Curr Hypertens Rep (2015) 17:49 DOI 10.1007/s11906-015-0565-x
NOVEL TREATMENTS FOR HYPERTENSION (T UNGER, SECTION EDITOR)
New Hypertension Guidelines: Progression or a Step Backwards in Hypertension? Markus van der Giet 1 & Markus Tölle 1
# Springer Science+Business Media New York 2015
Abstract In the last years, many hypertension guidelines have been published as new or revised versions. They follow the general trend that only clinical evidence is relevant for guidelines. Expert opinion is downplayed. At present, guidelines from three major organizations have been produced: by the European Society of Hypertension, the International Society/American Society of Hypertension, and the US Joint National Committee. We discuss eight versions of these guidelines in this review. All of these include statements on blood pressure goals or treatment algorithms for patients with high blood pressure. The variability of practical tips is great, and the recommendations, which mainly rely on evidence-based medical information, show slight differences that have resulted in some confusion with specialists and also practitioners. In the current review, the changes in the guidelines in comparison to previous guidelines are discussed, and reasons for different recommendations are explained. The hope is to reduce confusion.
Keywords Hypertension . Treatment . Guidelines . Treatment recommendations
This article is part of the Topical Collection on Novel Treatments for Hypertension * Markus van der Giet [email protected] 1
Campus Benjamin Franklin, Med. Klinik mit SP Nephrologie, Charite - Universitätsmedizin Berlin, Hindenburgdamm 30, 12203 Berlin, Germany
Introduction Perhaps, the years 2013–2015 will be a turning point in medical guideline history. In these years, more than eight international or national guidelines for hypertension diagnosis and management have been published [1•, 2•, 3, 4•, 5–8]. One can speculate that more than a hundred experts in the field of hypertension worked thousands of hours on these various guidelines to establish evidence-based recommendations. Some of the guidelines had been published in previous years, and only an update was necessary. The guidelines show a variation in scale and details. The guidelines of American Society of Hypertension (ASH)/International Society of Hypertension (ISH) present their recommendations on 13 pages with 25 references [2•], and the European Society of Hypertension (ESH) present a guideline of 60 pages citing 735 references [1•]. The ESH also provide a more focused smaller version of the guidelines as a practical guideline [9] for everyday practice. It is a fact that the worldwide prevalence of hypertension is raising. In 2013, the world health organization (WHO) gave a global brief on hypertension (http://apps.who.int/iris/ bitstream/10665/79059/1/WHO_DCO_WHD_2013.2_eng. pdf?ua=1). More than one billion people suffer from hypertension. In everyday practice, we see that hypertension often has no real symptoms and hypertension does not hurt directly. But hypertension is one of the main causes for the excessive number of cardiovascular events and deaths worldwide. The WHO wants to play a critical leadership role in efforts to tackle hypertension, as well as its causes and consequences. Cardiovascular diseases cost the countries billions of euros, and many countries cannot afford it. For these reasons, it is essential to have guidelines on how to diagnose and manage hypertension to overcome the potential health economic burden. Currently, there are no recommendations or guidelines established by the WHO.
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Purpose of Guidelines in Hypertension Management The purpose of guidelines in the world is very variable. It depends on the goals that are set. Nearly every guideline wants to give clinical practice guidance for physicians in diagnosis and therapy. Depending on the persons or groups writing the guidelines, not only medical/evidence reasons but also health economic might influence the result of the guidelines. The Kidney Disease Improving Global Outcomes (KDIGO) initiative (www.kdigo.org/) tried to develop guidelines on thorough literature research and then defined the true existing treatment evidence. Pharmaceutical industry or governmental aspects should not influence the experts commenting the evidence. Evidence was systematically analyzed with mathematical or statistical methods. At the end of every recommendation, especially the scientific needs for every disease or open questions are given. Therapeutic recommendations are strictly graded on evidence level. Within this process, we often find at the end that a lot of evidence is missing and no evidence-based recommendation can be given. International independent guideline writers who do not have to follow any economic necessities or national/local problems usually try to perform the way of only following evidence. Economic resources and also local specialties often influence national guidelines, especially in the case that certain goals (e.g., awareness of hypertension, successful treatment of hypertension) must be achieved. A very good example for this approach is the UK NICE guideline for hypertension (http:// www.nice.org.uk/guidance/cg127). A third guideline type wants to explicitly give practical tips for management of diseases in everyday practice. The new French recommendations [4•] are designed in this way. These guidelines should be practical: easy-to-read format, usefulness for clinical practice, and even comprehensive writing for nonphysicians. The idea of the French guideline is to improve awareness and treatment quality of hypertension. Of course, every actual guideline follows the evidence-based principles, but expert opinions are more or less pronounced. This is definitively not wrong and might be missing in the strict evidence designed guidelines. The main problems of the many international and national guidelines with their different approaches are sometimes confusing results. The recommendations might vary on closer inspection in diagnosis of hypertension, treatment algorithm, or even the definition of blood pressure goals. This is especially complex for countries, which do not publish their own guidelines. Germany follows ESH guidelines. France has published its own guidelines following mainly the argumentation of ESH but giving more simple practical tips that are missing in the ESH guidelines. In the USA, there are two guidelines published within a short period of time, which even have nuances of interpretation within their guidelines. Which guideline should a physician follow?
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Many guidelines within the last few years have been rewritten or revisited: What has really changed? In the following paragraphs, we focus on three prominent—international— guidelines by ESH, ASH/ISH, and Eighth Joint National Committee (JNC 8) to define changes to previous versions and variations between guidelines. The reasons for different consequences are critically discussed.
