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CPD

Hypertension Case Studies With Single-Pill Combinations

  • Authors: Bryan Williams, MD, FRCP, FESC, FMedSci; Alta E. Schutte, PhD, FESC, FRRSAf, ISHF; Konstantinos Tsioufis, MD, FESC, FACC
  • CPD Released: 9/9/2022
  • Valid for credit through: 9/9/2023
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  • Credits Available

    Non-US Physicians - maximum of 0.50 CPD

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Target Audience and Goal Statement

This educational activity is intended for an international audience of non-US cardiologists, primary care physicians, and nephrologists.

The goal of this activity is that clinicians will be better able to select appropriate first-line, single-pill combinations for treatment of hypertension.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Guidelines for management of hypertension
  • Have greater competence related to
    • Selecting first-line, single-pill combinations for treatment of hypertension
    • Application of treatment strategies in the management of hypertension


Disclosures

WebMD Global requires every individual in a position to control educational content to disclose all financial relationships with ineligible companies that have occurred within the past 24 months. Ineligible companies are organizations whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.

All relevant financial relationships for anyone with the ability to control the content of this educational activity are listed below and have been mitigated. Others involved in the planning of this activity have no relevant financial relationships with ineligible companies.


Faculty

  • Bryan Williams, MD, FRCP, FESC, FMedSci

    Chair of Medicine, University College London (UCL)
    Director, NIHR UCL Hospitals Biomedical Research Centre
    Director of Research, UCL Hospitals NHS Foundation Trust
    National Institute for Health Research Senior Investigator Emeritus
    London, United Kingdom

    Disclosures

    Bryan Williams, MD, FRCP, FESC, FMedSci, has the following relevant financial relationships: 
    Speaker or member of speakers bureau for: Boehringer Ingelheim; Daiichi Sankyo; Menarini; Novartis; Pfizer; Servier 

  • Alta E. Schutte, PhD, FESC, FRRSAf, ISHF

    SHARP Professor and Principal Theme Lead of Cardiac, Vascular and Metabolic Medicine
    Faculty of Medicine and Health at UNSW 
    Sydney, Australia
    Professorial Fellow
    George Institute for Global Health
    Newtown NSW, Australia

    Disclosures

    Alta E. Schutte, PhD, FESC, FRRSAf, ISHF, has the following relevant financial relationships: 
    Speaker or member of speakers bureau for: Abbott; Aktiia; Sanofi; Servier; Sun Pharma

  • Konstantinos Tsioufis, MD, FESC, FACC

    Professor of Cardiology
    Director of 1st Cardiology Clinic
    National and Kapodistrian University of Athens
    Hippokration Hospital Greece
    Athens, Greece

    Disclosures

    Konstantinos Tsioufis, MD, FESC, FACC, has no relevant financial relationships.

Editor

  • Grace O’Malley, PhD

    Associate Medical Education Director, WebMD Global, LLC
     

    Disclosures

    Grace O’Malley, PhD, has no relevant financial relationships.

Compliance Reviewer

  • Susan L. Smith, MN, PhD

    Associate Director, Accreditation and Compliance

    Disclosures

    Susan L. Smith, MN, PhD, has no relevant financial relationships.


Accreditation Statements

    For Physicians

  • The Faculty of Pharmaceutical Medicine of the Royal Colleges of Physicians of the United Kingdom (FPM) has reviewed and approved the content of this educational activity and allocated it 0.50 continuing professional development credits (CPD).

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For questions regarding the content of this activity, contact the accredited provider for this CME/CE activity noted above. For technical assistance, contact [email protected]


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CPD

Hypertension Case Studies With Single-Pill Combinations

Authors: Bryan Williams, MD, FRCP, FESC, FMedSci; Alta E. Schutte, PhD, FESC, FRRSAf, ISHF; Konstantinos Tsioufis, MD, FESC, FACCFaculty and Disclosures

CPD Released: 9/9/2022

Valid for credit through: 9/9/2023

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Activity Transcript

Bryan Williams, MD, FRCP, FESC, FMedSci: Hello. I'm Bryan Williams. I'm chair of medicine at University College, London, and I was the ESC chair of the 2018 ESC/ESH Hypertension Guideline Task Force, and I'm now president elect of the International Society of Hypertension. It's my pleasure to chair this session, and welcome to this program, which is entitled "Hypertension Case Studies With Single Pill Combinations."

