Journal of Renin-Angiotensin-Aldosterone System Effect of angiotensin receptor blockade on central haemodynamics in essential hypertension: results of a
Markus P Schneider, Christian Delles, Arnfried U Klingbeil, Malte Ludwig, Rainer E Kolloch, Michael Krekler, Klaus O Stumpe Journal of Renin-Angiotensin-Aldosterone System The online version of this article can be found at: can be found at:
Journal of Renin-Angiotensin-Aldosterone System
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Effect of angiotensin receptor blockade on central
haemodynamics in essential hypertension: results of a
randomised trial

Markus P Schneider,* Christian Delles,* Arnfried U Klingbeil,* Malte Ludwig,+ Rainer E Kolloch,§Michael Krekler,Klaus O Stumpe,+ Roland E Schmieder* Key words:
the opportunity to study the level of augmentation Objective. Angiotensin-converting enzyme (ACE) of central SBP, or the central augmentation index blood pressure,
blood vessels,

inhibitors have been shown to lower central (cAI), caused by reflection of pulse waves in the renin-angiotensin
augmentation index (cAI), an index of arterial periphery. Increased pulse wave velocity from stiff large arteries and increased peripheral vascular therapeutics
wave reflection, more than β-blockers.We testedwhether this is also true for long-term treatment resistance are two major causes for an earlier with an angiotensin receptor blocker (ARB).
return, and a higher amplitude of the reflected Medicine IV/Nephrology,University of Erlangen- Methods. One-hundred and fifty-six subjects with pulse wave, respectively. Earlier return of the essential hypertension were randomised to reflected pulse wave shifts central BPaugmentation from diastole into late systole, and treatment with either irbesartan or atenolol. cAI and central blood pressure (BP) were determined by therefore leads to augmentation of central SBP pulse wave analysis from the radial and the carotid and hence cardiac afterload. In addition to artery after six and after 18 months treatment.
detrimental effects on the heart, elevated central Results. Peripheral and central systolic and SBP is also thought to be a major determinant of diastolic BP were reduced to a similar extent in the the risk for stroke and indeed several studies have two groups. cAI was reduced with irbesartan, but already confirmed an independent predictive increased with atenolol (derived from the carotid value of cAI.5,6 To derive cAI, recording of a more artery: -6±10 vs. -4±12% after six months, p<0.001; proximal arterial waveform, such as from the –4±12 vs. +1±11% after 18 months; p=0.011).
carotid artery, has recently been shown to be Correspondence to:Professor Dr med Roland Furthermore, central to peripheral pulse pressure more accurate compared with the recording from (PP) amplification was unaffected by treatment the rather distal radial artery.7 However, because correct recording from the carotid artery is more with irbesartan, but decreased with atenolol.
difficult and time-consuming, most studies have irbesartan and atenolol similarly decreased been limited to recordings from the radial artery.
peripheral and central BP, only treatment with irbesartan had beneficial effects on arterial wave In the two largest, prospective antihypertensive reflection and preserved PP amplification.These treatment studies employing this new technology, haemodynamic effects may at least partly explain combination therapy including an angiotensin- the reported differential effects of ARB versus converting enzyme (ACE)-inhibitor has been β-blocker treatment on cardiovascular mortality shown to have superior effects on central systolic in patients with essential hypertension.