Relevant Changes in ESH Guidelines What are the main changes in ESH guidelines? The ESH published guidelines in 2007 [10]. In 2009, a reappraisal of the European guidelines was necessary due to new study results especially challenging hypertension treatment goals. In 2013, the ESH published new completely rewritten guidelines [1•]. A smaller version of the guideline was published as a practical guideline [9]. These practical guidelines however are only an excerpt of the larger version. Mainly, the tables and figures from the larger version were published with condensed text. There are no real practical tips given in these Bpractical guidelines.^ In addition to the new guidelines, additional recommendations on the management of patients with obstructive sleep apnea [11] and a position paper on ambulatory blood pressure measurement [12] were published. The main changes between 2007 and 2013 are the changes in the blood pressure treatment goals. There are now no differences regarding blood pressure goals in patients with comorbidities like chronic kidney disease (CKD) and diabetes. All patients should have blood pressure below 140/90 mmHg. Patients with an age over 80 years can have blood pressure goals up to 150 mmHg systolic. In 2007, the guidelines followed the general concept that the lowest achievable blood pressure might be the best. This assumption was based on a meta-analysis, where it could be demonstrated that a systolic blood pressure reduction to 126 mmHg in comparison to 131 mmHg is favorable. Similar results were shown for systolic blood pressure of 140 versus 145 mmHg [13]. The data observed in these studies were all post hoc analysis. This approach usually leads to the loss of randomization in these studies. In addition, with a more reduced blood pressure, we see a flattening of hypertension-associated risks for these patients. Then, real positive effects are difficult to analyze. An alternative to the concept Bthe lower the better^ is the concept of Jcurve. Behind this concept, there is the assumption that blood pressure should not fall below a certain value not to induce critical low organ perfusion with consecutive increase in negative events. Until now, only meta-analyses confirm this hypothesis. There is no randomized controlled trial that could identify the J-shaped phenomenon so far. The investigators of the hypertension optimal treatment (HOT) study tried to identify a threshold for diastolic blood pressure [14]. Also, other studies tried to find evidence for the J-shape
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phenomenon, but the data are conflicting [15]. So, current recommendations for blood pressure goals can only be deduced from clinical hypertension treatment trials. We know that systolic blood pressure reduction below 140 mmHg reduces cardiovascular events. In the FEVER trial, it was very elegantly demonstrated that even blood pressure reduction from 142 mmHg systolic to 137 mmHg in patients without relevant cardiovascular risk or in patients with diabetes and elevated cardiovascular risk reduces event rates by 11 and 17 %, respectively [16]. But there is no evidence for further positive effects of even lower systolic blood pressure reductions. The ESH guidelines use this argumentation to define the systolic blood pressure threshold of below 140 mmHg for all patients. Blood pressure goals for patients over 80 years of age have been modified. The goals are not as ambitious as they were in previous guidelines. It is very well-known that blood pressure reduction in elderly persons is reasonable [17], but the reason to relax blood pressure goals from below 140 mmHg systolic to 150 mmHg systolic is more a consequence of practical reasons and missing true evidence. Most studies investigating also patients with age over 80 years did not reach a blood pressure target below 140 mmHg [18], and there is conflicting evidence whether tight control below 140 mmHg systolic really has clinical relevant effects for this group of patients [16, 19]. Increasing the dosages of antihypertensive medication to achieve blood pressure goals below 140 mmHg systolic increases side effects like orthostatic hypotension and the risk for serious fall injuries [20••]. In the ESH guideline from 2007, patients with high cardiovascular risk profile, as observed in patients with diabetes mellitus and/or chronic renal failure, had blood pressure targets of below 130 mmHg systolic. In the new guidelines, this limit disappeared for two reasons. The guidelines now strictly follow an evidence-based concept. In 2007, the recommendations were not only based on evidence but also on expert opinions. As there was missing evidence about blood pressure targets in diabetes or CKD, it was thought that evidence should come with forthcoming studies. This was the expert opinion at this time point. However, we had to learn that evidence sometimes might not follow expert opinion. For instance, in the ACCORD study, systolic blood pressure targets of 119 versus 133 mmHg were not superior with respect to further reduction of cardiovascular event in diabetic patients [21]. In patients with CKD, a more intense blood pressure reduction was recommended in the ESH 2007 guidelines. This recommendation was withdrawn in the current version of ESH guidelines. The authors argue that there are definitively some hints that patients with chronic renal failure and proteinuria might profit from more intensive blood pressure reduction, but the evidence is not sufficient to give a special recommendation [22]. As a consequence, the blood pressure targets have been
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substantially relaxed in the current ESH guidelines. In this part of the guidelines, the existing evidence plays the essential role to determine the results. Concerning the blood pressure therapy in patients, there are no substantial changes in the current ESH guidelines compared to the 2007 guidelines. Early combination therapy should be initiated to control blood pressure. The most prominent change is the essential focus on encouraging patients for life style changes at any stage or comorbidity of hypertension. The authors of the ESH guidelines do not recommend a special treatment algorithm with specialized medication sequence of medication. There is a hexagram showing possible good combination therapies. They notice that in principle, the following antihypertensive drugs: β-blockers, calcium channel blockers (CCB), angiotensin-converting enzyme (ACE) inhibitors (ACEI)/angiotensin receptor blockers (ARB), or thiazide-type diuretics (thiazides) may be equally used as first-line antihypertensive drugs. It is noticed that some medications might have negative metabolic effects, but this is not considered sufficient to eliminate one or two drugs as first-line antihypertensive. The ESH acknowledges that a meta-analysis on βblockers gives the impression that these substances might be inferior to other blood pressure reducing agents [23], but the ESH argues that this inferior effect of beta-blockers is not attributable to every β-blocker used. For the ESH, the results of the above-mentioned meta-analysis are not sufficient to generally neglect β-blockers as first-line antihypertensive drugs. This is a bit a confusing: In the blood pressure target section, it is argued that pure evidence should define the blood pressure target range. However, concerning β-blockers, the rule of evidence is not fulfilled optimally since there is no evidence that all β-blockers really are equal to e.g., ARB or ACEI. The ESH guidelines recommend certain combination therapies for hypertension treatment. None of these is recommended definitively as superior. The ESH writers cite the ACCOMPLISH study [24••, 25, 26]. In this study, it was tried to identify which antihypertensive combination therapy might be the best. The ACE inhibitor benazepril was combined with either the thiazide diuretic bendroflumethiazide or the calcium channel blocker amlodipine, and the ACEI/CCB combination turned out to be superior to the ACEI/thiazide combination. However, as this is only one study, this was not sufficient evidence for the ESH to recommend the combination of ACEI/CCB as a favorite combination therapy. In general, a clear and simple treatment algorithm for hypertension is missing in the ESH guidelines. The reader itself has to extract this for himself. A clear statement on how to deal with resistant hypertension is also missing. There is no precise statement on what we can do with additional antihypertensive drugs and how these might be tested. The still more experimental interventional approaches are shortly discussed, and reference is given to a position paper of the ESH on renal denervation treatment [27].
