From MedscapeCME Cardiology

Raising Awareness of Resistant Hypertension: Burden, Diagnosis, and Emerging Therapies

Michael A. Weber, MD

Published: 07/31/2009

Introduction

Resistant hypertension is defined as blood pressure that remains above target goals despite concurrent use of 3 antihypertensive medications of different classes, including a diuretic, all at optimal doses.[1-3] The exact prevalence of resistant hypertension is not well defined, and there is no current standard of care for its management. Overall, resistant hypertension remains understudied and additional knowledge is needed to better identify and treat patients with the condition. Clinical data on novel therapeutic options for the management of treatment-resistant hypertension were highlighted at this year's meeting of the European of Society of Hypertension (ESH), held June 12-16, 2009 in Milan, Italy. To provide a context for these results, Linda Brookes, MSc, on behalf of MedscapeCME Cardiology, spoke with Michael A. Weber, MD, Professor of Medicine, SUNY Downstate College of Medicine, Brooklyn, New York. In the following interview, Dr. Weber discusses the global burden of the condition, diagnosis, and current and emerging treatment options.
Burden of Resistant Hypertension

MedscapeCME: Hypertension management guidelines are consistent about the definition of resistant hypertension as failure to achieve blood pressure goal (<>

Michael A. Weber, MD: Resistant hypertension may occur in only about 10% to 15% of all cases of hypertension, but bearing in mind that there are over 70 million people with hypertension in the United States, this means that there are several million people with resistant hypertension.[4] So if this were a disease all by itself, it would be regarded as a relatively common condition.

MedscapeCME: Is this why resistant hypertension seems to have been the subject of so much attention recently?

Dr. Weber: In many places around the world, physicians are pressured to do a better job in treating common chronic conditions and to demonstrate that they are doing everything they possibly can to treat them. In hypertension, they must show either that they have the patient's blood pressure well controlled or at least that they have gone through all the steps to try and get it well controlled. Yet there will be a proportion of patients who will be difficult to treat, and I believe experts are focused on that problem now.
Challenges in Diagnosing and Managing Resistant Hypertension

MedscapeCME: What about the diagnosis of resistant hypertension? This seems to involve 3 questions: What makes hypertension truly "resistant?" How early can it be recognized? And is there a genotype or a typical phenotype associated with resistant hypertension?

Dr. Weber: For a start, there isn't a recognized genotype. And there really isn't an obvious predictive finding that tells you in advance that a particular patient is going to have treatment-resistant hypertension. Many people with treatment-resistant hypertension emerge with that classification only after several weeks or months of disappointments for the physician trying to manage the hypertension.

MedscapeCME: So how does a physician confirm that a patient has resistant hypertension?

Dr. Weber: First, it is important to ensure, as best you can, that the patients are actually taking their medications. This may involve a lot of detailed discussion with patients to satisfy doctors that the patients really are following their treatment. If they are, the next question is whether the treatment regimen is a logical one. For instance, does it include drugs that ought to be part of any hypertension treatment plan, such as a diuretic and a blocker of the renin-angiotensin system, and are the drugs being given at appropriate doses?

In terms of diuretics, I believe that our efforts in the past few years have sometimes been inadequate in that we have tended to often rely on low-dose hydrochlorothiazide (HCTZ). This works well in most hypertensive patients when it is paired with a drug such as an angiotensin-receptor blocker (ARB), an angiotensin-converting enzyme (ACE) inhibitor, or a calcium-channel blocker. However, in people with resistant hypertension, who often have diminished renal function, HCTZ at a dose of 12.5 or 25 mg may not be effective and chlorthalidone should be considered instead. Also, much of the clinical trial experience demonstrating prevention of major outcomes, such as stroke, has been with chlorthalidone rather than HCTZ.[5-9]

So if the right drugs are being prescribed in the right doses and the patient is taking their medications, is something happening to prevent these drugs from working effectively? One explanation may be that the patient has an underlying so-called "secondary cause'" for hypertension that does not respond to drugs -- for example, an adrenal cortex tumor, a pheochromocytoma, renal artery stenosis, or advanced kidney disease.[2] The other main cause of not responding adequately despite a good treatment regimen is that the patient is taking a medication that is raising blood pressure and interfering with the actions of the antihypertensive drugs.[2] Culprits include nonsteroidal anti-inflammatory drugs (NSAIDs), oral contraceptives, and some common cold remedies.

MedscapeCME: Wouldn't patients usually be warned about taking other medications at the start of their treatment?