BP and cAI compared to β-blockers.8,9 In addition, therapy with an ACE-inhibitor preserved the Introduction
central to peripheral amplification of pulse Accepted for publication22nd October 2007 Although it has been known for several years that pressure (PP), whereas atenolol reduced this central haemodynamic effects differ substantially natural amplification. This is important, as the JRAAS 2008;9:49–56
between various antihypertensive agents,1,2 the disappearance of PP amplification has been shown importance of these central effects has only to independently predict cardiovascular mortality.10 recently been appreciated. A practical reason for Overall, these unfavourable effects of β-blockers increasing interest also lies in the recent on haemodynamics are at least partly responsible availability of non-invasive methods for the for the recent questioning of their role as first-line assessment of central haemodynamics, such as therapeutic agents in essential hypertension.11-13 provided by pulse wave analysis.3,4 In conjunction Journal of
with conventional measurement of peripheral Whether treatment with an angiotensin receptor the Renin-
blood pressure (BP) for calibration, central blocker (ARB) has similar long-term beneficial Angiotensin-
systolic blood pressure (SBP) and diastolic blood effects on haemodynamics in patients with Aldosterone
pressure (DBP) can be derived from the arterial essential hypertension as ACE-inhibitors has not been studied. We therefore examined the effects waveform of a peripheral artery, such as the radial artery, by use of a mathematical transfer of irbesartan versus atenolol on peripheral and function.3,4 In addition, this method also provides central haemodynamics by pulse wave analysis from both the radial and the carotid artery in a waves were accepted only if variation of peak and bottom pressures of single pressure waves was< 5%. The central pressure wave was then automatically synthesised from the radial pressures by a built-in generalised transfer function. In This randomised, double-blind, community-based addition, pressure wave measurement was also trial was conducted at 14 university affiliated performed at the right carotid artery as it has been centres in Germany. After withdrawal of previous suggested that cAI may be more accurately derived antihypertensive therapy (if applicable) and a from this vascular site.7,14,15 Prior to analysis, a visual single-blind placebo lead-in period of three check for correct detection of inflection points was weeks, patients were randomised 1:1 to receive performed in each radial and central pressure either irbesartan 150 mg or atenolol 50 mg once wave by an independent blinded investigator.
daily. After four weeks doses were doubled if BP From the derived central waveforms, data is given exceeded 150 mmHg SBP or 90 mmHg DBP. If BP on central systolic and diastolic BP, time to the first was still uncontrolled after another four-week, shoulder determined by the outgoing pressure hydrochlorothiazide, 12.5 mg, uptitrated to a determined by the reflected pressure wave (cP2), amlodipine, 5 mg, uptitrated to a maximum of either absolutely or as percent of ejection duration 10 mg, respectively, could be added at four week (ED), as well as augmentation pressure (AP) as the intervals. The trial was conducted according to the pressure height difference between cP2–cP1, and Declaration of Helsinki. Informed written consent cAI defined as: (pressure difference between was obtained prior to participation in the trial. The cP2–cP1)/pulse pressure. In addition, central to protocol of the trial was approved by each local peripheral differences of SBP and PP as indices of University Investigation Ethics Committee.
SBP and PP amplification are given both inabsolute terms, Trial participants
SBP/central SBP and peripheral PP/central PP).
Males and females between 25 and 65 years ofage, with a SBP of 150–200 mmHg and/or a DB) Statistics
of 95–115 mmHg were eligible. Subjects were All statistical analyses were carried out using excluded for known or suspected secondary SPSS-software (release 15.0, SPSS Inc., Chicago, IL, USA). Based on a previous study,16 a sample size of at least 70 patients in each treatment disease, renovascular disease, insulin-dependent group was needed to detect a 5% change of cAI, as the primary end point of the study, with an dependent diabetes mellitus, history of intolerance estimated standard deviation of 12%, given a two- to atenolol, irbesartan, hydrochlorothiazide or sided p-value of 0.05 at a power of 90%. Taking a amlodipine and pre-treatment with an ACE- maximum drop-out rate of 20% over the course of inhibitor or an ARB within the last six months.
18 months into account, 84 patients wererandomised to each group. Normal distribution of Measurement of arterial wave reflection
data was confirmed by the Kolmogorov–Smirnov and central BP
test before further analysis. Normally distributed To derive the central arterial waveform, a clinical baseline data were compared by unpaired validated system (Sphygmocor™; AtCor Medical, student t-tests. Duration of hypertension, age, Sydney, Australia) was used that employs high- glucose and high-density lipoprotein (HDL) fidelity applanation tonometry (Millar) for non- cholesterol identified as not-normally distributed invasive registration of peripheral arterial pressure data were compared by Mann–Whitney-U tests.