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In conclusion, the main changes in the ESH guidelines are the slight changes of blood pressure target levels, in particular giving up the strict levels for patients with diabetes and CKD. The new target levels are more relaxed. The recommendations on how to treat hypertension have not been substantially changed. A treatment algorithm is missing. In everyday practice, physicians have to draw their own conclusions from these guidelines. The practical aspect is missing, despite the fact that the guidelines are excellently written and represent a very thorough analysis of the current literature and evidence. Changes in JNC 8 and Comparison to ESH 2013 In 2014, the panel members appointed to the Eighth Joint National Committee (JNC 8) published a report [3]. It is not the long-awaited revision of the JNC 7 guidelines from 2003 [28]. For the 2014 guidelines, the authors decided to define a systematic and restrictive methodology, mainly focusing on evidence-based medicine. Randomized controlled trials had to fulfill certain criteria to qualify for guideline influence. Prior to design of any guideline, the authors defined certain relevant questions with the highest priority in hypertension treatment. As a consequence, the report is not a revision of the 2003 guidelines, but features a completely new design. The authors did not want to present guidelines for as many incidences in hypertension as possible. Expert opinion is not presented in the guidelines. When reading these guidelines, one can read between the lines that discussions were not easy and consensus was sometimes difficult to find. The blood pressure targets defined in JNC 8 are very similar to the ESH recommendations. This fact is not very surprising because randomized trials analyzed for these guidelines were very similar. The argumentation to skip special blood pressure limits for patients with diabetes or chronic renal failure is in line with ESH. The only difference is the recommendation of blood pressure targets for patients with the age greater than 60 with no diabetes or CKD in history. In these patients, blood pressure reduction should be initiated when blood pressure is above 150 mmHg. The ESH guidelines recommend this goal for patients older than 80 years of age. Interestingly, the JNC 8 recommendation is termed a grade A recommendation. How do the experts come to this conclusion? The essential reason is that ESH did not ask this question, whereas JNC 8 wanted to know whether blood pressure over 60 should be differentially treated from those patients below 60. This was one question before writing the new guidelines. The panel of JNC 8 investigated the question and found definitive evidence that reduction of systolic blood pressure below 150 mmHg reduces event rates significantly, but the panel’s opinion after thorough analysis of trials like SHEP, HYVET, Syst-Eur, JATOS, VALISH, and Cardio-Sis [17, 19, 29–32] is that the evidence to reduce blood pressure below 140 mmHg in patients >60 is an expert opinion and not
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sufficiently evidence-based. The main point is that in the two different guidelines, different questions were asked, and the consequence is confusion. The argumentation of JNC 8 is comprehensible, but it is definitively debatable whether the right question was asked. As a reaction to the new recommendation not to reduce blood pressure below 150 mmHg systolic, the investigators of the International Verapamil SRTrandolapril (INVEST) study [33] reanalyzed their data. The INVEST investigators could demonstrate that achieving a blood pressure target 140 to 150 mmHg (as recommended by the JNC 8 panel) provided less benefit than a target below 140 mmHg in hypertensive patients with coronary artery disease who are older than 60 years of age [34••]. Thus, the JNC 8 recommendation is questionable and should be revisited. After such a revision, the ESH and JNC 8 guidelines would have no real difference any more concerning blood pressure levels. First-line antihypertensive treatment in the recommendation of the JNC 8 panel is more restrictive than in the ESH guidelines. The JNC 8 panel recommends ACEI/ARB, CCB, or thiazides as first-line therapy. The panel refuses β-blockers the status as first-line antihypertensive drug. They state that the Losartan Intervention For Endpoint (LIFE) study delivers sufficient arguments that the use of β-blockers resulted in a higher rate of the primary composite outcome of cardiovascular death, myocardial infarction, or stroke compared to the use of ARB [35]. Mainly, the stroke incidence was higher in the β-blocker group of the LIFE study. In addition, other nonselective α 1/β-blockers (carvedilol) or vasodilating βblockers (e.g., nebivolol) are not recommended as first-line therapy due to missing adequate randomized trials. This statement was also made for central α2-adrenergic agonists (e.g., clonidine), direct vasodilators (e.g., hydralazine), aldosterone receptor antagonists (e.g., spironolactone), and loop diuretics (furosemide). The JNC 8 panel recommendations are focused on blood pressure goals and antihypertensive treatment in comparison to ESH guidelines. Other hypertension relevant questions, i.e., blood pressure measurement and diagnostic of secondary hypertension, are not discussed. JNC 8 presents very straightforward practical guidelines. For the US health system, guidelines are of the highest importance. The US health authorities and the government have a very strong focus on optimizing health risks in their system. A recent NHANES report has demonstrated that awareness of hypertension has been increasing over years up to 80 %. Treatment rates in patients with hypertension are high, but effective control rates have increased until 2010 and thereafter slightly decreased [36]. The uncontrolled hypertension rates are low in the USA, but an essential question concerns the impact of the more relaxed blood pressure rates of JNC 8 on uncontrolled hypertension rates [37]. The percentage of the US population labeled as suffering from
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uncontrolled hypertension has changed from 16.6 to 12.8 %. However, this is mainly a consequence of reclassification and not of better treatment. Interestingly, the greatest impact of reclassification is on elderly, females, and those with diabetes. Recently, the potential economic cost-effectiveness of successful implementation of JNC 8 guidelines was analyzed [38••]. It was calculated that the implementation of these guidelines could prevent about 56,000 cardiovascular events and 13.000 deaths annually. At the same time, a substantial cost saving could be identified. From a European view, one can only be jealous how systematically the US health systems analyze epidemiology of all facets of hypertension, how guidelines are developed, and how the economic consequences are calculated. We can be sure that in some years, the success of implementing the guidelines will be analyzed. ASH-ISH Guidelines Parallel to the JNC 8 panel recommendations, the American Society of Hypertension (ASH) in cooperation with the International Society of Hypertension (ISH) and endorsed by the Asia