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Date: 25-04-2013 Management of Refractory Hypertension

By Dr. Upendra Kaul, New Delhi

Dr. Upendra Kaul:


I am going to speak on a problem, which is not uncommon, that is, refractory or resistant hypertension.  Very often it is actually not resistant, but you know we are getting pressures, which we don't like, so it is first very important to define and find out whether the person is really suffering from refractory or resistant hypertension or is it something else, lack of compliance or you know white-coat hypertension, whenever he sees, his pressure is high, but it is actually not high.  Well we all know that when we treat hypertension, we have to come to the goals and that has been spoken so many times since yesterday that uncomplicated hypertension we always like the pressures to be less than 140/90 and in some states like diabetes and chronic kidney disease we strive to go to low levels.  Whether going to less than 130/80 has relevance, we did talk about it.  It is difficult to get to that level and there is some rethinking going on that possibly it is not required and it does not change the outcomes.  Resistant hypertension is a common problem and it is increasing, 15 to 20% of the patients who come to you with uncontrolled hypertension have resistant hypertension and it is very interesting that in spite of us having so many new drugs now.  Every conference we have a new calcium blocker, some new beta blockers, renin-angiotensin blockers, RAAS inhibitors, very effective drugs, we would have thought that the problem of resistant hypertension should come down, but unfortunately it is not happening, it is increasing and there has been 62% increase in the numbers of patients with resistant hypertension in the last 20 years as per 1 or 2 publications and whether the reason for this is stress, changed lifestyle, possible.  Very important to know, that not all patients who come with uncontrolled hypertension have resistant hypertension; they could have inadequate treatment regimes, wrong kind of drugs, poor adherence and may be undetected secondary hypertension.  We call a person to be suffering from resistant hypertension if the blood pressure remains above the goal with maximum tolerated dose of 3 or more than 3 antihypertensive agents in which one of them really should be a diuretic and you must be sure that the person is really taking those drugs.  Needless to say, treatment of resistant hypertension is associated with substantially increased risk of cardiovascular events.  A person with controlled hypertension will have 5% chance of a cardiovascular event in 5-6 years, but a person who is resistant to hypertension has four-fold risk of getting into a cardiovascular event and this difference starts quite early.  It is not that after years this happens.  It starts quite early and a gap goes on widening.


What is the pathophysiology of real resistant hypertension?  Well, kidney is a central regulator of the electrical, chemical and mechanical forces that control blood pressure.  The electrical factors could be the sympathetic nervous system originating from the brain, chemical could be renin-angiotensin system, cytokines, neurohormones and the mechanical ones can be vasodilatation or vasoconstriction, volume control and heart rate and kidney has a central role in regulating all this.  We know that sympathetic nervous system is a part of the body's autonomic nervous system.  It operates without conscious control.  The sympathetic nervous system connects the brain to heart, the blood vessels, the kidneys and each one has an important role to play in the regulation of blood pressure, this we know from our physiology days.  The renal sympathetic activation, the efferent nerve which start from the central nervous system innervate the kidney and the stimulation leads to renin release and we know that renin release leads to renin angiotensin system activation, which leads to sodium retention, which leads to vasoconstriction and renal blood flow impairment and very interesting that afferent sympathetic nerves from the kidney go and innervate a host of organs.  Important ones are the brain, the heart which leads to hypertrophy, arrhythmia, increased oxygen consumption, some disturbances of brain, insulin resistance, vasoconstriction which in turn leads to atherosclerosis.  So, this is a very very important circle and sympathetic drive is not only seen in resistant hypertension, it is a very important player in a number of situations, even normotensives.  You have increase in the sympathetic nervous system activity, pressures go up.  High normals, white-coat hypertension, borderline hypertension, all sympathetic nervous system has a very important role to play.  Essential hypertension of any variety with or without target organ damage, sympathetic nervous system is a single unit defense, which has a very important role.


Now, who is at risk for developing resistant hypertension?  We know that old age.  There is some debate about sex, but most people, authorities believe female sex, excessive intake of salt, which is very common in our system society, patient who have already left ventricle hypertrophy whose baseline blood pressures have always been high, diabetes, chronic kidney disease, black race, obesity.  Interesting, that on obesity Dr. Weber in one of his recent articles in Lancet, which is based upon the analysis of ACCOMPLISH study has shown that in that particular subset of patients obese hypertensives had a better prognosis as compared to lean people.  He has some explanations for that; that only means that you know science evolving and we are not sure what we are saying today is true tomorrow.  Which of these patients, you know, so many hypertensives, 30% of the people in metro cities have hypertension as per several studies, which of these patients have treatment-resistant hypertension, one has to really focus down on that.  Treatment-resistant hypertension is always a diagnosis of exclusion requiring a systematic approach, evaluation, and management.  There is no one particular test, which will tell you well you will have resistant hypertension and then a systemic approach consisting of so many things, which are simple and have been discussed again and again.  You confirm the accuracy of BP measurement whether the BP is being measured by the appropriately sized cuff; rule out white-coat effect, which is extremely important; address lifestyle barriers; dietary salt intake; alcohol consumption; and you must make sure that the pharmacotherapy, which is being taken is optimal and the person is really adhering to it.  Intensify the pharmacological therapy in case and some of these patients, a small number of patient were really resistant, possibly should be referred to people who are very interested in the management of hypertension.  Unfortunately, we do not have many hypertension experts in our country.  Nobody likes himself to be called as a hypertension expert, everybody wants to be called as an angioplasty expert and you know all kinds of experts, diabetes and cardiologist, so many of them, but nobody says that I am expert because everybody is hypertension expert.