waves and appropriate computer software for Gender distribution between treatment groups pressure wave analysis (Sphygmocor™).3,4 was compared by Fisher’s exact test. Analysis of Pressure calibration was accomplished through variance (ANOVA) was used to compare the data automatically, non-invasively obtained supine BP of the brachial artery of the dominant arm after a treatment groups. In addition, ANOVA was used to 30-minute rest (Dinamap Compact T; Johnson & compare data obtained during therapy to baseline Johnson Medical Ltd, Newport, UK). BP was data. If ANOVA comparison indicated a significant measured five times over 10 minutes and the difference, the Bonferroni method was applied for mean of the last three measurements were taken subsequent paired comparisons between data Journal of
from six months versus baseline and 18 months the Renin-
versus baseline, respectively. Multivariate analysis Angiotensin-
Pressure wave recording was then performed at of variance (MANOVA) based on the general Aldosterone
the radial artery of the same arm with the wrist linear model was used to determine the impact of System
(Including other
gently hyperextended. The pressure wave was concomitant therapy with hydrochlorothiazide averaged from single pressure waves recorded and amlodipine as covariates on the effects of consecutively for eight seconds. Averaged pressure irbesartan versus atenolol treatment as a fixed Table 1
Baseline clinical characteristics of patients randomised to treatment with either irbesartan or atenolol.
Irbesartan (n=75)
Atenolol (n=81)
Key: BMI = body mass index; DBP = diastolic blood pressure; HDL = high-density lipoprotein; HTN = arterial hypertension;
LDL = low-density lipoprotein; SBP = systolic blood pressure.
factor on all major outcome variables. Two-tailed absolute time to the reflected wave (cP2 in ms) p-values < 0.05 were considered statistically was prolonged with atenolol, when normalised for significant. Data in the text and in the tables are ED, timing of the reflected wave was similar in the two treatment groups (cP2 in % of ED).
Normalising for ED also revealed a slightly earlier timing of the outgoing pressure wave when From 168 patients with essential hypertension patients were being treated with atenolol for initially randomised, 156 patients completed the six months. There were no differences in terms study. Forty-five percent of patients in the of the height of the outgoing pressure wave irbesartan and 41% in the atenolol group had never (cP1 height) during the course of the study.
received any prior antihypertensive medication, Augmentation pressure (cAP) and in particular and no patient had ever received ACE-inhibitor or augmentation index (cAI) were disparately ARB treatment. Moving from the local area was affected in the two treatment arms after six stated as the main reason for not completing the and after 18 months: irbesartan decreased cAI after study. The subsequent analysis is based on the 75 18 months whereas, atenolol increased cAI after patients in the irbesartan and 81 patients in the six months. There was a correlation between the atenolol group completing the study, although decrease in heart rate and the increase of cAI in intention-to-treat analysis gave similar results (not the atenolol group (r=-0.59, p<0.001 after six shown). Table 1 gives the baseline clinical months and r=-0.67, p<0.001 after 18 months).
characteristics of patients randomised to eitherirbesartan or atenolol. Brachial SBP and DBP and In table 3, the results of the pulse wave analysis all other recorded clinical parameters were similar from the carotid artery are given. Again, the between the two groups at baseline. Only 22% of reductions in carotid SBP and DBP and in the patients in the irbesartan and 28% in the atenolol derived central SBP and DBP were similar between group required additional hydrochlorothiazide, measurements from the radial artery, there were no treatment. With irbesartan, heart rate did not differences in timing of outgoing and reflected change after six and after 18 months (-0.3±8.9 and pressure waves when normalised to changes in -1.6±9.9; n.s.), whereas atenolol led to a decrease ejection duration. Again, cAP was reduced only of heart rate after six and after 18 months with irbesartan while cAI at baseline was higher in compared to baseline (-9.1±10.2 and -7.0±10.3, the atenolol group. This was most likely due to small, non-significant differences in baseline heartrate (table 1), because of the correlations between Table 2 gives the results of the pulse wave heart rate and augmentation index at baseline analysis from the radial artery. Radial SBP and (r=-0.49, p<0.001 in the atenolol group, r=-0.31, DBP were reduced to a similar degree in the p<0.001 in the irbesartan group). During treatment, two treatment groups. Central SBP and DBP cAI was reduced in the irbesartan group after six Journal of
derived from the radial artery by generalised and after 18 months, but increased in the atenolol the Renin-
transfer function were also reduced to a similar group after six months compared to baseline.