Pacific Society of Hypertension published a statement and a clinical practice guideline [2•]. These guidelines are completely new. In the introduction, the authors describe the methodology of their guideline development. They clearly state that there is insufficient published data from clinical trials in hypertension to create recommendations that are completely evidence-based. They acknowledge that some of the recommendations also reflect expert opinion and experience. The authors also interpret their guidelines as an initial version, which might be followed by discussions and revisions to come. The guidelines are about the same length as the JNC 8 recommendations but try to cover all relevant aspects in diagnosis, therapeutic goals, and treatment. In principal, the guidelines are in line with ESH 2013. Blood pressure goals are defined in the same way. The ISH/ASH guidelines recommend ACEI/ARB, CCB, or thiazide as first-line drugs but also differentiate that non-black patients 60 years should get CCB or thiazide as first-line treatment. There is no explanation for this recommendation that can be followed. The authors are very well aware of the fact that recommendations cannot be very directive, as the choice of drugs will further be influenced by their availability and affordability. In many countries, it might be necessary to take the drug provided by the government or other agencies. For blood pressure over 160/100 mmHg, the guidelines recommend to start with two antihypertensive drugs right away. In contrast, JNC 8 and ESH 2013 see this as one option among others. ISH/ASH and JNC 8 have a statement on first-line antihypertensive drugs in black patients. This should be CCB or thiazide. This recommendation is derived from a subgroup analysis of the ALLHAT trial [39]. JNC 8 regarded the evidence
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from this trial as high enough that CCB or thiazides are more effective in improving cerebrovascular, heart failure, and combined cardiovascular outcomes compared to ACEI in black patients. The ASH/ISH guidelines are very practical.
Conclusion There are now three major new hypertension guidelines presented which come to very similar conclusions and feature only slight variations of the same recommendations. This is not very surprising, as every guideline wants to be as evidence-based as possible and the guideline authors use the same literature for evidence. But, as written in the ISH/ASH guidelines, it is often difficult to find evidence for every aspect in hypertension diagnosis, treatment goals, or therapy. Personal opinion or experience is also still of importance. The biggest surprise, perhaps in consequence the most confusing recommendation, is the different blood pressure goals for patients without CKD or diabetes between 60 and 80 years of age. JNC 8 recommends initiation of drug therapy with systolic values >150 mmHg. On the other side, ASH/ISH or ESH 2014 recommend initiation of a therapy with systolic blood pressure values >140 mmHg. This confusing result indeed is more a consequence of different approaches by the individual panels writing the three guidelines. ESH 2013 thoroughly revisited guidelines of 2007. There was no new restructuring of guidelines. ISH/ASH define the typical hypertension patient between 55 and 80 years of age and follow the ideas of ESH. Their guidelines should work in everyday practice. JNC 8 completely re-designed their guidelines and before starting the guideline process, they asked relevant questions. JNC 8 defined two ages for blood pressure: younger patients below 60 years of age and older patients greater than 60 years of age. Thus, the very old people with age greater than 80 years also influence the target values for hypertension treatment in patients between 60 and 80 years of age. Here, we encounter a dilemma of all guideline writings: the results depend on the approach used to write. In consequence, this leads to confusion regarding the everyday management of hypertension by physicians outside guideline committees or academic institutions. Especially for the general practitioner, the subtle differences between international guidelines are too complex to understand or to follow. For the future, it would be desirable to have only one Bglobal^ guideline. In a second step, national hypertension societies can follow the general guidelines/ recommendations and integrate national characteristics or peculiarities, which might also include aspects of medication reimbursement or general national health goals. The current guidelines represent definitively some progress as they discuss and reflect the dilemma of missing evidence in many aspects of hypertension diagnosis and treatment. However, the current guidelines are also a step back: too many
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guidelines with slight variations are confusing. While we definitively do not want to criticize the many authors of the various guidelines who have put so much effort in their work, we feel that it is time for a global hypertension initiative, like KDIGO, since, at present, the numerous different hypertension guidelines with small nuances are not really helpful for daily practice.
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Compliance with Ethics Guidelines Conflict of Interest Markus van der Giet reports grants, personal fees, and travel fees from Novartis Pharma; personal fees from IEM, Stolberg, Germany; travel fees from Otsuka Pharma; and personal fees from BMS. Markus Tölle declares no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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Verdecchia P, Staessen JA, Angeli F, de Simone G, Achilli A, Ganau A, et al. Usual versus tight control of systolic blood pressure in non-diabetic patients with hypertension (Cardio-Sis): an openlabel randomised trial. Lancet. 2009;374(9689):525–33. Pepine CJ, Handberg EM, Cooper-DeHoff RM, Marks RG, Kowey P, Messerli FH, et al. A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial. JAMA. 2003;290(21): 2805–16. Bangalore S, Gong Y, Cooper-DeHoff RM, Pepine CJ, Messerli FH. 2014 Eighth Joint National Committee panel recommendation for blood pressure targets revisited results from the INVEST study. J Am Coll Cardiol. 2014;64(8):784–93. Thorough reanalysis of INVEST Study showing that blood pressure of between 140– 150 is relevant for therapy. Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359(9311):995–1003. Egan BM, Li J, Hutchison FN, Ferdinand KC. Hypertension in the United States, 1999 to 2012: progress toward Healthy People 2020 goals. Circulation. 2014;130(19):1692–9. Sakhuja A, Textor SC, Taler SJ. Uncontrolled hypertension by the 2014 evidence-based guideline: results from NHANES 2011–2012. J Hypertens. 2015;33(3):644–52. Moran AE, Odden MC, Thanataveerat A, Tzong KY, Rasmussen PW, Guzman D, et al. Cost-effectiveness of hypertension therapy according to 2014 guidelines. N Engl J Med. 2015;372(5):447–55. Relevant analysis how the implementation of guidelines might affect economic costs. Officers A, Coordinators for the ACRGTA, Lipid-Lowering Treatment to Prevent Heart Attack T. Major outcomes in highrisk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288(23):2981–97.
