACCOMPLISH data (despite my conflict of interest: participating on the steering committee of the study and writing several of the papers). We do not have an explanation as to why there was an advantage to the CCB over the thiazide diuretic with the ACE inhibitor. My suspicion is that tolerability is a key factor, but there may also be metabolic differences between the two combinations in favor of the ACE/CCB. In my experience, women have a tougher time tolerating higher doses of amlodipine, compared to men. Realistically, if I can’t get to goal with lower doses of well tolerated medicines, I might even use three medications. There are even single pill combinations of thiazides, calcium blockers, and RAS inhibitors. I think this is a very reasonable approach if one needs lower doses of three drugs to avoid side effects.

Since hypertension is a lifelong, progressive, largely asymptomatic disease process, I think we have to be mindful of that as we pursue our therapeutic choices.

DR. BASILE: Alan, how do you feel? JNC 72 responded to the results of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), and placed a lot of stock in that particular outcomes trial. Shawna suggested that the ISHIB guidelines put a lot of stock in the ACCOMPLISH trial,6,7 again, only one trial. It will be interesting to see if JNC 8 changes the philosophy that JNC 7 had, recommending a thiazide-diuretic for “most” as initial therapy or as part of the initial combination therapy in the treatment of hypertension. What is your thinking on that?