A Woman With Treatment-Resistant Hypertension
Presentation of Case
Although this is not a particularly unusual or rare case of hypertension, it highlights the challenges we have as clinicians in managing such patients. The patient, a 60 year-old woman, was referred to the tertiary blood pressure clinic at Glasgow’s Western Infirmary 5 years ago by a consultant cardiologist for management of resistant hypertension. This lady has a vasculopathy with ongoing intermittent claudication and had previous bilateral superficial femoral artery occlusions on a background of hypercholesterolemia and a significant smoking history. The patient has problematic underlying ischemic heart disease, having had angina since 2001, numerous percutaneous interventions, and a 2-vessel coronary artery bypass graft. Despite this, she had a non–ST-segment–elevation myocardial infarction (MI) 2 years before presentation.
Blood pressure at first visit to the clinic was 182/106 mm Hg despite numerous antihypertensive medications, including an angiotensin-converting enzyme inhibitor, calcium channel blocker, 2 different diuretics, α-blocker, and β-blocker in addition to her antianginal and secondary preventative medications (Table). Review of case notes and previous clinic documentation revealed that clinic blood pressure was elevated for at least 10 years with systolic readings ranging from 150 to 200 and diastolic between 90 and 100 mm Hg.
The patient was admitted to the investigation ward for a week of workup. During this time, routine biochemistry showed normal renal function and electrolytes. Urine albumin/creatinine ratio was within the microalbuminuric range at 4.2 mg/mmol. Cardiac and mediastinal contours seemed normal on chest x-ray, and neither ECG nor echocardiogram showed significant left ventricular hypertrophy (LVH). No biochemical evidence to suggest pheochromocytoma or primary aldosteronism was found. Renal ultrasound exhibited 2 normal sized nonobstructed kidneys with no evidence of cortical thinning, and magnetic resonance angiography displayed normal renal vasculature with no evidence of renal artery stenosis. The patient also had an isotope renogram that displayed normal tracer uptake, excretion, and drainage and revealed that both kidneys were contributing equally to renal function.
Professor Christian Delles: I want to take the opportunity to go through the list of medications again (Table); she is on a large number of antihypertensive agents. Treatment-resistant hypertension is commonly defined as being uncontrolled with a blood pressure of >140/90 mm Hg despite ≥3 antihypertensive agents of which one should be a diuretic. So, the patient fulfills the criteria for resistant hypertension.
There are many epidemiological studies on the prevalence of resistant hypertension. The majority agree that 8% to 10% of the hypertensive population are treatment resistant,1 but this may also be a discussion point from your own experience: how many patients do we really see with this condition? It is quite typical that these patients are often already on a large number of drugs when they are referred to us as specialists. The European Society of Hypertension guideline chart shows a number of combination therapies that are recommended, and I think most of the treatment-resistant patients that we see have all of these drugs already.2 However, when we look beyond, the treatment that is usually recommended the guidelines are very, very vague. For example, if you look at the European Society of Hypertension guidelines, you do not find a lot of drugs that are named for treatment options of resistant hypertension or for hypertension where the first-, second-, or third-line treatment does not work anymore.2
Of the possible fourth- or fifth-line therapies available, the one drug that stands out is spironolactone because there is reasonable trial evidence demonstrating benefit, albeit from small studies. For example, an analysis of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) data showed that addition of spironolactone to the usual antihypertensive medication reduced blood pressure significantly.3 Spironolactone is suggested in many guidelines, but the guidelines do not mention much about any other antihypertensive agents that we may consider. There is also some development of new antihypertensive drugs, but it is probably fair to say that none of them has really reached the market yet.4 So, I think at the moment, we need to work with what is available.
Professor Rhian Touyz: We have here a very interesting patient who has presented with resistant hypertension. She is on the classical drugs that we would expect based on the guidelines. I have some questions, but at this point, we will open the questions to the floor.
Professor Jan Staessen: First of all, why was this patient on a thiazide diuretic plus a loop diuretic? The second question is I don’t know the normal values of renin in your lab but if a patient is on ramipril, a thiazide diuretic and a loop diuretic, what you would expect is an increase in renin activity if the patient is adherent, even if she is taking a β-blocker. So, please inform us on the range of renin values in your lab and whether it was elevated, normal, or low. The third question, I think the most important one, I have not seen ambulatory blood pressure and that is the gold standard. These days you cannot diagnose, treat, or manage any patient with hypertension or referred for hypertension without ambulatory blood pressure monitoring.