NOVEL TREATMENTS FOR HYPERTENSION (T UNGER, SECTION EDITOR)
New Hypertension Guidelines: Progression or a Step Backwards in Hypertension? Markus van der Giet 1 & Markus Tölle 1
# Springer Science+Business Media New York 2015
Abstract In the last years, many hypertension guidelines have been published as new or revised versions. They follow the general trend that only clinical evidence is relevant for guidelines. Expert opinion is downplayed. At present, guidelines from three major organizations have been produced: by the European Society of Hypertension, the International Society/American Society of Hypertension, and the US Joint National Committee. We discuss eight versions of these guidelines in this review. All of these include statements on blood pressure goals or treatment algorithms for patients with high blood pressure. The variability of practical tips is great, and the recommendations, which mainly rely on evidence-based medical information, show slight differences that have resulted in some confusion with specialists and also practitioners. In the current review, the changes in the guidelines in comparison to previous guidelines are discussed, and reasons for different recommendations are explained. The hope is to reduce confusion.
Keywords Hypertension . Treatment . Guidelines . Treatment recommendations
This article is part of the Topical Collection on Novel Treatments for Hypertension * Markus van der Giet [email protected] 1
Campus Benjamin Franklin, Med. Klinik mit SP Nephrologie, Charite - Universitätsmedizin Berlin, Hindenburgdamm 30, 12203 Berlin, Germany
Introduction Perhaps, the years 2013–2015 will be a turning point in medical guideline history. In these years, more than eight international or national guidelines for hypertension diagnosis and management have been published [1•, 2•, 3, 4•, 5–8]. One can speculate that more than a hundred experts in the field of hypertension worked thousands of hours on these various guidelines to establish evidence-based recommendations. Some of the guidelines had been published in previous years, and only an update was necessary. The guidelines show a variation in scale and details. The guidelines of American Society of Hypertension (ASH)/International Society of Hypertension (ISH) present their recommendations on 13 pages with 25 references [2•], and the European Society of Hypertension (ESH) present a guideline of 60 pages citing 735 references [1•]. The ESH also provide a more focused smaller version of the guidelines as a practical guideline [9] for everyday practice. It is a fact that the worldwide prevalence of hypertension is raising. In 2013, the world health organization (WHO) gave a global brief on hypertension (http://apps.who.int/iris/ bitstream/10665/79059/1/WHO_DCO_WHD_2013.2_eng. pdf?ua=1). More than one billion people suffer from hypertension. In everyday practice, we see that hypertension often has no real symptoms and hypertension does not hurt directly. But hypertension is one of the main causes for the excessive number of cardiovascular events and deaths worldwide. The WHO wants to play a critical leadership role in efforts to tackle hypertension, as well as its causes and consequences. Cardiovascular diseases cost the countries billions of euros, and many countries cannot afford it. For these reasons, it is essential to have guidelines on how to diagnose and manage hypertension to overcome the potential health economic burden. Currently, there are no recommendations or guidelines established by the WHO.
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Purpose of Guidelines in Hypertension Management The purpose of guidelines in the world is very variable. It depends on the goals that are set. Nearly every guideline wants to give clinical practice guidance for physicians in diagnosis and therapy. Depending on the persons or groups writing the guidelines, not only medical/evidence reasons but also health economic might influence the result of the guidelines. The Kidney Disease Improving Global Outcomes (KDIGO) initiative (www.kdigo.org/) tried to develop guidelines on thorough literature research and then defined the true existing treatment evidence. Pharmaceutical industry or governmental aspects should not influence the experts commenting the evidence. Evidence was systematically analyzed with mathematical or statistical methods. At the end of every recommendation, especially the scientific needs for every disease or open questions are given. Therapeutic recommendations are strictly graded on evidence level. Within this process, we often find at the end that a lot of evidence is missing and no evidence-based recommendation can be given. International independent guideline writers who do not have to follow any economic necessities or national/local problems usually try to perform the way of only following evidence. Economic resources and also local specialties often influence national guidelines, especially in the case that certain goals (e.g., awareness of hypertension, successful treatment of hypertension) must be achieved. A very good example for this approach is the UK NICE guideline for hypertension (http:// www.nice.org.uk/guidance/cg127). A third guideline type wants to explicitly give practical tips for management of diseases in everyday practice. The new French recommendations [4•] are designed in this way. These guidelines should be practical: easy-to-read format, usefulness for clinical practice, and even comprehensive writing for nonphysicians. The idea of the French guideline is to improve awareness and treatment quality of hypertension. Of course, every actual guideline follows the evidence-based principles, but expert opinions are more or less pronounced. This is definitively not wrong and might be missing in the strict evidence designed guidelines. The main problems of the many international and national guidelines with their different approaches are sometimes confusing results. The recommendations might vary on closer inspection in diagnosis of hypertension, treatment algorithm, or even the definition of blood pressure goals. This is especially complex for countries, which do not publish their own guidelines. Germany follows ESH guidelines. France has published its own guidelines following mainly the argumentation of ESH but giving more simple practical tips that are missing in the ESH guidelines. In the USA, there are two guidelines published within a short period of time, which even have nuances of interpretation within their guidelines. Which guideline should a physician follow?
