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8/7/13 Does True Treatment-Resistant Hypertension Exist? (printer-friendly)

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This article is a CME certified activity. To earn credit for this activity visit:

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CME Information

CME Released: 07/31/2013; Valid for credit through 07/31/2014

Target Audience

This activity is intended for general and interventional cardiologists, nephrologists, endocrinologists, and primary care

physicians involved in the management of patients with refractory hypertension.

Goal

The goal of this activity is to educate clinicians on the definitions and prevalence of true resistant hypertension and

potential treatment strategies.

Learning Objectives

Upon completion of this activity, participants will be able to:

1. Discuss the role of nonadherence in treatment-resistant hypertension

2. Review the clinical consequences of uncontrolled hypertension

3. Develop strategies to treat uncontrolled/treatment-resistant hypertension

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All other healthcare professionals completing continuing education credit for this activity will be issued a certificate of

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Authors

Henry Krum, MBBS, PhD

Chair, Medical Therapeutics; Professor, Department of Medicine; Director, Monash Centre of Cardiovascular

Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University,

Melbourne, Australia

Disclosure: Henry Krum, MBBS, PhD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Medtronic, Inc.

Served as a speaker or a member of a speakers bureau for: Medtronic, Inc.

Received grants for clinical research from: Medtronic, Inc.

Dr Krum does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by theFDA for use in the United States.

Dr Krum does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by

the FDA for use in the United States.

David A. Calhoun, MD

Professor of Medicine; Medical Director, Vascular Biology and Hypertension Program, University of Alabama at

Birmingham

Disclosure: David A. Calhoun, MD, has disclosed the following relevant financial relationships:

Received grants for clinical research from: Medtronic, Inc.

Dr Calhoun does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved

by the FDA for use in the United States.

Dr Calhoun does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved

by the FDA for use in the United States.

Joseph L. Izzo, MD


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Professor of Medicine; Vice Chair of Medical Research, Department of Medicine, State University of New York at

Buffalo

Disclosure: Joseph L. Izzo, MD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Novartis Pharmaceuticals Corporation

Received grants for clinical research from: Abbott Laboratories; Amylin Pharmaceuticals, Inc.; Forest Laboratories,

Inc.; Novartis Pharmaceuticals Corporation

Dr Izzo does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by


Dr Izzo does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by


Editor

Tricia Ward

Scientific Director, Medscape, LLC

Disclosure: Tricia Ward has disclosed no relevant financial relationships.

Steering Committee

George L. Bakris, MD

Professor of Medicine; Director, Hypertensive Diseases Unit, University of Chicago Pritzker School of Medicine,

Chicago, Illinois

Disclosure: George L. Bakris, MD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Abbott Laboratories; CVRx, Inc.; Medtronic, Inc.; Takeda Pharmaceuticals

North America, Inc.

Served as a speaker or a member of a speakers bureau for: Takeda Pharmaceuticals North America, Inc.

Received grants for clinical research from: Forest Laboratories, Inc.; Novartis Pharmaceuticals Corporation

Deepak L. Bhatt, MD, MPH

Chief of Cardiology, VA Boston Healthcare System; Director, Integrated Interventional Cardiovascular Program,

Brigham and Women's Hospital, Boston, Massachusetts

Disclosure: Deepak L. Bhatt, MD, MPH, has disclosed the following relevant financial relationships:

Received grants for clinical research from: Amarin Corporation plc; AstraZeneca Pharmaceuticals LP; Bristol-Myers

Squibb Company; Eisai Inc.; Ethicon, Inc.; Medtronic, Inc.; sanofi-aventis; The Medicines Company

Michael Bhm, MD, PhD

President, German Society for Cardiology; Chairman, Department of Internal Medicine, University of Saarland,


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Homburg/Saar, Germany

Disclosure: Michael Bhm, MD, PhD, has disclosed the following relevant financial relationships:

Received grants for clinical research from: Adrian Pharmaceuticals; Boehringer Ingelheim Pharmaceuticals, Inc.;

Medtronic, Inc.

Served as an advisor or consultant for: AstraZeneca Pharmaceuticals LP; Boehringer Ingelheim Pharmaceuticals,

Inc.; Pfizer Inc

Served as a speaker or a member of a speakers bureau for: AstraZeneca Pharmaceuticals LP; Boehringer Ingelheim

Pharmaceuticals, Inc.; Daiichi Sankyo, Inc.; Medtronic, Inc.; Pfizer Inc

Henry Krum, MBBS, PhD

As stated above.

Roland Schmieder, MD

Professor of Internal Medicine, Nephrology and Hypertension; Head, Clinical Research Competence Unit of

Hypertension and Vascular Medicine; Vice Chair, Department of Nephrology and Hypertension, University Hospital

Erlangen-Nrnberg, Erlangen, Germany

Disclosure: Roland E. Schmieder, MD, has disclosed the following relevant financial relationships:Served as an advisor or consultant for: Boehringer Ingelheim Pharmaceuticals, Inc.; Novartis Pharmaceuticals

Corporation; SERVIER

Served as a speaker or a member of a speakers bureau for: AstraZeneca Pharmaceuticals LP; Boehringer Ingelheim

Pharmaceuticals, Inc.; Pfizer Inc; sanofi-aventis; SERVIER Received grants for clinical research from: Ardian, Inc.