Now, eliminating white-coat effect is extremely important.  When a doctor in a white-coat measures the blood pressure it is sometimes high.  Elevated blood pressure, which is significantly lower when the person goes home and it is in one of the recent studies from Spain, up to 35% of people have been shown to have white-coat hypertension.  White-coat hypertension should be thought of, if the person whenever he comes to you, he or she says I have been taking all these medicines, you measure the pressure it is 170, 180; yet overall these years, there is no sign, no iota of any target organ damage, everything is fine.  There is no LVH in the ECG, so those are some of the situations and you think am I dealing with white-coat hypertension.  So, consider repeat at home blood pressure measurement as has been highlighted in the Indian guidelines also that home BP measurement is very good and 24 hours ambulatory BP monitoring actually is the method, very important method, and its use is now growing.  Previously hardly any hospital used to have it.  Now, I find that many hospitals have this facility and after the NICE guidelines have shown that this is one of the very important ways to start treatment in hypertensive, it is actually cost-effective, is being implemented in many places and I am sure it will grow up.  Then the combination of drugs with complimentary mechanism of action should be there and we have had talks by Dr. Hiremath and many other doctors where we know what are the combinations like ACE inhibitors and calcium blocker is a combination or ARB with calcium blocker is a good combination, diuretic with ACE inhibitor or calcium blocker is a good combination.  Similarly calcium blockers with beta blocker could be a good combination.  So, one has to see that one is not combining wrong kind, you are not combining beta blocker with a diuretic and then 2 drugs have gone.  So, judicious use of the drugs in combination which have been shown to be more effective than other combination without their having any adverse effects are to be chosen, and most of us know about this and a number of talks have already been done on this, I am not going to repeat it.


Then, spironolactone, we must always think about a drug called spironolactone, which all of us know.  Actually, this came from the ASCOT study where uncontrolled blood pressure extension, there were 1400 patients who had been given spironolactone by the treating physicians, 25 mg a day, and what they found was there was a significant, more than 20 mm, fall in systolic pressure and around 10 mm fall in diastolic pressure with spironolactone.  Spironolactone can be effective in many patients with treatment resistant hypertension and all of us in the last 3 or 4 years have seen that it probably works quite well.


Poor adherence is a common cause of pseudoresistance.  When you start a person on multiple drugs for the treatment of hypertension within one year about one in three patients has already discontinued this medications.  This was again highlighted by Dr. Siddharth Shah in the morning and after 10 years because hypertension is a longterm disease and we have to take medicines for decades if we want to prevent a stroke or a heart attack or nephropathy almost 2 in 3 patients in particularly in this analysis did not stick to their antihypertensive drug continuously.  They stop, they again restart, change the medicine, then they come back, aren't any better medicines available, I have stopped it now because I am told newer medicines are available, so this is important and signs of nonadherence should be looked for.  If a person whom you call once in 2 months for visit is not coming, so this is one of the signs of nonadherence.  If he is not coming to see you, he is not going to somebody else also that means possibly he is also missing the drugs.  Lack of physiological evidence of therapy.  You are increasing the drug, blood pressure is not at all coming down and absence of anticipated common side effect of the drug.  You started him on 100 mg of metoprolol, he comes his heart rate is still 80, so you should suspect that possibly he is not.  Similarly, some other side effects, so very important to discuss the medication use with his family members, his spouse, verifying the prescription.  Very simple logical things to find out whether the gentleman is taking medicines or not and that is very important before you start advising him to take some very expensive combination of drugs or renal denervation therapy and other things, get into these simple things.


Some interfering substance, all of us know that nonsteroidal antiinflammatory drugs very often, obese, hypertensive with arthritis, arthralgias, aches and pains, keeps on swallowing these pills of pain killers, COX-2 inhibitors, they all lead to uncontrol of hypertension.  Sympathomimetic drugs like frequent use of nasal drops and amphetamines, some herbal supplements.  You should see what else is he taking and at times that is the answer.