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Many guidelines within the last few years have been rewritten or revisited: What has really changed? In the following paragraphs, we focus on three prominent—international— guidelines by ESH, ASH/ISH, and Eighth Joint National Committee (JNC 8) to define changes to previous versions and variations between guidelines. The reasons for different consequences are critically discussed.
Relevant Changes in ESH Guidelines What are the main changes in ESH guidelines? The ESH published guidelines in 2007 [10]. In 2009, a reappraisal of the European guidelines was necessary due to new study results especially challenging hypertension treatment goals. In 2013, the ESH published new completely rewritten guidelines [1•]. A smaller version of the guideline was published as a practical guideline [9]. These practical guidelines however are only an excerpt of the larger version. Mainly, the tables and figures from the larger version were published with condensed text. There are no real practical tips given in these Bpractical guidelines.^ In addition to the new guidelines, additional recommendations on the management of patients with obstructive sleep apnea [11] and a position paper on ambulatory blood pressure measurement [12] were published. The main changes between 2007 and 2013 are the changes in the blood pressure treatment goals. There are now no differences regarding blood pressure goals in patients with comorbidities like chronic kidney disease (CKD) and diabetes. All patients should have blood pressure below 140/90 mmHg. Patients with an age over 80 years can have blood pressure goals up to 150 mmHg systolic. In 2007, the guidelines followed the general concept that the lowest achievable blood pressure might be the best. This assumption was based on a meta-analysis, where it could be demonstrated that a systolic blood pressure reduction to 126 mmHg in comparison to 131 mmHg is favorable. Similar results were shown for systolic blood pressure of 140 versus 145 mmHg [13]. The data observed in these studies were all post hoc analysis. This approach usually leads to the loss of randomization in these studies. In addition, with a more reduced blood pressure, we see a flattening of hypertension-associated risks for these patients. Then, real positive effects are difficult to analyze. An alternative to the concept Bthe lower the better^ is the concept of Jcurve. Behind this concept, there is the assumption that blood pressure should not fall below a certain value not to induce critical low organ perfusion with consecutive increase in negative events. Until now, only meta-analyses confirm this hypothesis. There is no randomized controlled trial that could identify the J-shaped phenomenon so far. The investigators of the hypertension optimal treatment (HOT) study tried to identify a threshold for diastolic blood pressure [14]. Also, other studies tried to find evidence for the J-shape
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phenomenon, but the data are conflicting [15]. So, current recommendations for blood pressure goals can only be deduced from clinical hypertension treatment trials. We know that systolic blood pressure reduction below 140 mmHg reduces cardiovascular events. In the FEVER trial, it was very elegantly demonstrated that even blood pressure reduction from 142 mmHg systolic to 137 mmHg in patients without relevant cardiovascular risk or in patients with diabetes and elevated cardiovascular risk reduces event rates by 11 and 17 %, respectively [16]. But there is no evidence for further positive effects of even lower systolic blood pressure reductions. The ESH guidelines use this argumentation to define the systolic blood pressure threshold of below 140 mmHg for all patients. Blood pressure goals for patients over 80 years of age have been modified. The goals are not as ambitious as they were in previous guidelines. It is very well-known that blood pressure reduction in elderly persons is reasonable [17], but the reason to relax blood pressure goals from below 140 mmHg systolic to 150 mmHg systolic is more a consequence of practical reasons and missing true evidence. Most studies investigating also patients with age over 80 years did not reach a blood pressure target below 140 mmHg [18], and there is conflicting evidence whether tight control below 140 mmHg systolic really has clinical relevant effects for this group of patients [16, 19]. Increasing the dosages of antihypertensive medication to achieve blood pressure goals below 140 mmHg systolic increases side effects like orthostatic hypotension and the risk for serious fall injuries [20••]. In the ESH guideline from 2007, patients with high cardiovascular risk profile, as observed in patients with diabetes mellitus and/or chronic renal failure, had blood pressure targets of below 130 mmHg systolic. In the new guidelines, this limit disappeared for two reasons. The guidelines now strictly follow an evidence-based concept. In 2007, the recommendations were not only based on evidence but also on expert opinions. As there was missing evidence about blood pressure targets in diabetes or CKD, it was thought that evidence should come with forthcoming studies. This was the expert opinion at this time point. However, we had to learn that evidence sometimes might not follow expert opinion. For instance, in the ACCORD study, systolic blood pressure targets of 119 versus 133 mmHg were not superior with respect to further reduction of cardiovascular event in diabetic patients [21]. In patients with CKD, a more intense blood pressure reduction was recommended in the ESH 2007 guidelines. This recommendation was withdrawn in the current version of ESH guidelines. The authors argue that there are definitively some hints that patients with chronic renal failure and proteinuria might profit from more intensive blood pressure reduction, but the evidence is not sufficient to give a special recommendation [22]. As a consequence, the blood pressure targets have been
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substantially relaxed in the current ESH guidelines. In this part of the guidelines, the existing evidence plays the essential role to determine the results. Concerning the blood pressure therapy in patients, there are no substantial changes in the current ESH guidelines compared to the 2007 guidelines. Early combination therapy should be initiated to control blood pressure. The most prominent change is the essential focus on encouraging patients for life style changes at any stage or comorbidity of hypertension. The authors of the ESH guidelines do not recommend a special treatment algorithm with specialized medication sequence of medication. There is a hexagram showing possible good combination therapies. They notice that in principle, the following antihypertensive drugs: β-blockers, calcium channel blockers (CCB), angiotensin-converting enzyme (ACE) inhibitors (ACEI)/angiotensin receptor blockers (ARB), or thiazide-type diuretics (thiazides) may be equally used as first-line antihypertensive drugs. It is noticed that some medications might have negative metabolic effects, but this is not considered sufficient to eliminate one or two drugs as first-line antihypertensive. The ESH acknowledges that a meta-analysis on βblockers gives the impression that these substances might be inferior to other blood pressure reducing agents [23], but the ESH argues that this inferior effect of beta-blockers is not attributable to every β-blocker used. For the ESH, the results of the above-mentioned meta-analysis are not sufficient to generally neglect β-blockers as first-line antihypertensive drugs. This is a bit a confusing: In the blood pressure target section, it is argued that pure evidence should define the blood pressure target range. However, concerning β-blockers, the rule of evidence is not fulfilled optimally since there is no evidence that all β-blockers really are equal to e.g., ARB or ACEI. The ESH guidelines recommend certain combination therapies for hypertension treatment. None of these is recommended definitively as superior. The ESH writers cite the ACCOMPLISH study [24••, 25, 26]. In this study, it was tried to identify which antihypertensive combination therapy might be the best. The ACE inhibitor benazepril was combined with either the thiazide diuretic bendroflumethiazide or the calcium channel blocker amlodipine, and the ACEI/CCB combination turned out to be superior to the ACEI/thiazide combination. However, as this is only one study, this was not sufficient evidence for the ESH to recommend the combination of ACEI/CCB as a favorite combination therapy. In general, a clear and simple treatment algorithm for hypertension is missing in the ESH guidelines. The reader itself has to extract this for himself. A clear statement on how to deal with resistant hypertension is also missing. There is no precise statement on what we can do with additional antihypertensive drugs and how these might be tested. The still more experimental interventional approaches are shortly discussed, and reference is given to a position paper of the ESH on renal denervation treatment [27].