I'm delighted to be joined today by Alta Schutte, professor and principal theme lead of cardiac vascular metabolic medicine at the University of New South Wales in Sydney in Australia, and also a past president of the International Society of Hypertension. And as well as Kostas Tsioufis, professor of cardiology and director of the first cardiology clinic at the National University of Athens in Greece, and he's a past president of the European Society of Hypertension. So, a lot of presidents.

And today, we will discuss the use of single-pill combinations in the treatment of hypertension. And we'll use case studies to illustrate some of the key principles outlined in treatment guidelines. Over to you, Alta.

Alta E. Schutte, PhD, FESC, FRRSAf, ISHF: Excellent. Thank you, Bryan. Delighted to join you all today. So I will be speaking on the guidelines on single-pill combination therapy. Perhaps a good place to start off with is to just have a quick look at the international profile, especially for high income countries in blood pressure control rates as it has been reported by the NCD Risk Factor Collaboration. You will see the different control rates of several high-income countries, and then you will see that all of these countries basically have very poor blood pressure control rates. For Spain, for example, it's 29% in women and 25% in men. And many of these countries have control rates less than 50%. So one needs to ask yourself if high blood pressure is such a common condition, and blood pressure medication is widely available, and it's relatively low cost, why are we still having these situations?

The European Society of Hypertension guidelines have included several reasons why they consider that the current treatment strategy has failed to achieve better control rates. And one of these arguments are that there's insufficient use of combination treatment. And that is indeed an important issue, because it's been shown that monotherapy is likely to be inadequate therapy in most patients. Indeed, almost all patients in randomized controlled trials have required combinations of drugs to control their blood pressures.

Another important argument is the complexity of current treatment strategies and also the effect that we have with the increased pill burden, particularly in a condition such as patients having comorbidities, apart from hypertension, also having diabetes, having dyslipidemia, having chronic kidney disease. All of these conditions require more medication, and there's been a lot of evidence showing that increasing pill burden is associated with a lower treatment adherence. And that is why combination therapy, single-pill combination, or fixed-dose combination therapy is really an important strategy to overcome this challenge.

So, in 2018, the European guidelines were published. And I'm joined by my 2 colleagues here today, who've both been co-authors of this important guideline. And in these guidelines, several new key concepts were introduced. One of these key concepts is single-pill combination therapy.

So first of all, dual therapy is important. So not initiating treatment with a single monotherapy, but to have 2 drugs, and especially having them in a single pill is ideal to address the adherence problem. In terms of the fact that these are guidelines for most people, and that is why we are here today, to also address some of the cases where it's not the case, and where there may be some challenges in deciding which of these single-pill combinations should be used, or whether they should be used at all.

So just to demonstrate the importance of single-pill combinations contributing to adherence to medication, you can see in this systematic review meta-analysis that fixed-dose combination, or single-pill combination, is in all trials included, in fact, favored ahead of the free equivalent combinations. And also, and here we are looking at actual blood pressure control compared to monotherapy. We see that free combinations, dual combinations, are better in terms of getting blood pressure under control, and single-pill combination is even better than the free combinations.

So in 2020, the International Society of Hypertension Guidelines followed suit, and also, it clearly indicated single-pill combination therapy wherever possible, starting with a low dose combination of angiotensin receptor blocker or ACE inhibitor, and a calcium channel blocker. As a next step, going to full dose, adding a third drug. And what is important to note is that there are exceptions or special conditions where other strategies may be more effective. For example, monotherapy may be more ideal in frail patients or in patients that are very old. And in other cases, for example, post stroke, incipient heart failure, very elderly, or those with calcium channel blocker intolerance, for consideration for ACE inhibitors or angiotensin receptor blockers and diuretics should be preferred. And in Black patients, it's also a different combination of either a calcium channel blocker and diuretic, or an ACE inhibitor and calcium channel blocker. So it's important to know that there are some of these exceptions.

So last year, the World Health Organization has also followed suit and published their guidelines strategy from pharmacological treatment strategy for hypertension, and again confirmed that initial treatment should preferably be single-pill combination therapy. So there's clear consensus amongst all international guidelines now, and therefore, we should make sure that this message really gets across to clinical practice.