Michael A. Weber, MD

Professor of Medicine, State University of New York, Downstate College of Medicine, Brooklyn, New York

Disclosure: Michael A. Weber, MD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Boehringer Ingelheim Pharmaceuticals, Inc.; Bristol-Myers Squibb Company;Daiichi Sankyo, Inc.; Forest Laboratories, Inc.; Novartis Pharmaceuticals Corporation; Takeda Pharmaceuticals North

America, Inc.

Served as a speaker or a member of a speakers bureau for: Daiichi Sankyo, Inc.; Forest Laboratories, Inc.; Novartis

Pharmaceuticals Corporation; Takeda Pharmaceuticals North America, Inc.

CME Reviewer

Nafeez Zawahir, MD

CME Clinical Director, Medscape, LLC

Disclosure: Nafeez Zawahir, MD, has disclosed no relevant financial relationships.

From Medscape Education Cardiology

Henry Krum, MBBS, PhD; David A. Calhoun, MD; Joseph L. Izzo, MD

Does True Treatment-Resistant Hypertension Exist? CME

CME Released: 07/31/2013; Valid for credit through 07/31/2014
http://www.medscape.org/cardiology


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Slide 1.

Henry Krum, MD: Hello, I am Henry Krum, chair of medical therapeutics and professor of medicine at Monash

University in Melbourne, Australia. I would like to welcome you to this program titled "Does True Treatment-Resistant

Hypertension Exist?" I will be moderating a minidebate between my friends and colleagues: David Calhoun, who is

professor of medicine and medical director of the Vascular Biology and Hypertension Program at the University of

Alabama at Birmingham, and Joseph Izzo, professor of medicine, State University of New York at Buffalo and chief of

medicine, Erie County Medical Center, Buffalo, New York.

Before we begin, please take a moment to test your knowledge on this topic by answering a few questions that will

be presented in a moment.

Educational Impact Challenge

Assess your clinical knowledge by completing this brief survey. Answering these questions again after the activity wi

allow you to see what you learned and to compare your answers with those of your peers. (Note: The following

questions were developed by an independent consulting group with expertise in assessing the effectiveness of

medical education.)

Case #1: A colleague refers a 44-year-old, morbidly obese white man for further evaluation of what he

referred to as "resistant hypertension." The patient had been intolerant of two medications initiated by

the referring physician and came to your office only currently taking HCTZ 25 mg, which he admitted

to the RN that he forgot to take that morning. He also reports having eaten a bacon, egg, and cheese

sandwich with salt, pepper, and ketchup prior to arrival in your office, where he had a measured blood

pressure of 178/106 mm Hg.


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Does this patient's measured office blood pressure meet criteria for resistant hypertension?

Yes, his systolic blood pressure is >160 mm Hg and diastolic blood pressure is >90 mm Hg

Yes, he clearly has markedly elevated blood pressure and has been a very challenging patient

from a treatment strategy standpoint

No, by definition he must have a blood pressure >140/90 mm Hg on at least 3 anti-hypertensive

medications at optimal doses

No, morbidly obese patients cannot be classified as having resistant hypertension

Which of the following is the most common cause of pseudoresistant hypertension?

Obstructive sleep apnea

Alcohol abuse

Job and psychosocial stresses

Medication noncompliance

The patient remarks that when he was younger a doctor told him he probably has White Coat

Hypertension (WCH) and wants to know if this is a "real thing?" How do you answer him?No, WCH is not a true entity but rather a mask for noncompliance and poor lifestyle habits

Yes, WCH is a real entity and may account for up to 40% of all cases of resistant HTN

Yes, it does exist, but WCH typically elevates the systolic blood pressure by 3-5 mm Hg

No, WCH is not a true disease and could never account for blood pressure readings above

150/90 mm Hg

How would you best exclude WCH in your work up of the hypertensive patient?

Avoid wearing white coats in the office

Have the patient take his medication immediately prior to his office visitHave the patient perform home blood pressure monitoring with ambulatory blood pressure

recordings

Request visiting nurse services to perform home visits for BP checks at his home

Case #1 (cont.): After getting married, the above patient has shown up in the office having lost nearly

twenty pounds by eating a healthy diet and exercising regularly. He is ready now to try and manage

his blood pressure, which has remained persistently above 160/90 mm Hg despite treatment with

ramipril 10 mg and amlodipine 10 mg daily. He states that he is faithful with his medications and his

home blood pressure recordings are similar to the values measured in your office.

In optimizing his medical regimen, which of the following regimens would you choose for him now?

Clonidine

Losartan

Minoxidil

Chlorthalidone

Case cont'd: After initiating treatment with a third medication, the patient begins to complain about his

medication regimen and asks if he really is at risk for harm, being so young.


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Which of the following statements would you use in your response to this patient?

Every 10 mm Hg drop in systolic BP decreases stroke mortality by 20%

Every 10 mm Hg drop in systolic BP lowers the risk of stroke death by 40%

Every 10 mm Hg drop in systolic BP decreases the risk of ischemic heart disease/vascular

death by 40%

Case #1 (cont.): The addition of the chosen medication has not yielded the benefit you had hoped

and despite perfect medication compliance along with diet and exercise, the patient's blood pressurestill appears to be routinely over 150/90 mm Hg.

