Hot Issues in Hypertension

The ESH web Editor meets the world experts in hypertension: An Interview with Josep Redon

Josep Redon is Scientific Director of INCLIVA Research Institute, Hospital Clinico Universitario Valencia, University of ValenciaHe is past-President of the European Society of Hypertension and has published over 300 articles in internationally recognized journals and is the author of more than ten books. He is a member of the editorial board of several international journals in the field of hypertension, such as Hypertension, Journal of Hypertension, Blood Pressure Monitoring.

The initial evaluation of Target Organ Damage for risk stratification and management of patients with hypertension is well established and assimilated in clinical practice. Is there additional benefit from the evaluation of TOD during antihypertensive treatment?

The presence of TOD upgrades the risk category for a given BP value and other CV risk factors. There is a consensus that if TOD is present in different organs they seem to have additive prognostic value, implying increased cardiovascular risk. Subjects with low or moderate risk are those whose risk may be potentially upgraded the most after assessing TOD, and a panel of TOD was included in the 2007 guidelines. Recently, the convenience of repeating TOD assessment during the follow-up of the patients has been encouraged. The changes in electrocardiographic or echocardiographic LVH, induced by treatment, reflect the effects on cardiovascular events. Likewise, some recent solid evidence suggests that this is also the case for treatment-induced changes in urinary protein excretion.

Despite the great bulk of information available demonstrating an association between regression of TOD during antihypertensive treatment and decreased mortality, and cardiovascular and renal morbidity, some key questions for the clinical use of TOD remain unmet. Among them are: the marker or markers to be used; the most appropriate timing to repeat it; and whether or not changes in one organ can be assumed to occur in the other organs. Finally, a question to consider is if some of these TOD should be targeted during the antihypertensive treatment beyond the BP reduction. In the meantime, while awaiting solid information to support recommendations, it is interesting to speculate on selection and timing of the TOD measurements to be used for follow-up during antihypertensive treatment. The most important factors are availability, cost, sensitivity to detect changes, time necessary for observing the changes and finally the evidence for prognostic value of the changes.

As an expert in the field, could you provide guidance for the degree of RAS blockade in patients with microalbuminuria?

All guidelines recommend drugs blocking the renin angiotensin system (RAS) for use in patients with an increment in urinary albumin excretion since the reduction in the excretion is greater than that obtained with other drug classes at the same level of blood pressure reduction. Likewise, it has been claimed that renal protection is also better obtained with the RAS blockade. Despite the above outlined being generally accepted, grounded information is lacking. There is no doubt that reduction of urinary albumin excretion is better with RAS but it is in part due to the reduction in glomerular filtration rate and consequently the amount of filtered albumin. Whether or not this is translated to long-term renal function protection is not well established.

The practical question is, if urinary albumin excretion should be targeted during the antihypertensive treatment. To do this, the use of only one RAS blocking drug with 24-hour antihypertensive activity is recommended, increasing the dose step by step. In the albuminuria range, it is not recommended to combine two RAS drugs.

Should evening drug dosing be used to control nocturnal hypertension?

The information available about the prognostic value of nocturnal blood pressure in developing cardiovascular and/or renal disease brings the concept of targeting nocturnal BP to reduce risk. Consequently, giving treatment in the evening is recommended in order to achieve enough blood pressure reduction at night. The question here is, if shifting treatment at night improves blood pressure control or not, when we use drugs with 24-hour activity. When results of different groups are confronted, results are controversial, with some authors reporting large benefits in terms of systolic and diastolic blood pressure reduction, while others do not.

While more grounded information is being obtained, the most recommended is in monotherapy and two drug-combination therapy, the drugs should be given in the morning. When three or more drugs are given, one of them can be shifted to the evening.

Given the recent academic interest in resistant hypertension and the huge volume of research in the field do you believe that the definition of resistant hypertension should be officially revised? Is time for ambulatory blood pressure to replace office blood pressure?

Resistant hypertension is a key issue in the field of hypertension which has received more relevance recently with the introduction of methods to treat patients in which antihypertensive drugs are not able to control the high blood pressure values. As a consequence of the renewed interest, new definitions have emerged in addition to the classic, which require uncontrolled hypertension under treatment with three drugs, well combined in adequate doses and at least one of them diuretic. Today it is considered resistant hypertension also when patients with four drugs even the blood pressure was lower than 140/90 mmHg. Considering that resistant hypertension can be produced by many factors that can be solved, it is better to name this situation as “Apparently Treatment Resistant Hypertension” until clinical workup excluded potential causes for resistance. The actions should include out-of-office blood pressure measurements, mainly 24-hour monitoring. The necessity to use ambulatory blood pressure monitoring in this special situation does not preclude that it can replace office blood pressure.