So to conclude, the latest evidence guidelines have consensus and advise, strongly recommend single-pill combination therapy as initial treatment for most patients, because it improves adherence, it simplifies the approach, it includes persistence to medication, and importantly improves blood pressure control. But there are some difficult cases and some challenges sometimes in the clinic to know who to treat and how to treat them, and that's why we are here today. So I hand back to Bryan to start introducing some of the cases. Thank you.

Dr Williams: Thank you, Alta, for that great overview. And we'll now look at how these treatments are actually applied with the use of some case studies.

And this is a 55-year-old man who works as a truck driver around the country. He leads a sedentary lifestyle and, because of his job, he tends to eat takeaway fast food as mealtimes. He's a non-smoker. He considers his general health to be very good, and he's had no significant illness in the past. But he does recognize that he's overweight and because of his lifestyle, he struggles to lose weight. And at a recent health check for his driving license medical, he was diagnosed as having high blood pressure.

So when we saw him in clinic, his office blood pressure was 150/86 using a large cuff, and that's an important qualification here. And so he had grade 1 hypertension, and this was confirmed on 24-hour ambulatory blood pressure measurement, where his 24-hour blood pressure was 142/82. He would be classified as obese with a BMI of 33. His cardiovascular exam was completely normal, and his urine dip was negative for blood and protein. His fundi on examination showed no evidence of retinopathy, and his ECG showed normal sinus rhythm with no criteria for left ventricular hypertrophy. However, on echo he does have mild concentric left ventricular hypertrophy and some borderline left atrial enlargement, and these are characteristic features of early hypertensive cardiac change. His renal function and electrolytes were normal with an eGFR of 83, but he did have a borderline fasting blood glucose at 6.5 mmol per liter, which would put him into the prediabetic category.

His total cholesterol was 5.2, not untypical of European populations, but he has a high LDL at 3.8, because his HDL is low at 0.9, and he has high fasting triglycerides. And this high fasting triglyceride, low HDL, borderline diabetes are consistent with a diagnosis of a metabolic syndrome, which is quite common in patients with hypertension, particularly when they're overweight.

Now, his 10-year risk according to the SCORE2 chart, which we use in the ESC, is a 5%. That would put him at moderate risk. But because he's got early hypertension-mediated organ damage, he'd be classified as moderate to high risk.

Now, if we look at what the guidelines say, in grade 1 hypertension, he would get lifestyle advice immediately, and because he has early evidence of hypertension-mediated organ damage, he would be classified as high or very high risk and therefore, would qualify for immediate drug therapy. And in terms of lifestyle advice, the 3 things that are important in this context are, firstly, sodium restriction. If he's eating a takeaway diet, he's bound to be eating lots of salt in processed food, and we need to try and address that. Secondly, obviously, and he knows this himself, he needs to try and get his body weight under control by adjusting his diet and taking more exercise to try and reduce his sedentary lifestyle.

Now having covered the lifestyle, the next is treatment and how low we should go. He's in the younger patient category, according to the European guidance. The blood pressure target for all patients, actually, is to try and get blood pressure below 140/90 in the office as the first target. And then, in this patient, aim to try and get blood pressure down to 130/80 or lower. So that's quite consistent with guidelines around the world, particularly for younger patients.

Now in terms of treatment, this is now a well-recognized treatment strategy, a RAS blocker in combination with a CCB or a thiazide/thiazide-like diuretic. We could consider giving him monotherapy, but because he's at least 20 mmHg over his target systolic blood pressure, we would start with single-pill combination in this patient. And because this patient has prediabetes, we wouldn't want to risk worsening that with a diuretic. And so I chose to treat him with a RAS blocker and a CCB as a single pill, particularly as he was not keen on taking any medication at all.

And just to show you how effective that kind of treatment can be, 3 months later, he turned up with an office blood pressure 126/77, but also lost a bit of weight and had modified his diet.

And the last consideration was whether we would also add a statin therapy to his treatment. That's because he's also at moderate to high risk. The European Hypertension Guideline recognize that we need to take a holistic approach and really manage cardiovascular risk in general. And we recommended statins for all patients at high and very high risk, but also to consider statins in patients at low to moderate risk as well. And in this case, I recommended to him that he also took a low-dose statin to further reduce his cardiovascular risk. So that's case number 1.

Any comments on the treatment strategy that we've deployed here?