Dr Gemma Currie: Your point on ambulatory blood pressure monitoring is absolutely correct and that will be presented in the next phase of discussion. From the point of view of medication, we are not saying this is an example of the gold standard way to manage a case. I think there was potentially an element of “too many cooks” since this woman was also attending a number of secondary and tertiary referral clinics with everyone making adjustments to her medication. That is probably the reason for some counter intuitive treatment decisions.
Professor Delles: The renin levels were in the normal range. It is probably worth discussing how much we can interpret these results. I fully agree with you that a number of these drugs should have increased the renin, on the other hand, she was on a β-blocker as you quite rightly said. I’m not sure if we really have hard data to say how to interpret plasma renin if someone is on an angiotensin receptor blocker, a diuretic and a β-blocker.
Professor Anna Dominiczak: I have a related question. I am worried that a woman with such high blood pressure presumably for a considerable amount of time has no LVH at all, and I still worry about adherence. I have been very taken by a talk given yesterday by Professor Bryan Williams where they showed that people on 6 drugs are 100% nonadherent. So, does she really have resistant hypertension or is it a case of well-covered “I always take my tablets, doctor” type of noncompliant, nonadherent patient. Please persuade me.
Professor Delles: We will discuss the adherence issue in a minute, and we certainly had the same queries as yourself.
There is organ damage in this lady: she has had MIs and has peripheral artery disease. So, I would not agree that she has a falsely high blood pressure and no organ damage just because we didn’t find LVH. So, how far do we rely on these typical organ damages like renal failure, increased albumin/creatinine ratio, and LVH? Would we not say that this patient also has hypertensive organ damage already because she had an MI?
Dr Pervaiz Iqbal: My question is about compliance, and this particular patient is in a lucky position to be in the hospital where a treatment could be given under direct supervision. Was that done?
Dr Currie: We can give you the answer to that shortly.
Professor Garry Jennings: I just take issue with the last point of Professor Delles that there is target organ damage in this lady. She has 40 pack years of tobacco smoking behind her. She has hypercholesterolemia. She has high cardiovascular risk anyway and you would almost be surprised if she didn’t have atherosclerosis irrespective of what her blood pressure was.
Professor Delles: Yes. We will show something on her carotid ultrasound in a bit. I think it would be interesting to find out what the audience thinks because we do see patients who definitely have high blood pressure but relatively little organ damage. Let’s not discuss it with this patient specifically, but we have patients where we think it is kind of the wrong way around and we do not understand the mechanism very well.
Professor Touyz: Professor Delles brings up a really important point. We see increasingly in our clinics patients with confirmed very high blood pressure based on ambulatory readings, and yet absolutely normal renal function, no evidence of LVH, no ischemic heart disease. We don’t really understand what is happening and we often question whether there might be a differential between central blood pressure and peripheral blood pressure. Perhaps this is something we may be able to discuss later as we progress this case.
Professor Staessen: You also asked which drug we would not prescribe to this patient. I think this lady is extremely vulnerable to heart failure because she has previous MI. She has coronary heart disease even if she doesn’t have LVH. Because of her blood pressure level, she is prone to develop heart failure. Now if you look at the trials of moxonidine, there is an increased mortality in patients with heart failure. That drug I would certainly not have prescribed to this patient, although it is very popular among cardiologists.
Professor Delles: Thank you very much for confirming this. This was the only drug that I mentioned in some of the clinic letters specifically and said this is the one I don’t want her to take for exactly the reasons that you said.
Audience participant: It is amazing not to have more pronounced albuminuria and “just” to have heart disease. It’s not just about organ damage because maybe she would also have atherosclerotic disease, so there are very stiff arteries. I think this is something we have in mind for this patient.
Professor Delles: You are prompting us in a wonderful way.