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In conclusion, the main changes in the ESH guidelines are the slight changes of blood pressure target levels, in particular giving up the strict levels for patients with diabetes and CKD. The new target levels are more relaxed. The recommendations on how to treat hypertension have not been substantially changed. A treatment algorithm is missing. In everyday practice, physicians have to draw their own conclusions from these guidelines. The practical aspect is missing, despite the fact that the guidelines are excellently written and represent a very thorough analysis of the current literature and evidence. Changes in JNC 8 and Comparison to ESH 2013 In 2014, the panel members appointed to the Eighth Joint National Committee (JNC 8) published a report [3]. It is not the long-awaited revision of the JNC 7 guidelines from 2003 [28]. For the 2014 guidelines, the authors decided to define a systematic and restrictive methodology, mainly focusing on evidence-based medicine. Randomized controlled trials had to fulfill certain criteria to qualify for guideline influence. Prior to design of any guideline, the authors defined certain relevant questions with the highest priority in hypertension treatment. As a consequence, the report is not a revision of the 2003 guidelines, but features a completely new design. The authors did not want to present guidelines for as many incidences in hypertension as possible. Expert opinion is not presented in the guidelines. When reading these guidelines, one can read between the lines that discussions were not easy and consensus was sometimes difficult to find. The blood pressure targets defined in JNC 8 are very similar to the ESH recommendations. This fact is not very surprising because randomized trials analyzed for these guidelines were very similar. The argumentation to skip special blood pressure limits for patients with diabetes or chronic renal failure is in line with ESH. The only difference is the recommendation of blood pressure targets for patients with the age greater than 60 with no diabetes or CKD in history. In these patients, blood pressure reduction should be initiated when blood pressure is above 150 mmHg. The ESH guidelines recommend this goal for patients older than 80 years of age. Interestingly, the JNC 8 recommendation is termed a grade A recommendation. How do the experts come to this conclusion? The essential reason is that ESH did not ask this question, whereas JNC 8 wanted to know whether blood pressure over 60 should be differentially treated from those patients below 60. This was one question before writing the new guidelines. The panel of JNC 8 investigated the question and found definitive evidence that reduction of systolic blood pressure below 150 mmHg reduces event rates significantly, but the panel’s opinion after thorough analysis of trials like SHEP, HYVET, Syst-Eur, JATOS, VALISH, and Cardio-Sis [17, 19, 29–32] is that the evidence to reduce blood pressure below 140 mmHg in patients >60 is an expert opinion and not
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sufficiently evidence-based. The main point is that in the two different guidelines, different questions were asked, and the consequence is confusion. The argumentation of JNC 8 is comprehensible, but it is definitively debatable whether the right question was asked. As a reaction to the new recommendation not to reduce blood pressure below 150 mmHg systolic, the investigators of the International Verapamil SRTrandolapril (INVEST) study [33] reanalyzed their data. The INVEST investigators could demonstrate that achieving a blood pressure target 140 to 150 mmHg (as recommended by the JNC 8 panel) provided less benefit than a target below 140 mmHg in hypertensive patients with coronary artery disease who are older than 60 years of age [34••]. Thus, the JNC 8 recommendation is questionable and should be revisited. After such a revision, the ESH and JNC 8 guidelines would have no real difference any more concerning blood pressure levels. First-line antihypertensive treatment in the recommendation of the JNC 8 panel is more restrictive than in the ESH guidelines. The JNC 8 panel recommends ACEI/ARB, CCB, or thiazides as first-line therapy. The panel refuses β-blockers the status as first-line antihypertensive drug. They state that the Losartan Intervention For Endpoint (LIFE) study delivers sufficient arguments that the use of β-blockers resulted in a higher rate of the primary composite outcome of cardiovascular death, myocardial infarction, or stroke compared to the use of ARB [35]. Mainly, the stroke incidence was higher in the β-blocker group of the LIFE study. In addition, other nonselective α 1/β-blockers (carvedilol) or vasodilating βblockers (e.g., nebivolol) are not recommended as first-line therapy due to missing adequate randomized trials. This statement was also made for central α2-adrenergic agonists (e.g., clonidine), direct vasodilators (e.g., hydralazine), aldosterone receptor antagonists (e.g., spironolactone), and loop diuretics (furosemide). The JNC 8 panel recommendations are focused on blood pressure goals and antihypertensive treatment in comparison to ESH guidelines. Other hypertension relevant questions, i.e., blood pressure measurement and diagnostic of secondary hypertension, are not discussed. JNC 8 presents very straightforward practical guidelines. For the US health system, guidelines are of the highest importance. The US health authorities and the government have a very strong focus on optimizing health risks in their system. A recent NHANES report has demonstrated that awareness of hypertension has been increasing over years up to 80 %. Treatment rates in patients with hypertension are high, but effective control rates have increased until 2010 and thereafter slightly decreased [36]. The uncontrolled hypertension rates are low in the USA, but an essential question concerns the impact of the more relaxed blood pressure rates of JNC 8 on uncontrolled hypertension rates [37]. The percentage of the US population labeled as suffering from