Konstantinos Tsioufis, MD, FESC, FACC: I absolutely agree with the proposed treatment strategy, Bryan, the first objective is to control the blood pressure, and of course, it would be better if we could achieve this target by selecting the most appropriate single pill combination. As in your case, a RAS blocker with CCBs, due to cardiometabolic profile of the patient.

Dr  Williams: Great. And, Alta, any comment on the first case?

Dr Schutte: Thank you, Bryan. I was just wondering, in terms of the statin treatment, do you think a SPC with an antihypertensive and statin combination could also be considered?

Dr Williams: Yeah, I mean, it is a possibility. I mean, many patients don't like taking multiple pills. You notice, in this particular case, I focused on getting the blood pressure down first, because I think that was the most important thing to target. And then in a subsequent discussion, we talked about risk reduction and adding in a low-dose statin. It's very common here in this country to give statins to hypertensive patients as part of the strategy to reduce risk. But I agree, we're beginning to see combinations of drugs with statins as well. And I think it's a really good suggestion.

I'd now like to present a second case from our clinic, and this is a slightly different challenge. So this is a 79-year-old female who's a retired secretary. She still leads a very active lifestyle for her age. She's really out and about, independent, but she has noted that she's getting more breathless, particularly on climbing stairs and on exertion recently. She eats a healthy diet, but does, like many older people, like to add salt to her food. She is a past smoker, but stopped 40 years ago, and has a total of a 10 pack-year history. Her general health is reasonable, apart from the fact that she's developed a bit of arthritis in her hip. And she has noticed that her memory is not quite as good as it was some years ago.

Now, she was diagnosed hypertensive 15 years ago at a routine health check, and she was treated at that time, but she decided to stop treatment because she developed a cough, an irritating cough. And she was so disappointed that she developed side effects of treatment that she'd not gone back to the doctor, and she'd never had any intervention ever since. She does take occasional NSAIDs for hip pain, but no other treatment.

When we saw her, her office blood pressure was 174/68. And importantly, in the elderly, there was no significant postural drop. However, she clearly has isolated systolic hypertension. Systolic elevated, diastolic, if anything, low normal. 24-hour blood pressure consistent with that diagnosis of 158/66. BMI was normal. Cardiovascular exam was normal, except she had an added fourth heart sound on cardiac auscultation. Urine dipstick again was negative for blood and protein. Fundi showed some characteristic aging features, silver wiring, and grade 2 changes in the retina, consistent with hypertension.

And ECG showed normal sinus rhythm, but there were occasional atrial ectopics, and she had voltage criteria for left ventricular hypertrophy with an early strain pattern. An echo showed a moderate concentric left ventricular hypertrophy, a normal ejection fraction at 58%, but clearly evidence of impaired diastolic relaxation, and some left atrial enlargement. And these would be consistent with the kind of findings that you see in later stage hypertension with left ventricular hypertrophy, and really the antecedent of heart failure with preserved ejection fraction. Her renal function was normal for age, eGFR of 62, and her glucose and lipids were normal.

Now her SCORE, 10-year risk is high, but largely driven by her age.

She comes into the grade 2 category, And again, if we look at lifestyle, the only thing we can really focus on in this patient is her salt intake, and ask her to stop adding salt into food, or alternatively, consider a salt substitute, which as many of you will know, have recently been shown to reduce mortality in patients who consume excess salt. In terms of the target, again, trying to get blood pressure below 140/90 as a first target. People often talk about targets in the elderly as though they're easy to achieve, but actually it's not easy to get to that level of control in older patients, particularly with quite high systolic pressures. But the aim is to get below 140/90, and try if possible, to get down towards 130 systolic.

Now I wanted to just make a comment on the low diastolic, which is very common in older patients due to arterial stiffening. And low diastolic we know is associated with increased cardiovascular risk and mortality; however, this is primarily due to the fact that it's a marker of associated arterial disease. And we also know from many studies that treating isolated systolic hypertension, even though it lowers diastolic pressure further with treatment, that patients benefit from the systolic pressure reduction in this very high-risk group, and the benefit is substantial. So we said in guidelines, the concern about a low diastolic should never be prioritized over the effective treatment of systolic hypertension. Having said that, we need to be really careful, because if the diastolic is low, the patients will be more sensitive to side effects from blood pressure lowering. That's why in the elderly, we pay particular emphasis to say you must monitor for side effects of treatment.