We Learn More…
Between 2010 and 2012, the patient continued to attend the blood pressure clinic on a regular basis. Body mass index was relatively normal, ≈26 kg/m2, but some dietary changes in terms of calorie and salt restriction were made resulting in a 3-kg reduction in weight over a 6-month period. The antihypertensive regime was adjusted: furosemide dose was increased, ramipril was doubled, α-blockade was doubled, and spironolactone was added at a dose of 25 mg once daily. Again, this patient is attending many clinics, seeing cardiologists, vascular surgeons, and the blood pressure service. It does not seem that all of these changes were made by the staff at the blood pressure clinic.
Parallel to this, ischemic heart disease continued to be problematic, and a further non–ST-segment–elevation MI occurred toward the end of 2010 requiring another percutaneous procedure. Ivabradine was then commenced for control of angina.
The first ambulatory blood pressure monitor for this patient in 2011 had a suboptimal number of readings. Nevertheless, it confirmed that overall blood pressure was 155/90 mm Hg but with quite a degree of variation in readings. The minimum blood pressure was 119/56 mm Hg and maximum 203/119 mm Hg.
The audience raised many discussion points; the first of which was the issue of compliance. During this patient’s week on the ward, the antihypertensives were administered by nursing staff, and 12-hour daytime average blood pressure during admission was 144/86 mm Hg.
The next interesting point is a note in a clinic letter following one of several percutaneous coronary interventions. It states that the invasively monitored central blood pressure was significantly less than the peripheral reading. Systolic blood pressure during the procedure ranged between 83 and 130 mm Hg and diastolic blood pressure between 45 and 55 mm Hg. This raises the question of whether the peripheral blood pressure readings are falsely high because of increased vascular stiffness.
Adherence and Vascular Stiffness
Professor Delles: Two points we would like to discuss are adherence and vascular stiffness leading to probably falsely high peripheral pressures.
We have data for patients who were worked up for renal denervation, which we will discuss later during the case.5 One should assume that these patients were fully investigated before admission for an invasive procedure. But if you look at these data, treatment adjustment normalized blood pressure in almost half of these patients. There were many other considerations, such as nonexcluded secondary hypertension and other factors that may account for apparent treatment resistant hypertension.
We think that we at least adjusted drug treatment, whether it was in the optimal way is still open for discussion. We are fairly sure that we have not missed too many reasons for secondary hypertension. However, poor drug adherence is still quite a significant contributor to resistant hypertension.
Also to prompt the discussion, we now have methods for drug metabolite monitoring available. Would this really play a role in patient management? Very briefly, what these data from Tomaszewski et al6 in Leicester show is that people who have no discrepancy (near 0) between the number of drugs prescribed and the number of drugs found in their urine as metabolites have much lower blood pressure than people with discrepancy of ≤6. That accounts for all clinic and ambulatory blood pressure measurement. Do these new methods have a role in clinical practice or is it more useful as a research tool for very specific cases? How do we actually handle such information? If we obtain it, how do we inform the patients that we do these measurements?
The other issue mentioned by Dr Currie is that the patient may have increased vascular stiffness, which could certainly lead to a high peripheral blood pressure, whereas the central blood pressure may be much lower.
The patient recently attended our noninvasive vascular phenotyping clinic in the clinical research facility for vascular functional and structural studies. The carotid intima-media thickness is slightly increased at 1.6 mm that is higher than expected for her age. She does not have significant carotid stenosis, but images showed a small plaque. This confirms some organ damage, at least atherosclerotic disease.
Pulse wave velocity was also measured using the new SphygmoCor system that uses oscillometric assessment. Measurement was performed repeatedly, and we present the best tracing obtained. It shows a pulse wave velocity of 11.4 m/s that is not extremely high. It would actually be in the normal range for someone at that age. At the time of investigation, peripheral blood pressure was 152/88 mm Hg and central estimated/calculated blood pressure was 145/89 mm Hg. There is not a large discrepancy.
What is the relevance of central blood pressure if it can be reliably measured? There are reference values now available for central blood pressure, published last year by Annie Herbert in the European Heart Journal,7 but would this really influence treatment? Would we be brave enough to target our treatment to central blood pressure? In one of the recent issues of Artery Research, there was a very nice discussion about whether we should use central blood pressure in the clinic.8,9
There are some data from the Conduit Artery Functional Endpoint (CAFE) study showing that blood pressure medication affects central and peripheral blood pressure differently; specifically, it was very clear that amlodipine-based therapy lowered both central and peripheral blood pressure, whereas the β-blocker atenolol lowered only the peripheral blood pressure.10
Professor Staessen: I would like to make a comment on the last slide you showed from the CAFE study. I think when you look at the Table of this article, there is absolutely no difference in predictive value of peripheral and central pulse pressure. I think that looking at central pressure will not, at least at this stage of scientific development, help in managing treatment of hypertensive patients. I think measuring central pressure is a nice tool for research but not for clinical practice.