Which one of the following medication classes would you select as your most reasonable next step?

Angiotensin receptor blockers

Alpha-antagonists

Direct renin inhibitors

Aldosterone blockers

Case #1 (cont.): Despite adhering to his regimen of four anti-hypertensive medications, this patientcontinues to have blood pressures over 150/90 mm Hg on his home blood pressure cuff monitoring.

He has been successfully ruled out for common secondary causes of resistant hypertension and is

now wondering if there are any other modalities available.

What possible strategies exist beyond medications that have shown benefit?

Massage therapy/acupuncture

There are no additional therapies that can be offered at this time

Catheter-based sympathetic renal denervation

Surgical sympathetic denervation

Save and Proceed


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Slide 2.

Now, by way of background, let us first address what we mean by the term "resistant hypertension." If we look at

definitions -- and this is generally agreed upon by guideline bodies around the world -- it is defined as blood pressure

not at target despite a patient taking 3 or more antihypertensive agents of different drug classes. [1] Ideally, 1 of the 3

agents should be a diuretic, and also ideally, all agents should be prescribed at optimal doses. Blood pressure that is

controlled but requires 4 or more antihypertensive agents of different drug classes is also considered resistant

hypertension.


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Slide 3.

In considering these issues going forward, this is the first question I have: Is resistant or refractory or difficult-to-treat

hypertension the same? Are there differences? Probably even more importantly, does it matter? Are resistant

hypertension patients different from mild hypertension patients, or are they just part of the same continuum? Why

does the same antihypertensive therapy produce markedly different blood pressure responses in different patients?

And of course, how do we best treat refractory hypertension when it is identified? Hopefully we will tackle these

issues going forward within the debate and the discussion that follows.

David, you are going to go first and take the pro position. Your position is yes, there is such a thing as resistant

hypertension.

David A. Calhoun, MD: Thank you, Henry, and welcome, Joe. In my mind there is no doubt that resistant

hypertension exists. What is the prevalence of resistant hypertension? There have been a number of survey studies

recently that give us some idea of that number.


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Slide 4.

I think probably the best data available, at least for the United States, are from a study by Bill Elliott using the

National Health and Nutrition Examination Surveys (NHANES) data set and using that American Heart Association

(AHA) definition of uncontrolled on 3 or more medications or controlled on 4 or more. [2] You can see here that the

prevalence has been estimated by different time intervals. Around 1990 or so, the prevalence of resistant hypertension

was estimated in this analysis at about 8% or 9%. Ten years later it was as high as 15%, and then most recently, in

2008, you can see that the prevalence is estimated to have increased to 21%.

I think this analysis makes two very important points: One is that not only does resistant hypertension (based on tha

definition) exist, but unfortunately, it is very common. Perhaps even more discouraging is that it seems to be

increasing in prevalence at a very rapid rate. That, to me, at least is not surprising. Two of the most common risk

factors for having resistant hypertension are older age and obesity. We are getting older and heavier as a population,

and as that happens, unfortunately, we can anticipate more and more difficult-to-treat hypertension.


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Slide 5.

The prevalence of resistant hypertension is not the same as uncontrolled hypertension. I think Joe will agree with

that. In fact, most uncontrolled hypertension is not resistant hypertension; it is what we might call apparent resistant

hypertension or pseudoresistant hypertension. Probably the most common cause of apparent resistant hypertension,

but not true resistant hypertension, is simply poor adherence. Patients are not taking their medications as

prescribed; it could be any number of reasons, but obviously, if you are not taking the medication then you cannot

say that you are resistant to it.

Other common causes of apparent or pseudoresistant hypertension would include a lack of treatment or

undertreatment. Studies have shown that there is a lot of clinical inertia on the part of the physician in terms of

treatment resistance, and that it is not the same as resistant hypertension. The white-coat effect is an important

cause of apparent resistant hypertension.

Having excluded those causes, we are left, I think, with true resistant hypertension. What is that prevalence?


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Slide 6.

We did an analysis in our clinic looking at patients who were truly resistant -- having excluded white coat and having

monitored adherence as best as possible -- and we estimated that among those patients referred to us for resistant

hypertension, the prevalence is about 10%, 10% of those patients referred to us. [3] Overall, that likely represents a

small percentage, but still there is clearly a subgroup of patients that remain uncontrolled in spite of our best efforts.

Yes, I think it does exist, and I think it is unfortunately common and getting even more so.

Dr Krum: Before we have a panel discussion, Joe, you have been assigned the contrarian role today. I believe you

are an excellent contrarian, so here is your 5 minutes.

Joseph L. Izzo, MD: Thank you, Henry. I have certainly made a career out of being a contrarian. It is a little difficult

to argue with David, the voice of reason over here. In order for me to take this position, I have to play a little bit with

the words. I would say that there is really no such thing as benefit-resistant hypertension. I think we can treat

everybody. But I think David has already hit on the most important point, although perhaps not emphasized: Are all

hypertensives the same? Are we dealing with one syndrome here, or are we dealing with multiple syndromes?