Now, I think in view of the fact that she has a heart failure with preserved ejection fraction, is high risk of progression of that, and we know in the elderly, in older patients with symptomatic heart failure, even HFpEF, we would give an ARB and a diuretic in low dose as initial therapy, checking lying and standing blood pressure, and monitoring kidney function and other side effects very closely, because of the isolated systolic hypertension and low diastolic. And then, if that wasn't successful in controlling pressure, the option of going to a higher dose of that dual therapy, and also remembering in view of the evidence now available about considering even the addition of an SGLT2 inhibitor, which would act as an additional diuretic therapy as well, and improve blood pressure further, because of this patient's diagnosis of HFpEF. And then the third option would be to add in a CCB in low dose, if needed to try and get down towards that target.

Dr Schutte: Bryan, I fully agree with the strategy. I was wondering in the case where her diastolic blood pressure does indeed drop to let's say 50 mmHg, which is, I think, a very challenging patient to treat in that case. What would you consider in terms of changing that treatment?

Dr Williams: Well, it always comes up in discussion this, about the diastolic. And actually, a few years ago, I wrote an editorial for The Lancet suggesting that in people with isolated systolic hypertension, we should stop measuring diastolic blood pressure, because it just actually creates problems, because you get nervous when you see a drop. And actually, quite a lot of elderly patients have unrecordable diastolic blood pressures on treatment. I think the point I was trying to make is what's really important, I think, is actually to monitor the side effects, because if your diastolic is too low, you will see reduction in renal perfusion in the elderly, you will see side effects of tiredness, dizziness. So that's why the guidelines emphasize not so much to be hung up on the numbers, but actually to focus on monitoring tolerability in the elderly. And I think that's critical.

The danger is people don't treat the systolic because of this theoretical concern about diastolic. And isolated systolic hypertension is the highest risk condition in terms of hypertension. So that was the point I was trying to make.

Dr Tsioufis: Yeah, I think that HFpEF is a significant comorbidity. Actually, in my understanding, HFpEF means uncontrolled hypertension. It means isolated systolic hypertension. In these lines, Bryan, although I understand why you select the therapy as with diuretic, given that CCB has a proven favorable effect on arterial elastic properties, and also isolated select hypertension means increased arterial stiffness. How let's say wrong would it be to select a RAS blocker with CCB in these patients instead of selecting diuretic?

Dr Williams: Yeah, I think it's perfectly reasonable. The main reason I went for diuretic is because the evidence of preventing heart failure and hospitalization for heart failure is much stronger with diuretic based therapy. But CCB a perfect option. And actually, I think in this case, she'll probably end up on all 3 eventually, in low dose, alongside the SGLT2 inhibitor to try and protect her heart, but also get her blood pressure optimally controlled.

Okay. So we can now move on to our third case. And it's my pleasure again, to bring in Kostas Tsioufis. Over to you, Kostas.

Dr Tsioufis : Thank you, Bryan. As an introduction, let me remind you the huge burden of chronic kidney disease. Mortality from CKD is projected to become the 50 global cause of death by 2040. And over 80% of CKD patients have a history of hypertension while diabetes mellitus accounts for more than 40% of the CKD disease.

Let's come into our case, we have a 65-year-old male diagnosed with hypertension 2 months ago. He's obese, but without snoring during the sleep. He's under treatment with metformin and SGLT2 inhibitors for diabetes mellitus, and for high cholesterol level with atorvastatin 20 mg. Office blood pressure was high, 150 for systolic, 95 for diastolic, 3 readings by using automated device with the appropriate cuff size. First measurements in both arms in the sitting and standing position, according to what the European Hypertension Guidelines recommend. And the diagnosis of hypertension was confirmed by home blood pressure measurements, as well as by a blood pressure monitor.