And then the other thing is I noticed there was a very big difference between systolic and diastolic pressures. Now you have the heart rate relatively high, so did you look at the aortic valve? I also noticed that if you look at the tracing of the artery, there is no incisura, so no sign of closure of the aortic valve and she has calcification. Is there calcification of the aortic valve? Is there aortic insufficiency? This might explain the big difference between systolic and diastolic pressures.
Dr Currie: Your point with the central blood pressure reading is well taken and I think that was the point we were trying to make. Although these tools are available and we have reference ranges for them, we still don’t really know how to use them or interpret them in the clinical context. I don’t think anyone would in their clinical day to day practice rely on a central rather than a peripheral blood pressure reading.
Her aortic valve was normal in echocardiogram on admission to the investigation unit, but I should raise the point that these vascular studies were only done last week and there has not been a repeat echo in the recent past. Therefore, we cannot be sure whether there has been a change and her valve has become more calcified.
Professor Delles: We had discussions as well in recent sessions at this meeting about the workup of patients with resistant hypertension and workup of patients with secondary hypertension. I think one of the messages that was very, very clear is that we should not just do our investigations at a single time point. Generally, clinicians are reluctant to do too many echocardiograms in “normal” hypertensive patients because there is not much to gain from this, but in this patient with resistant hypertension, we should definitely have performed another echo more recently.
Professor Touyz: I think Professor Dominiczak and I both have questions regarding her treatment. I just want to go back to the therapy. She is now on 3 diuretics, is this correct?
Professor Delles: That is correct.
Professor Touyz: Why is she still on 3 diuretics and does she have any evidence of heart failure, and if not, why is she still on furosemide?
Delles: Well spotted. If we want to criticize something in the management, then it is probably this: there were multiple teams involved. The cardiologists were reasonably keen on the furosemide for reasons that I do not fully understand. It was also a subjective factor that the patient required the furosemide to some extent. As mentioned by Professor Staessen, this combination of the thiazide and the loop diuretic to start with was probably not a very rational idea. Then to add the spironolactone because we think we have some evidence, but not realizing that this adds a third diuretic was probably not the cleverest step. I cannot 100% defend this.
Professor Dominiczak: Could I come back to the drug screen measuring metabolites in the urine? Having heard and seen presentations at this meeting and read the previous paper that you referred to, this is really a cheap and good way to check adherence and compliance. I think we don’t use it enough, and one message for me from this case is that it would have been much easier to do a drug screen earlier even if you need to send the urine somewhere and make sure that it is done properly. In another room, just an hour ago, we were talking about measuring thousands of metabolites for research. Why can’t we measure 6 drug metabolites that are well known to toxicologists in the urine of our patients? It seems rational, easy, and I think a patient confronted with the result where there is zero drug level might start taking tablets. It is not just for your knowledge, but it is for the benefit of the patient who might become compliant being confronted with the truth.
Professor Touyz: You bring up a really interesting point there because the question then arises why is the patient not taking the medication and exactly how do you confront the patient? I think there is some evidence that confronting patients in such a way actually pushes them away even further and they do not come back to the clinic for follow-up. We have something quite interesting with respect to behavioral changes and how one as a clinician and healthcare provider deals with these very complex psychological factors that we haven’t really thought about in the past.
Dr Melvin D. Lobo: Coming back to the idea of which drugs you may or may not give somebody with uncontrolled hypertension, I would take issue with what has been said so far. I would say that if you prove extremely refractory hypertension, there are no holds barred on any drug that you might prescribe to get blood pressure down. Because in the face of an unremitting afterload, your options are actually dictated by getting the afterload down. You can worry about various studies that don’t incorporate this kind of patient or you can just get on and sort out the blood pressure.
