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Doi:10.1016/s0002-8703(03)00366-

Comparison of the effect of valsartan and lisinopril
on autonomic nervous system activity in chronic
heart failure
Elisabetta De Tommasi, MD,a,b Massimo Iacoviello, MD,a,b Roberta Romito, MD,c Claudio Ceconi, MD,d
Pietro Guida, MS,a,b Francesco Massari, MD,c Gloria Francolini, BSc,d Federico Bertocchi, MD,e
Roberto Ferrari, MD,f Paolo Rizzon, MD,a,b and Maria Vittoria Pitzalis, MD, PhDa,b Bari, Italy

Background In chronic heart failure (CHF), the derangement of autonomic nervous system activity has a deep im-
pact on the progression of the disease. It has been demonstrated that modulation of the renin-angiotensin aldosterone sys-
tem (RAAS) increases autonomic control of heart rate and reduces adrenergic activity. We sought to evaluate, in CHF, the
different effects of an ACE inhibitor (lisinopril) and of an AT1 receptor antagonist (valsartan) on heart rate variability,
baroreflex sensitivity and norepinephrine plasma levels.
Methods Ninety patients (61 Ϯ 10 years, 2.3 Ϯ 0.5, New York Heart Association class) with CHF and left ventricu-
lar ejection fraction Ͻ40% were randomly assigned in a double-blind fashion to receive lisinopril (uptitrated to 20 mg/d)
or valsartan (uptitrated to 160 mg/d) therapy for 16 weeks. Heart rate variability (evaluated by measuring standard devi-
ation of normal R-R intervals on 24-hour ECG recordings), spontaneous baroreflex sensitivity and aldosterone and norepi-
nephrine plasma levels were assessed before and after drug therapy.
Results There were no significant differences between valsartan and lisinopril in their effects on left ventricular func-
tion, arterial pressure, aldosterone plasma levels and autonomic control of heart rate. Both lisinopril and valsartan signifi-
cantly reduced plasma norepinephrine levels, but the reduction induced by valsartan was significantly greater than that
observed for lisinopril (27% vs 6%, P Ͻ .05).
Conclusions This study shows a comparable effect of ACE inhibition (lisinopril) and of AT1 receptor antagonism
(valsartan) on cardiac vagal control of heart rate, whereas valsartan has shown a more effective modulation of sympa-
thetic activity measured by plasma norepinephrine levels. (Am Heart J 2003;146:e17.)
Autonomic nervous system activity plays a pivotal derangement occurring in the setting of CHF pro- pathophysiologic role in the progression of chronic In particular, the renin-angiotensin-aldo- heart failure (CHF), and impairments in the parameters sterone system (RAAS), which plays a key role in reflecting its function have been shown to predict a CHF pathophysiology, has been demonstrated to in- fluence largely autonomic nervous system evident with regard to heart rate barore- Angiotensin II (ATII) and aldosterone are able to en- Autonomic nervous system abnormality is, at least and RAAS blunting is able to modulate the auto- in part, the result of the complex neurohormonal nomic nervous system balance In pa-tients with CHF, the level of RAAS modulation, thatis, ACE inhibition or AT1 receptor antagonism, is From aInstitute of Cardiology, University of Bari, Bari, bInnovative Technologies for Sig-nal Detection and Processing Center, University of Bari, cCardiology, “Salvatore Maugeri” Foundation, IRCCS, Cassano, dFondazione Salvatore Maugeri, Clinica del ever, the administration of an AT1 receptor antago- Lavoro e della Riabilitazione, IRCCS, Cardiovascular Pathophysiology Research Cen- nist in addition to prescribed CHF therapy, includ- ter, Gussago, Brescia, eNovartis Pharma, Origgio, Varese, and fUniversity of Ferrara,Cardiology and Intensive Cardiology Care Unit, S. Anna Hospital, Ferrara. Submitted December 10, 2002; accepted March 10, 2003. of a different autonomic effect but synergistic activ- Reprint requests: Maria Vittoria Pitzalis, MD, PhD, FESC, Institute of Cardiology-Univer-sity of Bari, Piazza Giulio Cesare 11, 70124 Bari, Italy. ity of these interventions. However, up to now it E-mail: [email protected] has not been convincingly demonstrated that the 2003, Mosby, Inc. All rights reserved. two classes of drugs have a different effect on auto- 0002-8703/2003/$30.00 ϩ 0doi:10.1067/S0002-8703(03)00366-1 2 De Tommasi et al
After the first visit, eligible patients entered a single-blind placebo run-in period and received placebo, 1 capsule dailyfor 2 weeks. At the second visit, patients were randomly as-signed to receive valsartan or lisinopril, both orally adminis-tered with forced titration for 6 weeks, in a double-blindfashion. During the first 6 weeks, the dose was increased ev-ery 2 weeks for valsartan (40 mg/d, 80 mg/d, and 160 mg/d)as well as for lisinopril (5 mg/d, 10 mg/d, and 20 The maximum tolerated dose was administered for a further10 weeks.