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Slide 7.

If we look at the distribution of blood pressure as already articulated, the far right-hand portion of this curve could be

defined as, certainly, higher blood pressure and therefore have the potential for greater resistance to hypertension, bu

that is probably too simple.[4] No doubt that we have to couple this information about blood pressure distribution with

risk. In order to do that, we need to go back to the old 20/10 rule.


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Slide 8.

For each 20-mm Hg increment in systolic blood pressure (SBP) above 115 or 120, each 10-mm increment in diastolic

pressure, cardiovascular disease (CVD) risk doubles.[5] What this means is that hypothetically, any 20-mm reduction

in systolic or 10 in diastolic has the potential to halve CVD risk. This is especially true for stroke. It is also true for

cardiac disease. If you take the position that everyone can benefit from therapy, there is no benefit-resistant

hypertension. I fully realize I am playing with the concepts and the words, but it is a litt le tortured to say there is no

such thing as resistant hypertension.

I think I might quibble a little bit further with what we mean, in functional terms, by the subgroups. David has shown

you the work that he did for the American Heart Association in the statement, and I think it is fair to include those

categories. He also showed you his personal experience, and I am actually more interested in that. I, too, have some

ideas about that.


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Slide 9.

What I would say from my years practicing hypertensionology is that age is the first issue; I want to focus on that in

closing. Second is suboptimal drug therapy. I do not want to see 3 -blockers combined with 2 angiotensin-converting

enzyme (ACE) inhibitors. I do not think that is emphasized enough. Certainly including a diuretic as part of the

definition is a wise choice. We have to have drugs of different classes; for me, it starts with calcium channel blockers

renin-angiotensin blockers, and diuretics. Beyond that, we are talking about more difficult-to-treat people.

Certainly, we have therapeutic nonadherence for a whole variety of reasons, which we may discuss later. David has

also mentioned white-coat hypertension (WCH), for sure. Prevalence is probably about 7%, but it is very real. I have

people who have 80-mm white-coat hypertension (Editor's Note:In data currently under review, Dr Izzo and

colleagues determined an overall prevalence rate of 7% for WCH. However, rates of WCH depend upon the definition

applied and the overall blood pressure level. The prevalence of a marked white-coat effect -- defined as an office

SBP 20 mmHg above daytime mean SBP -- can be as high as 40% in patients with resistant hypertension ).

Another area completely ignored by the community is psychosocial and personality type issues: cynics; "anger-in"

type people; and people who are in difficult life situations such as divorces, unhappy retirements, or bad jobs. You

cannot treat that blood pressure with standard medication.

Then we come to the more classical secondary hypertension. Of course, each of those has a more or less pre-

prescribed pattern because of the pathogenetic differences. Then there are smaller subgroups, what some people

consider artifacts of blood pressure, such as pulse pressure amplification and the concept of arm blood pressure not

representing what we see at the heart.

Clearly, this is a heterogeneous syndrome. That is the first thing. Although we can lump it together as a uniform

distribution, as shown in my first slide, we really cannot operate that way therapeutically. I think if we use such a

term as resistant hypertension, we are not paying fair homage to these highly heterogeneous people with different

needs.


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Slide 10.

Let me return to the age issue, because I really think this is the lion's share of the problem. In the United States and

any industrialized society, systolic pressure is linear with age: If we are 20 years old the systolic is about 120, if we

are 80 years old the systolic mean in the population is about 150. [6] What do we do about that? Previous treatment

guidelines, and I am party to some of those, have said we need a fixed definition of blood pressure. [7]

Upon further review, I do not think that is a good idea because it just goes against Mother Nature. We have to take

this into account because I think as we all know at this point, we are dealing with at least two phenomena in the

aging population from a pathophysiologic point of view. One, of course, is the hypertension itself. It starts, probably at

an earlier age in most people. Two, is the arteriosclerosis, wide pulse pressure.

How do we get around this? I guess my recommendation would be to debate this again. How do I establish a target

that is realistic? Here is my suggestion: We should go back to a combined use of systolic and diastolic but in a

different way.


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Slide 11.

If we estimate the mean arterial pressure, for example, given the widely varying pulse pressures we know exist over

age, if we, for example, took 100 as a therapeutic target, that would mean in younger people, 130/85 mm Hg would

not be a bad target; for slightly older people, 140/80 or 150/75 mm Hg; or in the most elderly, 160/70 mm Hg. You

have to do that because if you try to reduce the blood pressure further than that it becomes dangerous to the patient,

but we are not doing that so far. Europeans have begun to do it. I agree with them. Maybe you can simplify this, but I

think this is a pretty good algorithm.

I have probably exceeded my time, but I want to say that I think anyone can benefit. We can reduce risks. The

debate is how do we do that in a given patient?

Dr Krum: Great. Thanks, Joe. Before we leave that very interesting and provocative suggestion, I must ask David's

opinion on that. First, what do you think? And second, are there data to support this, both epidemiologically and in

terms of intervention?

Dr Calhoun: I think it is certainly a provocative idea. I think intuitively, it makes sense. Joe is always coming up with

great ideas. I think that it would have to be validated in outcome studies. I am not aware that those data exist yet.