Now, is this woman actually hypertensive? I haven’t heard any discussion of why the blood pressure is normal in the cardiac catheterization lab, which is the greatest stimulus to hypertension man knows. We frequently have patients sent back from cardiac catheterization because they are so nervous about the procedure. Why isn’t intra-arterial monitoring giving us these blood pressures?
Then observed tablet taking in hospital, how well was it done? Did you actually check her mouth afterward to ensure the tablets had been ingested?
Professor Delles: The blood pressure in the cardiac catheterization laboratory was probably the feature that was really striking for us. She should have been a little bit more hypertensive there, but again it is unknown exactly how sedated the patient was at that time so that may have contributed.
As you know, cardiologists do not assess blood pressure very precisely during these procedures. If this was really measured in parallel or if at some point, they had a central pressure that was lower but did not have the corresponding peripheral blood pressure at exactly the same time, it is difficult to say.
Dr Currie: With regard to observed medication taking, this is something that our inpatient nurses do regularly. I would be fairly convinced that they check the patient has ingested the medication and would be quite alert to observing any behavior that might suggest it was not ingested. Although the 12-hour daytime blood pressure during inpatient stay was significantly lower, I think if the patient wasn’t taking all of those 7 antihypertensive agents and then suddenly took them all as an inpatient, would we not expect it to be even lower? Would she be symptomatically hypotensive?
Professor Jennings: I want to talk about the issue of drug metabolites which I think are the thing of the future. I think they are very, very useful and we certainly do it. However, we’ve already encountered a well-known form of nonadherence. That is people would take the drugs just before they go to see the doctor and sometimes that presents as masked hypertension. So, I wouldn’t want us to get too carried away that this is going to solve all our issues in terms of nonadherence.
Professor Delles: When we talk about adherence we usually mean a longer term adherence and not adherence in terms of taking the tablets on the day before the visit.
Dr Iqbal: Just to continue on the same point, I have a poster in the session tomorrow about 3 patients who were brought to hospital with resistant hypertension and a blood pressure of over 200 mm Hg systolic. Within 24 hours of admission, all 3 patients had systolic blood pressure close to 100 mm Hg and that was only because the nurses stood by the bedside and made sure all drugs were taken. One of the patients unfortunately ended up suffering a transient ischemic attack due to low blood pressure.
Professor Ji-Guang Wang: I want to add 2 things. The first is whenever you measure blood pressure invasively, for instance in the catheter lab, you have to also measure noninvasive blood pressure simultaneously. Otherwise, you would have under estimation in the invasively measured blood pressure.
The other issue is about home blood pressure monitoring. I don’t know whether this patient has ever measured blood pressure at home regularly. Going to the current guidelines, you should measure blood pressure in the morning and in the evening for at least 5 successive days, preferably 7 days. Then you may evaluate according to these home blood pressure monitoring results.
Professor Delles: I think your first point doesn’t need further comments, I fully agree with this. In terms of home blood pressure monitoring, we have not done this formally in this case. I agree, in retrospect, this would have been a very good tool because any additional information would help in this case.
Professor Touyz: Could I ask you one more question about the patient? Could you just remind us what her pulse rate was?
Professor Delles: In the original measurements, it was about 80 bpm.
Professor Touyz: And she was on a β-blocker?
Professor Delles: Yes.
Professor Touyz: Isn’t that in itself a little bit curious.
Professor Delles: Yes, and we will see that it is getting more curious now.
The question was how to proceed next with this patient. She was discussed at our blood pressure multidisciplinary team meeting. Perhaps another clue toward her compliance is that the patient expressed that she no longer wanted to take any additional antihypertensive medications. The decision at that point was made to refer for consideration of renal denervation.
A quick reminder of the procedure: the renal sympathetic nerves are destroyed as they travel along the renal artery using a radiofrequency ablation catheter that is inserted percutaneously through the groin.11 This was not a routine procedure in our clinical practice; therefore, she was referred to take part in a clinical study that was ongoing in Glasgow using the Medtronic catheter.
In the context of this study, all the procedures were carried out by the same interventional radiologist who attempted to use a rotational ablation and administered at least 5 burns on each side.
The patient’s noninvasively measured blood pressure before procedure was 170/90 mm Hg and that was on the 7 antihypertensive medications. During the procedure, this lady became profoundly hypotensive with blood pressure of 84/42 mm Hg and developed a profound bradycardia at 34 bpm. Resuscitation with intravenous fluids and administration of intravenous atropine were required.