Once-daily dosing of valsartan and forced titration was cho- sen on the basis of the safety demonstrated in phase II trials,because the study design was planned before phase III stud-ies. Lisinopril has been chosen as one of the most used drugsin the indication CHF, with a dose-titration similar to thatadopted in the Multicentre Lisinopril-Captopril CongestiveHeart Failure Study Group At the second and final visits, heart rate variability, barore- flex sensitivity (BRS), and aldosterone and norepinephrineplasma values were assessed Study design and patient dosage details according to studyprogress.
Heart rate variability. The measurements were obtained
by means of 24-hour ECG recordings (Del Mar AvionicsModel 445A, Irvine, Calif), which were analyzed by using an Therefore, the aim of the current study was to evalu- ELA Medical system (Elatec System, Montrouge, France) to ate whether in patients with stable CHF, AT1 receptor measure the mean normal R-R cycle length (NN) and the antagonism and ACE inhibition lead to a differential standard deviation of normal R-R intervals (SDNN). The ECG modulation of the autonomic control of heart rate and recordings Ͻ16 hours in duration or with Ͻ90% of the re-cording suitable for analysis were Arterial baroreflex sensitivity. Spontaneous BRS was as-
sessed by using sequence (BRS-Seq; ms/mm Hg) and spectral (BRS-Spec; ms/mm Hg) Time series of fingerarterial blood pressure and heart rate signals recorded during 10 minutes of metronome-guided respiration at 0.25 Hz were The study was conducted in accordance with good clinical analyzed. The BRS-Seq was calculated by the slope of the re- practice and the Declaration of Helsinky. The study was ap- gression line (if r Ն0.80) between systolic pressure and R-R proved by the local Committee on Medical Ethics, and all interval changes (ie, either a progressive rise in systolic pres- patients gave their written informed consent.
sure and lengthening in R-R interval or a decrease in systolicpressure and shortening in R-R interval). The BRS-Spec was calculated as the square root ratio of the R-R interval and sys-tolic pressure in the respiratory band, when squared coher- This study was a randomized, double-blind, forced-titration, ence function between the two signals was Ͼ0.5.
parallel-group, active-controlled trial. Eligible patients were18 to 80 years of age, with CHF (New York Heart Associationclass II-IV) beginning at least 3 months before the first visit.
Other inclusion criteria were sinus rhythm and left ventricu- Venous blood samples were drawn after 30 minutes of su- lar ejection fraction Ͻ40% by 2-dimensional echocardiogra- phy within 2 weeks before the first visit. The patients should Plasma aldosterone measurement. Samples (2.5 mL) were
have not received an ACE inhibitor or an ATII receptor antag- collected in plastic tubes without anticoagulant. They were onist or a ␤-blocker during the last month before the first left to coagulate at room temperature for approximately 1 visit. During the 2 weeks of placebo run-in period, CHF med- hour and then centrifuged at room temperature for 15 min- ications were at a stable dosage regimen and patients were in utes at 1700g. The serum was stored at Ϫ20°C. Plasma aldo- stable clinical condition. Exclusion criteria were history of sterone levels were measured by competitive radioimmunoas- heart transplantation, myocardial infarction or cardiac surgery say (RADIM cod KS17CT Spa Pomezia-RO-Italy). Intra-assay within the past 3 months, unstable angina, need of revascu- coefficient of variation was: 6.6% to 8.6%; interassay coeffi- larization procedures, syncopal episodes, sustained ventricu- cient of variation was: 8.4% to 9.4%.
lar arrhythmia within the past 3 months, and hypersensitivity Plasma norepinephrine measurement. Samples (5 mL)
or contraindication to ATII receptor antagonists or ACE inhib- were collected in prerefrigerated tubes containing 125 ␮L EDTA bisodium (5%) and 75 ␮L of sodium metabisulphite De Tommasi et al 3
(Na S O 10 mM), immediately placed on ice, and then cen- Table I. Clinical characteristics of randomized population
trifuged at 4°C for 15 minutes at 1700g. Plasma was stored atϪ70°C. Norepinephrine measurements were performed by Lisinopril
Valsartan
high-performance liquid chromatography.
Data are related to intention-to-treat population. The effect of the two drugs on the studied variables was assessed by using the Student t test for dependent samples or Wilcoxon test when appropriated. Demonstration of a difference be- tween valsartan and lisinopril on variables with normal distri- bution was assessed by means of analysis of covariance on the last measured parameters, considering the study treat- ment as factor and baseline values as covariate. Demonstra- tion of a different effect on non-normal variables was as- sessed through comparison of percentage variations between final and baseline values. Continuous variables were ex- pressed as mean and standard deviation. The tests were con- sidered significant for P Ͻ .05. All statistical tests were per- Among the 95 eligible patients, 90 were randomly assigned, 45 for each group. Baseline characteristics of patients and the causes of discontinuation are shown percentage reduction in norepinephrine levels caused by valsartan was significantly greater than that caused two groups in terms of baseline clinical characteristics.