Before we can recommend this tier approach it would have to be really tested.

Dr Izzo: I will be dead before you have validated the studies. I have got to do something now.

Dr Krum: You could go back retrospectively to existing data sets and validate that one.

Dr Izzo: Of course, Stan Franklin has done that a little bit, and others have looked at this issue. [8] It is the

intersection of pulse pressure and mean pressure. How do we do it? I think it is not easy, but as long as we are

thinking about it, these are artificial targets anyway. We need to recognize that not everybody will fit 140/90 mm Hg.

Dr Krum: Let's move on. Before we leave the definitional aspects of this discussion, let me ask about ambulatory


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monitoring. Ambulatory monitoring is not part of any existing guideline definitions. Do either of you gentlemen think it

should be, given that it really provides more accurate blood pressure data?

Dr Izzo: If I may be so bold as to correct you, it is a part of some guidelines that we do not think about. For example

the Japanese guidelines have included it for quite a while. Should we use ambulatory BP? I have always used home

blood pressures, I am very glad I did. It was not evidence-based, David. It was, if you will, logic-based. I think that

there is clearly a difference between the two. If we have these severe white-coat hypertensives, it is irrelevant to look,

in one sense, at the office blood pressures because they do not fall with therapy, at least not with antihypertensive

drug therapy. Other behavioral measures may be effective.

Slide 12.

Dr Calhoun: The revised National Institute for Health and Care Excellence (NICE) guidelines do, in fact, include the

ambulatory monitoring as part of confirming the diagnosis. [9]

Dr Krum: They may actually mandate it.

Dr Calhoun: I would argue, and I think Joe would probably agree, that it is especially true for patients with seemingly

resistant hypertension. Studies have suggested the prevalence of a substantial white-coat effect, maybe as high as40% in these patients with apparent resistant hypertension.[10] I think it is essential that we either do ambulatory

monitoring or what we do probably more often, and I think what Joe does: Encourage out-of-office blood pressures --

home pressures or office or work pressures -- to try to really establish what the true blood pressure is.

Dr Izzo: The other thing that it does is it tends to engage the patient in the process. I want that patient engaged in

the process.

Dr Krum: Absolutely. Physiologically, why do you think those people do not respond to drug therapy, assuming

adherence is not a factor? Why do they not respond?


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Dr Calhoun: I think it is multifactorial. If you look at risk factors associated with resistant hypertension, it is a

number of things: older age, I think, related to progressive vascular stiffness. Obesity is a very strong risk factor for

resistant hypertension. Chronic kidney disease is a very strong risk factor. We have shown, and others have shown,

that aldosterone excess is a very important contributor to resistant hypertension.[11,12] Dietary intake of high salt is

an important factor. I do not think there is any one reason in most cases. It is rare that you are going to find that true

secondary hypertension that you can reverse with intervention, like renal arterial stenosis. I think in most cases it is

multifactorial; those contributing factors have to be identified and hopefully approached individually.

Dr Izzo: Yes, and there is still room for hypertension experts, believe it or not. I had a 26-year-old woman going tothe emergency room with a blood pressure of 250/150 mm Hg. She is a little tricky. She has dysautonomia. I called

the emergency room doctor and said, "This girl needs 4 liters of normal saline." When I say things like that, they

think I am nuts, but that is what she needed. Basically 6 hours later, she was at about 150/90 mm Hg. It is that kind

of different case that you have to respect as well. Not everybody needs lots of diuretics. Some people actually need

volume loading, or anti-aldosterone therapy. I think David is perfectly right. We need to properly dissect this group.

Dr Krum: Let us segue into therapy. Let me paint a scenario: a youngish patient. You have checked adherence and

compliance, you have done ambulatory monitoring, and they are truly refractory to your treatment. They are on

decent doses of appropriate medications, the combination that you referred to earlier. What is your thinking going

forward? You have excluded secondary causes as well. What sort of treatment algorithm do you adopt in this

refractory patient, say, sitt ing at 170 mm Hg systolic despite all of the above?

Dr Calhoun: I think that is where the art of treating hypertension comes in. You really have to individualize it to the

patient in terms of their diagnostic evaluation and also in terms of treatment approach. If you truly have maximized

treatment and have tried every available class of agent, then that, I think, is a unique patient who has true refractory

hypertension. They are failing antihypertensive therapy. At this point, at least in the United States, there is really little

recourse.

Dr Krum: Can I draw you out on that? When you say every therapy, how far do you go?

Dr Calhoun: I have patients, and I am sure Joe does, too -- not many but some -- who are certainly taking 7 different

classes of agents, including certainly vasodilators, centrally acting agents, multiple diuretics, - and -adrenergicantagonists. We throw everything we have at them, but still I think there is truly a subgroup of patients who are

completely refractory to even that level of intervention. That is where, as I said, in the United States we do not really

have a recourse for that patient other than doing medical therapy, lifestyle changes, low-salt diet.