extent with irbesartan and atenolol. ED was Aldosterone

prolonged by treatment with atenolol only, and In table 4, results are given for absolute changes was strongly correlated with the decrease in heart of peripheral to central SBP amplification and PP rate (r=-0.76, p<0.001 after six months and amplification. SBP amplification and the ratio of r=-0.80, p<0.001 after 18 months). Although the peripheral to central SBP decreased only in Table 2
Central and peripheral haemodynamics derived from the radial artery.
Irbesartan (n=75)
Atenolol (n=81)
Journal of
the Renin-

Table 2 continued
Central and peripheral haemodynamics derived from the radial artery.
Irbesartan (n=75)
Atenolol (n=81)
Key: cAI = central augmentation index; CAP = central augmentation pressure; cDBP = central diastolic blood pressure;
cP1 = central pressure height 1 ; cP2 = central pressure height 2; cSBP = central systolic blood pressure; ED = ejection
duration; rDBP = radial diastolic blood pressure; rSBP = radial systolic blood pressure; * = p<0.05, ** = p<0.01,
*** = p<0.001 compared to baseline by Bonferroni post-hoc test; Δ = respective changes from baseline.
patients treated with atenolol. Similarly, PP treatment with an ARB lowers cAI. In contrast to amplification and its ratio decreased only in the previous studies, cAI was also derived from the atenolol, but not in the irbesartan group.
waveform of the carotid artery, which has been Concomitant treatment with hydrochlorothiazide or amlodipine had no significant effect on any waveform of the radial artery.7,14,15 Numerous major outcome variables (e.g. ΔSBP-Amp 18 effects of ARB treatment have been demonstrated months: p=0.027 irbesartan vs. atenolol, with that may account for this beneficial effect on wave hydrochlorothiazide and amlodipine treatment reflection, including effects on vascular function21 and structure.22 These effects might be mediatedby reduction of angiotensin II type 1 receptor Discussion
activation and/or increased angiotensin II type 2 ACE-inhibitors have recently been shown to have receptor activation, although a role for increased more beneficial effects on central SBP, cAI and angiotensin (1-7) levels during ARB treatment has central to peripheral PP amplification compared to β-blockers,8-9 but the long-term effects of ARBtreatment on these parameters have not been Our data also confirm that treatment with studied so far. In the current study we could atenolol leads to a significant increase in cAI.9,18 show that long-term treatment with irbesartan has The decrease in heart rate during β-blocker beneficial effects on cAI and that PP amplification therapy has been shown to contribute sub- can be preserved with irbesartan but not with β- stantially to the increase in cAI by increasing blocker treatment. These effects of ARB treatment systolic ejection duration,25 and also in our study, may have contributed to their superiority heart rate was strongly correlated with cAI at demonstrated in the Losartan for End point baseline and during active therapy. However, the timing of the reflected wave was not substantiallyaltered by atenolol when normalised to ejection duration. This indicates that the lesser reduction compared the effects of an ARB against those of of cAI with atenolol may at least in part be due a β-blocker on these parameters,18 although to lesser lowering of the intensity of wave beneficial effects of ARB treatment on cAI had reflection compared to treatment with an ARB. A likely explanation for this would be the lack of contexts.16,19 In this smaller study in 21 patients vasodilatory properties of atenolol. It has also with essential hypertension over a duration of six been shown that these unfavourable haemo- weeks, treatment with eprosartan led to a greater dynamic effects of atenolol lead to an increase of decrease of central SBP and a decrease of cAI, brain natriuretic peptide, as a marker of cardiac whereas atenolol led to an increase of cAI. These afterload.26,27 The role of β-blockers has been beneficial effects of eprosartan on central questioned recently,11-13 and the new British haemodynamics were achieved despite a lesser guidelines for the treatment of hypertension have decrease of pulse wave velocity, as an index of even removed these agents now from the list of large artery stiffness, although studies have first-line agents (http://www.nice.org.uk/CG034).