Baseline BRS-spec and baseline BRS-seq were analyz-able in 53 of 90 and 85 of 90 patients, respectively (P Discussion
The renin-angiotensin aldosterone and adrenergic systems play a key role in the pathophysiology of CHFprogression and are closely interrelated. Sympathetic In the lisinopril group, final evaluation was not ob- overactivity leads to increased ATII plasma levels by tained in 3 patients. Lisinopril was able to reduce dia- stimulating the production and the release of stolic and systolic arterial pressure significantly On the other hand, experimental studies have demon- It did not affect heart rate or baroreflex sensitivity, strated that ATII and aldosterone enhance sympathet- whereas it improved SDNN Lisinopril signifi- cantly reduced both aldosterone (from 188 Ϯ 123 to RAAS should therefore have favorable effects on auto- 102 Ϯ 74 pg/mL) and norepinephrine plasma levels nomic nervous system activity. Considering the data published so far, it seems that the two principalclasses of drugs able to modulate RAAS (ie, ACE inhibi- tors and AT1 receptor antagonists) do not have identi- In the valsartan group, final evaluation was not ob- cal effects. Most of the findings concern the effect of tained in 1 patient. Valsartan significantly reduced dia- ACE inhibitors. These drugs have been shown to im- stolic and systolic arterial pressure, whereas no effect was found when heart rate variability and baroreflex sensitivity parameters were considered Aldo- There are few studies in human beings that have sterone (from 216 Ϯ 173 to 117 Ϯ 84 pg/mL) as well explored the effects of chronically administered AT1 as norepinephrine plasma levels (from 284 Ϯ 209 to receptor antagonists. Valie et did not find any ef- 189 Ϯ 136 pg/mL) were significantly reduced by val- fect on the autonomic control of heart rate. Con- versely, Petretta et found that AT1 receptor antag-onists improved heart rate variability. Considering Comparison between lisinopril and valsartan these results, one might be allowed to draw the con- No differences were found between the two drugs clusion of a greater effect of ACE inhibitors in favor- when the final values for arterial pressure, autonomic ably modulating autonomic nervous system response.
control of heart rate and mean plasma aldo- Unfortunately, a number of methodologic issues ham- 4 De Tommasi et al
Table II. Effects of lisinopril and valsartan on cardiovascular parameters and autonomic control of heart rate
Lisinopril group
Valsartan group
treatment
treatment
treatment
treatment
P
BRS-seq, Baroreflex sensitivity assessed by means of sequence method; BRS-spec, baroreflex sensitivity by means of spectral method; LVEF, left ventricular ejection fraction;NN, mean RR interval during 24 hour ECG monitoring; SDNN, RR interval SD during 24 hour ECG monitoring.
*P Ͻ .05 versus baseline at Student t test for dependent samples; P refers to ANCOVA analysis.
A, Aldosterone plasma levels in lisinopril and valsartan groups
A, Mean norepinephrine plasma level percentage reductions after
before (white columns) and after (gray columns) drug administra- lisinopril (white column) and valsartan (gray column) administra- tion. B, Norepinephrine plasma levels in lisinopril and valsartan
tion. B, Mean aldosterone plasma level percentage reductions af-
groups before (white columns) and after (gray columns) drug ad- ter lisinopril (white column) and valsartan (gray column) adminis- ministration. Data are shown as mean Ϯ SEM.
tration. Data are shown as mean Ϯ SEM.
per this conclusion. In particular, differences exist in the two classes of drugs. When in our series the reflex terms of number of patients studied, the degree of vagal control of heart rate was taken into consider- functional impairment, the methods chosen for analyz- ation, no difference was found between the two ing the autonomic control of heart rate and, finally, drugs. From the methodological point of view, our the period of drug administration before evaluation as results suggest that the BRS assessed by spectral tech- well as the dosages of drugs. Our study was prospec- nique is not optimal in heart failure. In fact, we found tively designed to compare lisinopril and valsartan on that BRS could be determined in almost 50% of the those parameters reflecting the different aspects of patients using spectral analysis and this value rises to autonomic control of the cardiovascular system, also 94% when using sequence method (a value similar to deserving prognostic information in patients with CHF.
In accordance with what was previously reported, the In accordance with most of the previous studies, we ACE inhibitor was able to enhance SDNN, a parameter found that ACE inhibition is able to decrease norepi- generally considered to reflect a tonic vagal control of heart rate. However, we were not able to find any sta- of AT1 receptor antagonism on plasma norepinephrine tistically significant difference between the effects of has not been well clarified. Our findings show a signifi- De Tommasi et al 5
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