Dr. Weber: Not necessarily. Some physicians overlook the fact that drugs such as NSAIDs might be a problem, and second, they may not always know that a patient is taking drugs like ibuprofen or naproxen because they are usually acquired over the counter and not reported to the doctor. So it is necessary to think proactively about drugs that could be interfering with blood pressure-lowering medications.

MedscapeCME: Presumably it is fairly straightforward to deal with those sorts of problems, but identifying or ruling out secondary causes is more complicated and time-consuming?

Dr. Weber: That is correct. The modern approach to looking for secondary causes typically involves some sort of imaging -- for example, an angiogram, computerized tomography scan, or magnetic resonance imaging. So it can be a fairly major commitment to consider a secondary cause of hypertension. It has to be on the list of possible causes to check, however. You have to decide that these conditions are unlikely before you can conclude that a patient truly has treatment-resistant hypertension.

MedscapeCME: At that point should a patient have been referred to a clinical hypertension specialist?

Dr. Weber: Yes. If you are really pursuing secondary hypertension, the patient is probably served best in the hands of a specialist who has experience in working up these kinds of conditions. In reality, these conditions are relatively uncommon and most physicians have probably not had much experience in the latest diagnostic methods for identifying underlying causes of hypertension. So the patient should be referred to a hypertension specialist, or if there isn't one readily available, then a nephrologist or other specialist who has experience with secondary hypertension.

MedscapeCME: What about primary aldosteronism -- is that a common secondary cause?

Dr. Weber: A fair number of people with resistant hypertension have high aldosterone levels, so the simplest, most effective approach might be to try an aldosterone-receptor blocker, such as spironolactone or eplerenone, for a few weeks and see whether it works. Experience suggests that this should produce a good result quite often,[10-14] especially in African American patients, although there have not been comprehensive studies to confirm this.

MedscapeCME: Even after trying an aldosterone-receptor blocker, there are a number of other classes of drugs that might be tried, such as beta-blockers and centrally acting alpha-agonists. How does a physician decide which one to add?

Dr. Weber: A beta-blocker, preferably one that does not carry the metabolic and symptomatic side effects of the more traditional beta-blockers, may be effective (ie, nebivolol or carvedilol). Then you can consider the centrally acting drugs, such as clonidine, which can be quite efficacious even though they may cause drowsiness in some patients.[1] It is possible to consider even older drugs like reserpine, although it has been shown that some patients experience negative emotional disturbances with the drug.[1] Hydralazine can be effective; it is a vasodilator, but it causes fluid retention, so you should ensure that the patient is getting a good diuretic. It can also accelerate the heart rate, so you usually need to give a beta-blocker as well. If you want to be more aggressive than hydralazine, you can give a stronger vasodilator, minoxidil, which can be effective in patients with complicated cases of refractory hypertension and concomitant kidney disease.[1] In short, some of these older drugs work, but they can be difficult to use.
Emerging Therapeutic Options

MedscapeCME: So it appears that even after exercising all of these options, there are some patients whose blood pressure remains uncontrolled. What is the future, as far as new drugs are concerned, with different mechanisms of action?

Dr. Weber: There are a number of investigational drugs and interventions in development for the management of resistant hypertension. The effects of endothelin antagonism, for example, were discussed at this year's ESH meeting.

We presented the results of the phase 3 clinical trial, DAR-311 (also known as DORADO), which evaluated the use of darusentan (Gilead Sciences; Foster City, California), an investigational oral, once-daily endothelin- receptor antagonist for the treatment of resistant hypertension.[15] As reported at the American Society of Hypertension (ASH) meeting in San Francisco[16] and at the ESH meeting,[17] the findings showed that compared with placebo, darusentan was associated with significant reductions in blood pressure in patients with resistant hypertension.

All patients enrolled in the DAR-311 trial were already taking at least 3 well-selected and well-dosed drugs -- in fact, 60% were taking 4 or more drugs -- so they were getting good treatment. With the addition of darusentan they achieved close to an additional 10-mm Hg decrease in systolic blood pressure compared with placebo. Previously in a phase 2 study, darusentan was seen to decrease mean systolic and diastolic blood pressure and was well tolerated compared with placebo in over 100 patients with resistant hypertension.[18]

MedscapeCME: Darusentan is a selective endothelin type A-receptor antagonist. Do these phase 3 data tell us more about the role of endogenous endothelin in hypertension?

Dr. Weber: We know theoretically that endothelin could have adverse vascular effects that might be associated with the major cardiovascular outcomes of hypertension. However, there are many endogenous factors that potentially could have adverse vascular effects, so we must be careful that we don't overinterpret our results. Although the findings with endothelin blockade are interesting, we should be cautious about using these data to speculate about underlying causes of resistant hypertension.