Dr Izzo: Yes, I think you are perfectly right. First of all, it is real. It is not an anomaly of blood pressure

measurement. We have had them hospitalized on maximum doses of 8 medications. I have studied the

hemodynamics, the neuroendocrine, the sympathetic physiology. Things work, baroreflexes and so forth, but the set

point is way up there. They are not always tachycardic, but this is a different group of people.

Why we do not move more quickly to some interventional therapy is the next question. Of course there are ongoing

studies with renal nerve ablation, and of course people have been interested in baroreflex surgery. The group we aretalking about now has failed all known drug therapies. It is a small group, but it is real. If a patient comes to me at

220/120 mm Hg, having a bad day -- maybe a good day is 180/110 mm Hg -- I tell them that that a 40-mm Hg blood

pressure reduction matters because on a hypothetical risk reduction, it is still 75% from a much higher absolute risk

rate; I just bang on them to take their medication anyway. They are not benefit-resistant, that is to say, we can get

the lion's share of the good from that first 40-mm Hg drop from say, 200 to 160 mm Hg.

Dr Krum: Just before we leave drugs, you mentioned that these patients may be uniquely secreting excess

aldosterone or that system may be more activated, so where do you so see the role of antialdosterone therapy?

Should everyone be tried on antialdosterone?


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Slide 13.

Dr Calhoun: Yes, I would argue that aldosterone antagonists should be part of the standard approach, if you will, for

treating resistant hypertension. We would use it routinely as a fourth drug. I like to see patients who are on an ACE

or an angiotensin receptor blocker (ARB), a calcium channel blocker, and a thiazide diuretic, which, in our clinic, now

is mostly chlorthalidone. Then, if they are still uncontrolled on that triple combination, we almost always add in

spironolactone as a fourth drug at that point, with good results. [13]

Dr Izzo: I think that is good advice. I have tried to simplify that a little bit, especially in the elderly patients. I have a

lot of them on amlodipine/spironolactone combinations. It is very effective, with low side effects, and the patients

appreciate it because it is simpler.


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Slide 14.

Dr Krum: Leading into procedure- and device-based therapy, what sort of patient, assuming it was available clinically

would you be looking at? Would it be the one we just talked about?

Dr Calhoun: Right off the bat, it would be that patient. Joe and I know there are those patients whom we would love

to have something available for because they are failing maximum treatment. Those are the patients we would

certainly want to treat initially. I think the question is beyond that. You might control someone's blood pressure with 6

or 7 medicines, but might they still be better off having had a device intervention and then doing as well on 3 or 4

medicines? I think that is certainly something that needs to be determined.

Dr Krum: That is one of many ongoing questions that need answering.

Dr Izzo: Let me approach that a little differently. In a previous lifetime I used to do sympathetic nervous system

physiology. The sympathetic nervous system is part of hypertension in 100% of cases. If you give, say, a drug like

clonidine, you will get a reduction in blood pressure of 10 or 15 mm Hg in anybody with hypertension. I am not

suggesting we give every patient clonidine. It is simply an illustrative point. We need to get into this mechanism. Now

of course, all of the existing antisympathetic medications have horrible side effect profiles. We will never get around

that. Then you come to the business end of the sympathetic system on either the blood vessels or the kidney. How

are you going to get into this mechanism? I think that is the challenge going forward. David is right; we will all start

with the worst cases. We always do. How far do you extend beyond that? I think there is a universality to this issue,

too, about the role of the sympathetic and including the renal sympathetics in the business of hypertension.

Dr Krum: We have, of course, some emerging data with renal denervation in the types of patients we have been

talking about. Let me ask you both: What is your take on the data for renal sympathetic denervation, and indeed, for

the baroreflex therapy approach?[14,15]


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Slide 15.

Dr Izzo: I will start. I do not have a lot of personal experience with the new baroreflex stimulators. I have talked to the

people, but having not had that personal experience, I am not the best judge. I think it is possible that with random

stimulation, which is a different notion compared to the old-fashioned way that it was done, there may be benefit. I

would reserve it for these worst cases. As to renal denervation, I think the big question mark is how far should we be

going with this? I think that remains to be seen.


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Slide 16.

Dr Calhoun: Yes, I think the data are certainly very compelling, and no doubt there is a subset of patients that are

going to benefit. I think immediately it would be those worst case patients that seemingly are getting large reductions

in blood pressure. As I said, there is no doubt that there will be a group of patients who will really benefit from this.

The question is, how big is that group going to be? That needs to be determined by clinical trials.

Dr Krum: OK. Any final thoughts before we wrap up?

Dr Calhoun: No, I think we would agree that there is certainly a subset of patients who are failing therapy, who are

very resistant to treatment. I think with the use of effective combinations, which may not be as big a group as some of

these observational studies suggest, but nonetheless, there are patients who truly cannot be controlled. Those are

the patients who are the biggest challenge for us as hypertension clinicians, and who may benefit the most from new

interventions.

Dr Izzo: David, you have beaten me down again. I surrender. There is resistant hypertension after all.

Dr Krum: You are ready to concede because I was going to call it a draw, but I think that is all we have time for. In

wrapping up, let me think about my take-home points from all of this. I think what I have learned today is thatresistant hypertension is probably more prevalent than I had previously thought, driven primarily by obesity and the

elderly. We have effective medical therapies, but clearly, in patients in whom they are appropriately applied -- and tha

includes the use of antialdosterone therapy -- there are some who are just truly resistant.