Finally, based on your experience, we would like a comment on the advantages and restrictions of the use of electronic health records for hypertension research.

The EHR systems can help to identify complex interactions among cardiovascular risk factors, treatments, social factors, and to gain more knowledge about unexplained factors related to the development of cardiovascular diseases. This is a unique opportunity to carry out whole population studies for cardiovascular disease prevention and managing hypertension. Whole population studies can help to monitor risk factors, incidence and case fatality, quality of care measures, effectiveness of interventions, health inequities and epidemics among high-risk groups. In addition to the support systems that introduce personal records and guide patients during treatment.

Costas Tsioufis
Web Editor

Hot Issues in Hypertension

The ESH web Editor meets the world experts in hypertension: An Interview with Giuseppe Mancia

Giuseppe Mancia is past-President of the International Society of Hypertension (ISH), the European Society of Hypertension (ESH), the European Society of Clinical Investigation and the Italian Society of Hypertension (SIIA). His research interests are pathophysiology, clinical pharmacology and therapy of hypertension, congestive heart failure and other cardiovascular diseases. He has published more than 1100 papers in International journals and is the editor of the ESH Manual of Hypertension. His papers have received more than 35.000 citations.

After the publication of the PURE trial do you believe that the correlation of salt consumption with outcomes is best described by a J curve and if so, is there a need for reconsideration of current recommendations?

I found the data obtained by the PURE study quite convincing and believe that a J-curve relationship between sodium intake and outcomes not only makes sense, but it is also supported by pathophysiological data. Years ago, for example, evidence was produced that in animals a marked reduction of sodium intake was accompanied by an alteration of blood pressure homeostasis which led, among other inconveniences, to a greater animal fragility against haemorrhage. Furthermore, we have shown that in hypertensive patients reducing salt consumption is associated with a persistent activation of the sympathetic nervous system as well as to an impairment of the baroreflex ability to modulate autonomic functions. Sodium is a fundamental element in the process that leads to cell excitability and it is may be unwise to pursue its too drastic reduction in the diet. As stated by several guidelines recommend, it is rather an excessive consumption that should be avoided.

How would you translate in clinical practice the results of the ELSA trial regarding the effect of antihypertensive treatment on white coat hypertension?
The recent analysis of the ELSA long-term data provide solid evidence that in white coat hypertension antihypertensive treatment markedly and persistently reduces office blood pressure while it does not have any effect on ambulatory blood pressure which, over the 4 years of the study, showed instead a slight progressive increase. There were, however, no event data in the ELSA publication and no such data are available in any other study. Thus, the fundamental question whether antihypertensive treatment provides cardiovascular protection in white coat hypertension cannot be given an evidence-based answer. My personal opinion, however, is that this may be the case for at least two considerations. One, as clearly shown by the Pamela study, white coat hypertensive individuals have a greater cardiovascular risk than normotensive controls. Two, because of its high prevalence, white coat hypertension probably accounted for up to 40% of the population recruited in trials on mild uncomplicated hypertension. It seems unlikely that these trials would have shown a beneficial effect if the white coat hypertension subgroup was not involved in the benefit.

After the clinical and research “moratorium” in renal denervation, imposed by the results of SYMPLICITY HTN 3, what would be the next denervation trial that you would expect the most significant data (population, design, outcome)?
A moratorium on renal denervation after the negative results of the SIMPLICITY- 3 trial is legitimate. However, I am among those who believe that although the attempt to have a sham control group was in principle commendable, the SIMPLICITY-3 trial had several limitations, which makes its data open to confounding. Further trials are thus needed, and I believe they should not have a sham control group again. I would like to see a trial against what we could really call the best possible drug treatment strategy, with an overall number of patients large enough to give the data an unequivocal statistical power to show whether a between-group difference in (ambulatory) blood pressure occurs. Of course, the ultimate goal would be to prove that renal denervation saves events in resistant hypertension, but this seems to me to be a difficult issue to address, given the problem of what might be the comparison group. I would love to see, as the next best research option, however, more data on the effects of renal denervation on organ damage with documented prognostic significance.

During the last two years we have witnessed a debate between the coasts of the Atlantic regarding the philosophy behind the development and scope of practice guidelines. As the Chairperson of the Task Force of the more comprehensive and evidence based European Guidelines, do you believe that there should be a turn towards more concise and real world based guidance?
The debate has been going on for many years and questions about simplicity vs complexity of guidelines surface at almost every meeting. My personal view is that, albeit it may seem an attractive option, guidelines cannot and should not be too simple. This is because recommendations issued as a few simple line statements (with no explanation of the evidence  behind) inevitably sound as coercive or prescriptive, loosing what is one of the guidelines’ main purposes, i.e. to be educational. This is necessary also because many recommendations reflect expert opinions rather than evidence. A compromise between the need to be educational and simple was adopted by the European Hypertension guidelines. On any given topic, the evidence available was discussed but at the end a few lines of summary was provided.