Because of the dramatic response to the procedure, she remained an inpatient for 48 hours after procedure, during which time her hemoglobin, renal function, and ECG were all shown to be normal. On discharge from hospital 48 hours later, peripheral blood pressure was 105/64 mm Hg, and she continued to complain of orthostatic symptoms for at least the next 6 months after the procedure. Her ECG immediately post procedure shows that she is in sinus rhythm at the rate of 56 bpm that is slower than her previous resting heart rate. At the point of discharge, she remained on bisoprolol, nifedipine, and furosemide.
Because of her profound bradycardia, she was referred as an outpatient for 24-hour ECG, and this confirmed that she remained significantly bradycardic with the lowest heart rate of 38 bpm. At this point, the β-blocker and ivabradine were discontinued.
Summary of Treatment Pre and Post Procedure
Before denervation, the patient was on 7 agents. Immediately after the procedure, she was on 3 mg, and most recently in 2015, she remains on just 20 mg of furosemide and 30 mg of nifedipine (Table). I believe that there have been attempts to discontinue the furosemide. We have no evidence of heart failure, whatsoever, but this lady subjectively feels that her ankles become swollen and uncomfortable every time it is withdrawn.
A second ambulatory monitor was done 1 month post procedure. Again, there are a suboptimal number of readings, but nonetheless, mean blood pressure is much reduced at 117/73 mm Hg. There is also far less variability in the minimum and maximum readings, although there is only 1 overnight reading. The reduction in blood pressure has been sustained to 10 months post procedure with a mean blood pressure at that stage of 134/78 mm Hg (Figure S1 in the online-only Data Supplement).
Renal Denervation Response: Is It Possible to Predict?
The story started with the Symplicity Hypertension (HTN)-1 proof of concept study.12 Fifty patients were enrolled with quite a significant blood pressure response demonstrated. The true efficacy was questioned by the most recent Symplicity HTN-3 trial that was a sham-controlled randomized trial.13 Between the 2 treatment arms, there was no significant difference in the blood pressure response.
In the United Kingdom, there is currently a moratorium on the routine use of renal denervation.14 Clinical research studies continue, but the procedure is not offered to routine patients in the clinic because of the experience from the Symplicity HTN-3 study.
The Symplicity HTN-3 study was not yet published at the time this patient underwent the procedure. Today, everybody reports that they have patients responding dramatically to the procedure as our patient has. The question is could this have been predicted? Is it possible to identify preprocedure those who will be treatment responders versus nonresponders?
If denervation is done properly, sympathetic nerve activity will be reduced post procedure, which is a measure of the success of the intervention.11 However, it is still very difficult to predict which patients will respond to treatment using readily available markers. Traditional markers, such as age or blood pressure, do not seem to predict the response to treatment. In such circumstances, biomarker studies may be more informative.
One such study published by Dörr et al15 occurred when the authors realized that there were a few patients who respond extremely well to the procedure and others did not respond at all. Many biomarkers were examined, but the discrimination is not particularly good; so these biomarkers will not be clinically useful to predict response to renal denervation. A very cautious commentary in the same issue of Hypertension indicated that there is still a long way to go to find predictors of response.16
Professor Delles: Thinking back 2 years ago, would you also have used renal denervation in this patient? Or would you think it is a dangerous procedure given the patient’s other vascular conditions? And, is there anything in the case that explains this response? What have we done to this lady’s sympathetic nervous system?
Professor Staessen: We did an individual subject meta-analysis of patients undergoing renal denervation in the European Network Coordinating Research on Renal Denervation in Treatment-Resistant Hypertension (ENCOReD) network. There were 2 patients like yours who had a dramatic fall in blood pressure, and when you go to our publication in the Journal of Human Hypertension,17 you will see that there are really outliers in the percent decrease in the blood pressure level. There were 2 patients who did not tolerate any drug. So, they probably were not taking any drug, they were renally denervated, and there was a dramatic fall in pressure. These were 2 Lausanne patients who needed supportive measurements for their blood pressure to be sustained afterward.