We see that the diabetes mellitus was well controlled, while the GFR was reduced, 42. And the patient also has some degree of microalbuminuria, the urinary albumin excretion rate was 85 mg/g. ECG revealed sinus rhythm without any abnormalities and also no left ventricular hypertrophy was detected in cardiac echocardiogram. In this, for the management of this patient, we have to address the following 3 questions. Starting from the first question, and based on taking into consideration that the patient has a history of diabetes mellitus with microalbuminuria and also reduced GFR of 42, the patient is classified in the category of high cardiovascular risk

The most important point is what should be the blood pressure targets in this patient? We have data from randomized controlled trials, the SPRINT that included patients with chronic kidney disease but not patients with diabetes mellitus, while we have data also from the ACCORD study, which included diabetic patients. And all these standards compared the intensive blood pressure control compared to standard blood pressure control. And despite the same data from these randomized controlled trials, different scientific societies provide different interpretation and different recommendation regarding the blood pressure targets in these patients with chronic kidney disease.

We see here that the European Hypertension Guidelines recommend to go below 140, but avoid going below 130, irrespective of the age of the patient over 65 or less than 65, while the American guidelines recommend to go below 130. And recently, the KDIGO recommend to go even lower, below 120. And particularly for this recommendation, there are a lot of criticism. First of all, this recommendation was based on the data from only one single randomized trial, which has not included diabetic patients. On the other hand, we know that SPRINT used the standardized methods for measuring blood pressure, and not the repeat method that all the trials have used. And that this was one of the reasons for different recommendation.

Additionally, this target of below 120 will increase the side effects, particularly in these patients of CKD who are in the majority elderly patients, frail. And we know that lower blood pressure is associated with side effects. And in the end, it's very difficult in the everyday clinical practice to achieve this target below 120, since no one study has achieved this value up to now.

How to achieve these blood pressure targets? The European Hypertension Guidelines recommend that RAS blockers should be a part of the treatment strategy in these hypertensive patients in the presence of microalbuminuria or proteinuria.

So coming back to our case, I think that there is no doubt about the need this patients to be treated with hypertension medication. And also about the target. At least we have to target below 140, below 90 for diastolic. No question that RAS blockers should be the base of our antihypertensive strategy, but we know very well that monotherapy will not be enough to achieve the blood pressure target. And polypharmacy and poor medication adherence is very common. So for this reason, the European Hypertension Guidelines recommend single pill combination therapy for the most patients with chronic kidney disease, for the most patients with hypertension and diabetes mellitus, RAS blockers with CCBs or diuretic.

Of course, we provide advice for reducing the excessive body weight. At follow up after 2 weeks, office blood pressure was controlled, 130 to 135, 80 for diastolic, and also similar readings with home blood pressure measurements. And at 26 months later, the albumin-creatinine ratio was completely reduced. So I think by with this strategy, we provide a holistic approach to our hypertensive patient. Thank you.

Dr Williams: Kostas, really interesting case that you presented, and a really challenging problem of diabetes, chronic kidney disease, and you raised a very controversial issue of blood pressure targets.

Dr Schutte: Yeah, it is indeed a complex case. It was well presented, Kostas. You mentioned a treatment target of 130 to 140 for systolic. For diastolic, would that then be the target of 70 to 80 mmHg?

Dr Tsioufis : I think that this is the target below 100, and below 80, but I wouldn't go below 70. But I would agree with what Bryan previously said. The first objective is to control systolic blood pressure. Take into consideration how well the patient tolerate the diastolic blood pressure.

Dr Williams: Yeah. And I was going to ask you about the sort of macho approach to blood pressure targets, where wherever one gets recommended, you get somebody else coming out with a lower one. And really, I mean, I haven't got any patients with chronic kidney disease in this age group with a systolic blood pressure below 120. I don't know how people achieve it.

Dr Tsioufis : It's not realistic to recommend to go below 120. Take into consideration that the vast majority of patients with CKD with diabetes mellitus have resistant or difficult to control hypertension, this is our problem. This is the problem of dealing with these patients. How to achieve at least below 140. You can imagine how let's say efficiently it is to go below 130, apart from the fact that this is not, this may be dangerous for the patient.

Dr Williams: Yeah. And also I think what tends to happen when you get down to those low levels of pressure, you start seeing reductions in renal perfusion pressure and kidney function deteriorating more rapidly, and people get very anxious. And also, I generally have a philosophical view when writing guidelines that you shouldn't really recommend things that aren't achievable. And I think it's pretty despairing and demoralizing if you get a target that only a small percentage of patients will be able to achieve. Anyway, I think we can close the discussion. There's been a really great discussion, and thank you very much. And thank you for participating in this activity.

This transcript has not been copyedited.

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