Journal of
shown that arterial wave reflection can be However, most of the evidence against β- the Renin-
blockers is derived from studies with atenolol.11,13 Angiotensin-
Newer β-blockers, such as nebivolol, which has Aldosterone
significant differences in central SBP lowering in additional vasodilatory properties, may have System
(Including other
the irbesartan versus the atenolol group, we can more favourable effects on haemodynamics, and confirm in a larger number of patients and over might be more suitable for the treatment of a long treatment duration of 18 months that Table 3
Central and peripheral haemodynamics derived from the carotid artery.
Irbesartan (n=75)
Atenolol (n=81)
Journal of
the Renin-

Table 3 continued
Central and peripheral haemodynamics derived from the carotid artery.
Irbesartan (n=75)
Atenolol (n=81)
Key: cAI = and central augmentation index; cAP = central augmentation pressure; caSBP = carotid systolic blood pressure;
caDBP = Carotid diastolic blood pressure; cDBP = central diastolic blood pressure; cP1 = central pressure height 1 ;
cP2 = central pressure height 2; cSBP = central systolic blood pressure; ED = ejection duration; * = p<0.05, ** = p<0.01,
*** = p<0.001 compared to baseline by Bonferoni post-hoc test; Δ = respective changes from baseline.
Table 4
SBP-Amp calculated as peripheral-central SBP; SBP-Amp ratio (peripheral/central SBP), PP-Amp; peripheral PP-central PP, and
PP-Amp ratio (peripheral PP/central PP) as measures of peripheral pressure amplification.
Irbesartan (n=75)
Atenolol (n=81)
Key: SBP-Amp = systolic blood pressure amplification; PP-Amp = pulse pressure amplification; * = p<0.05, ** = p<0.01,
*** = p<0.001 compared to baseline by Bonferroni post-hoc test.
Interestingly, although the changes of cAI from with atenolol.29 Additionally, the decrease of baseline were still significantly different between heart rate with atenolol was numerically less irbesartan and atenolol after 18 months, when after 18 months compared to after six months directly comparing cAI at 18 months there was (-9.1±10.2 versus -7.0±10.3 bpm; p=0.01 by no difference, regardless of whether cAI was ANOVA), and this might have attenuated the derived from the radial or the carotid artery. This seemed to be based on an attenuation of thedetrimental effects of atenolol on cAI after 18 In addition to these disparate effects on cAI, we could also show that irbesartan treatment Journal of
observation is currently unclear. It is conceivable preserved the natural central to peripheral the Renin-
that long-term treatment with atenolol may affect amplification of SBP and PP. In contrast, atenolol Angiotensin-
vascular structure and/or function indirectly via led to a reduction of both the SBP and the PP Aldosterone

effects on cardiac output or via lowering of BP, gradient, again, more markedly after six months although previous studies have not been able to than after 18 months. These disparate effects of demonstrate a reduction of total peripheral irbesartan versus atenolol are most likely of vascular resistance after one year of treatment clinical relevance, as an attenuation of these parameters has been shown to independently Chen CH, Ting CT, Nussbacher A et al. Validation of carotid artery tonometry as a means of estimating augmentation index of ascending aortic pressure. Hypertension 1996;27:168-75.
15. Kelly RP, Hayward CS, Ganis J, Daley J, Avolio A, Our study shows that treatment of essential O'Rourke M. Non-invasive registration of the arterial pressure hypertension with irbesartan has beneficial pulse waveform using high-fidelity applanation tonometry. J effects on cAI and preserves central to peripheral PP amplification, whereas atenolol increases cAI 16. Klingbeil AU, John S, Schneider MP, Jacobi J, Weidinger and leads to an attenuation of PP amplification.
These effects on haemodynamics may at least augmentation index: a double-blind, randomised, controlled partly explain the differential effects of these drugs on cardiovascular mortality in patients with 17. Dahlof B, Devereux RB, Kjeldsen SE et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a References
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(Including other

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