Professor Delles: Personally, without being able to give you evidence, I’m quite convinced that this is also the case in this patient. But just to draw the alternative explanation, perhaps this is a lady with an extremely high sympathetic drive that was not blocked properly despite treatment with β-blockers, so she still had a raised heart rate. She would have had such a high sympathetic drive that we needed to disrupt this, resulting in much lower sympathetic drive post procedure. This would explain both the blood pressure and the heart rate response. I do not have direct evidence to prove this, but both cases are possible.
Dr Dan K. Gikonyo: I have only 2 small points. One, I still take exception to using loop diuretics as primary antihypertensives because they are not in the guidelines. For this particular patient, furosemide and nifedipine combination does not seem a wise choice. We know that nifedipine itself does sometimes cause fluid retention and swelling around the ankles. If this lady is still having some swelling around that area maybe the answer is not to use furosemide but just withdraw the nifedipine and maybe use another type of calcium channel or another type of drug that does not cause fluid retention.
Number 2, by the time a patient becomes dishonest with his doctor, because that is what noncompliance means, basically the question is, is it the patient or is it the physician? Is it us who are not taking enough time to explain to the patient why they need to use this medication? Because in my experience, the most important treatment for hypertension is the first visit with the patient. They must understand why they have to take the medication. What is the risk? How long must they take medication and what are the benefits? If you don’t have enough time to explain that on the first visit, we end up with a lot of noncompliance. Sometimes we blame the patient and confront them when in fact, we should be blaming ourselves (audience applause).
Dr Currie: You make a couple of excellent points. Once again, regarding her antihypertensive treatment, we are by no means saying that this is a shining example of the gold standard of how to manage these patients. There are a number of decisions, when we look back through her case records, we think are somewhat illogical. I will reiterate the point that there were numerous specialists involved in this lady’s care.
But you are absolutely right. Patients are not going to necessarily comply with their medication unless they are absolutely convinced of the reason behind this.
Professor Jennings: Two small points in relation to fluid balance. The fact that this lady with normal renal and cardiac function doesn’t like being off her furosemide just raises the possibility of cyclical edema. Somebody who is taking tablets for a few days and then getting a rebound and then thinks they need it. Perhaps another pointer toward an adherence issue in this particular lady.
Professor Delles: Very much so and especially with this ridiculous once daily 20 mg that is not a therapeutic dose, not really following the half-life of the drug.
Professor Jennings: The second point is in relation to fluid balance. We often feel a little smug when we get someone in the hospital and find that their previously uncontrolled blood pressure is normal. But there is an effect of recumbency and in the first 72 hours after hospitalization, you have a significant diuresis and should expect blood pressure to be somewhat lower. It doesn’t always nail the issue of nonadherence.
Dr David Silverstein: We were all thinking in the beginning she wasn’t taking her blood pressure medicine. Her dramatic response would certainly suggest, as you thought also, that she probably was taking her medicine. And to say that her pulse was a little too high for β-blockers, we know that way back it used to be called a hyperadrenergic β-syndrome, when I was a medical student 100 years ago. I have cases of inordinate tachycardias certainly where I have one nursing student who weighs around 45 kg who is on 400 mg of metoprolol twice a day and I am just getting her pulse down to the high 70s.
I also suspected this was a case of noncompliance. However, we know that there are outliers like that who really respond to renal denervation, who have very strong sympathetic nervous systems.
Professor Delles: Thanks for your support.
Professor Wang: I just want to comment that the results of renal denervation in this particular patient should encourage us to do more research in that direction. Especially, try to find the patients who could be responsive to renal denervation. For instance, this patient apparently had increased number of bursts that could be used for identification of patients.
Professor Delles: I apologize for the confusion. In fact, this was not her tracing, rather from the review by Krum et al.11
Professor Staessen: I think the tracing you showed was a single patient at the height of the hype for renal denervation but what I can add maybe is that we are now looking at renal nerve stimulation as a procedural measure of the success of the renal denervation. Together with other groups, what we see is that you stimulate renal nerves, in the renal artery you see an increase in pressure and increase in heart rate. If you successfully denervate, this increase in pressure and heart rate is almost abolished. But it is more important if you look at the ambulatory blood pressure monitoring response after 3 or 6 months, you see the abolition in the acute response in the procedure. The abolishment of the increase in pressure and increase in heart rate in response to renal nerve stimulation. If that goes, you get a significant correlation in the order of 0.7 with a decrease in systolic ambulatory blood pressure monitoring. That might be the future to go on.