Refractory hypertension may be an important indication for renal denervation, and it may go further into less severe

forms. I think all of us have a lot of work in front of us.


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Slide 17.

With that, may I close this and thank everyone. I thank you, David and Joseph, of course, and I thank everyone for

participating in this activity. You may now revisit those questions presented at the beginning of the activity to see

what you have learned by clicking on the Earn CME credit link. The CME posttest will follow. Please also take a

moment to complete the program evaluation at the end. Thank you.

This transcript has been edited for style and clarity.

Clinical Case Challenge

How will you improve your practice? Please click on the "Next" button to assess your performance in comparison

with your peers by completing this brief survey.

(Note: the following questions were developed by an independent consulting group with expertise in assessing the

effectiveness of medical education.)

Clinical Case Challenge

Case #1: A colleague refers a 44-year-old, morbidly obese white man for further evaluation of what he

referred to as "resistant hypertension." The patient had been intolerant of two medications initiated by

the referring physician and came to your office only currently taking HCTZ 25 mg, which he admitted

to the RN that he forgot to take that morning. He also reports having eaten a bacon, egg, and cheese

sandwich with salt, pepper, and ketchup prior to arrival in your office, where he had a measured blood

pressure of 178/106 mm Hg.


26/29



Does this patient's measured office blood pressure meet criteria for resistant hypertension?

Yes, his systolic blood pressure is >160 mm Hg and diastolic blood pressure is >90 mm Hg

Yes, he clearly has markedly elevated blood pressure and has been a very challenging patient

from a treatment strategy standpoint

No, by definition he must have a blood pressure >140/90 mm Hg on at least 3 anti-hypertensive

medications at optimal doses

No, morbidly obese patients cannot be classified as having resistant hypertension

Which of the following is the most common cause of pseudoresistant hypertension?

Obstructive sleep apnea

Alcohol abuse

Job and psychosocial stresses

Medication noncompliance

The patient remarks that when he was younger a doctor told him he probably has White Coat

Hypertension (WCH) and wants to know if this is a "real thing?" How do you answer him?

No, WCH is not a true entity but rather a mask for noncompliance and poor lifestyle habits

Yes, WCH is a real entity and may account for up to 40% of all cases of resistant HTN

Yes, it does exist, but WCH typically elevates the systolic blood pressure by 3-5 mm Hg

No, WCH is not a true disease and could never account for blood pressure readings above

150/90 mm Hg

How would you best exclude WCH in your work up of the hypertensive patient?

Avoid wearing white coats in the office

Have the patient take his medication immediately prior to his office visit

Have the patient perform home blood pressure monitoring with ambulatory blood pressure

recordings

Request visiting nurse services to perform home visits for BP checks at his home

Case #1 (cont.): After getting married, the above patient has shown up in the office having lost nearly

twenty pounds by eating a healthy diet and exercising regularly. He is ready now to try and manage

his blood pressure, which has remained persistently above 160/90 mm Hg despite treatment with

ramipril 10 mg and amlodipine 10 mg daily. He states that he is faithful with his medications and his

home blood pressure recordings are similar to the values measured in your office.

In optimizing his medical regimen, which of the following regimens would you choose for him now?

Clonidine

Losartan

Minoxidil

Chlorthalidone

Case cont'd: After initiating treatment with a third medication, the patient begins to complain about his

medication regimen and asks if he really is at risk for harm, being so young.


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Which of the following statements would you use in your response to this patient?

Every 10 mm Hg drop in systolic BP decreases stroke mortality by 20%

Every 10 mm Hg drop in systolic BP lowers the risk of stroke death by 40%

Every 10 mm Hg drop in systolic BP decreases the risk of ischemic heart disease/vascular

death by 40%

Case #1 (cont.): The addition of the chosen medication has not yielded the benefit you had hopedand despite perfect medication compliance along with diet and exercise, the patient's blood pressure

still appears to be routinely over 150/90 mm Hg.

Which one of the following medication classes would you select as your most reasonable next step?

Angiotensin receptor blockers

Alpha-antagonists

Direct renin inhibitors

Aldosterone blockers

Case #1 (cont.): Despite adhering to his regimen of four anti-hypertensive medications, this patient

continues to have blood pressures over 150/90 mm Hg on his home blood pressure cuff monitoring.

He has been successfully ruled out for common secondary causes of resistant hypertension and is

now wondering if there are any other modalities available.

What possible strategies exist beyond medications that have shown benefit?

Massage therapy/acupuncture

There are no additional therapies that can be offered at this time

Catheter-based sympathetic renal denervation

Surgical sympathetic denervation

Based on your experience, which of the following is the most significant barrier to the optimal

management of patients with resistant hypertension?

Medication nonadherence

Lack of knowledge on appropriate dose/combinations

Physician inertia (physician timing for therapy adjustment)

Nonadherence to diet and lifestyle changes

Lack of safe, efficacious therapy

Please indicate how relevant this CME activity is to your practice: Approximately, how many patients

with hypertension do you treat weekly?