Costas Tsioufis
Web Editor

The ESH web Editor meets the world experts in hypertension: An Interview with Anna Dominiczak

Anna Dominiczak is Regius Professor of Medicine, Vice Principal and Head of College of Medical, Veterinary and Life Sciences at the University of Glasgow. Her major research interests are in hypertension, cardiovascular genomics and systems medicine. She was Associate Editor of the Journal of Hypertension between 2009 and 2011 and is Editor-in-Chief of Hypertension as from January 2012.


What have we learnt from the GWAS studies in hypertension?

The GWAS studies in hypertension have taught us several things:

  • There are several very strong “hits”, which are highly reproducible, have very low p value and thus show a genome wide significance;
  • These single nucleotide polymorphisms (SNPs) can be used to calculate genetic risk scores;
  • The most valuable findings are those which discover new pathways, which were not previously known to contribute to hypertension, especially if they might lead to new drug targets.

Will the whole genome next generation sequencing become useful in hypertension and other cardiovascular diseases?

It seems more than likely that hypertension and other cardiovascular diseases will benefit from the whole genome next generation sequencing with the major use being in the stratified or precision medicine applications.  The aim would be to use genomic markers to predict the most efficacious antihypertensive drug or drug combination for large subgroups of patients.

Please explain why stratified or precision medicine has been making inroads in cancer clinical practice but not yet in hypertension.

There are special features of cancer medicine which facilitate stratified or precision medicine approaches.  These include the ability to sequence both germline and somatic (tumour) genomes as well as readiness of the oncology community to quickly embrace novel diagnostic modalities and to translate these to clinical application.  It is imperative that cardiovascular medicine practitioners use similar translational approaches.

Should we study the Y chromosome to understand the genetic differences between hypertensive phenotype in men and women?

There are interesting options to utilize  the increasing knowledge of the precise genetic makeup of both sex chromosomes.  However, it is also important to remember that the Y chromosome is very small and with only few genes.  The Y chromosome is therefore unlikely to be the only answer, hormonal influences as well as nurture versus nature are also important.

Costas Tsioufis
Web Editor

Hot Issues in Hypertension

The ESH web Editor meets the world experts in hypertension: An interview with Alberto Zanchetti

Alberto Zanchetti is Professor Emeritus of Internal Medicine at the University of Milan, and is Scientific Director of Istituto Auxologico Italiano, a research hospital in Milan (Italy). He is current Editor-in-Chief of the Journal of Hypertension, a Past-President of ESH, and has been in the Task Force preparing all three editions (2003, 2007 and 2013) of the ESH-ESC hypertension guidelines.


Should antihypertensive drug treatment be given to all patients with grade 1 hypertension when their CV risk is low-to-moderate?

There is no single antihypertensive treatment trial having exclusively enrolled patients with grade 1 hypertension (that is SBP between 140 and 149 or DBP between 90 and 99 mmHg in absence of any concurrent antihypertensive drug), either at low-moderate or high cardiovascular risk. Previous trials on so-called “mild hypertension”, mostly conducted in the 1970s and 1980s, used BP classifications different from the present ones, which were founded exclusively on DBP values, and their results cannot be translated directly into current guidelines. Therefore, the 2013 ESH-ESC hypertension guidelines are correct stating that no evidence based recommendation can be given to treat grade 1 hypertensive individuals (at any level of cardiovascular risk), and guidelines are also careful in pointing out that absence of evidence does not mean evidence against, and wisely conclude that initiation of antihypertensive treatment can be considered also in grade 1 hypertensives at low-moderate risk when they do not respond to lifestyle changes.

This positive opinion of the ESH-ESC Task Force has been put on more solid grounds by a recent meta-analysis of blood pressure lowering trials stratified as grade 1, 2 or 3 according to the average SBP/DBP values at baseline in hypertensive patients without baseline antihypertensive therapy (Thomopoulos, Parati and Zanchetti, in publication on the Journal of Hypertension, December 2014). This meta-analysis shows that relative risk reduction of all types of cardiovascular event (including mortality) is not different at all grades of hypertension, and also shows a significant and consistent reduction of the relative and absolute risk of all major events in a subgroup of trials of low-moderate risk grade 1 trials. Meta-analyses are not a substitute for specific trials, and in particular our meta-analysis classified hypertension grades on the basis of the average baseline SBP/DBP, what makes it likely that a minority of patients were out of the BP ranges defining each specific grade. Nonetheless, these new data provide the cautious recommendation of the 2013 guidelines to initiate antihypertensive treatment in all individuals with SBP 140 mmHg or higher with a much stronger support than simple experts’ opinion.