Lifestyle modification should always be insisted upon and this slide I think in very different colors has been shown by many of our speakers that if you go by the guidelines of reducing weight, the diet, reducing sodium intake, increasing physical activity it can act by reducing the blood pressure by 15-20 mmHg as long as you are very strict on that.


Which are the patients where as an expert on hypertension or a person who is good at controlling blood pressure and who goes into further analysis.  First of all treatment of secondary causes of hypertension, intensive management of true treatment resistant hypertension and then an upcoming therapy called the renal denervation therapy and we know that about 5-6% of so called resistant hypertension may have secondary hypertension, they may have renal artery disease, parenchymal disease, renal artery stenosis, aldosteronism, very rarely coarctation of aorta, which usually these days is not missed, but you are occasionally surprised that a coarctation can be missed because femoral artery was not being felt and then disease like pheochromocytoma and Cushing's.  So, one should always think of some secondary causes.


Then the promising treatment based upon sympathetic nervous system and in one of the slides, I think the first in the morning Dr. Siddharth Shah showed, in 60s sympathectomy was one of the standard treatment when we had only some ganglion blockers of veratrum alkaloids, but that was very difficult.  It meant a big surgery with morbidity, it never picked up, but then we know that renal denervation is a therapeutic approach now and important is that the renal sympathetic nerves innervate the renal arteries both sides and the nerves arborize, the media and the adventitia are the nerves, so they become amenable to something if you can do from the lumen and that is likely radiofrequency ablation.  Ablation is done in the operation room by the cautery and in the cath labs for radiofrequency ablation of arrhythmias, so nothing new in the energy source and what one is to do is to put in a catheter in both renal arteries and make 5 or 6 touches here for a few minutes and denervate the renal arteries and simple equipments, simple catheter, which is being refined.  I am told that at least 47 or 48 companies which have come out with various innovative catheters which are better and better, but still being investigational.


There is a strong preclinical evidence in more than 300 swines that by doing it significant reduction and renal tissue norepinephrine was seen without any bad effects.  There were no big scars, there were no narrowings and very few injuries, which mattered, and then there is a clinic evidence and number of studies called the Simplicity studies, Simplicity-1 and Simplicity-2.  Simplicity-1 was a first in man study, first 45 patients and then extended to 153 patients; all of them were on 3 or more than 3 drugs with 1 as diuretic.  All kinds of drugs were there as you can see, still the pressures were high. 38 minutes for the procedure, a percutaneous procedure, some narcotic analgesic or sedative to be given because it can produce some pain.  No major complication.  There was one renal artery dissection, which could be handled with the stent and some puncture site problem, which can happen with any kind of an angiography and as you can see there was a significant fall in the blood pressure within a month by 20 to 30 mm and this goes on up to 36 months.  So, Simplicity hypertension 1 trial at the end of three year showed that the very few downsides, hardly any complication, 1 or 2 patients, and there was no severe hypotension requiring hospitalization and there were no observed changes in electrolytes or any renal function or renal injury markers.  Simplicity-2 was a study in which half the patients were given the treatment, half were not given, 40% patients were diabetics and they were equally matched, 50 patients each, and once again you could see that within six months 30 mm fall in systolic blood pressure and 12 in diastolic, which is sustained at 1 year.  Mind it in both the studies the drugs were not allowed to be lowered to see the efficacy of the drug.  Just to see that over and above the drugs, how much does it work and once again very safe.  The eGFR did not reduce.


The conclusion of these two studies has been that the treatment of resistant hypertension by catheter based renal denervation resulted in significant fall in pressure.  The magnitude of pressure could be predicted to the effect development of hypertension-related diseases.  The technique had very, very few complications and it is concluded that it is beneficial for patient with treatment resistant essential hypertension.  We have this Simplicity, hypertension study, which is to be started, we are just waiting for the DCGI to give us permission, but there are some complication there, Supreme Court ruling and all that, but I think within a few weeks it should start in 10 centers, 50 patients, and this is basically for getting approval for this procedure in the country.


If I have to conclude:

·         15-20% of uncontrolled hypertensives are resistant to treatment.

  • BP that remains above the goal despite our treatment with optimal three or more agents is called refractory hypertension.
  • Treatment resistant hypertension is an important thing because it is associated with significantly higher vascular events.
  • Kidney is a central regulator of electrical, chemical, and mechanical forces, which control the blood pressure.
  • Sympathetic drive is elevated in many types of hypertension.
  • Treatment approach consists of confirming the accuracy of BP measurement, optimizing the pharmacotherapy, addressing the lifestyle barriers.
  • Ruling out secondary hypertension.
  • If hypertension is still resistant there is a promising role of renal sympathetic denervation.  This has already been approved in Europe, Australia, New Zealand and it is to be approved in our India and for the United States the major trial is going on, the Symplicity US trial.


Thank you very much.

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