Professor Touyz: I would like to ask you one last question. Does this lady still smoke?
Dr Currie: She had stopped smoking just before referral to the clinic following her first MI.
Professor Touyz: So maybe there is some hope still.
We will now illustrate this patient’s clinical progress in the 3 years following denervation. Despite her dramatic response to renal denervation, she has had continued progression of her vascular disease. Because of ongoing claudication symptoms, bilateral external iliac angioplasties were required last year plus a femoral-popliteal bypass, a couple of months ago. In addition to this, her ischemic heart disease has remained very problematic. She has ongoing angina. She had further coronary disease on her recent angiogram and required more percutaneous intervention. And interestingly, in the report of that procedure, she was hypertensive throughout.
We hope that we have highlighted many interesting discussion points, including treatment of resistant hypertension. Where do we go after 3 drugs? How do we prove that patients are taking their medications? Urine metabolite profiling certainly is interesting, but patients may indeed take their tablets in the 2 or 3 days before they come to clinic. How do we interpret in that context? We have discussed a bit about the role of assessing vascular stiffness and central blood pressure in these patients, and also perhaps device-based therapies will still be discussed at these meetings for many years to come.
We acknowledge the significant contribution of Drs Taylor and Mark who oversaw the renal denervation procedure and were responsible for immediate postprocedural care and of Professor Jon Moss who performed the renal denervation. We thank Drs Iqbal, Lobo, Gikonyo, and Silverstein and all audience participants who shared a comment or asked a question for their contributions to the discussion.
Sources of Funding
The patient took part in the Glasgow Renal Artery Sympathectomy Study that was funded by a charitable bequest (the Clark Bequest) administered by the University of Glasgow.
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
Presented as part of the Clinical–Pathological Conference chaired by Professor Anna F. Dominiczak and Professor Rhian Touyz at the 25th European Meeting on Hypertension and Cardiovascular Protection (ESH 2015), Milan, Italy, June 14, 2015. Drs Currie and Delles presented the case and literature review.
The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.115.06756/-/DC1.
- © 2015 American Heart Association, Inc.
- Persell SD
- Mancia G,
- Fagard R,
- Narkiewicz K,
- et al
- Chapman N,
- Dobson J,
- Wilson S,
- Dahlöf B,
- Sever PS,
- Wedel H,
- Poulter NR
- Persu A,
- Jin Y,
- Baelen M,
- et al
- Tomaszewski M,
- White C,
- Patel P,
- Masca N,
- Damani R,
- Hepworth J,
- Samani NJ,
- Gupta P,
- Madira W,
- Stanley A,
- Williams B
- Herbert A,
- Cruickshank JK,
- Laurent S,
- Boutouyrie P
- Williams B,
- Lacy PS,
- Thom SM,
- Cruickshank K,
- Stanton A,
- Collier D,
- Hughes AD,
- Thurston H,
- O’Rourke M
- Krum H,
- Schlaich M,
- Sobotka P,
- Scheffers I,
- Kroon AA,
- de Leeuw PW
- Krum H,
- Schlaich M,
- Whitbourn R,
- Sobotka PA,
- Sadowski J,
- Bartus K,
- Kapelak B,
- Walton A,
- Sievert H,
- Thambar S,
- Abraham WT,
- Esler M
- Bhatt DL,
- Kandzari DE,
- O’Neill WW,
- D’Agostino R,
- Flack JM,
- Katzen BT,
- Leon MB,
- Liu M,
- Mauri L,
- Negoita M,
- Cohen SA,
- Oparil S,
- Rocha-Singh K,
- Townsend RR,
- Bakris GL
- Lobo MD,
- de Belder MA,
- Cleveland T,
- Collier D,
- Dasgupta I,
- Deanfield J,
- Kapil V,
- Knight C,
- Matson M,
- Moss J,
- Paton JF,
- Poulter N,
- Simpson I,
- Williams B,
- Caulfield MJ
- Dörr O,
- Liebetrau C,
- Möllmann H,
- Gaede L,
- Troidl C,
- Rixe J,
- Hamm C,
- Nef H
- Schlaich M