0

1-10

11-20

21-30

31-40

41-50


28/29



>50

What percent of your patients with hypertension have resistant hypertension?

0%

1-10%

11-20%

21-30%

31-40%

>40%

Save and Proceed



AbbreviationsABPM = ambulatory blood pressure monitoring

ACE = angiotensin-converting enzyme

AHA = American Heart Association

ARB = angiotensin receptor blocker

BP = blood pressure

CVD = cardiovascular disease

DBP = diastolic blood pressure

HBPM = home blood pressure monitoring

HTN = hypertension

IHD = ischemic heart diseaseISH = isolated systolic hypertension

NHANES = National Health and Nutrition Examination Survey

NICE = National Institute for Health and Care Excellence

RHTN = resistant hypertension

SBP = systolic blood pressure

SD = standard deviation

WCH = white-coat hypertension

References

1. Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis, evaluation, and treatment. A

scientific statement from the American Heart Association Professional Education Committee of the Council fo

High Blood Pressure Research. Hypertension. 2008;51:1403-1419.Abstract

2. Roberie DR, Elliott WJ. What is the prevalence of resistant hypertension in the United States? Curr Opin

Cardiol. 2012;27:386-391.

3. Acelajado MC, Pisoni R, Dudenbostel T, et al. Refractory hypertension: definition, prevalence, and patient

characteristics. J Clin Hypertens (Greenwich). 2012;14:7-12.Abstract

4. Schwartz LM, Woloshin S. Changing disease definitions: implications for disease prevalence. Analysis of the
http://www.medscape.org/medline/abstract/22235818http://www.medscape.org/medline/abstract/18391085http://www.medscape.org/viewarticle/808534


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Third National Health and Nutrition Examination Survey, 1988-1994. Eff Clin Pract. 1999;2:76-85. Abstract

5. Lewington S, Clarke R, Qizilbash N, Peto R, Colllins R; Prospective Studies Collaboration. Age-specific

relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults

in 61 prospective studies. Lancet. 2002;360:1903-1913.Abstract

6. Burt VL, Whelton P, Roccella EJ, et al. Prevalence of hypertension in the US adult population: results from the

Third National Health and Nutrition Examination Survey, 1988-1991. Hypertension. 1995;25:305-313. Abstract

7. Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on Prevention,

Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560-2571.

Abstract8. Franklin SS, Lopez VA, Wong ND, et al. Single versus combined blood pressure components and risk for

cardiovascular disease: the Framingham Heart Study. Circulation. 2009;119:243-250.Abstract

9. Hypertension: clinical management of primary hypertension in adults, CG127. National Institute for Health and

Care Excellence; 2011. http://www.nice.org.uk/guidance/CG127 Accessed June 16, 2013.

10. de la Sierra A, Segura J, Banegas JR, et al. Clinical features of 8295 patients with resistant hypertension

classified on the basis of ambulatory blood pressure monitoring. Hypertension. 2011;57:898-902. Abstract

11. Calhoun DA, Nishizaka MK, Zaman MA, Thakkar RB, Weissman P. Hyperaldosteronism among black and

white subjects with resistant hypertension. Hypertension. 2002;40:892-896.Abstract

12. Eide IK, Torjesen PA, Drolsum A, Babovic A, Lilledahl NP. Low-renin status in therapy-resistant hypertension:

a clue to efficient treatment. J Hypertens. 2004;22:2217-2226.Abstract

13. Clark D III, Ahmed MI, Calhoun DA. Resistant hypertension and aldosterone: an update. Can J Cardiol.

2012;28:318-325.Abstract

14. Bisognano JD, Bakris G, Nadim MK, et al. Baroreflex activation therapy lowers blood pressure in patients with

resistant hypertension: results from the double-blind, randomized, placebo-controlled Rheos pivotal trial. J Am

Coll Cardiol. 2011;58:765-773.Abstract

15. Esler MD, Krum H, Schlaich M, et al. Renal sympathetic denervation for treatment of drug-resistant

hypertension: one-year results from the Symplicity HTN-2 randomized, controlled trial. Circulation.

2012;126:2976-2982.Abstract

Disclaimer

The educational activity presented above may involve simulated case-based scenarios. The patients depicted in thesescenarios are fictitious and no association with any actual patient is intended or should be inferred.

The material presented here does not necessarily reflect the views of Medscape, LLC, or companies that support

educational programming on medscape.org. These materials may discuss therapeutic products that have not been

approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare

professional should be consulted before using any therapeutic product discussed. Readers should verify all

information and data before treating patients or employing any therapies described in this educational activity.

Medscape Education 2013 Medscape, LLC


http://www.medscape.org/viewarticle/808534http://www.medscape.org/medline/abstract/23248063http://www.medscape.org/medline/abstract/21816315http://www.medscape.org/medline/abstract/22521297http://www.medscape.org/medline/abstract/15480108http://www.medscape.org/medline/abstract/12468575http://www.medscape.org/medline/abstract/21444835http://www.medscape.org/medline/abstract/19118251http://www.medscape.org/medline/abstract/12748199http://www.medscape.org/medline/abstract/7875754http://www.medscape.org/medline/abstract/12493255http://www.medscape.org/medline/abstract/10538480

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