MedscapeCME: Can you comment on the cardiac side effects associated with darusentan that occurred in the phase 3 trial?

Dr. Weber: We reported a number of cardiac side effects, but it is important to understand that the treatment-resistant patients we studied were a high-risk group: 40% of them had diabetes, about one third had kidney disease, and about one third had a history of coronary disease. This group was at high cardiovascular risk and it shouldn't be a surprise that 2 patients taking darusentan had nonfatal myocardial infarctions and 1 patient on placebo had sudden cardiac death. There were also some patients who had the clinical findings of heart failure. One case was a patient known to have heart failure before the study began and should not have been enrolled in the trial. The other heart failure cases in patients receiving darusentan appeared to be related to fluid retention and manifested as pulmonary congestion. In fact, the patients with heart failure all had preserved left ventricular systolic function with normal ejection fractions. My personal belief is that these patients, who responded rapidly to appropriate diuretic therapy, most likely represented an unmasking of underlying left ventricular diastolic dysfunction in patients with long-standing severe hypertension. Bearing in mind that these events, with concomitant fluid retention, became apparent in the first few weeks of therapy, it seems unlikely that the drug affected heart function independently of its volume effects. This phenomenon has also been observed with other vasodilatory drugs used in hypertension.

We did learn a lesson, though, which was that in using vasodilatory drugs like darusentan, we cannot assume that the low doses of HCTZ typically prescribed in hypertension will be adequate. In patients who have diabetes or kidney disease or a history of coronary events, this type of diuretic therapy is not sufficient. I believe that we either need to use higher doses of HCTZ or, even better, work with a drug like chlorthalidone or consider a long-acting loop diuretic like torsemide (rather than furosemide, which is difficult to work with long-term in hypertensive patients).

MedscapeCME: Is there another phase 3 trial ongoing with darusentan?

Dr. Weber: A long-term extension of the recently completed trial and an additional phase 3 study (DAR-312 [also known as DORADO-AC]) comparing darusentan with active treatment rather than with placebo are being done.[19] I believe that the latter trial will be finished before the end of the year.

We have shown that darusentan is an effective strategy in treatment-resistant hypertension. Our next task is to devise clear information for physicians on its use -- in other words, how to choose the correct dose and how to optimize the other drugs that are taken with it. These are areas that we have an obligation to study.

MedscapeCME: What about the other investigational drugs in clinical development for resistant hypertension?

Dr. Weber: LCI699 (Novartis AG; Basel, Switzerland) is an aldosterone-synthase inhibitor in clinical trials for resistant hypertension.[20] This is an interesting drug, as it provides an alternative to aldosterone-receptor blockers but may be better tolerated than spironolactone. Another promising strategy for the future may be LCZ696 (Novartis Pharmaceuticals; East Hanover, New Jersey), a novel vasopeptidase inhibitor that acts as a dual ARB inhibitor plus neutral endopeptidase (NEP) inhibitor. Unlike omapatrilat, a dual ACE inhibitor plus NEP inhibitor that was effective but associated with severe angioedema, LCZ696 has been shown to be effective but apparently without major adverse effects.[21,22] I have also heard about a nicotinic-channel blocker, TC-5214 (Targacept, Inc; Winston-Salem, North Carolina), that is being looked at as a possible augmentation therapy for resistant hypertension.[23,24]

MedscapeCME: There are 2 interventional approaches that are being developed for patients with resistant hypertension: the Rheos® Hypertension Therapy system (CVRx, Inc; Minneapolis, Minnesota), an implantable device that has been shown in clinical trials to lower blood pressure through activation of carotid baroreceptors[25]; and renal sympathetic denervation, a catheter-based interventional procedure, which has been shown to be effective in a proof-of-concept study.[26]

Dr. Weber: These approaches have shown encouraging results, although they both involve significant interventions. They should be studied further because there are so many patients who are very hard to treat.

Perspective

MedscapeCME: Are you hopeful for the future treatment of resistant hypertension in general?

Dr. Weber: One of the good things about these recent developments is that they have drawn a lot of physicians' attention to resistant hypertension. These cases can draw nihilism after 3 or 4 drugs have been tried without success. This new focus on resistant hypertension will, I believe, energize many physicians to try a little longer and a little harder with their patients to find an answer to their hypertension problems.

This activity is supported by an independent educational grant from Gilead Sciences, Inc.