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uncontrolled hypertension has changed from 16.6 to 12.8 %. However, this is mainly a consequence of reclassification and not of better treatment. Interestingly, the greatest impact of reclassification is on elderly, females, and those with diabetes. Recently, the potential economic cost-effectiveness of successful implementation of JNC 8 guidelines was analyzed [38••]. It was calculated that the implementation of these guidelines could prevent about 56,000 cardiovascular events and 13.000 deaths annually. At the same time, a substantial cost saving could be identified. From a European view, one can only be jealous how systematically the US health systems analyze epidemiology of all facets of hypertension, how guidelines are developed, and how the economic consequences are calculated. We can be sure that in some years, the success of implementing the guidelines will be analyzed. ASH-ISH Guidelines Parallel to the JNC 8 panel recommendations, the American Society of Hypertension (ASH) in cooperation with the International Society of Hypertension (ISH) and endorsed by the Asia Pacific Society of Hypertension published a statement and a clinical practice guideline [2•]. These guidelines are completely new. In the introduction, the authors describe the methodology of their guideline development. They clearly state that there is insufficient published data from clinical trials in hypertension to create recommendations that are completely evidence-based. They acknowledge that some of the recommendations also reflect expert opinion and experience. The authors also interpret their guidelines as an initial version, which might be followed by discussions and revisions to come. The guidelines are about the same length as the JNC 8 recommendations but try to cover all relevant aspects in diagnosis, therapeutic goals, and treatment. In principal, the guidelines are in line with ESH 2013. Blood pressure goals are defined in the same way. The ISH/ASH guidelines recommend ACEI/ARB, CCB, or thiazide as first-line drugs but also differentiate that non-black patients 60 years should get CCB or thiazide as first-line treatment. There is no explanation for this recommendation that can be followed. The authors are very well aware of the fact that recommendations cannot be very directive, as the choice of drugs will further be influenced by their availability and affordability. In many countries, it might be necessary to take the drug provided by the government or other agencies. For blood pressure over 160/100 mmHg, the guidelines recommend to start with two antihypertensive drugs right away. In contrast, JNC 8 and ESH 2013 see this as one option among others. ISH/ASH and JNC 8 have a statement on first-line antihypertensive drugs in black patients. This should be CCB or thiazide. This recommendation is derived from a subgroup analysis of the ALLHAT trial [39]. JNC 8 regarded the evidence
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from this trial as high enough that CCB or thiazides are more effective in improving cerebrovascular, heart failure, and combined cardiovascular outcomes compared to ACEI in black patients. The ASH/ISH guidelines are very practical.
Conclusion There are now three major new hypertension guidelines presented which come to very similar conclusions and feature only slight variations of the same recommendations. This is not very surprising, as every guideline wants to be as evidence-based as possible and the guideline authors use the same literature for evidence. But, as written in the ISH/ASH guidelines, it is often difficult to find evidence for every aspect in hypertension diagnosis, treatment goals, or therapy. Personal opinion or experience is also still of importance. The biggest surprise, perhaps in consequence the most confusing recommendation, is the different blood pressure goals for patients without CKD or diabetes between 60 and 80 years of age. JNC 8 recommends initiation of drug therapy with systolic values >150 mmHg. On the other side, ASH/ISH or ESH 2014 recommend initiation of a therapy with systolic blood pressure values >140 mmHg. This confusing result indeed is more a consequence of different approaches by the individual panels writing the three guidelines. ESH 2013 thoroughly revisited guidelines of 2007. There was no new restructuring of guidelines. ISH/ASH define the typical hypertension patient between 55 and 80 years of age and follow the ideas of ESH. Their guidelines should work in everyday practice. JNC 8 completely re-designed their guidelines and before starting the guideline process, they asked relevant questions. JNC 8 defined two ages for blood pressure: younger patients below 60 years of age and older patients greater than 60 years of age. Thus, the very old people with age greater than 80 years also influence the target values for hypertension treatment in patients between 60 and 80 years of age. Here, we encounter a dilemma of all guideline writings: the results depend on the approach used to write. In consequence, this leads to confusion regarding the everyday management of hypertension by physicians outside guideline committees or academic institutions. Especially for the general practitioner, the subtle differences between international guidelines are too complex to understand or to follow. For the future, it would be desirable to have only one Bglobal^ guideline. In a second step, national hypertension societies can follow the general guidelines/ recommendations and integrate national characteristics or peculiarities, which might also include aspects of medication reimbursement or general national health goals. The current guidelines represent definitively some progress as they discuss and reflect the dilemma of missing evidence in many aspects of hypertension diagnosis and treatment. However, the current guidelines are also a step back: too many
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guidelines with slight variations are confusing. While we definitively do not want to criticize the many authors of the various guidelines who have put so much effort in their work, we feel that it is time for a global hypertension initiative, like KDIGO, since, at present, the numerous different hypertension guidelines with small nuances are not really helpful for daily practice.
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Compliance with Ethics Guidelines Conflict of Interest Markus van der Giet reports grants, personal fees, and travel fees from Novartis Pharma; personal fees from IEM, Stolberg, Germany; travel fees from Otsuka Pharma; and personal fees from BMS. Markus Tölle declares no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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