Should elderly patients with a SBP between 140 and 160 mmHg be given antihypertensive drug treatments?
All randomized trials of antihypertensive treatment that showed benefits (very definite benefits) in the elderly deliberately enrolled patients with SBP of 160 mmHg and above, so the 2013 ESH-ESC guidelines correctly say it is strongly recommended to lower blood pressure in elderly people with SBP values of 160 mmHg and above. Once again, as I mentioned before, lack of evidence does not mean evidence against, and it seems wise to suggest, as the ESH-ESC guidelines do, that, especially in the younger and fit elderly, BP lowering therapy may be useful even when SBP is in the 140-159 mmHg range. The recent recommendation of the JNC-8 in USA to prescribe antihypertensive drugs to the elderly with SBP 150 mmHg or higher appears a compromise between evidence and opinion, and it is not evidence based as the JNC-8 committee members claim.

Should antihypertensive drug treatment be started in the high normal BP range and, if so, in which patients?
If, as I pointed out earlier, the evidence in favor of prescribing BP lowering drugs to grade 1 hypertensives is not overwhelming yet, even less is known about effects of BP lowering in individuals with BP in the so-called high-normal range (SBP 130-139, DBP 85-89 mmHg). There are good reasons, however, not to recommend antihypertensive treatment in these patients.

First, in the high-normal BP range the risk of a quite small BP elevation is rather small and equally small can be expected to be the benefit of BP lowering. Drug lowering of high-normal BP has sometimes been suggested in the context of the so-called metabolic syndrome (or pre-diabetes), but in the DREAM and NAVIGATOR trials in prediabetic patients reduction of an average BP in the high-normal range at randomization by an ACE-inhibitor or an angiotensin receptor blocker was not accompanied by any reduction of cardiovascular events.

Is there enough evidence to support BP lowering below 140/85mmHg in patients with diabetes mellitus?
Among BP lowering trials in hypertensive patients with diabetes, mean achieved SBP during treatment was slightly below 140 mmHg in two trials: these trials are MICROHOPE (a subgroup of HOPE) and the diabetic subgroup of FEVER. Therefore it is reasonable to recommend a SBP target somewhat below 140 mmHg in diabetics. As to DBP, a target below 85 is indicated by the results in the diabetic subgroup of HOT (a protocol predetermined analysis) and in UKPDS.

Which is the better measure to interpret the results of the trials: relative risk reduction, absolute risk reduction or residual risk?
Both relative and absolute risk reduction are significant measures of the results of a trial. Treatment is meaningful if it can reduce risk by a consistent proportion, but if the baseline risk is very low even a consistent relative reduction may cause an absolute benefit of little clinical significance: hence, the importance of also calculating absolute risk. However, any enthusiasm for basing antihypertensive treatment on absolute risk benefit only, reserving it to those at high cardiovascular risk, should be tempered by the findings of a recent meta-analysis of our group (Thomopoulos, Parati and Zanchetti, Journal of Hypertension in publication, December 2014) showing that, despite the greater absolute reduction in risk at the highest level of initial risk, the residual risk (that is, the risk level that is found after BP lowering) remains much higher when treatment is initiated at the highest rather than at the lowest stratum of cardiovascular risk. These data and considerations further support the recommendation of the 2013 ESH-ESC hypertension guidelines to initiate antihypertensive treatment in all individuals with grade 1 hypertension even when their overall cardiovascular risk is in the low-moderate range: in these individuals the absolute risk reduction to be expected is not negligible, and deferring intervention to a time when level of risk is higher is likely to lead to a higher residual risk, that is to a greater proportion of treatment failures.

Is there any indication for renal denervation in resistant hypertension?
Renal denervation is an interesting investigational procedure for the treatment of resistant hypertension, that is hypertension not fully responding to drug treatment. The data are still controversial, particularly because of the failure of the Simplicity-3 trial to confirm the more favorable data of earlier studies. The argument raised that in Simplicity-3 the operators were not sufficiently trained in the procedure and therefore in many patients denervation might have been unsuccessful appears a reasonable explanation, but, at the same time, strengthens the ESH recommendation that renal denervation still has to be reserved to experienced hypertension centres, where a balanced decision about intervention, a correct procedure and a precise evaluation of the results can be guaranteed.

Costas Tsioufis
ESH web Editor